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Successful Daily Practices of Inclusion Teachers of Children with Down Syndrome
This study asked 230 regular education teachers about their educational practices in teaching students with Down syndrome within their mainstream classes. Teachers completed surveys that asked about background experience; preparation for inclusion and the transition process; classroom information (curriculum, class arrangement, therapies, and support services); and classroom management, instruction, and behavioral strategies. Analysis of data from 120 surveys indicated that most of the students with Down syndrome attended their neighborhood schools and received some type of related services. Most of the classes had an inclusion aide who also worked with other students. Teachers considered the inclusion of children with Down syndrome successful, though there was room for improvement. Teachers found the experience challenging, rewarding, and of great value to their general education students as well as the child with Down syndrome. They noted that extra work was necessary for preparing modified class assignments, homework, and evaluation procedures. The best learning arrangements were 1:1 and small group instruction, with peer tutors, computers, and team teaching was sometimes effective. Praise was the best behavior management strategy.
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Results on the Tongue Protrusion in Downs, Following an Aspecific Antistress Drug Therapy. An Investigation on 88 Subjects
This investigation started from a consecutive series of 510 Down, selected with the exclusion of psychotic subjects. Among the 141 subjects = 27.65 % of the whole sample, who during the first consultation showed protrusion of their tongue, 88 of them (62.41%) had checked the result on this symptom following antistress drug therapy. The investigation on this subsample had the following features: as for gender they were 40 F + 48 M, with M/F = 120; the year of birth ranged between 1973 and 1993; the age at the first examination (in months) was average 40.42 +/- 35.39, with 6-183 range; distribution of the chromosomal anomalies: Four mosaicisms = 4.54%; 3 translocations = 3.41%; 80 standard trisomy 21 = 90.91%; 1 only clinical diagnosis = 1.14%; presence of the tongue protrusion: irregular in 4 = 4.65%; Frequent in 84 = 95.45%. A therapy with antistress drugs lasting average 14.73 months with range: 6-36, got the following results: 72 disappearances of the lingual protrusion = 81.82%; 8 irregular presence = 9.09%; Not varied frequent presence = 9.09%. The result is highly significant (p < 0.0001). The gender comparison suggests that there are not any meaningful differences both before and after drug therapy.
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The Free Radicals Hypothesis in Causing Dementia: High Probability Refutation in Down's Syndrome Subjects
The reduced inactivation of oxygen's free radicals is one of the hypotheses put forward to account for the onset of Alzheimer's dementia. However scarce conclusive experimental data may be to support this theory regarding human species, its refutation has not been established with any certainty either. Subjects affected by Down's syndrome have a documented increase in the enzyme superoxide-dismutase-1 and about 30% increase in the enzyme glutathione-peroxidase, both scavengers of oxygen's free radicals. For this reason Down subjects, who are less prone to cerebral palsy from prematurity and low birthweight (Cocchi, 1987; Cocchi and Branchesi, 1988), should also show a retardation in the onset of dementia, compared to normal individuals. This is not however the case as on the contrary it is regularly found that Down subjects anticipate by an average of 15 years roughly the onset of an Alzheimer type of dementia.
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PASS?
PASS? Say What? Vol. 2, No. 6, June 15, 2005, Future Planning for Families with Special Needs. Waddell & Reed, Inc.
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Language Impairment Is Associated With Decreased Plasma Coenzyme Q10 Levels in Children With Down Syndrome
Objective: Coenzyme Q10 (CoQ10) is an important endogenous cofactor for oxidative phosphorylation and potent antioxidant. Children with Down syndrome (DS) have decreased plasma CoQ10 compared with healthy children. The current follow-up report describes a relationship between CoQ10 and language impairment in children with DS. Materials & Methods: Twenty-two children with trisomy 21 previously participated in a CoQ10 dosing study. In this post hoc analysis, baseline plasma CoQ10 and cholesterol test results from the dosing study [1] were related to language impairment. Preschool Language Score (PLS-3) results for 20 participants (10 males, mean 5.1 years, range 1.7-9.3 years) were collected from their clinical records (2 were missing). Data were stratified according to PLS-3, i.e. severe (PLS-3 <70) and mild-moderate (PLS-3 =70-84) language disorder groups. P-values =0.05 were considered significant. Results: Children with severe language disorders (n=14) have significantly lower cholesterol-adjusted CoQ10 levels than children with mild-moderate disorders (n=6), i.e. 0.19 vs. 0.25 umol CoQ10/mmol cholesterol, respectively (P=0.021, Mann Whitney U test). Also a weak correlation exists between CoQ10 levels and PLS-3 data (r=0.44, P=0.05). Conclusion: These preliminary findings suggest that language impairment in children with DS may be related to a CoQ10 deficiency. Because CoQ10 supplementation has been shown to provide functional and neuroprotective benefits in neurodegenerative diseases, we hypothesize that CoQ10 supplementation may improve language skills in some children with DS.
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He Has Up Syndrome Not Down Syndrome
Book excerpt, p.48-50.
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Down's Syndrome and Cancer
Down's syndrome is a genetic disorder that is caused by trisomy of chromosome 21. Individuals with Down's syndrome have an increase risk of leukemia (10-20 fold) and a decreased incidence of solid tumors. It has been speculated that the genes on chromosome 21 are responsible for this abnormal distribution of cancer. One of such genes is copper zinc superoxide dismutase which catalyzes the dismutation of superoxide into hydrogen peroxide. Endostatin, a potent angiogenesis inhibitor, is also upregulated by trisomy 21. The paper discusses the possible role of these two genes in the occurrence of cancer in Down's syndrome subjects.
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Puttin' For Down Syndrome
The Puttin' For Down Syndrome golf tournament raised $2,500 for the Down Syndrome Association and $2,500 for the Down Syndrome Center at St. Louis Children's Hospital. But the October event in Swansea, Ill., was priceless to a special group of kids who attended their own clinic during the tourney. More than a dozen children and young adults with Down syndrome took part in the clinic, courtesy of golf pro Dan Polites with the Clinton Hills Golf Club. Along with memories of perfecting their signature swing, each player got to take home his or her own personalized golf club.
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Visioning?
Visioning? Say What? Vol. 2, No. 7, July-August, 2005, Future Planning for Families with Special Needs. Waddell & Reed, Inc.
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Exploring the Neurobiological Basis for Cognitive Problems in Down Syndrome
The hypothesis that guides our work is that each cognitive abnormality in DS is due directly or indirectly to increased expression of a specific gene(s) on chromosome 21. By discovering the responsible gene(s) it may be possible to prevent or rescue the defect. Our studies place a particular emphasis on hippocampal circuits that mediate learning and memory. We examine mouse models of DS and define changes that recapitulate those seen in DS. The Ts65Dn mouse model has a third copy of a portion of mouse chromosome 16 which is very similar to human chromosome 21 in that it contains an extra copy of about 140 homologous genes. Importantly, these mice show abnormalities in cognitive tasks mediated by hippocampus, including defects in spatial learning and memory.
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Exploring the Neurobiological Basis for Cognitive Problems in Down Syndrome. Commentary
I would like to extend my thanks to Dr. Mobley's Stanford University Down Syndrome Research team. They are moving research into uncharted territory and uncovering positive discoveries for more treatment options. (Hippocampal Long-Term Potentiation Suppressed by Increased Inhibition in the Ts65Dn Mouse, a Genetic Model of Down Syndrome. J Neurosci. 2004 Sep 15; 24(37):8153-60) This is the most exciting time in the history of DS research with the advent of a genetically engineered DS mouse, this means to add or subtract a gene or genes to/from that mouse.
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The Five Goodbyes. Mothering My Child with Down Syndrome
Book excerpts: Prologue and Molly's First Day of Kindergarten.
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Taste of the Tier helps combat cystic fibrosis
I am always happy to tell people about an opportunity to have a great night out while helping a worthy cause -- this week it's Taste of the Tier, the annual benefit for the Cystic Fibrosis Foundation of Central ...
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Robbinsdale district educations lead the way on an upward climb
Taking steps toward a cure for cystic fibrosis has led to a friendship between two teachers with poignant stories, as well as the involvement of hundreds of their students.
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CF Raccoon Hunt Set This Weekend
The annual Raccoon Hunt and Dog Show benefiting the Cystic Fibrosis Foundation is set for Friday and Saturday in Atlanta, said Ashley Jamison, special events coordinator for the foundation's Tyler office.
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Norwich man receives award for advocacy of cystic fibrosis patients
NORWICH -- By his own account, Hal Soloff has been many things in his life; teacher, attorney, political activist and world-traveler, just to name a few.
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Cystic Fibrosis - Topix.net
News on Cystic Fibrosis continually updated from thousands of sources around the net.
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Cystic Fibrosis - Topix.net
News on Cystic Fibrosis continually updated from thousands of sources around the net.
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A night at The Bluebird
Tammy Cochran brought a taste of Nashville night life to the Geneva Veterans of Foreign Wars hall Friday night.
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Copernicus Therapeutics helps Parkinson's researcher
Categories: Breaking News University of Kentucky researcher David Yurek is using technology from Copernicus Therapeutics Inc.
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Phase II Cystic Fibrosis Study Closes Enrollment
SYDNEY, Australia, March 1 /Xinhua-PRNewswire-FirstCall/ -- Pharmaxis Ltd Array The study has entered 25 subjects.
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Cystic Fibrosis Leads Mother To Write Children's Book
Cystic fibrosis is an inherited disease and until the 1980s, most deaths occurred in children and teenagers.
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Cystic Fibrosis Program at New York-Presbyterian Among Nation's Best
The Cystic Fibrosis Program at NewYork-Presbyterian Hospital/Columbia University Medical Center and Morgan Stanley Children's Hospital of NewYork-Presbyterian is among the nation's best, according to an ...
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"physical medicine rehabilitation" - Yahoo! News Search Results
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Wheelchair Breakdowns Becoming More Common
Wheelchair-dependent patients with spinal cord injury (SCI) are reporting higher rates of wheelchair breakdowns requiring repairs, according to a study in American Journal of Physical Medicine & Rehabilitation (AJPM&R).
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Wheelchair breakdowns becoming more common, reports AJPM&R
( Wolters Kluwer Health ) Wheelchair users with spinal cord injury report very high rates of wheelchair breakdowns -- and the problem is getting worse, suggests a study in American Journal of Physical Medicine & Rehabilitation, the official journal of the Association of Academic Physiatrists, AJPM&R is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.
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Wheelchair Breakdowns on the Rise, Study Finds
Title: Wheelchair Breakdowns on the Rise, Study Finds Category: Health News Created: 5/9/2012 2:05:00 PM Last Editorial Review: 5/10/2012 12:00:00 AM
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Patients with spinal cord injury report higher rates of wheelchair breakdowns
Wheelchair-dependent patients with spinal cord injury (SCI) are reporting higher rates of wheelchair breakdowns requiring repairs, according to a study in American Journal of Physical Medicine & Rehabilitation (AJPM&R), the official journal of the Association of Academic Physiatrists, AJPM&R is published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.
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Congresswoman Slaughter Leaves The Hospital
She was undergoing rehab at Strong.
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Spinal cord injury researchers win Apple Award for article on niacin for dyslipidemia
( Kessler Foundation ) American Spinal Injury Association has awarded its 2012 Apple Award to the article by Mark Nash, Ph.D., et al, entitled, "Safety, tolerance, and efficacy of extended-release niacin monotherapy for treating dyslipidemia risks in persons with chronic tetraplegia: A randomized multicenter controlled trial." The study published in Archives of Physical Medicine and ...
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More Education Needed On Concussion Awareness Says Senator
Concussions are affecting children, teens and athletes alike, one state senator says sports organizations need to have more concussion awareness.
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Dr. DeLuca of Kessler Foundation participates in nationwide National MS Society webcast
( Kessler Foundation ) John DeLuca, Ph.D., VP of Research & Training at Kessler Foundation, is a panelist for the May 23 (7-8 pm ET) national webcast sponsored by National MS Society, "The Next Frontier: Understanding and Treating Progressive MS." Dr. DeLuca, an expert in cognition, joins Peter Calabresi, M.D., of Johns Hopkins Multiple Sclerosis Center and Daniel Reich, M.D., Ph.D., from NINDS ...
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Research and Markets: Neurotech Business Report - In-depth and Expert Analysis of one of the Newest and most Promising ...
Research and Markets has announced the addition of the "Neurotech Business Report" subscription to their offe
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Over 50 bicyclists participate in the 4th annual Erie Canal Ride Fundraiser
Over fifty bicyclists began a two-day, 70-mile ride along the Old Erie Canal Trail marking the start of the 4th annual Erie Canal Ride.
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physiatrist - Yahoo! News Search Results
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West Orange doctor who appeared on 'Real Housewives of N.J.' admits taking cash bribes
Dov Rand admitted during the hearing to taking two different kickbacks in exchange for referring two patients to the Orange Community MRI facility for MRI tests
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One doctor’s take on the state drug monitoring program: ‘I’m very happy that it’s here’
A bill that would require doctors, in most cases, to check an online database before prescribing highly addictive pain relievers, such as oxycodone and morphine, is awaiting action by the House. But, since I last wrote about the bill, a couple of doctors have contacted me to say that if state officials want more participation in the program, they need only advertise that it exists.
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Williford trial delayed due to juror conflict
Judge informed attorneys Monday that juror was not able to be present
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3 ways to lower your health care costs
It's inevitable -- as you age, your body requires more repair. But there are ways to lower your medical costs. .
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3 ways to lower your medical costs
It's inevitable -- as you age, your body requires more repair. But there are ways to lower your medical costs. .
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Push your health care insurer to pay more
It's inevitable -- as you age, your body requires more repair. But there are ways to lower your medical costs. .
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St. Francis hosting stroke information fair
St. Francis Medical Center will be hosting a stroke awareness event from 6 to 7:30 p.m. Tuesday in Conference Room 2/3. The public is welcome to learn about stroke risk factors and services to support survivors of stroke and their families.
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Health care savings advice
You managed to glide through your twenties and thirties without any major health issues. Yet, as the calendar pages turn, you're finding that a host of minor -- and perhaps a few major -- medical problems ...
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Health care savings strategies
It's inevitable -- as you age, your body requires more repair. But there are ways to lower your medical costs. .Money magazine gives you strategies to cut your costs by as much as 70% in six big areas ...
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Phl Embassy Conducts Outreach Mission During Memphis in May Festival
18 May 2012 - The Philippine Embassy in Washington conducted its first consular outreach mission ever in Memphis, Tennessee last May 12 and 13, coinciding with the Memphis in May Festival, which featured the Philippines as the 2012 honored country. During the one and a half day outreach held at the St. Francis Parish Life Center in Cordova, the Consular team, headed by Consul Arlene Magno ...
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physiatry - Yahoo! News Search Results
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Yahoo! Health News
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Fending off fitness fatigue
NEW YORK (Reuters) - Runners stumble, yogis yawn, and even the bulkiest body builders get bored. But fitness experts say there are specific tricks to help people get and stay motivated. Connecticut-based exercise physiologist Tom Holland, who has ...
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Blasting music tied to drinking and drugs: study
NEW YORK (Reuters Health) - Doctors know that drinking, drugs and risky sex go together in young people -- and a new study suggests loud music should be added to that list. In the report from The Netherlands, researchers found that teens and young...
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Aftershocks rattle Italy, residents sleep outdoors
FINALE EMILIA, Italy (Reuters) - Thousands of people in northern Italy slept in tents and cars overnight as more than 100 aftershocks rocked the area hit by a magnitude 6.0 earthquake that killed seven people and inflicted heavy damage to centurie...
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U.S. FDA staff cite missing data for J&J's Xarelto
WASHINGTON (Reuters) - U.S. drug reviewers said Johnson & Johnson's blood thinner Xarelto appeared to reduce the risk of new heart attacks and strokes in people with heart problems, but missing data raised doubts about whether the drug actuall...
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U.S. Teens Heading for Heart Trouble: Study
MONDAY, May 21 (HealthDay News) -- Many American teenagers, including some with a normal, healthy weight, already have one or more risk factors for heart disease, researchers say.
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Sigmoidoscopy an option for colon cancer screening
NEW YORK (Reuters Health) - Screening for colon cancer using a flexible tube -- which is less invasive and more convenient than colonoscopy -- may also help prevent new cases and deaths from the disease, a new study suggests. In a large trial of m...
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Georgia flesh-eating bacteria patient breathing on own: father
ATLANTA (Reuters) - A Georgia graduate student fighting a rare flesh-eating bacterial infection she contracted after being injured in a zip-line accident nearly three weeks ago is breathing on her own without the help of a ventilator, her father s...
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On your bike, Portland top U.S. city for cycling
NEW YORK (Reuters) - With the most cyclists per capita and even coffee shops that cater to two-wheelers, Portland has been named America's best cycling city, according to a new ranking released on Monday. It knocked Minneapolis, which was tops...
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Health Highlights: May 21, 2012
Here are some of the latest health and medical news developments, compiled by the editors of HealthDay:
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Study Supports Value of Sigmoidoscopy, an Alternative to
Colonoscopy
MONDAY, May 21 (HealthDay News) -- New research confirms that sigmoidoscopies -- less-invasive alternatives to colonoscopies that don't require sedation -- are effective in lowering the risk of colon cancer.
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Health Tip: Comforting Baby's Pain
(HealthDay News) -- When your baby is in pain -- be it from things like a circumcision, vaccine or incoming tooth -- parents can take steps to soothe, comfort and ease the pain as much as possible.
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Keeping Your Family Safe From Dog Bites
SATURDAY, May 19 (HealthDay News) -- More than 4.7 million Americans are bitten by dogs each year, and more than half of those victims are younger than age 14, experts say.
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Health Tip: Use Proper Form When Running
(HealthDay News) -- Using proper running form can help prevent injuries and make running a little easier and more comfortable.
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"Pre-diabetes," diabetes rising among U.S. teens
By Amy Norton NEW YORK (Reuters Health) - The percentage of U.S. teenagers with "pre-diabetes" or full-blown type 2 diabetes has more than doubled in recent years -- though obesity and other heart risk factors have held steady, governmen...
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Not all ICUs need a specialist at night: study
NEW YORK (Reuters Health) - Among hospital intensive care units (ICUs) with a daytime physician specially trained in critical care, adding a specialist to cover the night shift does not improve patients' survival, according to a new study. Amo...
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The making of the term 'pink slime'
"Pink slime" was almost "pink paste" or "pink goo."
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Obese Teens Can Have Heart Damage Without Showing Signs
MONDAY, May 21 (HealthDay News) -- Heart damage can be present in obese teens who don't have any symptoms of heart disease, a small, preliminary study found.
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Statins May Help Prevent Enlarged Prostate: Study
MONDAY, May 21 (HealthDay News) -- Statin drugs commonly used to lower cholesterol levels may also slow the unhealthy growth of the prostate in men with elevated blood levels of prostate-specific antigen, a new study finds.
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Moveable Magnets Used to Forge Gastric Bypass in Pigs
MONDAY, May 21 (HealthDay News) -- In a scenario reminiscent of the film Fantastic Voyage, researchers have found a way to perform nearly surgery-free gastric bypass procedures in pigs using only a local anesthetic.
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Breathing Smog While Pregnant May Worsen Asthma in
Offspring
SUNDAY, May 20 (HealthDay News) -- Exposure to air pollution while in the womb might harm the lung-function development of children with asthma, a new study finds.
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Sleep Apnea Linked to Higher Cancer Death Risk
SUNDAY, May 20 (HealthDay News) -- Sleep apnea has already been linked to a host of adverse health problems, such as high blood pressure and heart disease. Now, new research suggests that in people who already have cancer, the sleep disorder may r...
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Study Ties Secondhand Smoke to Bladder Irritation in Kids
SUNDAY, May 20 (HealthDay News) -- Parents who smoke may put their children at greater risk for bladder irritation, according to a small new study.
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Lung cancer tests advised for some heavy smokers
NEW YORK (Reuters Health) - New recommendations from chest and cancer doctors call for lung cancer screening in older adults with a long history of smoking a pack a day or more -- but also highlight the possible harms of screening, including a hig...
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Screening for Lung Cancer Might Benefit Those at Highest
Risk
SUNDAY, May 20 (HealthDay News) -- Using low-dose CT scans to screen for lung cancer might save the lives of patients at the greatest risk for the disease, a new analysis suggests.
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Obese More Likely to Be Diagnosed With Advanced Thyroid
Cancer
MONDAY, May 21 (HealthDay News) -- Obese patients are more likely than other patients to have advanced, aggressive forms of papillary thyroid cancer when they're diagnosed with the disease, a new study has found.
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Yahoo! Health News
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Fending off fitness fatigue
NEW YORK (Reuters) - Runners stumble, yogis yawn, and even the bulkiest body builders get bored. But fitness experts say there are specific tricks to help people get and stay motivated. Connecticut-based exercise physiologist Tom Holland, who has ...
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Blasting music tied to drinking and drugs: study
NEW YORK (Reuters Health) - Doctors know that drinking, drugs and risky sex go together in young people -- and a new study suggests loud music should be added to that list. In the report from The Netherlands, researchers found that teens and young...
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Aftershocks rattle Italy, residents sleep outdoors
FINALE EMILIA, Italy (Reuters) - Thousands of people in northern Italy slept in tents and cars overnight as more than 100 aftershocks rocked the area hit by a magnitude 6.0 earthquake that killed seven people and inflicted heavy damage to centurie...
-
U.S. FDA staff cite missing data for J&J's Xarelto
WASHINGTON (Reuters) - U.S. drug reviewers said Johnson & Johnson's blood thinner Xarelto appeared to reduce the risk of new heart attacks and strokes in people with heart problems, but missing data raised doubts about whether the drug actuall...
-
U.S. Teens Heading for Heart Trouble: Study
MONDAY, May 21 (HealthDay News) -- Many American teenagers, including some with a normal, healthy weight, already have one or more risk factors for heart disease, researchers say.
-
Sigmoidoscopy an option for colon cancer screening
NEW YORK (Reuters Health) - Screening for colon cancer using a flexible tube -- which is less invasive and more convenient than colonoscopy -- may also help prevent new cases and deaths from the disease, a new study suggests. In a large trial of m...
-
Georgia flesh-eating bacteria patient breathing on own: father
ATLANTA (Reuters) - A Georgia graduate student fighting a rare flesh-eating bacterial infection she contracted after being injured in a zip-line accident nearly three weeks ago is breathing on her own without the help of a ventilator, her father s...
-
On your bike, Portland top U.S. city for cycling
NEW YORK (Reuters) - With the most cyclists per capita and even coffee shops that cater to two-wheelers, Portland has been named America's best cycling city, according to a new ranking released on Monday. It knocked Minneapolis, which was tops...
-
Health Highlights: May 21, 2012
Here are some of the latest health and medical news developments, compiled by the editors of HealthDay:
-
Study Supports Value of Sigmoidoscopy, an Alternative to
Colonoscopy
MONDAY, May 21 (HealthDay News) -- New research confirms that sigmoidoscopies -- less-invasive alternatives to colonoscopies that don't require sedation -- are effective in lowering the risk of colon cancer.
-
Health Tip: Comforting Baby's Pain
(HealthDay News) -- When your baby is in pain -- be it from things like a circumcision, vaccine or incoming tooth -- parents can take steps to soothe, comfort and ease the pain as much as possible.
-
Keeping Your Family Safe From Dog Bites
SATURDAY, May 19 (HealthDay News) -- More than 4.7 million Americans are bitten by dogs each year, and more than half of those victims are younger than age 14, experts say.
-
Health Tip: Use Proper Form When Running
(HealthDay News) -- Using proper running form can help prevent injuries and make running a little easier and more comfortable.
-
"Pre-diabetes," diabetes rising among U.S. teens
By Amy Norton NEW YORK (Reuters Health) - The percentage of U.S. teenagers with "pre-diabetes" or full-blown type 2 diabetes has more than doubled in recent years -- though obesity and other heart risk factors have held steady, governmen...
-
Not all ICUs need a specialist at night: study
NEW YORK (Reuters Health) - Among hospital intensive care units (ICUs) with a daytime physician specially trained in critical care, adding a specialist to cover the night shift does not improve patients' survival, according to a new study. Amo...
-
The making of the term 'pink slime'
"Pink slime" was almost "pink paste" or "pink goo."
-
Obese Teens Can Have Heart Damage Without Showing Signs
MONDAY, May 21 (HealthDay News) -- Heart damage can be present in obese teens who don't have any symptoms of heart disease, a small, preliminary study found.
-
Statins May Help Prevent Enlarged Prostate: Study
MONDAY, May 21 (HealthDay News) -- Statin drugs commonly used to lower cholesterol levels may also slow the unhealthy growth of the prostate in men with elevated blood levels of prostate-specific antigen, a new study finds.
-
Moveable Magnets Used to Forge Gastric Bypass in Pigs
MONDAY, May 21 (HealthDay News) -- In a scenario reminiscent of the film Fantastic Voyage, researchers have found a way to perform nearly surgery-free gastric bypass procedures in pigs using only a local anesthetic.
-
Breathing Smog While Pregnant May Worsen Asthma in
Offspring
SUNDAY, May 20 (HealthDay News) -- Exposure to air pollution while in the womb might harm the lung-function development of children with asthma, a new study finds.
-
Sleep Apnea Linked to Higher Cancer Death Risk
SUNDAY, May 20 (HealthDay News) -- Sleep apnea has already been linked to a host of adverse health problems, such as high blood pressure and heart disease. Now, new research suggests that in people who already have cancer, the sleep disorder may r...
-
Study Ties Secondhand Smoke to Bladder Irritation in Kids
SUNDAY, May 20 (HealthDay News) -- Parents who smoke may put their children at greater risk for bladder irritation, according to a small new study.
-
Lung cancer tests advised for some heavy smokers
NEW YORK (Reuters Health) - New recommendations from chest and cancer doctors call for lung cancer screening in older adults with a long history of smoking a pack a day or more -- but also highlight the possible harms of screening, including a hig...
-
Screening for Lung Cancer Might Benefit Those at Highest
Risk
SUNDAY, May 20 (HealthDay News) -- Using low-dose CT scans to screen for lung cancer might save the lives of patients at the greatest risk for the disease, a new analysis suggests.
-
Obese More Likely to Be Diagnosed With Advanced Thyroid
Cancer
MONDAY, May 21 (HealthDay News) -- Obese patients are more likely than other patients to have advanced, aggressive forms of papillary thyroid cancer when they're diagnosed with the disease, a new study has found.
|
|
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|
Yahoo! Health News
|
-
Fending off fitness fatigue
NEW YORK (Reuters) - Runners stumble, yogis yawn, and even the bulkiest body builders get bored. But fitness experts say there are specific tricks to help people get and stay motivated. Connecticut-based exercise physiologist Tom Holland, who has ...
-
Blasting music tied to drinking and drugs: study
NEW YORK (Reuters Health) - Doctors know that drinking, drugs and risky sex go together in young people -- and a new study suggests loud music should be added to that list. In the report from The Netherlands, researchers found that teens and young...
-
Aftershocks rattle Italy, residents sleep outdoors
FINALE EMILIA, Italy (Reuters) - Thousands of people in northern Italy slept in tents and cars overnight as more than 100 aftershocks rocked the area hit by a magnitude 6.0 earthquake that killed seven people and inflicted heavy damage to centurie...
-
U.S. FDA staff cite missing data for J&J's Xarelto
WASHINGTON (Reuters) - U.S. drug reviewers said Johnson & Johnson's blood thinner Xarelto appeared to reduce the risk of new heart attacks and strokes in people with heart problems, but missing data raised doubts about whether the drug actuall...
-
U.S. Teens Heading for Heart Trouble: Study
MONDAY, May 21 (HealthDay News) -- Many American teenagers, including some with a normal, healthy weight, already have one or more risk factors for heart disease, researchers say.
-
Sigmoidoscopy an option for colon cancer screening
NEW YORK (Reuters Health) - Screening for colon cancer using a flexible tube -- which is less invasive and more convenient than colonoscopy -- may also help prevent new cases and deaths from the disease, a new study suggests. In a large trial of m...
-
Georgia flesh-eating bacteria patient breathing on own: father
ATLANTA (Reuters) - A Georgia graduate student fighting a rare flesh-eating bacterial infection she contracted after being injured in a zip-line accident nearly three weeks ago is breathing on her own without the help of a ventilator, her father s...
-
On your bike, Portland top U.S. city for cycling
NEW YORK (Reuters) - With the most cyclists per capita and even coffee shops that cater to two-wheelers, Portland has been named America's best cycling city, according to a new ranking released on Monday. It knocked Minneapolis, which was tops...
-
Health Highlights: May 21, 2012
Here are some of the latest health and medical news developments, compiled by the editors of HealthDay:
-
Study Supports Value of Sigmoidoscopy, an Alternative to
Colonoscopy
MONDAY, May 21 (HealthDay News) -- New research confirms that sigmoidoscopies -- less-invasive alternatives to colonoscopies that don't require sedation -- are effective in lowering the risk of colon cancer.
-
Health Tip: Comforting Baby's Pain
(HealthDay News) -- When your baby is in pain -- be it from things like a circumcision, vaccine or incoming tooth -- parents can take steps to soothe, comfort and ease the pain as much as possible.
-
Keeping Your Family Safe From Dog Bites
SATURDAY, May 19 (HealthDay News) -- More than 4.7 million Americans are bitten by dogs each year, and more than half of those victims are younger than age 14, experts say.
-
Health Tip: Use Proper Form When Running
(HealthDay News) -- Using proper running form can help prevent injuries and make running a little easier and more comfortable.
-
"Pre-diabetes," diabetes rising among U.S. teens
By Amy Norton NEW YORK (Reuters Health) - The percentage of U.S. teenagers with "pre-diabetes" or full-blown type 2 diabetes has more than doubled in recent years -- though obesity and other heart risk factors have held steady, governmen...
-
Not all ICUs need a specialist at night: study
NEW YORK (Reuters Health) - Among hospital intensive care units (ICUs) with a daytime physician specially trained in critical care, adding a specialist to cover the night shift does not improve patients' survival, according to a new study. Amo...
-
The making of the term 'pink slime'
"Pink slime" was almost "pink paste" or "pink goo."
-
Obese Teens Can Have Heart Damage Without Showing Signs
MONDAY, May 21 (HealthDay News) -- Heart damage can be present in obese teens who don't have any symptoms of heart disease, a small, preliminary study found.
-
Statins May Help Prevent Enlarged Prostate: Study
MONDAY, May 21 (HealthDay News) -- Statin drugs commonly used to lower cholesterol levels may also slow the unhealthy growth of the prostate in men with elevated blood levels of prostate-specific antigen, a new study finds.
-
Moveable Magnets Used to Forge Gastric Bypass in Pigs
MONDAY, May 21 (HealthDay News) -- In a scenario reminiscent of the film Fantastic Voyage, researchers have found a way to perform nearly surgery-free gastric bypass procedures in pigs using only a local anesthetic.
-
Breathing Smog While Pregnant May Worsen Asthma in
Offspring
SUNDAY, May 20 (HealthDay News) -- Exposure to air pollution while in the womb might harm the lung-function development of children with asthma, a new study finds.
-
Sleep Apnea Linked to Higher Cancer Death Risk
SUNDAY, May 20 (HealthDay News) -- Sleep apnea has already been linked to a host of adverse health problems, such as high blood pressure and heart disease. Now, new research suggests that in people who already have cancer, the sleep disorder may r...
-
Study Ties Secondhand Smoke to Bladder Irritation in Kids
SUNDAY, May 20 (HealthDay News) -- Parents who smoke may put their children at greater risk for bladder irritation, according to a small new study.
-
Lung cancer tests advised for some heavy smokers
NEW YORK (Reuters Health) - New recommendations from chest and cancer doctors call for lung cancer screening in older adults with a long history of smoking a pack a day or more -- but also highlight the possible harms of screening, including a hig...
-
Screening for Lung Cancer Might Benefit Those at Highest
Risk
SUNDAY, May 20 (HealthDay News) -- Using low-dose CT scans to screen for lung cancer might save the lives of patients at the greatest risk for the disease, a new analysis suggests.
-
Obese More Likely to Be Diagnosed With Advanced Thyroid
Cancer
MONDAY, May 21 (HealthDay News) -- Obese patients are more likely than other patients to have advanced, aggressive forms of papillary thyroid cancer when they're diagnosed with the disease, a new study has found.
|
|
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Notice: Only variable references should be returned by reference in /var/www/vhosts/pmandr.com/httpdocs/includes/domit/xml_domit_nodemaps.php on line 166
|
Yahoo! Health News
|
-
Fending off fitness fatigue
NEW YORK (Reuters) - Runners stumble, yogis yawn, and even the bulkiest body builders get bored. But fitness experts say there are specific tricks to help people get and stay motivated. Connecticut-based exercise physiologist Tom Holland, who has ...
-
Blasting music tied to drinking and drugs: study
NEW YORK (Reuters Health) - Doctors know that drinking, drugs and risky sex go together in young people -- and a new study suggests loud music should be added to that list. In the report from The Netherlands, researchers found that teens and young...
-
Aftershocks rattle Italy, residents sleep outdoors
FINALE EMILIA, Italy (Reuters) - Thousands of people in northern Italy slept in tents and cars overnight as more than 100 aftershocks rocked the area hit by a magnitude 6.0 earthquake that killed seven people and inflicted heavy damage to centurie...
-
U.S. FDA staff cite missing data for J&J's Xarelto
WASHINGTON (Reuters) - U.S. drug reviewers said Johnson & Johnson's blood thinner Xarelto appeared to reduce the risk of new heart attacks and strokes in people with heart problems, but missing data raised doubts about whether the drug actuall...
-
U.S. Teens Heading for Heart Trouble: Study
MONDAY, May 21 (HealthDay News) -- Many American teenagers, including some with a normal, healthy weight, already have one or more risk factors for heart disease, researchers say.
-
Sigmoidoscopy an option for colon cancer screening
NEW YORK (Reuters Health) - Screening for colon cancer using a flexible tube -- which is less invasive and more convenient than colonoscopy -- may also help prevent new cases and deaths from the disease, a new study suggests. In a large trial of m...
-
Georgia flesh-eating bacteria patient breathing on own: father
ATLANTA (Reuters) - A Georgia graduate student fighting a rare flesh-eating bacterial infection she contracted after being injured in a zip-line accident nearly three weeks ago is breathing on her own without the help of a ventilator, her father s...
-
On your bike, Portland top U.S. city for cycling
NEW YORK (Reuters) - With the most cyclists per capita and even coffee shops that cater to two-wheelers, Portland has been named America's best cycling city, according to a new ranking released on Monday. It knocked Minneapolis, which was tops...
-
Health Highlights: May 21, 2012
Here are some of the latest health and medical news developments, compiled by the editors of HealthDay:
-
Study Supports Value of Sigmoidoscopy, an Alternative to
Colonoscopy
MONDAY, May 21 (HealthDay News) -- New research confirms that sigmoidoscopies -- less-invasive alternatives to colonoscopies that don't require sedation -- are effective in lowering the risk of colon cancer.
-
Health Tip: Comforting Baby's Pain
(HealthDay News) -- When your baby is in pain -- be it from things like a circumcision, vaccine or incoming tooth -- parents can take steps to soothe, comfort and ease the pain as much as possible.
-
Keeping Your Family Safe From Dog Bites
SATURDAY, May 19 (HealthDay News) -- More than 4.7 million Americans are bitten by dogs each year, and more than half of those victims are younger than age 14, experts say.
-
Health Tip: Use Proper Form When Running
(HealthDay News) -- Using proper running form can help prevent injuries and make running a little easier and more comfortable.
-
"Pre-diabetes," diabetes rising among U.S. teens
By Amy Norton NEW YORK (Reuters Health) - The percentage of U.S. teenagers with "pre-diabetes" or full-blown type 2 diabetes has more than doubled in recent years -- though obesity and other heart risk factors have held steady, governmen...
-
Not all ICUs need a specialist at night: study
NEW YORK (Reuters Health) - Among hospital intensive care units (ICUs) with a daytime physician specially trained in critical care, adding a specialist to cover the night shift does not improve patients' survival, according to a new study. Amo...
-
The making of the term 'pink slime'
"Pink slime" was almost "pink paste" or "pink goo."
-
Obese Teens Can Have Heart Damage Without Showing Signs
MONDAY, May 21 (HealthDay News) -- Heart damage can be present in obese teens who don't have any symptoms of heart disease, a small, preliminary study found.
-
Statins May Help Prevent Enlarged Prostate: Study
MONDAY, May 21 (HealthDay News) -- Statin drugs commonly used to lower cholesterol levels may also slow the unhealthy growth of the prostate in men with elevated blood levels of prostate-specific antigen, a new study finds.
-
Moveable Magnets Used to Forge Gastric Bypass in Pigs
MONDAY, May 21 (HealthDay News) -- In a scenario reminiscent of the film Fantastic Voyage, researchers have found a way to perform nearly surgery-free gastric bypass procedures in pigs using only a local anesthetic.
-
Breathing Smog While Pregnant May Worsen Asthma in
Offspring
SUNDAY, May 20 (HealthDay News) -- Exposure to air pollution while in the womb might harm the lung-function development of children with asthma, a new study finds.
-
Sleep Apnea Linked to Higher Cancer Death Risk
SUNDAY, May 20 (HealthDay News) -- Sleep apnea has already been linked to a host of adverse health problems, such as high blood pressure and heart disease. Now, new research suggests that in people who already have cancer, the sleep disorder may r...
-
Study Ties Secondhand Smoke to Bladder Irritation in Kids
SUNDAY, May 20 (HealthDay News) -- Parents who smoke may put their children at greater risk for bladder irritation, according to a small new study.
-
Lung cancer tests advised for some heavy smokers
NEW YORK (Reuters Health) - New recommendations from chest and cancer doctors call for lung cancer screening in older adults with a long history of smoking a pack a day or more -- but also highlight the possible harms of screening, including a hig...
-
Screening for Lung Cancer Might Benefit Those at Highest
Risk
SUNDAY, May 20 (HealthDay News) -- Using low-dose CT scans to screen for lung cancer might save the lives of patients at the greatest risk for the disease, a new analysis suggests.
-
Obese More Likely to Be Diagnosed With Advanced Thyroid
Cancer
MONDAY, May 21 (HealthDay News) -- Obese patients are more likely than other patients to have advanced, aggressive forms of papillary thyroid cancer when they're diagnosed with the disease, a new study has found.
|
|
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Notice: Only variable references should be returned by reference in /var/www/vhosts/pmandr.com/httpdocs/includes/domit/xml_domit_nodemaps.php on line 166
|
Yahoo! Health News
|
-
Fending off fitness fatigue
NEW YORK (Reuters) - Runners stumble, yogis yawn, and even the bulkiest body builders get bored. But fitness experts say there are specific tricks to help people get and stay motivated. Connecticut-based exercise physiologist Tom Holland, who has ...
-
Blasting music tied to drinking and drugs: study
NEW YORK (Reuters Health) - Doctors know that drinking, drugs and risky sex go together in young people -- and a new study suggests loud music should be added to that list. In the report from The Netherlands, researchers found that teens and young...
-
Aftershocks rattle Italy, residents sleep outdoors
FINALE EMILIA, Italy (Reuters) - Thousands of people in northern Italy slept in tents and cars overnight as more than 100 aftershocks rocked the area hit by a magnitude 6.0 earthquake that killed seven people and inflicted heavy damage to centurie...
-
U.S. FDA staff cite missing data for J&J's Xarelto
WASHINGTON (Reuters) - U.S. drug reviewers said Johnson & Johnson's blood thinner Xarelto appeared to reduce the risk of new heart attacks and strokes in people with heart problems, but missing data raised doubts about whether the drug actuall...
-
U.S. Teens Heading for Heart Trouble: Study
MONDAY, May 21 (HealthDay News) -- Many American teenagers, including some with a normal, healthy weight, already have one or more risk factors for heart disease, researchers say.
-
Sigmoidoscopy an option for colon cancer screening
NEW YORK (Reuters Health) - Screening for colon cancer using a flexible tube -- which is less invasive and more convenient than colonoscopy -- may also help prevent new cases and deaths from the disease, a new study suggests. In a large trial of m...
-
Georgia flesh-eating bacteria patient breathing on own: father
ATLANTA (Reuters) - A Georgia graduate student fighting a rare flesh-eating bacterial infection she contracted after being injured in a zip-line accident nearly three weeks ago is breathing on her own without the help of a ventilator, her father s...
-
On your bike, Portland top U.S. city for cycling
NEW YORK (Reuters) - With the most cyclists per capita and even coffee shops that cater to two-wheelers, Portland has been named America's best cycling city, according to a new ranking released on Monday. It knocked Minneapolis, which was tops...
-
Health Highlights: May 21, 2012
Here are some of the latest health and medical news developments, compiled by the editors of HealthDay:
-
Study Supports Value of Sigmoidoscopy, an Alternative to
Colonoscopy
MONDAY, May 21 (HealthDay News) -- New research confirms that sigmoidoscopies -- less-invasive alternatives to colonoscopies that don't require sedation -- are effective in lowering the risk of colon cancer.
-
Health Tip: Comforting Baby's Pain
(HealthDay News) -- When your baby is in pain -- be it from things like a circumcision, vaccine or incoming tooth -- parents can take steps to soothe, comfort and ease the pain as much as possible.
-
Keeping Your Family Safe From Dog Bites
SATURDAY, May 19 (HealthDay News) -- More than 4.7 million Americans are bitten by dogs each year, and more than half of those victims are younger than age 14, experts say.
-
Health Tip: Use Proper Form When Running
(HealthDay News) -- Using proper running form can help prevent injuries and make running a little easier and more comfortable.
-
"Pre-diabetes," diabetes rising among U.S. teens
By Amy Norton NEW YORK (Reuters Health) - The percentage of U.S. teenagers with "pre-diabetes" or full-blown type 2 diabetes has more than doubled in recent years -- though obesity and other heart risk factors have held steady, governmen...
-
Not all ICUs need a specialist at night: study
NEW YORK (Reuters Health) - Among hospital intensive care units (ICUs) with a daytime physician specially trained in critical care, adding a specialist to cover the night shift does not improve patients' survival, according to a new study. Amo...
-
The making of the term 'pink slime'
"Pink slime" was almost "pink paste" or "pink goo."
-
Obese Teens Can Have Heart Damage Without Showing Signs
MONDAY, May 21 (HealthDay News) -- Heart damage can be present in obese teens who don't have any symptoms of heart disease, a small, preliminary study found.
-
Statins May Help Prevent Enlarged Prostate: Study
MONDAY, May 21 (HealthDay News) -- Statin drugs commonly used to lower cholesterol levels may also slow the unhealthy growth of the prostate in men with elevated blood levels of prostate-specific antigen, a new study finds.
-
Moveable Magnets Used to Forge Gastric Bypass in Pigs
MONDAY, May 21 (HealthDay News) -- In a scenario reminiscent of the film Fantastic Voyage, researchers have found a way to perform nearly surgery-free gastric bypass procedures in pigs using only a local anesthetic.
-
Breathing Smog While Pregnant May Worsen Asthma in
Offspring
SUNDAY, May 20 (HealthDay News) -- Exposure to air pollution while in the womb might harm the lung-function development of children with asthma, a new study finds.
-
Sleep Apnea Linked to Higher Cancer Death Risk
SUNDAY, May 20 (HealthDay News) -- Sleep apnea has already been linked to a host of adverse health problems, such as high blood pressure and heart disease. Now, new research suggests that in people who already have cancer, the sleep disorder may r...
-
Study Ties Secondhand Smoke to Bladder Irritation in Kids
SUNDAY, May 20 (HealthDay News) -- Parents who smoke may put their children at greater risk for bladder irritation, according to a small new study.
-
Lung cancer tests advised for some heavy smokers
NEW YORK (Reuters Health) - New recommendations from chest and cancer doctors call for lung cancer screening in older adults with a long history of smoking a pack a day or more -- but also highlight the possible harms of screening, including a hig...
-
Screening for Lung Cancer Might Benefit Those at Highest
Risk
SUNDAY, May 20 (HealthDay News) -- Using low-dose CT scans to screen for lung cancer might save the lives of patients at the greatest risk for the disease, a new analysis suggests.
-
Obese More Likely to Be Diagnosed With Advanced Thyroid
Cancer
MONDAY, May 21 (HealthDay News) -- Obese patients are more likely than other patients to have advanced, aggressive forms of papillary thyroid cancer when they're diagnosed with the disease, a new study has found.
|
|
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Fluids and Barriers of the CNS - Latest Articles
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Brain pericytes from stress-susceptible pigs increase blood-brain barrier permeability in vitro
Background:
The function of pericytes remains questionable but with improved cultured technique and theuse of genetically modified animals, it has become increasingly clear that pericytes are anintegral part of blood-brain barrier (BBB) function, and the involvement of pericytedysfunction in certain cerebrovascular diseases is now emerging. The porcine stresssyndrome (PSS) is the only confirmed, homologous model of malignant hyperthermia (MH)in veterinary medicine. Affected animals can experience upon slaughter a range of symptoms,including skeletal muscle rigidity, metabolic acidosis, tachycardia and fever, similar to thehuman syndrome. Symptoms are due to an enhanced calcium release from intracellularstores. These conditions are associated with a point mutation in ryr1/hal gene, encoding theryanodine receptor, a calcium channel. Important blood vessel wall muscle modificationshave been described in PSS, but potential brain vessel changes have never been documentedin this syndrome.
Methods:
In the present work, histological and ultrastructural analyses of brain capillaries from wildtype and ryr1 mutated pigs were conducted to investigate the potential impairment ofpericytes, in this pathology. In addition, brain pericytes were isolated from the three porcinegenotypes (wild-type NN pigs; Nn and nn pigs, bearing one or two (n) mutant ryr1/halalleles, respectively), and tested in vitro for their influence on the permeability of BBBendothelial monolayers.
Results:
Enlarged perivascular spaces were observed in ryr1-mutant samples, corresponding to apartial or total detachment of the astrocytic endfeet. These spaces were electron lucent andsometimes filled with lipid deposits and swollen astrocytic feet. At the ultrastructural level,brain pericytes did not seem to be affected because they showed regular morphology andcharacteristics, so we aimed to check their ability to maintain BBB properties in vitro. Ourresults indicated that pericytes from the three genotypes of pigs had differing influences onthe BBB. Unlike pericytes from NN pigs, pericytes from Nn and nn pigs were not able tomaintain low BBB permeability.
Conclusions:
Electron microscopy observations demonstrated brain capillary modifications in PSScondition, but no change in pericyte morphology. Results from in vitro experiments suggestthat brain pericytes from ryr1 mutated pigs, even if they are not affected by this condition atthe ultrastructural level, are not able to maintain BBB integrity in comparison with pericytesfrom wild-type animals.
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Blood-brain barrier disruption in CCL2 transgenic mice during pertussis toxin-induced brain inflammation
Background:
The chemokine CCL2 has an important role in the recruitment of inflammatory cells into the central nervous system (CNS). A transgenic mouse model that overexpresses CCL2 in the CNS shows an accumulation of leukocytes within the perivascular space surrounding vessels, which infiltrate into the brain parenchyma following the administration of pertussis toxin (PTx).
Methods:
This study uses contrast-enhanced magnetic resonance imaging (MRI) to quantify the extent of blood-brain barrier (BBB) disruption in this model pre- and post-PTx administration compared to wild type mice. Contrast-enhanced MR images were obtained before and 1, 3, and 5 days after PTx injection in each animal. After the final imaging session fluorescent dextran tracers were administered intravenously to each mouse and brains were examined histologically for cellular infiltrates, BBB leakage and tight junction protein.
Results:
BBB breakdown, defined as a disruption of both the endothelium and glia limitans, was found only in CCL2 transgenic mice following PTx administration seen on MR images as focal areas of contrast enhancement and histologically as dextrans leaking from blood vessels. No evidence of disruption in endothelial tight junctions was observed.
Conclusion:
Genetic and environmental stimuli were needed to disrupt the integrity of the BBB in this model of neuroinflammation.
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Visualisation of cerebrospinal fluid flow patterns in albino Xenopus larvae in vivo
Background:
It has long been known that cerebrospinal fluid (CSF), its composition and flow, play an important part in normal brain development, and ependymal cell ciliary beating as a possible driver of CSF flow has previously been studied in mammalian fetuses in vitro. Lower vertebrate animals are potential models for analysis of CSF flow during development because they are oviparous. Albino Xenopus laevis larvae are nearly transparent and have a straight, translucent brain that facilitates the observation of fluid flow within the ventricles. The aim of these experiments was to study CSF flow and circulation in vivo in the developing brain of living embryos, larvae and tadpoles of Xenopus laevis using a microinjection technique.
Methods:
The development of Xenopus larval brain ventricles and the patterns of CSF flow were visualised after injection of quantum dot nanocrystals and polystyrene beads (3.1 or 5.8 μm in diameter) into the fourth cerebral ventricle at embryonic/larval stages 30-53.
Results:
The fluorescent nanocrystals showed the normal development of the cerebral ventricles from embryonic/larval stages 38 to 53. The polystyrene beads injected into stage 47-49 larvae revealed three CSF flow patterns, left-handed, right-handed and non-biased, in movement of the beads into the third ventricle from the cerebral aqueduct (aqueduct of Sylvius). In the lateral ventricles, anterior to the third ventricle, CSF flow moved anteriorly along the outer wall of the ventricle to the inner wall and then posteriorly, creating a semicircle. In the cerebral aqueduct, connecting the third and fourth cerebral ventricles, CSF flow moved rostrally in the dorsal region and caudally in the ventral region. Also in the fourth ventricle, clear dorso-ventral differences in fluid flow pattern were observed.
Conclusions:
This is the first visualisation of the orchestrated CSF flow pattern in developing vertebrates using a live animal imaging approach. CSF flow in Xenopus albino larvae showed a largely consistent pattern, with the exception of individual differences in left-right asymmetrical flow in the third ventricle.
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In vitro effects of fetal rat cerebrospinal fluid on viability and neuronal differentiation of PC12 cells
Background:
Fetal cerebrospinal fluid (CSF) contains many neurotrophic and growth factors and has been shown to be capable of supporting viability, proliferation and differentiation of primary cortical progenitor cells. Rat pheochromocytoma PC12 cells have been widely used as an in vitro model of neuronal differentiation since they differentiate into sympathetic neuron-like cells in response to growth factors. This study aimed to establish whether PC12 cells were responsive to fetal CSF and therefore whether they might be used to investigate CSF physiology in a stable cell line lacking the time-specific response patterns of primary cells previously described.
Methods:
In vitro assays of viability, proliferation and differentiation were carried out after incubation of PC12 cells in media with and without addition of fetal rat CSF. An MTT tetrazolium assay was used to assess cell viability and/or cell proliferation. Expression of neural differentiation markers (MAP-2 and beta-III tubulin) was determined by immunocytochemistry. Formation and growth of neurites was measured by image analysis.
Results:
PC12 cells differentiate into neuronal cell types when exposed to bFGF. Viability and cell proliferation of PC12 cells cultured in CSF-supplemented medium from E18 rat fetuses were significantly elevated relative to the control group. Neuronal-like outgrowths from cells appeared following the application of bFGF or CSF from E17 and E19 fetuses but not E18 or E20 CSF. Beta-III tubulin was expressed in PC12 cells cultured in any media except that supplemented with E18 CSF. MAP-2 expression was found in control cultures and in those with E17 and E19 CSF. MAP2 was located in neurites except in E17 CSF when the whole cell was positive.
Conclusions:
Fetal rat CSF supports viability and stimulates proliferation and neurogenic differentiation of PC12 cells in an age-dependent way, suggesting that CSF composition changes with age. This feature may be important in vivo for the promotion of normal brain development. There were significant differences in the effects on PC12 cells compared to primary cortical cells. This suggests there is an interaction in vivo between developmental stage of cells and the composition of CSF. The data presented here support an important, perhaps driving role for CSF composition, specifically neurotrophic factors, in neuronal survival, proliferation and differentiation. The effects of CSF on PC12 cells can thus be used to further investigate the role of CSF in driving development without the confounding issues of using primary cells.
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Phosphorylated tau/amyloid beta 1-42 ratio in ventricular cerebrospinal fluid reflects outcome in idiopathic normal pressure hydrocephalus
Background:
Idiopathic normal pressure hydrocephalus (iNPH) is a potentially reversible cause of dementia and gait disturbance that is typically treated by operative placement of a ventriculoperitoneal shunt. The outcome from shunting is variable, and some evidence suggests that the presence of comorbid Alzheimer's disease (AD) may impact shunt outcome. Evidence also suggests that AD biomarkers in cerebrospinal fluid (CSF) may predict the presence of AD. The aim of this study was to investigate the relationship between the phosphorylated tau/amyloid beta 1-42 (ptau/Aβ1-42) ratio in ventricular CSF and shunt outcome in patients with iNPH.
Methods:
We conducted a prospective trial with a cohort of 39 patients with suspected iNPH. Patients were clinically and psychometrically assessed prior to and approximately 4 months after ventriculoperitoneal shunting. Lumbar and ventricular CSF obtained intraoperatively, and tissue from intraoperative cortical biopsies were analyzed for AD biomarkers. Outcome measures included performance on clinical symptom scales, supplementary gait measures, and standard psychometric tests. We investigated relationships between the ptau/Aβ1-42 ratio in ventricular CSF and cortical AD pathology, initial clinical features, shunt outcome, and lumbar CSF ptau/Aβ1-42 ratios in the patients in our cohort.
Results:
We found that high ptau/Aβ1-42 ratios in ventricular CSF correlated with the presence of cortical AD pathology. At baseline, iNPH patients with ratio values most suggestive of AD presented with better gait performance but poorer cognitive performance. Patients with high ptau/Aβ1-42 ratios also showed a less robust response to shunting on both gait and cognitive measures. Finally, in a subset of 18 patients who also underwent lumbar puncture, ventricular CSF ratios were significantly correlated with lumbar CSF ratios.
Conclusions:
Levels of AD biomarkers in CSF correlate with the presence of cortical AD pathology and predict aspects of clinical presentation in iNPH. Moreover, preliminary evidence suggests that CSF biomarkers of AD may prove useful for stratifying shunt prognosis in patients being evaluated and treated for this condition.
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Expression and localization of claudins-3 and -12 in transformed human brain endothelium
Background:
The aim of this study was to characterize the hCMEC/D3 cell line, an in vitro model of the human Blood Brain Barrier (BBB) for the expression of brain endothelial specific claudins-3 and -12.FindingshCMEC/D3 cells express claudins-3 and -12. Claudin-3 is distinctly localized to the TJ whereas claudin -12 is observed in the perinuclear region and completely absent from TJs. We show that the expression of both proteins is lost in cell passage numbers where the BBB properties are no longer fully conserved. Expression and localization of claudin-3 is not modulated by simvastatin shown to improve barrier function in vitro and also recommended for routine hCMEC/D3 culture.
Conclusions:
These results support conservation of claudin-3 and -12 expression in the hCMEC/D3 cell line and make claudin-3 a potential marker for BBB characteristics in vitro.
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Detection of oligoclonal IgG kappa and IgG lambda bands in cerebrospinal fluid and serum with HevyliteTM antibodies. Comparison with the free light chain oligoclonal pattern.
Background:
Oligoclonal IgG bands in cerebrospinal fluid that are absent in serum indicate intrathecal IgG synthesis and are a sensitive marker of CNS inflammatory diseases, in particular multiple sclerosis. It may be of interest to determine whether these bands are predominantly IgGκ or IgGλ.
Methods:
We have used Hevylite™ antibodies and developed a technique for detection of oligoclonal IgGκ and IgGλ bands by means of isoelectric focusing followed by immunoblotting. The same technique was used for oligoclonal free κ and free λ detection. Among several techniques tested, affinity immunoblotting appears to be the most sensitive; it can detect less than 1 ng of IgGκ or IgGλ paraprotein. We compared oligoclonal IgG profiles with those of oligoclonal IgGκ and IgGλ. There was good agreement concerning the presence or absence of intrathecal synthesis. We observed the ratios between oligoclonal IgGκ and IgGλ bands, and they did not always match the ratios between free κ and free λ bands. We were also able to detect antigen-specific CSF-restricted oligoclonal IgGκ and IgGλ bands in neuroborreliosis. It remains to be determined subsequently by a clinically-oriented prospective study, whether predominant IgGκ/IgGλ or free κ/free λ can be observed more frequently in particular diseases with oligoclonal IgG synthesis.DiscussionVery sensitive detection of oligoclonal IgGκ and IgGλ bands in cerebrospinal fluid with Hevylite antibodies is feasible; detection of antigen-specific IgGκ or IgGλ is possible as well. In particular situations, e.g. when difficulties arise in distinguishing between oligoclonal and monoclonal pattern, the test may be of considerable clinical value.
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Evaluation of blood-brain barrier transport and CNS drug metabolism in diseased and control brain after intravenous L-DOPA in a unilateral rat model of Parkinson's disease
Background:
Changes in blood-brain barrier (BBB) functionality have been implicated in Parkinson's disease. This study aimed to investigate BBB transport of L-DOPA transport in conjunction with its intra-brain conversion, in both control and diseased cerebral hemispheres in the unilateral rat rotenone model of Parkinson's disease.
Methods:
In Lewis rats, at 14 days after unilateral infusion of rotenone into the medial forebrain bundle, L-DOPA was administered intravenously (10, 25 or 50 mg/kg). Serial blood samples and brain striatal microdialysates were analysed for L-DOPA, and the dopamine metabolites DOPAC and HVA. Ex-vivo brain tissue was analyzed for changes in tyrosine hydroxylase staining as a biomarker for Parkinson's disease severity. Data were analysed by population pharmacokinetic analysis (NONMEM) to compare BBB transport of L-DOPA in conjunction with the conversion of L-DOPA into DOPAC and HVA, in control and diseased cerebral hemisphere.
Results:
Plasma pharmacokinetics of L-DOPA could be described by a 3-compartmental model. In rotenone responders (71%), no difference in L-DOPA BBB transport was found between diseased and control cerebral hemisphere. However, in the diseased compared with the control side, basal microdialysate levels of DOPAC and HVA were substantially lower, whereas following L-DOPA administration their elimination rates were higher.
Conclusions:
Parkinson's disease-like pathology, indicated by a huge reduction of tyrosine hydroxylase as well as by substantially reduced levels and higher elimination rates of DOPAC and HVA, does not result in changes in BBB transport of L-DOPA. Taking the results of this study and that of previous ones, it can be concluded that changes in BBB functionality are not a specific characteristic of Parkinson's disease, and cannot account for the decreased benefit of L-DOPA at later stages of Parkinson's disease.
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Temporal course of cerebrospinal fluid dynamics and amyloid accumulation in the aging rat brain from three to thirty months
Background:
Amyloid accumulation in the brain parenchyma is a hallmark of Alzheimer's disease (AD) and is seen in normal aging. Alterations in cerebrospinal fluid (CSF) dynamics are also associated with normal aging and AD. This study analyzed CSF volume, production and turnover rate in relation to amyloid-beta peptide (Aβ) accumulation in the aging rat brain.
Methods:
Aging Fischer 344/Brown-Norway hybrid rats at 3, 12, 20, and 30 months were studied. CSF production was measured by ventriculo-cisternal perfusion with blue dextran in artificial CSF; CSF volume by MRI; and CSF turnover rate by dividing the CSF production rate by the volume of the CSF space. Aβ40 and Aβ42 concentrations in the cortex and hippocampus were measured by ELISA.
Results:
There was a significant linear increase in total cranial CSF volume with age: 3-20 months (p < 0.01); 3-30 months (p < 0.001). CSF production rate increased from 3-12 months (p < 0.01) and decreased from 12-30 months (p < 0.05). CSF turnover showed an initial increase from 3 months (9.40 day-1) to 12 months (11.30 day-1) and then a decrease to 20 months (10.23 day-1) and 30 months (6.62 day-1). Aβ40 and Aβ42 concentrations in brain increased from 3-30 months (p < 0.001). Both Aβ42 and Aβ40 concentrations approached a steady state level by 30 months.
Conclusions:
In young rats there is no correlation between CSF turnover and Aβ brain concentrations. After 12 months, CSF turnover decreases as brain Aβ continues to accumulate. This decrease in CSF turnover rate may be one of several clearance pathway alterations that influence age-related accumulation of brain amyloid.
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Intrastriatal convection-enhanced delivery results in widespread perivascular distribution in a pre-clinical model
Background:
Convection-enhanced delivery (CED), a direct method for drug delivery to the brain through intraparenchymal microcatheters, is a promising strategy for intracerebral pharmacological therapy. By establishing a pressure gradient at the tip of the catheter, drugs can be delivered in uniform concentration throughout a large volume of interstitial fluid. However, the variables affecting perivascular distribution of drugs delivered by CED are not fully understood. The aim of this study was to determine whether the perivascular distribution of solutes delivered by CED into the striatum of rats is affected by the molecular weight of the infused agent, by co-infusion of vasodilator, alteration of infusion rates or use of a ramping regime. We also wanted to make a preliminary comparison of the distribution of solutes with that of nanoparticles.
Methods:
We analysed the perivascular distribution of 4, 10, 20, 70, 150 kDa fluorescein-labelled dextran and fluorescent nanoparticles at 10 min and 3 h following CED into rat striatum. We investigated the effect of local vasodilatation, slow infusion rates and ramping on the perivascular distribution of solutes. Co-localisation with perivascular basement membranes and vascular endothelial cells was identified by immunohistochemistry. The uptake of infusates by perivascular macrophages was quantified using stereological methods.
Results:
Widespread perivascular distribution and macrophage uptake of fluorescein-labelled dextran was visible 10 min after cessation of CED irrespective of molecular weight. However, a significantly higher proportion of perivascular macrophages had taken up 4, 10 and 20 kDa fluorescein-labelled dextran than 150 kDa dextran (p < 0.05, ANOVA). Co-infusion with vasodilator, slow infusion rates and use of a ramping regime did not alter the perivascular distribution. CED of fluorescent nanoparticles indicated that particles co-localise with perivascular basement membranes throughout the striatum but, unlike soluble dextrans, are not taken up by perivascular macrophages after 3 h.
Conclusions:
This study suggests that widespread perivascular distribution and interaction with perivascular macrophages is likely to be an inevitable consequence of CED of solutes. The potential consequences of perivascular distribution of therapeutic agents, and in particular cytotoxic chemotherapies, delivered by CED must be carefully considered to ensure safe and effective translation to clinical trials.
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Cough - Latest Articles
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Seasonal variations of cough reflex sensitivity in elite athletes training in cold air environment
Background:
Exercise-induced cough is common among athletes. Athletes training in cold air often report an increasingly troublesome cough during the winter season. Chronic airway irritation or inflammation may increase the sensory response of cough receptors. The aim of this study was to evaluate the seasonal variability of cough reflex sensitivity to capsaicin in elite athletes.
Methods:
Fifty-three elite winter athletes and 33 sedentary subjects completed a respiratory questionnaire and a capsaicin provocation test during the summer, fall, and winter. Allergy skin prick tests, spirometry, eucapnic voluntary hyperpnea test (EVH), methacholine inhalation test (MIT), and induced sputum analysis were also performed.
Results:
In athletes, the prevalence of cough immediately after exercise was high, particularly during winter. Athletes often showed a late occurrence of cough between 2-8 h after exercise. The cough reflex sensitivity to capsaicin was unchanged through the seasons in both athletes and non-athlete subjects. No significant correlations were found in groups between cough reflex sensitivity to capsaicin and the number of years in sport training, the number of hours of training per week, EVH response (% fall in FEV1), airway responsiveness to methacholine (PC20), airway inflammation or atopy.
Conclusion:
The prevalence of cough immediately and a few hours after exercise is high in athletes and more frequently reported during winter. However, cough does not seem to be associated with cough reflex hypersensitivity to capsaicin, bronchoconstriction, or airway inflammation in the majority of athletes.
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An observational study on cough in children: epidemiology, impact on quality of sleep and treatment outcome
Background:
Cough is one of the most frequent symptoms in children and is the most common symptom for which children visit a health care provider.
Methods:
This is an observational study on acute cough associated with upper respiratory tract infection (URTI) in children. The study evaluates the epidemiology and impact of cough on quality of sleep and children's activities, and the outcome of cough with antitussive treatments in pediatric routine clinical practice. Study assessments were performed through a pediatric cough questionnaire (PCQ), developed by the Italian Society of Cough Study. A total of 433 children visited by family care pediatricians for acute cough due to a URTI were enrolled in this study, with mean age of 6.1 years (SD 3.6). Cough type, duration, severity and frequency, cough impact on sleep disturbances of children and parents and on school and sport activities were assessed at baseline. In a subset of 241 children who were either treated with antitussive drugs (levodropropizine n = 101, central antitussives n = 60) or received no treatment (n = 80), the outcome of cough after 6 days was analyzed in terms of resolution, improvement, no change, or worsening. Descriptive analysis, χ2 test, and multivariate analysis with stepwise logistic regression were performed.
Results:
Cough disturbed sleep in 88% of children and 72% of parents. In children treated with cough suppressants, the duration, type, intensity, and frequency cough were similar at baseline in the two groups respectively treated with levodropropizine and central antitussives (cloperastine and codeine). Both levodropropizine and central drugs reduced cough intensity and frequency. However, percentage of cough resolution was higher with levodropropizine than with central antitussives (47% vs. 28% respectively, p = 0.0012).
Conclusions:
Acute cough disturbs sleep in most children and their parents. Both levodropropizine and central antitussives reduced cough intensity, with levodropropizine producing a higher cough resolution rate.
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The objective assessment of cough frequency: accuracy of the LR102 device.
Background:
The measurement of cough frequency is problematic and most often based on subjective assessment. The aim of the study was to assess the accuracy of the automatic identification of cough episodes by LR102, a cough frequency meter based on electromyography and audio sensors.
Methods:
Ten adult patients complaining of cough were recruited in primary care and hospital settings. Participants were asked to wear LR102 for 4 consecutive hours during which they were also filmed.
Results:
Measures of cough frequency by LR102 and manual counting were closely correlated (r = 0.87 for number of cough episodes per hour; r = 0.89 for number of single coughs per hour) but LR102 overestimated cough frequency. Bland-Altman plots indicate that differences between the two measurements were not influenced by cough frequency.
Conclusions:
LR102 offers a useful estimate of cough frequency in adults in their own environment, while significantly reducing the time required for analysis.
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Perspective on the human cough reflex
This review dissects the complex human cough reflex and suggests hypotheses about the evolutionary basis for the reflex. A mechanosensory-induced cough reflex conveys through branches of myelinated Aδ nerve fibers is not chemically reactive (i.e., capsaicin, bradykinin); possibly, its evolution is to prevent the harmful effects of aspiration of gastric or particulate contents into the lungs. This became necessary as the larynx moves closer to the opening of the esophagus as human ancestors adapt phonation over olfaction beginning less than 10 million years ago. The second type of cough reflex, a chemosensory type, is carried by unmyelinated C fibers. Supposedly, its origin dates back when prehistoric humans began living in close proximity to each other and were at risk for infectious respiratory diseases or irritant-induced lung injury. The mechanism for the latter type of cough is analogous to induced pain after tissue injury; and, it is controlled by the identical transient receptor potential vanilloid cation channel (TRPV1). The airways do not normally manifest nociceptive pain from a stimulus but the only consistent response that capsaicin and lung inflammation provoke in healthy human airways is cough. TRPA1, another excitatory ion channel, has been referred to as the "irritant receptor" and its activation also induces cough. For both types of cough, the motor responses are identical and via coordinated, precisely-timed and sequential respiratory events orchestrated by complex neuromuscular networking of the diaphragm, chest and abdominal respiratory muscles, the glottis and parts of the brain.
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Posture influences patient cough rate, sedative requirement and comfort during bronchoscopy: An observational cohort study.
ObjectivesTo investigate differences between semi-recumbent and supine postures in terms of cough rate, oxygen desaturation, sedative use, and patient comfort during the initial phase of bronchoscopy.
Methods:
Consecutive bronchoscopy patients (n = 69) participated in this observational cohort study. Posture was determined by the bronchoscopist's usual practice. Patient demographics, spirometry, pulse, and SpO2 were recorded. The initial phase was defined as the time from bronchoscopy insertion to visualisation of both distal main bronchi. Cough rate, peak pulse, nadir SpO2, oxygen supplementation, and sedative use during the initial phase were recorded. A post-procedure questionnaire was administered to the patient and the attending nurse.
Results:
36 patients had bronchoscopy in the semi-recumbent posture, 33 in the supine posture. 3 of 5 bronchoscopists performed in both postures. There were no differences in baseline parameters between the groups. The semi-recumbent posture resulted in significantly less cough (mean (SD) 3.6 (2.3) vs. 6.1 (4.5) coughs/min, p = 0.007) and less fentanyl use (70 (29) vs. 88 (28) mcg, p = 0.011) in the initial phase. There were no significant differences in the nadir SpO2, fall in SpO2, oxygen supplementation, or increase in pulse rate between the groups. On 100 mm visual analogue scale, nurse perception of patient discomfort was lower in the semi-recumbent position (23 (21) vs. 39 (28) mm, p = 0.01), and there was a trend towards less patient perceived cough in the semi-recumbent group (28 (25) vs. 40 (28) mm, p = 0.06).
Conclusions:
Bronchoscopy performed in the semi-recumbent posture results in less cough and sedative requirement, and may improve patient comfort.
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Cough response to isocapnic hyperpnoea of dry air and hypertonic saline are interrelated
Background:
Mechanisms behind asthmatic cough are largely unknown. It is known that hyperosmolar challenges provoke cough in asthmatic but not in the healthy subjects. It has been postulated that isocapnic hyperpnea of dry air (IHDA) and hypertonic aerosols act via similar mechanisms in asthma to cause bronchoconstriction. We investigated whether there is an association between cough response induced by IHDA and hypertonic saline (HS) challenges.
Methods:
Thirty-six asthmatic and 14 healthy subjects inhaled HS solutions with increasing osmolalities administered via ultrasonic nebuliser until 15 cumulative coughs were recorded. The IHDA consisted of three three-minute ventilation steps: 30%, 60% and 100% of maximal voluntary ventilation with an end-point of 30 cumulative coughs. The challenges were performed on separate days at least 48 hours between them and within one week. Inhaled salbutamol (400 mcg) was administered before the challenges to prevent bronchoconstriction. The cough response was expressed as the cough-to-dose ratio (CDR) which is the total number of coughs divided by the maximal osmolality inhaled or the maximal ventilation achieved.
Results:
Cough response to IHDA correlated with the HS challenge (Rs = 0.59, p < 0.001). Cough response to IHDA was at its strongest during the first minute after the challenge. IHDA induced more cough among asthmatic than healthy subjects CDR being (mean ± SD) 0.464 ± 0.514 and 0.011 ± 0.024 coughs/MVV%, p < 0.001, respectively. Salbutamol effectively prevented bronchoconstriction to both challenges.
Conclusions:
Asthmatic patients are hypersensitive to the cough-provoking effect of hyperpnoea, as they are to hypertonicity. Cough response induced by IHDA and HS correlated well suggesting similar mechanisms behind the responses.
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Cough management: a practical approach
Cough is one of the most common symptoms for which patients seek medical attention from primary care physicians and pulmonologists. Cough is an important defensive reflex that enhances the clearance of secretions and particles from the airways and protects the lower airways from the aspiration of foreign materials. Therapeutic suppression of cough may be either disease-specific or symptom related. The potential benefits of an early treatment of cough could include the prevention of the vicious cycle of cough. There has been a long tradition in acute cough, which is frequently due to upper respiratory tract infections, to use symptom-related anti-tussives. Suppression of cough (during chronic cough) may be achieved by disease-specific therapies, but in many patients it is often necessary to use symptomatic anti-tussives, too. According to the current guidelines of the American College of Chest Physician on "Cough Suppressants and Pharmacologic Protussive Therapy" and additional clinical trials on the most frequent anti-tussive drugs, it should be possible to diagnose and treat cough successfully in a majority of cases. Among drugs used for the symptomatic treatment of cough, peripherally acting anti-tussives such as levodropropizine and moguisteine show the highest level of benefit and should be recommended especially in children. By improving our understanding of the specific effects of these anti-tussive agents, the therapeutic use of these drugs may be refined. The present review provides a summary of the most clinically relevant anti-tussive drugs in addition to their potential mechanism of action.
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Symptoms induced by environmental irritants and health-related quality of life in patients with chronic cough - a cross-sectional study
Background:
Chronic cough is a common condition, but some patients have no evident medical explanation for their symptoms. A group of patients has been identified, characterized by upper and lower airway symptoms triggered by chemicals and scents, and heightened cough sensitivity to inhaled capsaicin. Chronic cough is usually a prominent symptom in these patients, and it has been suggested that they suffer from sensory hyperreactivity.Our main aim was to analyse, in a group of patients with chronic cough, the presence of symptoms induced by environmental factors such as chemicals, scents, and cold air, and to measure the social and emotional influences of these symptoms in relation to quality of life. A second aim was to pilot-test a Swedish translation of a cough-specific questionnaire.
Methods:
A total of 119 patients with chronic cough were asked to answer three different questionnaires: a local symptom questionnaire, the Chemical Sensitivity Scale for Sensory Hyperreactivity (CSS-SHR), and the Nottingham Health Profile (NHP). In addition, a Swedish version of the Hull Airway Reflux Questionnaire (HARQ) was developed and answered by a subgroup of patients and healthy controls.
Results:
Sixty-two patients (52%) with mean cough duration of 10.6 years answered the local symptom questionnaire, the CSS-SHR, and the NHP. Of these, 39 (63%) claimed to have cough and other symptoms induced by chemicals and scents. Compared to population-based findings, the patients scored higher on the CSS-SHR, and the CSS-SHR score was significantly higher among chemical-sensitive individuals (p < 0.001). The NHP showed that the patients had a significantly reduced quality of life, which was most pronounced among chemical-sensitive individuals. The 31 patients who answered the HARQ had significantly higher scores (p < 0.0001) than 59 healthy controls.
Conclusions:
Among patients with chronic cough, a majority claimed that environmental factors induced coughing. Both the CSS-SHR and the HARQ score systems seem to be valuable instruments in the mapping of cough patients, supporting the novel paradigm of a cough hypersensitivity syndrome. Our results emphasize that cough is a substantial burden to the patient, influencing daily living and quality of life.
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Involvement of nitric oxide (NO) in cough reflex sensitivity between non-sensitized and OVA-sensitized guinea pigs
Background:
Exhaled nitric oxide (ENO) is elevated in bronchial asthma patients, and inhaled corticosteroid therapy lowers the elevated ENO levels in such patients. ENO appears to be an inflammatory marker, but its role in the pathophysiology of cough remains unclear. This study aimed to elucidate the relationship between NO and increased cough reflex sensitivity induced by allergic airway reactions.
Methods:
Cough reflex sensitivity to inhaled capsaicin was observed under NO depletion caused by NO synthase (NOS) inhibitors in non-sensitized and ovalbumin (OVA)-sensitized guinea pigs. The bronchoalveolar lavage fluid (BALF) was analyzed in an NO depletion setting using the inducible NOS (iNOS) inhibitor ONO1714 in OVA-sensitized guinea pigs.
Results:
NO depletion by the non-selective NOS inhibitor L-NAME suppressed cough reflex sensitivity in non-sensitized guinea pigs and OVA-induced increase in cough reflex sensitivity in sensitized guinea pigs; however, iNOS inhibition caused by ONO1714 partially suppressed the OVA-induced increase in cough reflex sensitivity, but not the normal cough response in non-sensitized guinea pigs. ONO1714 did not change BAL cell components in OVA-sensitized guinea pigs.
Conclusions:
The results suggest that NO may be involved not only in the normal cough reflex circuit, but also in the OVA-induced increase in cough reflex sensitivity, possibly via a different mechanism of action. Further studies are needed to clarify the precise mechanism.
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The assessment of quality of life in acute cough with the Leicester Cough Questionnaire (LCQ-acute)
IntroductionAcute cough has a significant impact on physical and psychosocial health and is associated with an impaired quality of life (QOL). The Leicester Cough Questionnaire (LCQ) is a validated cough-related health status questionnaire designed for patients with chronic cough. The purpose of this study was to validate the LCQ for the assessment of health related QOL in patients with acute cough and determine the clinical minimal important difference (MID).
Methods:
10 subjects with cough due to acute upper respiratory tract infection underwent focused interviews to investigate the face validity of the LCQ. The LCQ was also evaluated by a multidisciplinary team. 30 subjects completed the revised LCQ-acute and a cough visual analogue score (VAS: 0-100 mm) within one week of onset of cough and again <2 weeks later and at resolution of cough. The concurrent validity, internal reliability, repeatability and responsiveness of the LCQ-acute were also assessed. Patients also completed a Global Rating of Change Questionnaire that assessed the change in cough severity between visits. The MID was calculated as the change in LCQ-acute score for patients responding to GRCQ category representing the smallest change in health status that patients found worthwhile.
Results:
Health status was severely impaired at baseline affecting all domains; median (interquartile range) total LCQ-acute score 13.0 (3.4). All subjects found the LCQ-acute questionnaire acceptable for assessing their cough. Internal reliability of the LCQ-acute was good for all domains and total score, Cronbach's α coefficients >0.9. There was a significant correlation between LCQ-acute and VAS (ρ = -0.48, p = 0.007). The LCQ-acute and its domains were highly responsive to change; effect sizes 1.7-2.3. The MID for total LCQ and VAS were 2.5 and 13 mm respectively.
Conclusion:
The LCQ-acute is a brief, simple and valid instrument to assess cough specific health related QOL in patients with acute cough. It is a highly responsive tool suggesting that it will be particularly useful to assess the effect of antitussive therapy.
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Critical Care - Latest Articles
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ROTEM-guided coagulation factor concentrate therapy in trauma - 2-year experience in Venice, Italy
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Elevated plasma levels of heparin-binding protein in intensive care unit patients with severe sepsis and septic shock
IntroductionRapid detection of and optimized treatment for severe sepsis and septic shock is crucial for successful outcome. Heparin-binding protein (HBP), a potent inducer of increased vascular permeability, is a potentially useful biomarker for predicting outcome in patients with severe infections. Our aim was to study the systemic release and dynamics of HBP in plasma of patients with severe sepsis and septic shock in the intensive care unit (ICU).
Methods:
A prospective study of two patient cohorts treated in the ICU at Karolinska University Hospital Huddinge in Sweden. 179 patients were included, of whom 151 had sepsis (126 with septic shock and 25 patients with severe sepsis) and 28 a non-septic critical condition. Blood samples were collected at five time points during six days after admission.
Results:
HBP levels were significantly higher in the sepsis group as compared to the control group. At admission to the ICU, a plasma HBP concentration of [greater than or equal to]15 ng/mL and/or a HBP (ng/mL) / White blood cell count (109/L) ratio of >2 was found in 87.2% and 50.0% of critically ill patients with sepsis and non-septic illness, respectively. A lactate level of >2.5 mmol/L was detected in 64.9% and 56.0% of the same patient groups. Both in the sepsis group (n=151) and in the whole group (n=179), plasma HBP concentrations at admission and in the last measured sample within the 144 hour study period were significantly higher among 28-day non-survivors as compared to survivors, and in the sepsis group, an elevated HBP-level at baseline was associated with an increased case-fatality rate at 28 days.
Conclusions:
Plasma HBP levels were significantly higher in patients with severe sepsis or septic shock compared to patients with non-septic illness in the ICU. HBP was associated with severity of disease, and an elevated HBP at admission was associated with an increased risk of death. HBP that rises over time may identify patients with a deteriorating prognosis.Thus, repeated HBP measurement in the ICU may help monitor treatment and predict outcome in patients with severe infections.
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New strategies to manage complicated pleural effusions
Background:
More than 30% of patients with pleural infection either die or require surgery. Drainage of infected fluid is the key to successful treatment, but intrapleural fibrinolytic therapy did not improve outcomes in an earlier, large, randomized trial therapy (Multicenter Intrapleural Sepsis Trial [MIST1]).
Methods:
Objective: To evaluate the efficacy and safety of intrapleural DNase alone, alteplase alone, or the combination of both, to improve pleural drainage.DesignMulticenter, double-blind, double-dummy, 2x2 factorial randomized trial.Setting: Eleven centers in the United Kingdom (UK).Subjects: Adult patients (mean age 59 y, 72% men), who had clinical evidence of infection, and pleural fluid that had macroscopic purulence, a positive culture or Gram stain for bacteria, or a pH < 7.2.Intervention: Patients were assigned to 1 of the 4 study interventions for 3 days: double placebo, intrapleural tissue plasminogen activator (t-PA) and DNase, t-PA and placebo, or DNase and placebo.Outcomes: The primary outcome was the change in pleural opacity, measured as the percentage of the hemithorax occupied by effusion, on chest radiography on day 7 as compared with day 1. Secondary outcomes included referral for surgery, duration of hospital stay, and adverse events.
Results:
The mean (+/-SD) change in pleural opacity was greater in the t-PA-DNase group than in the placebo group (29.5+/-23.3% vs. 17.2+/-19.6%; difference, 7.9%; 95% confidence interval [CI], 13.4 to 2.4; P = 0.005). The change observed with t-PA alone and with DNase alone (17.2+/-24.3 and 14.7+/-16.4%, respectively) was not significantly different from that observed with placebo. The frequency of surgical referral at 3 months was lower in the t-PA-DNase group than in the placebo group (2 of 48 patients [4%] vs. 8 of 51 patients [16%]; odds ratio for surgical referral, 0.17; 95% CI, 0.03 to 0.87;P = 0.03) but was greater in the DNase group (18 of 46 patients [39%]) than in the placebo group (odds ratio, 3.56; 95% CI, 1.30 to 9.75; P = 0.01). Combined t-PA-DNase therapy was associated with a reduction in the hospital stay, as compared with placebo (difference, 6.7 days; 95% CI, 12.0 to 1.9; P = 0.006). Hospital stay with either agent alone was not significantly different from that with placebo. The frequency of adverse events did not differ significantly among the groups.
Conclusions:
Intrapleural t-PA-DNase therapy improved fluid drainage in patients with pleural infection and reduced the frequency of surgical referral and the duration of hospital stay. Treatment with DNase alone or t-PA alone was ineffective.CitationRahman NM, Maskell NA, West A, Teoh R, Arnold A, Mackinlay C, Peckham D, Davies CW, Ali N, Kinnear W, Bentley A, Kahan BC, Wrightson JM, Davies HE, Hooper CE, Lee YC, Hedley EL, Crosthwaite N, Choo L, Helm EJ, Gleeson FV, Nunn AJ, Davies RJ.N Engl J Med. 2011 Aug 11; 365(6):518-26.PMID: 21830966, available on www.pubmed.gov
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Red cell distribution width improves the simplified acute physiology score for risk prediction in unselected critically ill patients
IntroductionRecently, red cell distribution width (RDW), a measure of erythrocytes' size variability, has been shown to be a prognostic marker in critical illness. The aim of this study was to investigate whether adding RDW has the potential to improve the prognostic performance of the simplified acute physiology score (SAPS) to predict short and long term mortality in an independent, large and unselected population of intensive care unit (ICU) patients.
Methods:
This observational cohort study includes 17,922 ICU patients with available RDW measurements from different types of ICUs. We modeled the association between RDW and mortality using multivariable logistic regression, adjusting for demographic factors, comorbidities, hematocrit, and severity of illness using the SAPS.
Results:
ICU-, inhospital- and 1-year mortality rates in the 17,922 included patients were 7.6% (95%CI 7.2 to 8.0), 11.2% (95%CI 10.8 to 11.7) and 25.4% (95%CI 24.8 to 26.1). RDW was significantly associated with in-hospital mortality (OR per 1% increase in RDW [95%CI]) (1.14 (1.08, 1.19), P<0.0001), ICU mortality (1.10 (1.06, 1.15), P<0.0001), and 1-year mortality (1.20 (95%CI 1.14, 1.26), P<0.001). Adding RDW to SAPS significantly improved the AUC from 0.746 to 0.774 (P<0.001) for in-hospital mortality and 0.793 to 0.805 (P<0.001) for ICU mortality. Significant improvements in classification of SAPS were confirmed in reclassification analyses. Subgroups demonstrated robust results for gender, age categories, SAPS categories, anemia, hematocrit categories and renal failure.
Conclusions:
RDW is a promising independent short- and long-term prognostic marker in ICU patients and significantly improves risk stratification of SAPS. Further research is needed to better understand the pathophysiology underlying these effects.
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Combining intermediate levels of the endotoxin activity assay (EAA)
with other biomarkers in the assessment of patients with sepsis: results of an observational study
IntroductionThe Endotoxin Activity Assay (EAA) is a useful test to risk stratify patients with severe sepsis and assess for Gram negative infection. However, the significance of intermediate levels of EAA (0.4-0.59) at the bedside has not been well elucidated. The purpose of this study was to interpret intermediate EAA levels in clinical practice.
Methods:
This retrospective observational study included all adult patients with suspected sepsis admitted to our medico-surgical intensive care unit (ICU) in whom EAA was measured from July 2008 to September 2011. Data collected included EAA, white blood cell (WBC) count and differential, C-reactive protein (CRP), procalcitonin (PCT) and bacterial cultures. Data were analyzed by comparative statistics.
Results:
Two hundred and ten patients were studied. Ninety two (43 %) patients had culture documented gram negative infection. Patients with Gram-negative organisms in cultures had significantly higher EAA levels (0.47, IQR 0.27) than those without any Gram-negative organisms in cultures (0.34, IQR 0.22) (p < 0.0001). For patients with intermediate EAA levels (0.40 to 0.59), PCT levels and presence of left shift of WBC significantly differed between patients with Gram negative organisms in their blood oar other cultures and those who no organisms in any of the cultures (4.9 vs. 1.7 ng/mL, p < 0.05; 57.9 vs. 18.9 %, p < 0.0004, respectively).
Conclusions:
We confirm that high levels of EAA in our cohort of patients with suspected sepsis is strongly associated with gram negative infection. In those patients with intermediate elevation in EAA levels, use of PCT and WBC differential can provide additional diagnostic value to clinicians at the bedside.
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Apolipoprotein M - a new biomarker in sepsis
Sepsis is one of the leading causes of mortality in non-cardiac intensive care units, and the need for markers of progression and severity are high. Also, treatment of sepsis is highly debated and potential new targets of treatment are of great interest. In the previous issue of Critical Care Kumaraswamy and colleagues have investigated whether plasma apolipoprotein M (apoM) is affected during different grades of sepsis, septic shock and systemic inflammatory response syndrome. Interestingly, plasma apoM was significantly decreased in all groups of patients with a relationship to severity of disease. This identifies apoM as a potential new biomarker in sepsis. It also underscores the possibility that altered high-density lipoprotein in sepsis patients can affect the course of disease. Thus, since apoM is the carrier of Sphingosine-1-P (S1P), a molecule with great influence on vascular barrier function, the study presented raises the interest and relevance for further studies of apoM and S1P in relation to sepsis and inflammation.
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Multiple injuries after earthquakes: a retrospective analysis on 1871 injured patients from the 2008 Wenchuan earthquake
IntroductionMultiple injuries have been highlighted as an important clinical dimension of the injury profile following earthquakes, but studies are scarce. We investigated the pattern and combination of injuries among patients with two injuries following the 2008 Wenchuan earthquake. We also described the general injury profile, causes of injury, and socio-demographic characteristics of the injured patients.
Methods:
A retrospective hospital-based analysis of 1871 earthquake injured patients, totaling 3177 injuries, admitted between 12 and 31 May 2008 to the People's Hospital of Deyang city (PHDC). An electronic, webserver-based database with International Classification of Diseases (ICD)-10-based classification of earthquake-related injury diagnoses (IDs), anatomical sites, and additional background variables of the inpatients was used. We analyzed this dataset for injury profile and number of injuries per patient. We then included all patients (856) with two injuries for more in depth analysis. Possible spatial anatomical associations were determined a priori. Cross-tabulation and more complex frequency matrices for combination analyses were used to investigate the injury profile.
Results:
Out of the 1871 injured patients, 810 (43.3%) presented with a single injury. The rest had multiple injuries, 856 (45.8%) had two, 169 (9.0%) patients had three, 32 (1.7%) presented with four injuries while only 4 (0.2%) were diagnosed with five injuries. The injury diagnoses of patients presenting with two-injuries showed important anatomical intra-site or neighboring clustering, which explained 49.1% of the combinations. For fractures, the result was even more marked as spatial clustering, explaining 57.9% of the association pattern. The most frequent combination of IDs was a double-fracture, affecting 20.7% of the two-injury patients (n=177). Another 108 patients (12.6%) presented with fractures associated with crush injury and organ-soft tissue injury. Of the 3177 injuries, 1476 (46.5%) were fractures. Most injuries were located in the head (22.9%) and lower extremities (30.8%).
Conclusions:
Multiple injuries are put forward as an important component of the injury profile after this earthquake. A pattern of injury combinations and spatial aggregation of injuries was also found. Clinical diagnosis and treatment should be adapted to care of these patients. More studies are needed to generalize these findings.
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Review of "Neurology Emergencies" by Jonathon A. Edlow and Magdy H. Selim
None
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A pilot prospective study on closed loop controlled ventilation and oxygenation in ventilated children during the weaning phase
IntroductionThe present study is a pilot prospective safety evaluation of a new closed loop computerized protocol on ventilation and oxygenation in stable, spontaneously breathing children weighting more than 7kg, during the weaning phase of mechanical ventilation.
Methods:
Mechanically ventilated children ready to start the weaning process were ventilated for 5 periods of 60 minutes in the following order: Pressure Support Ventilation (PSV), Adaptive Support Ventilation (ASV), ASV plus a ventilation controller (ASV-CO2), ASV-CO2 plus an oxygenation controller (ASV-CO2-O2) and PSV again. Based on breath by breath analysis, the percentage of time with normal ventilation as defined by a respiratory rate (RR) between 10 and 40 breath/min, a tidal volume (VT) > 5 ml/kg of predicted body weight and an end tidal CO2 between 25 and 55 mmHg. The number of manipulations and changes on the ventilator were also recorded.
Results:
Fifteen children, median aged 45 months, were investigated. No adverse event and no premature protocol termination were reported. ASV-CO2 and ASV-CO2-O2, kept the patients within normal ventilation for respectively 94% [91 - 96] and 94% [87 - 96]) of the time. VT, RR, Peak inspiratory airway pressure (Paw-peak) and minute ventilation were equivalent with all modalities, although there were more automatic setting changes in ASV-CO2 and ASV-CO2-O2. PEEP modifications by ASV-CO2-O2 needs further investigation.
Conclusions:
Over the short study period and in this specific population, ASV-CO2 and ASV-CO2-O2 were safe and kept the patient with normal ventilation most of the time. Further research is needed, especially for PEEP modifications by ASV-CO2-O2.Trial registration: NCT01095406
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Antipsychotic use and diagnosis of delirium in the intensive care unit
IntroductionDelirium is an independent risk factor for prolonged hospital length of stay (LOS) and increased mortality. Several antipsychotics have been studied for the treatment of intensive care unit (ICU) delirium that has lead to a high variability in prescribing patterns for these medications. We hypothesize that in clinical practice the documentation of delirium is lower than the incidence of delirium reported in prospective clinical trials. The objective of this study was to document the incidence of delirium diagnosed in ICU patients and to describe the utilization of antipsychotics in the ICU.
Methods:
Retrospective observational cohort study conducted at seventy-one United States academic medical centers that reported data to the University HealthSystem Consortium Clinical Database/Resource Manager. Included all patients 18 years of age and older admitted to the hospital between January 1, 2010 and June 30, 2010 with at least one day in the ICU.
Results:
Delirium was diagnosed in 6% (10,034 of 164,996) of hospitalizations with an ICU admission. Antipsychotics were administered to 11% (17,764 of 164,996) of patients. Of the antipsychotics studied, the most frequently used were haloperidol (62%; n=10,958) and quetiapine (31%; n=5,448). Delirium was associated with increased ICU LOS (5 vs. 3 days, P<0.001) and hospital LOS (11 vs. 6 days, P<0.001), but not in-hospital mortality (8% vs. 9%, P=0.419). Antipsychotic exposure was associated with increased ICU LOS (8 vs. 3 days, P<0.001), hospital LOS (14 vs. 5 days, P<0.001) and mortality (12% vs. 8%, P<0.001). Of patients with antipsychotic exposure in the ICU, absence of a documented mental disorder (32%, n=5,760) was associated with increased ICU LOS (9 vs. 7 days, P<0.001), hospital LOS (16 vs. 13 days, P<0.001) and in-hospital mortality (19% vs. 9%, P<0.001) compared to patients with a documented mental disorder (68%, n=12,004).
Conclusions:
The incidence of documented delirium in ICU patients is lower than that documented in previous prospective studies with active screening. Antipsychotics are administered to one in every ten ICU patients. When administration occurs in the absence of a documented mental disorder, antipsychotic use is associated with an even higher ICU and hospital LOS, as well as in-hospital mortality.
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Diagnostic Pathology - Latest Articles
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Pathological and immunohistochemical study of
lethal primary brain stem injuries
Background:
Many of the deaths that occur shortly after injury or in hospitals are caused by mildtrauma. Slight morphological changes are often found in the brain stems of thesepatients during autopsy. The purpose of this study is to investigate thehistopathological changes involved in primary brain stem injuries (PBSI) and theirdiagnostic significance.
Methods:
A total of 65 patients who had died of PBSI and other conditions were randomlyselected. They were divided into 2 groups, an injury group (25 cases) and a controlgroup (20 cases). Slides of each patient's midbrain, pons, and medulla oblongata wereprepared and stained with HE, argentaffin, and immunohistochemical agents (GFAP,NF, amyloid-SZ, MBP). Under low power (x100) and NF staining, the diameter of thethickest longitudinal axon was measured at its widest point. Ten such diameters werecollected for each part of the brain (midbrain, pons, and medulla oblongata). Datawere recorded and analyzed statistically.
Results:
Brain stem contusions, astrocyte activity, edema, and pathological changes in theneurons were visibly different in the injury and control groups (P < 0.05).Characteristic changes occurred in the neural axons, axon diameter varied from axonto axon and even over different segments of one axon, and several pathologicalphenomena were observed. These included segmental thickening and curving,wave-like processing, disarrangement, and irregular swelling. A few axons rupturedand intumesced into retraction balls. Immunohistochemical MBP staining showedenlargement and curving of spaces between the myelin sheaths and axons in certainareas. The myelin sheaths lining the surfaces of the axons were in some casesincomplete and even exfoliated, and segmentation disappeared. These pathologicalchanges increased in severity over time (P < 0.05).
Conclusions:
These histopathological changes may prove beneficial to the pathological diagnosis ofPBSI during autopsy. The measurement of axon diameters provides a referentquantitative index for the diagnosis of the specific causes of death involved in PBSI.Virtual SlidesThe virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/1345298818712204
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Evaluation of inadequate, indeterminate, falsenegative
and false-positive cases in cytological
examination for breast cancer according to
histological type
Background:
We previously investigated the current status of breast cytology cancer screening at seveninstitutes in our area of southern Fukuoka Prefecture, and found some differences indiagnostic accuracy among the institutions. In the present study, we evaluated the casesinvolved and noted possible reasons for their original cytological classification as inadequate,indeterminate, false-negative and false-positive according to histological type.
Methods:
We evaluated the histological findings in 5693 individuals who underwent cytologicalexamination for breast cancer (including inadequate, indeterminate, false-negative and falsepositivecases), to determine the most common histological types and/or features in thesesettings and the usefulness/limitations of cytological examination for the diagnosis of breastcancer.
Results:
Among 1152 cytologically inadequate cases, histology revealed that 75/173 (43.6%) caseswere benign, including mastopathy (fibrocystic disease) in 38.6%, fibroadenoma in 24.0%and papilloma in 5.3%. Ninety-five of 173 (54.9%) cases were histologically malignant, withscirrhous growing type, invasive ductal carcinoma (SIDC) being significantly more frequent(49.5%) than papillotubular growing type (Papi-tub) (P < 0.0001), solid-tubular growing type(P = 0.0001) and ductal carcinoma in situ (DCIS) (P = 0.0001). Among 458 indeterminatecases, 54/139 (38.8%) were histologically benign (mastopathy, 30.0%; fibroadenoma, 27.8%;papilloma, 26.0%) and 73/139 (52.5%) were malignant, with SIDC being the most frequentmalignant tumor (37.0%). Among 52 false-negative cases, SIDC was significantly morefrequent (42.3%) than DCIS (P = 0.0049) and Papi-tub (P = 0.001). There were three falsepositivecases, with one each of fibroadenoma, epidermal cyst and papilloma.
Conclusions:
The inadequate, indeterminate, false-negative and false-positive cases showed similarhistological types, notably SIDC for malignant tumors, and mastopathy, fibroadenoma andpapilloma for benign cases. We need to pay particular attention to the collection andassessment of aspirates for these histological types of breast disease. In particular, severalinadequate, indeterminate and false-negative cases with samples collected by aspiration werediagnosed as SIDC. These findings should encourage the use of needle biopsy rather thanaspiration when this histological type is identified on imaging. Namely, good communicationbetween clinicians and pathological staff, and triple assessment (i.e., clinical, pathologicaland radiological assessment), are important for accurate diagnosis of aspiration samples.Virtual SlidesThe virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/7349809170055423
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Survivin regulates the expression of VEGF-C in
lymphatic metastasis of breast cancer
Background:
As a known regulator of apoptosis, survivin has positive relationship with lymphaticmetastasis in breast cancer. This study aims to detect the difference in expression betweensurvivin and vascular endothelial growth factor-C (VEGF-C) in treated breast cancer cellsand tissues, and to analyze the correlation among survivin, VEGF-C and lymphaticmetastasis.
Methods:
Plasmid with survivin and VEGF-C shRNA and lentivirus with survivin gene wereconstructed and transfected into breast cancer cell ZR-75-30. Then the expressions of the twogenes were examined using western blot analysis and real-time PCR. The change ofinvasiveness of breast cancer cells was assessed using matrigel invasion assay. Usingimmunohistochemistry, the expression of survivin and VEGF-C were analyzed in 108 clinicalbreast cancer cases with breast cancer tissue and lymph node.
Results:
Survivin regulated the expression of VEGF-C at both protein and mRNA levels in breastcancer cells. Immunohistochemical analysis showed that the level of VEGF-C expression wassignificantly related with that of survivin in breast cancer tissues (p<0.05). VEGF-C wasfound to participate in the process of breast cancer cells invasion mediated by survivin. Theco-expression of the two and the single expression of any one took significant difference inpositive lymph node (p<0.05).
Conclusions:
Survivin takes an important part in regulating the expression of VEGF-C. VEGF-C couldinfluence the invasive ability mediated by survivin. The co-expression of survivin andVEGF-C is more statistically significant to assess lymphatic metastasis in breast cancer.Virtual slidesThe virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/9193530897100952
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Primary central nervous system plasmablastic
lymphoma presenting in human immunodeficiency
virus-negative but Epstein-Barr virus-positive
patient: A case report
We report a 32-year-old Outer Mongolian man, with plasmablastic lymphoma (PBL)primarily occured in the central nervous system and diagnosed by surgical resection. Thispatient appeared headache and Magnetic resonance imaging (MRI) showed multiple lesionsin the right cerebral hemisphere including the right frontal-parietal lobe and right basalganglia and the left cerebellum, he was diagnosed as lymphoma by stereotactic biopsy inJanuary 2009 in local hospital, and was given radiotherapy 33 times after the biopsy. Thepatient was admitted to The Military General Hospital of Beijing PLA., Beijing, P.R. Chinaon March 9th, 2011, with chief complaints of right limbs convulsioned suddenly, then felldown and lose of his consciousness, then awoke after 4 to 5 minutes, with symptoms ofangulus oris numbness and the right upper limb powerless ten days ago.MRI of the brain revealed a well-defined hyperdense and enhancing mass in the left frontalparietallobe, the meninges are closely related, there was extensive peritumoural edema notedwith pressure effects, as evident by effacement of the left lateral ventricles and a 0.5 cm shiftof the midline to the right side.Surgical resection showed markedly atypical, large singly dispersed or cohesive proliferationof plasmacytoid cells with frequent abnormal mitoses and binucleation, some neoplastic cellswere large with round or oval nuclei and showed coarse chromatin and smaller or unapparentnucleoli, some neoplastic cells with prominent nucleoli, apoptosis and necrosis were oftenpresented. Immunohistochemistry staining and gene rearrangement together with othersupportive investigation confirmed the diagnosis of primary central nervous systemplasmablastic lymphoma. A month later, he was started on chemotherapy with R-CHOP(rituximab, cyclophosphamide, doxorubicin, leurocristime and prednisone) for a week. Othersupportive treatment was provided for symptomatic epilepsy. The patient regained musclestrength in both upper limbs and right lower limb and the symptomatic epilepsy wascontrolled after two weeks. Then the patient was discharged. Follow-up data shows thepatient to be alive eleven months after discharge.Virtual SlidesThe virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/1649317674697046
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Renal infarction due to polyarteritis nodosa in a patient with angioimmunoblastic T-cell lymphoma: a case report and a brief review of the literature
Angioimmunoblastic T-cell lymphoma (AITL) is one of the most common subtypes of peripheral T-cell lymphoma (15-20% of all cases), accounting for approximately 1-2% of all non-Hodgkin lymphomas. It often presents autoimmune phenomena including hemolytic anemia, thrombocytopenia, glomerulonephrities and circulating immune complexes (CIC). Polyarteritis nodosa (PAN) is an autoimmune disease characterized by necrotizing vasculitis of medium vessels, which rarely develops in association with hematological malignant disorders. Herein we report the case of a male patient with AITL who had a renal infarction secondary to PAN, mimicking a neoplastic lesion.A 40-year-old man underwent lymph node biopsy in the suspicious of sarcoidosis. On the basis of histological and immunohistochemical findings, a diagnosis of AITL was performed. The patient was successfully treated with a cytarabine-based regimen for 6 cycles. Three months after the initial diagnosis of AITL, a whole body CT-scan showed a lesion in the lower pole of the left kidney. A renal cell carcinoma was suspected, thus a nephrectomy was carried out. The histological findings were compatible with polyarteritis nodosa. To the best of our knowledge, the association between PAN and AITL has been described only once. This relation may be secondary to the induction of an autoimmune phenomenon by the lymphoma with the formation of circulating immune complexes, leading to vessel walls injury. A careful evaluation is needed in the management of AITL patients with signs of renal failure in order to avoid delay of treatment and organ damage.Key words: renal infarction, polyarteritis nodosa, T-cell lymphoma
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Sporadic Hemangioblastoma of the Kidney: a rare
renal tumor
Hemangioblastoma is a benign and morphologically distinctive tumor that can occursporadically or in association with von Hippel-Lindau disease in approximately 25 % of thecases, and which involves the central nervous system in the majority of the cases. Rareoccurrences of hemangioblastoma in peripheral nerves and extraneural tissues have beenreported. This report describes one case of sporadic renal hemangioblastoma happened in a16-year-old Chinese female patient, presenting with hematuria, and low back pain.Histologically, the tumors were circumscribed, and composed of sheets of large polygonalcells traversed by arborizing thin-walled blood vessels. The diagnosis of hemangioblastomawas confirmed by negative immunostaining for cytokeratin, and positive staining for alpha-inhibin, S100 and neuron-specific enolase (NSE). This benign neoplasm which can bemistaken for various malignancies such as renal cell carcinoma, epithelioidhemangiopericytoma and epithelioid angiomyolipoma, deserves wider recognition for itsoccurrence as a primary renal tumor.Virtual slidesThe virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/5445834246942699
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Introduction of virtual microscopy in routine
surgical pathology - a hypothesis and personal view
from Europe
The technology of whole image acquisition from histological glass slides (Virtual slides,(VS)) and its associated software such as image storage, viewers, and virtual microscopy(VM), has matured in the recent years. There is an ongoing discussion whether to introduceVM into routine diagnostic surgical pathology (tissue-based diagnosis) or not, and if these areto be introduced how best to do this. The discussion also centres around how to substantiallydefine the mandatory standards and working conditions related to introducing VM. Thisarticle briefly describes some hypotheses alongside our perspective and that of several of ourEuropean colleagues who have experienced VS and VM either in research or routine praxis.After consideration of the different opinions and published data the following statements canbe derived: 1. Experiences from static and remote telepathology as well as from daily routinediagnoses, confirm that VM is a diagnostic tool that can be handled with the same diagnosticaccuracy as conventional microscopy; at least no statistically significant differences (p >0.05) exist. 2. VM possesses several practical advantages in comparison to conventionalmicroscopy; such as digital image storage and retrieval and contemporary display of multipleimages (acquired from different stains, and/or different cases). 3. VM enables fast andefficient feedback between the pathologist and the laboratory in terms of ordered additionalstains, automated access to the latest research for references, and fast consultation withoutstanding telepathology experts. 4. Industry has already invested "big money" into thistechnology which certainly will be of influence in its future development. The mainconstraints against VM include the questionable reimbursement of the initial investment, themissing direct and short term financial benefit, and the loss of potential biological identitybetween the patient and the examined tissue. This article tries to analyze and evaluate thefactors that influence the implementation of VM into routine tissue-based diagnosis, forexample in combination with predictive diagnosis. It focuses on describing the advantages ofmodern and innovative electronically based communication technology.Virtual SlidesThe virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/1245603103708547
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Epididymis rhabdomyoma: A case report and
literature review
Genital rhabdomyoma is very rare tumor that usually occurs in the vulvar of young women.Epididymis rhabdomyoma in a young man is extremely uncommon and has rarely beenreported. Here, we report a case of epididymis rhabdomyoma of a 17-year-old man andreview the literatures.Virtual slideThe virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/1177628224692794
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Is there a link between diabetic glomerular injury and
crescent formation? A case report and literature review
Glomerular crescents are most commonly associated with rapidly progressive crescenticglomerulonephritis; however, they also develop in response to a wide range of primary andsecondary glomerular injuries. Since various kind of glomerulopathies occasionally overlaydiabetic glomerular injuries, the presence of crescents in renal biopsy specimens of diabeticsmay have stimulated a search for etiologies other than diabetes. In this report, we describe anunusual case of diabetic glomerulosclerosis with peculiar extracapillary proliferation.Although such a relationship has so far been ignored in most of the literature, the etiologicallinkage between diabetic glomerulosclerosis and the development of crescents may not beexceptional. We have reviewed the previous literature and herein discuss the pathologicalimplications of the development of crescents in patients with diabetic glomerulosclerosis.Virtual SlidesThe virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/3950457896920255
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Serum peptidome patterns of breast cancer based on
magnetic bead separation and mass spectrometry
analysis
Background:
Breast cancer is one of the most common cancers in the world, and the identification ofbiomarkers for the early detection of breast cancer is a relevant target. The present study aimsto determine serum peptidome patterns for screening of breast cancer.
Methods:
The present work focused on the serum proteomic analysis of 36 healthy volunteers and 37breast cancer patients using a ClinProt Kit combined with mass spectrometry (MS). Thisapproach allows the determination of peptidome patterns that are able to differentiate thestudied populations. An independent group of sera (36 healthy volunteers and 37 breastcancer patients) was used to verify the diagnostic capabilities of the peptidome patternsblindly. An immunoassay method was used to determine the serum mucin 1 (CA15-3) ofvalidation group samples.
Results:
Support Vector Machine (SVM) Algorithm was used to construct the peptidome patterns forthe identification of breast cancer from the healthy volunteers. Three of the identified peaksat m/z 698, 720 and 1866 were used to construct the peptidome patterns with 91.78%accuracy. Furthermore, the peptidome patterns could differentiate the validation groupachieving a sensitivity of 91.89% (34/37) and a specitivity of 91.67% (33/36) (> CA 15-3,P < 0.05).
Conclusions:
These results suggest that the ClinProt Kit combined with MS shows great potentiality for thediagnosis of breast cancer.Virtual slidesThe virtual slide(s) for this article can be found here:http://www.diagnosticpathology.diagnomx.eu/vs/1501556838687844
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Emerging Themes in Epidemiology - Latest Articles
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Carpet-dust chemicals as measures of exposure: Implications of variability
Background:
There is increasing interest in using chemicals measured in carpet dust as indicators of chemical exposures. However, investigators have rarely sampled dust repeatedly from the same households and therefore little is known about the variability of chemical levels that exist within and between households in dust samples.
Results:
We analyzed 9 polycyclic aromatic hydrocarbons, 6 polychlorinated biphenyls, and nicotine in 68 carpet-dust samples from 21 households in agricultural communities of Fresno County, California collected from 2003-2005. Chemical concentrations (ng per g dust) ranged from <2-3,609 for 9 polycyclic aromatic hydrocarbons, from <1-150 for 6 polychlorinated biphenyls, and from <20-7,776 for nicotine. We used random-effects models to estimate variance components for concentrations of each of these carpet-dust chemicals and calculated the variance ratio, lambda, defined as the ratio of the within-household variance component to the between-household variance component. Subsequently, we used the variance ratios calculated from our data, to illustrate the potential effect of measurement error on the attenuation of odds ratios in hypothetical case-control studies. We found that the median value of the estimated variance ratios was 0.33 (range: 0.13- 0.72). Correspondingly, in case-control studies of associations between these carpet-dust chemicals and disease, given the collection of only one measurement per household and a hypothetical odds ratio of 1.5, we expect that the observed odds ratios would range from 1.27 to 1.43. Moreover, for each of the chemicals analyzed, the collection of three repeated dust samples would limit the expected magnitude of odds ratio attenuation to less than 20%.
Conclusions:
Our findings suggest that attenuation bias should be relatively modest when using these semi-volatile carpet-dust chemicals as exposure surrogates in epidemiologic studies.
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Causal diagrams in systems epidemiology
Methods of diagrammatic modelling have been greatly developed in the past two decades. Outside the context of infectious diseases, systematic use of diagrams in epidemiology has been mainly confined to the analysis of a single link: that between a disease outcome and its proximal determinant(s). Transmitted causes ("causes of causes") tend not to be systematically analysed.The infectious disease epidemiology modelling tradition models the human population in its environment, typically with the exposure-health relationship and the determinants of exposure being considered at individual and group/ecological levels, respectively. Some properties of the resulting systems are quite general, and are seen in unrelated contexts such as biochemical pathways. Confining analysis to a single link misses the opportunity to discover such properties.The structure of a causal diagram is derived from knowledge about how the world works, as well as from statistical evidence. A single diagram can be used to characterise a whole research area, not just a single analysis - although this depends on the degree of consistency of the causal relationships between different populations - and can therefore be used to integrate multiple datasets.Additional advantages of system-wide models include: the use of instrumental variables - now emerging as an important technique in epidemiology in the context of mendelian randomisation, but under-used in the exploitation of "natural experiments"; the explicit use of change models, which have advantages with respect to inferring causation; and in the detection and elucidation of feedback.
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Using Geographical Information Systems Mapping to Identify Areas Presenting High Risk for Traumatic Brain Injury
Background:
The aim of this study is to show how geographical information systems (GIS) can be used to track and compare hospitalization rates for traumatic brain injury (TBI) over time and across a large geographical area using population based data.Results & DiscussionData on TBI hospitalizations, and geographic and demographic variables, came from the Ontario Trauma Registry Minimum Data Set for the fiscal years 1993-1994 and 2001-2002. Various visualization techniques, exploratory data analysis and spatial analysis were employed to map and analyze these data. Both the raw and standardized rates by age/gender of the geographical unit were studied. Data analyses revealed persistent high rates of hospitalization for TBI resulting from any injury mechanism between two time periods in specific geographic locations.
Conclusions:
This study shows how geographic information systems can be successfully used to investigate hospitalizaton rates for traumatic brain injury using a range of tools and techniques; findings can be used for local planning of both injury prevention and post discharge services, including rehabilitation.
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What do we have to know from migrants' past exposures to understand their health status? A life course approach
Empirical findings show that morbidity and mortality risks of migrants can differ considerably from those of populations in the host countries. However, while several explanatory models have been developed, most migrant studies still do not consider explicitly the situation of migrants before migration. Here, we discuss an extended approach to understand migrant health comprising a life course epidemiology perspective.The incorporation of a life course perspective into a conceptual framework of migrant health enables the consideration of risk factors and disease outcomes over the different life phases of migrants, which is necessary to understand the health situation of migrants and their offspring. Comparison populations need to be carefully selected depending on the study questions under consideration within the life course framework.Migrant health research will benefit from an approach using a life course perspective. A critique of the theoretical foundations of migrant health research is essential for further developing both the theoretical framework of migrant health and related empirical studies.
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Assessing causal relationships in genomics:
From Bradford-Hill criteria to complex gene-environment interactions and directed acyclic graphs
Observational studies of human health and disease (basic, clinical and epidemiological) are vulnerable to methodological problems -such as selection bias and confounding- that make causal inferences problematic. Gene-disease associations are no exception, as they are commonly investigated using observational designs. A rich body of knowledge exists in medicine and epidemiology on the assessment of causal relationships involving personal and environmental causes of disease; it includes seminal causal criteria developed by Austin Bradford Hill and more recently applied directed acyclic graphs (DAGs). However, such knowledge has seldom been applied to assess causal relationships in clinical genetics and genomics, even in studies aimed at making inferences relevant for human health. Conversely, incorporating genetic causal knowledge into clinical and epidemiological causal reasoning is still a largely unexplored area.As the contribution of genetics to the understanding of disease aetiology becomes more important, causal assessment of genetic and genomic evidence becomes fundamental. The method we develop in this paper provides a simple and rigorous first step towards this goal. The present paper is an example of integrative research, i.e., research that integrates knowledge, data, methods, techniques, and reasoning from multiple disciplines, approaches and levels of analysis to generate knowledge that no discipline alone may achieve.
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Defining neurotrauma in administrative data using the International Classification of Diseases Tenth Revision
Background:
It is essential to use a definition that is precise and accurate for the surveillance of traumatic brain injuries (TBI) and spinal cord injuries (SCI). This paper reviews the International Classification of Diseases 10th revision (ICD-10) definitions used internationally to inform the definition for neurotrauma surveillance using administrative data in Ontario, Canada.
Methods:
PubMed, Web of Science, Medline and the grey literature were searched for keywords "spinal cord injuries" or "brain injuries" and "international classification of diseases". All papers and reports that used an ICD-10 definition were included. To determine the ICD-10 codes for inclusion consensus across papers and additional evidence were sought to look at the correlation between the condition and brain or spinal injuries.
Results:
Twenty-four articles and reports were identified; 15 unique definitions for TBI and 7 for SCI were found. The definitions recommended for use in Ontario by this paper are F07.2, S02.0, S02.1, S02.3, S02.7, S02.8, S02.9, S06, S07.1, T90.2, and T90.5 for traumatic brain injuries and S14.0, S14.1, S24.0, S24.1, S34.1, S34.0, S34.3, T06.0, T06.1 and T91.3 for spinal cord injuries.
Conclusions:
Internationally, inconsistent definitions are used to define brain and spinal cord injuries. An abstraction study of data would be an asset in understanding the effects of inclusion and exclusion of codes in the definition. This paper offers a definition of neurotrauma for surveillance in Ontario, but the definition could be applied to other countries that have mandated administrative data collection.
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Relative survival: a useful tool to assess generalisability in longitudinal studies of health in older persons
Background:
Generalisability of longitudinal studies is threatened by issues such as choice of sampling frame, representativeness of the initial sample, and attrition. To determine representativeness, cohorts are often compared with the population of interest at baseline on demographic and health characteristics. This study illustrates the use of relative survival as a tool for assessing generalisability of results from a cohort of older people among whom death is a potential threat to generalisability.
Methods:
The authors used data from the 1921-26 cohort (n = 12,416, aged 70-75 in 1996) of the Australian Longitudinal Study on Women's Health (ALSWH). Vital status was determined by linkage to the National Death Index, and expected deaths were derived using Australian life tables. Relative survival was estimated using observed survival in the cohort divided by expected survival among women of the same age and State or Territory.
Results:
Overall, the ALSWH women showed relative survival 9.5% above the general population. Within States and Territories, the relative survival advantage varied from 6% to 23%. The interval-specific relative survival remained relatively constant over the 12 years (1996-2008) under review, indicating that the survival advantage of the cohort has not diminished over time.
Conclusion:
This study demonstrates that relative survival can be a useful measure of generalisability in a longitudinal study of the health of the general population, particularly when participants are older.
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Conceptualizing population health: from mechanistic thinking to complexity science
The mechanistic interpretation of reality can be traced to the influential work by René Descartes and Sir Isaac Newton. Their theories were able to accurately predict most physical phenomena relating to motion, optics and gravity. This paradigm had at least three principles and approaches: reductionism, linearity and hierarchy. These ideas appear to have influenced social scientists and the discourse on population health. In contrast, Complexity Science takes a more holistic view of systems. It views natural systems as being 'open', with fuzzy borders, constantly adapting to cope with pressures from the environment. These are called Complex Adaptive Systems (CAS). The sub-systems within it lack stable hierarchies, and the roles of agency keep changing. The interactions with the environment and among sub-systems are non-linear interactions and lead to self-organisation and emergent properties. Theoretical frameworks such as epi+demos+cracy and the ecosocial approach to health have implicitly used some of these concepts of interacting dynamic sub-systems. Using Complexity Science we can view population health outcomes as an emergent property of CAS, which has numerous dynamic non-linear interactions among its interconnected sub-systems or agents. In order to appreciate these sub-systems and determinants, one should acquire a basic knowledge of diverse disciplines and interact with experts from different disciplines. Strategies to improve health should be multi-pronged, and take into account the diversity of actors, determinants and contexts. The dynamic nature of the system requires that the interventions are constantly monitored to provide early feedback to a flexible system that takes quick corrections.
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The democratic fallacy in matters of clinical opinion: implications for analysing cause-of-death data
Arriving at a consensus between multiple clinical opinions concerning a particular case is a complex issue - and may give rise to manifestations of the democratic fallacy, whereby a majority opinion is misconstrued to represent some kind of "truth" and minority opinions are somehow "wrong". Procedures for handling multiple clinical opinions in epidemiological research are not well established, and care is needed to avoid logical errors. How to handle physicians' opinions on cause of death is one important domain of concern in this respect. Whether multiple opinions are a legal requirement, for example ahead of cremating a body, or used for supposedly greater rigour, for example in verbal autopsy interpretation, it is important to have a clear understanding of what unanimity or disagreement in findings might imply, and of how to aggregate case data accordingly.In many settings where multiple physicians have interpreted verbal autopsy material, an over-riding goal of arriving at a single cause of death per case has been applied. In many instances this desire to constrain findings to a single cause per case has led to methodologically awkward devices such as "TB/AIDS" as a single cause. This has also usually meant that no sense of disagreements or uncertainties at the case level is taken forward into aggregated data analyses, and in many cases an "indeterminate" cause may be recorded which actually reflects a lack of agreement rather than a lack of data on possible cause(s).In preparing verbal autopsy material for epidemiological analyses and public health interpretations, the possibility of multiple causes of death per case, and some sense of any disagreement or uncertainty encountered in interpretation at the case level, need to be captured and incorporated into overall findings, if evidence is not to be lost along the way. Similar considerations may apply in other epidemiological domains.
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Comparison of two approaches for measuring household wealth via an asset-based index in rural and peri-urban settings of Hunan province, People's Republic of China
Background:
There are growing concerns regarding inequities in health, with poverty being an important determinant of health as well as a product of health status. Within the People's Republic of China (P.R. China), disparities in socio-economic position are apparent, with the rural-urban gap of particular concern. Our aim was to compare direct and proxy methods of estimating household wealth in a rural and a peri-urban setting of Hunan province, P.R. China.
Methods:
We collected data on ownership of household durable assets, housing characteristics, and utility and sanitation variables in two village-wide surveys in Hunan province. We employed principal components analysis (PCA) and principal axis factoring (PAF) to generate household asset-based proxy wealth indices. Households were grouped into quartiles, from 'most wealthy' to 'most poor'. We compared the estimated household wealth for each approach. Asset-based proxy wealth indices were compared to those based on self-reported average annual income and savings at the household level.
Results:
Spearman's rank correlation analysis revealed that PCA and PAF yielded similar results, indicating that either approach may be used for estimating household wealth. In both settings investigated, the two indices were significantly associated with self-reported average annual income and combined income and savings, but not with savings alone. However, low correlation coefficients between the proxy and direct measures of wealth indicated that they are not complementary. We found wide disparities in ownership of household durable assets, and utility and sanitation variables, within and between settings.
Conclusion:
PCA and PAF yielded almost identical results and generated robust proxy wealth indices and categories. Pooled data from the rural and peri-urban settings highlighted structural differences in wealth, most likely a result of localized urbanization and modernization. Further research is needed to improve measurements of wealth in low-income and transitional country contexts.
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Environmental Health - Latest Articles
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Effects of temperature on mortality in Chiang Mai city, Thailand: a time series study
Background:
The association between temperature and mortality has been examined mainly in North America and Europe. However, less evidence is available in developing countries, especially in Thailand. In this study, we examined the relationship between temperature and mortality in Chiang Mai city, Thailand, during 1999-2008.MethodA time series model was used to examine the effects of temperature on cause-specific mortality (non-external, cardiopulmonary, cardiovascular, and respiratory) and age-specific non-external mortality (<=64, 65-74, 75-84, and > =85 years), while controlling for relative humidity, air pollution, day of the week, season and long-term trend. We used a distributed lag non-linear model to examine the delayed effects of temperature on mortality up to 21 days.
Results:
We found non-linear effects of temperature on all mortality types and age groups. Both hot and cold temperatures resulted in immediate increase in all mortality types and age groups. Generally, the hot effects on all mortality types and age groups were short-term, while the cold effects lasted longer. The relative risk of non-external mortality associated with cold temperature (19.35degreesC, 1st percentile of temperature) relative to 24.7degreesC (25th percentile of temperature) was 1.29 (95% confidence interval (CI): 1.16, 1.44) for lags 0-21. The relative risk of non-external mortality associated with high temperature (31.7degreesC, 99th percentile of temperature) relative to 28degreesC (75th percentile of temperature) was 1.11 (95% CI: 1.00, 1.24) for lags 0-21.
Conclusion:
This study indicates that exposure to both hot and cold temperatures were related to increased mortality. Both cold and hot effects occurred immediately but cold effects lasted longer than hot effects. This study provides useful data for policy makers to better prepare local responses to manage the impact of hot and cold temperatures on population health.
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Childhood brain tumours and use of mobile phones: comparison of a case-control study with incidence data
The first case-control study on mobile phone use and brain tumor risk among children and adolescents (CEFALO study) has recently been published. In a commentary published in Environmental Health, Soderqvist and colleagues argued that CEFALO suggests an increased brain tumor risk in relation to wireless phone use. In this article, we respond and show why consistency checks of case-control study results with observed time trends of incidence rates are essential, given the well described limitations of case-control studies and the steep increase of mobile phone use among children and adolescents during the last decade. There is no plausible explanation of how a notably increased risk from use of wireless phones would correspond to the relatively stable incidence time trends for brain tumours among children and adolescents observed in the Nordic countries. Nevertheless, an increased risk restricted to heavy mobile phone use, to very early life exposure, or to rare subtypes of brain tumors may be compatible with stable incidence trends at this time and thus further monitoring of childhood brain tumor incidence rate time trends is warranted.
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Mortality and morbidity study of petrochemical emplyees in a polluted site
Background:
The area of Gela was included among the 57 Italian polluted sites of national interest for environmental remediation because of its widespread contamination from a petrochemical complex. The present study investigates mortality and morbidity of the cohort of Gela petrochemical workers with the aim of disentangling occupational from residential risk.
Methods:
Mortality was assessed for 5,627 men hired from 1960, year of the plant start-up, to 1993; it was followed up for vital status in the period 1960-2002. Morbidity was analysed for 5,431 workers neither dead nor lost to follow-up from 1960 to 2001 and was based on Hospital Discharge Records in the period 2001-2006. The work experience was classified in terms of job categories such as blue collars, white collars, and both - workers who shifted from blue to white collar (95%) or vice versa. An ad hoc mobility model was applied to define qualitative categories of residence in Gela, as residents and commuters. Standardized Mortality Ratios (SMRs) and Mortality Rate Ratios (MRRs) were computed, the latter by using a Poisson regression model. Morbidity was analyzed in terms of Hospital Discharge Odds Ratios (HDORs) through a logistic regression model. While performing the internal comparisons, white collars was the reference category for the job analysis, and commuters was the reference category for the residential analysis.
Results:
In the light of epidemiological evidence about health risk from petrochemical industries in both occupational and environmental settings, and/or on the basis of information about occupational and residential contamination and health risk in the area of Gela, noteworthy results are shown for lung cancer [MRR: 2.11 (IC 90%; 0.96-4.63) in blue collars; 1.71 (1.09-2.69) in residents], respiratory diseases [HDOR: 2.0 (1.0-3.0) in blue collars; 1.4 (0.96-2.06) in residents] and genitourinary diseases [HDOR: 1.34 (1.06-1.68) in blue collars; 1.23 (1.04-1.45) in residents].
Conclusions:
The results support a role of the exposures in the occupational and residential settings, the latter due to the local ascertained contamination, in affecting the workers' health. These results underline the urgent need of water, soil, air and food-chain monitoring programs, to discover active sources of exposure and consequently define public health interventions.
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A measure for quantifying the impact of housing quality on respiratory health: a cross-sectional study
Background:
Damp and mould in homes have been established as risk factors for respiratory health. There is a need for a relatively straightforward assessment of the home that quantifies this risk.
Methods:
Using data from 891 New Zealand houses, the utility of a Respiratory Hazard Index quantifying key attributes related to damp and mould was tested by studying its associations with self-reported respiratory symptoms.
Results:
A dose-response relationship was found whereby each unit increase in the Respiratory Hazard Index was associated with an 11% increase in the odds of at least one episode of wheezing/whistling in the chest over the last 12 months (relative odds of 1.11 with a 95% CI 1.04%-1.20%). An 11% increase in the odds of an asthma attack over the last 12 months was estimated (relative odds of 1.11 with a 95% CI 1.01%-1.22%). These estimates were adjusted for household crowding levels, age, sex and smoking status. There was suggestive evidence of more steeply increasing odds of respiratory symptoms with increasing levels of the Respiratory Hazard Index for children aged under 7. In the worst performing houses according to the Index, a 33% reduction in the number of people experiencing respiratory symptoms (relative risk 0.67 with 95% CI 0.53 to 0.85) could be expected if people were housed in the best performing houses.
Conclusions:
This study showed that increased evidence of housing conditions supporting dampness and mould was associated with increased odds of respiratory symptoms. A valid housing assessment tool can provide a rational basis for investment in improved housing quality to improve respiratory health.
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The acceptability of rat trap use over pesticides for rodent control in two poor urban communities in South Africa
Background:
Rodent infestations are a public health problem in poor urban communities. The use of illegal street pesticides to control rodent infestations with resulting poisonings is an additional public health concern receiving limited attention in many developing countries, including South Africa.
Methods:
Participants in a household intervention in two poor urban areas of Cape Town, South Africa, received two high quality rat traps. Reported in this article are the results of a follow-up survey conducted six months after distribution to assess community perceived acceptability of using rat traps instead of toxic pesticides (N = 175).
Results:
Of the 175 respondents that were followed up, 88% used the traps and only 35% continued using pesticides after the intervention. The analysis identified perceived effectiveness of the traps (prevalence odds ratio 18.00, 95% confidence interval 4.62 to 70.14), being male (prevalence odds ratio 8.86, 95% confidence interval 1.73 to 45.19), and the willingness to buy traps from an informal market (prevalence odds ratio 17.75, 95% confidence interval 4.22 to 74.57) as significantly associated with the acceptance of trap use.
Conclusions:
Rat traps, when introduced to poor urban communities, are acceptable as an alternative to toxic pesticides for rodent control. Sustainability of trap use, however, needs to be researched, especially cost and cost-benefit.
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Effects of arsenic exposure on DNA methylation in cord blood samples from newborn babies and in a human lymphoblast cell line
Background:
Accumulating evidence indicates that in utero exposure to arsenic is associated with congenital defects and long-term disease consequences including cancers. Recent studies suggest that arsenic carcinogenesis results from epigenetic changes, particularly in DNA methylation. This study aimed to investigate DNA methylation changes as a result of arsenic exposure in utero and in vitro.
Methods:
For the exposure in utero study, a total of seventy-one newborns (fifty-five arsenic-exposed and sixteen unexposed newborns) were recruited. Arsenic concentrations in the drinking water were measured, and exposure in newborns was assessed by measurement of arsenic concentrations in cord blood, nails and hair by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). In the in vitro study, human lymphoblasts were treated with arsenite at 0-100 muM for two, four and eight hours (short-term) and at 0, 0.5 and 1.0 muM for eight-weeks period (long-term). DNA methylation was analyzed in cord blood lymphocytes and lymphoblasts treated with arsenite in vitro. Global DNA methylation was determined as LINE-1 methylation using combined bisulfite restriction analysis (COBRA) and total 5-methyldeoxycytidine (5MedC) content which was determined by HPLC-MS/MS. Methylation of p53 was determined at the promoter region using methylation-specific restriction endonuclease digestion with MspI and HpaII.
Results:
Results showed that arsenic-exposed newborns had significantly higher levels of arsenic in cord blood, fingernails, toenails and hair than those of the unexposed subjects and a slight increase in promoter methylation of p53 in cord blood lymphocytes which significantly correlated with arsenic accumulation in nails (p < 0.05) was observed, while LINE-1 methylation was unchanged. Short-term in vitro arsenite treatment in lymphoblastoid cells clearly demonstrated a significant global hypomethylation, determined as reduction in LINE-1 methylation and total 5-MedC content, and p53 hypermethylation (p < 0.05). However, a slight LINE-1 hypomethylation and transient p53 promoter hypermethylation were observed following long-term in vitro treatment.
Conclusions:
This study provides an important finding that in utero arsenic exposure affects DNA methylation, particularly at the p53 promoter region, which may be linked to the mechanism of arsenic carcinogenesis and the observed increased incidence of cancer later in life.
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Portrait of the journal as a young adult
Since its founding a decade ago, Environmental Health has received more than one thousand manuscripts. Last year marked the first time we published over 100 articles. The journal web site currently receives over 60,000 unique visitors every month, and the steady increase suggests that the number will soon exceed 100,000 monthly. Individual articles are usually accessed several thousand times within a few years of publication, the highest number for a single paper being close to 100,000. The access numbers suggest that the journal has a reach that goes much beyond narrow academic circles as represented by numbers of citations in scholarly journals. To further the goal of reaching the wider public health community and linking to environmental health promotion, we ask prospective Environmental Health authors to highlight the findings that are new or different along with the implications for future research and in terms of prevention of environmental hazards.
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Correcting for the influence of sampling conditions on biomarkers of exposure to phenols and phthalates: a 2-step standardization method based on regression residuals
Background:
Environmental epidemiology and biomonitoring studies typically rely on biological samples to assay the concentration of non-persistent exposure biomarkers. Between-participant variations in sampling conditions of these biological samples constitute a potential source of exposure misclassification. Few studies attempted to correct biomarker levels for this error. We aimed to assess the influence of sampling conditions on concentrations of urinary biomarkers of select phenols and phthalates, two widely-produced families of chemicals, and to standardize biomarker concentrations on sampling conditions.
Methods:
Urine samples were collected between 2002 and 2006 among 287 pregnant women from Eden and Pelagie cohorts, from which phthalates and phenols metabolites levels were assayed. We applied a 2-step standardization method based on regression residuals. First, the influence of sampling conditions (including sampling hour, duration of storage before freezing) and of creatinine levels on biomarker concentrations were characterized using adjusted linear regression models. In the second step, the model estimates were used to remove the variability in biomarker concentrations due to sampling conditions and to standardize concentrations as if all samples had been collected under the same conditions (e.g., same hour of urine collection).
Results:
Sampling hour was associated with concentrations of several exposure biomarkers. After standardization for sampling conditions, median concentrations differed by 38 % for 2,5-dichlorophenol to +80 % for a metabolite of diisodecyl phthalate. However, at the individual level, standardized biomarker levels were strongly correlated (correlation coefficients above 0.80) with unstandardized measures.
Conclusions:
Sampling conditions, such as sampling hour, should be systematically collected in biomarker-based studies, in particular when the biomarker half-life is short. The 2-step standardization method based on regression residuals that we proposed in order to limit the impact of heterogeneity in sampling conditions could be further tested in studies describing levels of biomarkers or their influence on health.
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Complex organochlorine pesticide mixtures as determinant factor for breast cancer risk: a population-based case-control study in the Canary Islands (Spain)
Background:
All the relevant risk factors contributing to breast cancer etiology are not fully known. Exposure to organochlorine pesticides has been linked to an increased incidence of the disease, although not all data have been consistent. Most published studies evaluated the exposure to organochlorines individually, ignoring the potential effects exerted by the mixtures of chemicals.
Methods:
This population-based study was designed to evaluate the profile of mixtures of organochlorines detected in 103 healthy women and 121 women diagnosed with breast cancer from Gran Canaria Island, and the relation between the exposure to these compounds and breast cancer risk.
Results:
The most prevalent mixture of organochlorines among healthy women was the combination of lindane and endrin, and this mixture was not detected in any affected women. Breast cancer patients presented more frequently a combination of aldrin, dichlorodiphenyldichloroethylene (DDE) and dichlorodiphenyldichloroethane (DDD), and this mixture was not found in any healthy woman. After adjusting for covariables, the risk of breast cancer was moderately associated with DDD (OR = 1.008, confidence interval 95% 1.001-1.015, p = 0.024).
Conclusions:
This study indicates that healthy women show a very different profile of organochlorine pesticide mixtures than breast cancer patients, suggesting that organochlorine pesticide mixtures could play a relevant role in breast cancer risk.
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Perceived annoyance from environmental odors and association with atmospheric ammonia levels in non-urban residential communities: a cross-sectional study
ObjectiveOdor exposure is an environmental stressor that is responsible of many citizens complains about air pollution in non-urban areas. However, information about the exposure-response relation is scarce. One of the main challenges is to identify a measurable compound that can be related with odor annoyance responses. We investigated the association between regional and temporal variation of ammonia (NH3) concentrations in five Danish non-urban regions and environmental odor annoyance as perceived by the local residents.
Methods:
A cross-sectional study where NH3 concentration was obtained from the national air quality monitoring program and from emission-dispersion modelling, and odor pollution perception from questionnaires. The exposure-response model was a sigmoid model. Linear regression analyses were used to estimate the model constants after equation transformations. The model was validated using leave-one-out cross validation (LOOCV) statistical method.
Results:
About 45% of the respondents were annoyed by odor pollution at their residential areas. The perceived odor was characterized by all respondents as animal waste odor. The exposure-annoyance sigmoid model showed that the prevalence of odor annoyance was significantly associated with NH3 concentrations (measured and estimated) at the local air quality monitoring stations (p < 0.01,R2 = 0.99; and p < 0.05,R2 = 0.93; respectively). Prediction errors were below 5.1% and 20% respectively. The seasonal pattern of odor perception was associated with the seasonal variation in NH3 concentrations (p < 0.001, adjusted R2 = 0.68).
Conclusion:
The results suggest that atmospheric NH3 levels at local air quality stations could be used as indicators of prevalence of odor annoyance in non-urban residential communities.
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Epidemiologic Perspectives & Innovations - Latest Articles
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Extending the sufficient component cause model to describe the Stable Unit Treatment Value Assumption (SUTVA)
Causal inference requires an understanding of the conditions under which association equals causation. The exchangeability or no confounding assumption is well known and well understood as central to this task. More recently the epidemiologic literature has described additional assumptions related to the stability of causal effects. In this paper we extend the Sufficient Component Cause Model to represent one expression of this stability assumption--the Stable Unit Treatment Value Assumption. Approaching SUTVA from an SCC model helps clarify what SUTVA is and reinforces the connections between interaction and SUTVA.
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Use of the integrated health interview series: trends in medical provider utilization (1972-2008)
The Integrated Health Interview Series (IHIS) is a public data repository that harmonizes four decades of the National Health Interview Survey (NHIS). The NHIS is the premier source of information on the health of the U.S. population. Since 1957 the survey has collected information on health behaviors, health conditions, and health care access. The long running time series of the NHIS is a powerful tool for health research. However, efforts to fully utilize its time span are obstructed by difficult documentation, unstable variable and coding definitions, and non-ignorable sample re-designs. To overcome these hurdles the IHIS, a freely available and web-accessible resource, provides harmonized NHIS data from 1969-2010. This paper describes the challenges of working with the NHIS and how the IHIS reduces such burdens. To demonstrate one potential use of the IHIS we examine utilization patterns in the U.S. from 1972-2008.
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Social network analysis and agent-based modeling in social epidemiology
The past five years have seen a growth in the interest in systems approaches in epidemiologic research. These approaches may be particularly appropriate for social epidemiology. Social network analysis and agent-based models (ABMs) are two approaches that have been used in the epidemiologic literature. Social network analysis involves the characterization of social networks to yield inference about how network structures may influence risk exposures among those in the network. ABMs can promote population-level inference from explicitly programmed, micro-level rules in simulated populations over time and space. In this paper, we discuss the implementation of these models in social epidemiologic research, highlighting the strengths and weaknesses of each approach. Network analysis may be ideal for understanding social contagion, as well as the influences of social interaction on population health. However, network analysis requires network data, which may sacrifice generalizability, and causal inference from current network analytic methods is limited. ABMs are uniquely suited for the assessment of health determinants at multiple levels of influence that may couple with social interaction to produce population health. ABMs allow for the exploration of feedback and reciprocity between exposures and outcomes in the etiology of complex diseases. They may also provide the opportunity for counterfactual simulation. However, appropriate implementation of ABMs requires a balance between mechanistic rigor and model parsimony, and the precision of output from complex models is limited. Social network and agent-based approaches are promising in social epidemiology, but continued development of each approach is needed.
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The use of complete-case and multiple imputation-based analyses in molecular epidemiology studies that assess interaction effects
Background:
In molecular epidemiology studies biospecimen data are collected, often with the purpose of evaluating the synergistic role between a biomarker and another feature on an outcome. Typically, biomarker data are collected on only a proportion of subjects eligible for study, leading to a missing data problem. Missing data methods, however, are not customarily incorporated into analyses. Instead, complete-case (CC) analyses are performed, which can result in biased and inefficient estimates.
Methods:
Through simulations, we characterized the performance of CC methods when interaction effects are estimated. We also investigated whether standard multiple imputation (MI) could improve estimation over CC methods when the data are not missing at random (NMAR) and auxiliary information may or may not exist.
Results:
CC analyses were shown to result in considerable bias and efficiency loss. While MI reduced bias and increased efficiency over CC methods under specific conditions, it too resulted in biased estimates depending on the strength of the auxiliary data available and the nature of the missingness. In particular, CC performed better than MI when extreme values of the covariate were more likely to be missing, while MI outperformed CC when missingness of the covariate related to both the covariate and outcome. MI always improved performance when strong auxiliary data were available. In a real study, MI estimates of interaction effects were attenuated relative to those from a CC approach.
Conclusions:
Our findings suggest the importance of incorporating missing data methods into the analysis. If the data are MAR, standard MI is a reasonable method. Auxiliary variables may make this assumption more reasonable even if the data are NMAR. Under NMAR we emphasize caution when using standard MI and recommend it over CC only when strong auxiliary data are available. MI, with the missing data mechanism specified, is an alternative when the data are NMAR. In all cases, it is recommended to take advantage of MI's ability to account for the uncertainty of these assumptions.
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Attributing the burden of cancer at work: three areas of concern when examining the example of shift-work
This commentary intends to instigate discussions about epidemiologic estimates and their interpretation of attributable fractions (AFs) and the burden of disease (BOD) of cancers due to factors at workplaces. By examining recent work that aims to estimate the number of cancers attributable to shift-work in Britain, we suggest that (i) causal, (ii) practical and (iii) methodological areas of concern may deter us from attributable caseload estimations of cancers at this point in time. Regarding (i), such calculations may have to be avoided as long as we lack established causality between shift-work and the development of internal cancers. Regarding (ii), such calculations may have to be avoided as long as we can neither abandon shift-work nor identify personnel that may be unaffected by shift-work factors. Regarding (iii), there are at least four methodological pitfalls which are likely to make AF calculations uninterpretable at this stage. The four pitfalls are: (1) The use of Levin's 1953 formula in case of adjusted relative risks; (2) The use of broad definitions of exposure in calculations of AFs; (3) The non-additivity of AFs across different levels of exposure and covariables; (4) The fact that excess mortality counts are misleading due to the fact that a human being dies exactly once - a death may occur earlier or later, but a death cannot occur more than once nor can it be avoided altogether for any given individual. Overall, causal, practical and methodological areas of concern should be diligently considered when performing and interpreting AF or BOD computations which - at least at the present time - may not be defensible.
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Clustering Based on Adherence Data
Adherence to a medical treatment means the extent to which a patient follows the instructions or recommendations by health professionals. There are direct and indirect ways to measure adherence which have been used for clinical management and research. Typically adherence measures are monitored over a long follow-up or treatment period, and some measurements may be missing due to death or other reasons. A natural question then is how to describe adherence behavior over the whole period in a simple way. In the literature, measurements over a period are usually combined just by using averages like percentages of compliant days or percentages of doses taken. In the paper we adapt an approach where patient adherence measures are seen as a stochastic process. Repeated measures are then analyzed as a Markov chain with finite number of states rather than as independent and identically distributed observations, and the transition probabilities between the states are assumed to fully describe the behavior of a patient. The patients can then be clustered or classified using their estimated transition probabilities. These natural clusters can be used to describe the adherence of the patients, to find predictors for adherence, and to predict the future events. The new approach is illustrated and shown to be useful with a simple analysis of a data set from the DART (Development of AntiRetroviral Therapy in Africa) trial in Uganda and Zimbabwe.
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Disease-specific prospective family study cohorts enriched for familial risk
Most common diseases demonstrate familial aggregation; the ratio of the risk for relatives of affected people to the risk for relatives of unaffected people (the familial risk ratio)) > 1. This implies there are underlying genetic and/or environmental risk factors shared by relatives. The risk gradient across this underlying 'familial risk profile', which can be predicted from family history and measured familial risk factors, is typically strong. Under a multiplicative model, the ratio of the risk for people in the upper 25% of familial risk to the risk for those in the lower 25% (the inter-quartile risk gradient) is an order of magnitude greater than the familial risk ratio. If familial risk ratio = 2 for first-degree relatives, in terms of familial risk profile: (a) people in the upper quartile will be at more than 20 times the risk of those in the lower quartile; and (b) about 90% of disease will occur in people above the median. Historically, therefore, epidemiology has compared cases with controls dissimilar for underlying familial risk profile. Were gene-environment and gene-gene interactions to exist, environmental and genetic effects could be stronger for people with increased familial risk profile. Studies in which controls are better matched to cases for familial risk profile might be more informative, especially if both cases and controls are over-sampled for increased familial risk. Prospective family study cohort (ProF-SC) designs involving people across a range of familial risk profile provide such a resource for epidemiological, genetic, behavioural, psycho-social and health utilisation research. The prospective aspect gives credibility to risk estimates. The familial aspect allows family-based designs, matching for unmeasured factors, adjusting for underlying familial risk profile, and enhanced cohort maintenance.
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WINPEPI updated: computer programs for epidemiologists, and their teaching potential
Background:
The WINPEPI computer programs for epidemiologists are designed for use in practice and research in the health field and as learning or teaching aids. The programs are free, and can be downloaded from the Internet. Numerous additions have been made in recent years.ImplementationThere are now seven WINPEPI programs: DESCRIBE, for use in descriptive epidemiology; COMPARE2, for use in comparisons of two independent groups or samples; PAIRSetc, for use in comparisons of paired and other matched observations; LOGISTIC, for logistic regression analysis; POISSON, for Poisson regression analysis; WHATIS, a "ready reckoner" utility program; and ETCETERA, for miscellaneous other procedures. The programs now contain 122 modules, each of which provides a number, sometimes a large number, of statistical procedures. The programs are accompanied by a Finder that indicates which modules are appropriate for different purposes. The manuals explain the uses, limitations and applicability of the procedures, and furnish formulae and references.
Conclusions:
WINPEPI is a handy resource for a wide variety of statistical routines used by epidemiologists. Because of its ready availability, portability, ease of use, and versatility, WINPEPI has a considerable potential as a learning and teaching aid, both with respect to practical procedures in the planning and analysis of epidemiological studies, and with respect to important epidemiological concepts. It can also be used as an aid in the teaching of general basic statistics.
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Reporting errors in infectious disease outbreaks, with an application to Pandemic Influenza A/H1N1
Background:
Effectively responding to infectious disease outbreaks requires a well-informed response. Quantitative methods for analyzing outbreak data and estimating key parameters to characterize the spread of the outbreak, including the reproductive number and the serial interval, often assume that the data collected is complete. In reality reporting delays, undetected cases or lack of sensitive and specific tests to diagnose disease lead to reporting errors in the case counts. Here we provide insight on the impact that such reporting errors might have on the estimation of these key parameters.
Results:
We show that when the proportion of cases reported is changing through the study period, the estimates of key epidemiological parameters are biased. Using data from the Influenza A/H1N1 outbreak in La Gloria, Mexico, we provide estimates of these parameters, accounting for possible reporting errors, and show that they can be biased by as much as 33%, if reporting issues are not accounted for.
Conclusions:
Failure to account for missing data can lead to misleading and inaccurate estimates of epidemic parameters.
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Shift work, cancer and "white-box" epidemiology:
Association and causation
This commentary intends to instigate discussions about upcoming epidemiologic research, and its interpretation, into putative links between shift work, involving circadian disruption or chronodisruption [CD], and the development of internal cancers.In 2007, the International Agency for Research on Cancer (IARC) convened an expert group to examine the carcinogenicity of shift work, inter alia characterized by light exposures at unusual times. After a critical review of published data, the following was stated: "There is sufficient evidence in experimental animals for the carcinogenicity of light during the daily dark period (biological night)". However, in view of limited epidemiological evidence, it was overall concluded: "Shiftwork that involves circadian disruption is probably carcinogenic to humans (Group 2A)".Remarkably, the scenario around shift work, CD and internal cancers provides a unique case for "white-box" epidemiology: Research at many levels - from sub-cellular biochemistry, to whole cells, to organs, to organisms, including animals and humans - has suggested a series of quite precise and partly related causal mechanisms. This is in stark contrast to instances of "black box" or "stabs in the dark" epidemiology where causal mechanisms are neither known nor hypothesized or only poorly defined. The overriding theme that an adequate chronobiological organization of physiology can be critical for the protection against cancer builds the cornerstone of biological plausibility in this case.We can now benefit from biological plausibility in two ways: First, epidemiology should use biologically plausible insights into putative chains of causation between shift work and cancer to design future investigations. Second, when significant new data were to become available in coming years, IARC will re-evaluate cancer hazards associated with shift work. Biological plausibility may then be a key viewpoint to consider and, ultimately, to decide whether (or not) to pass from statistical associations, possibly detected in observational studies by then, to a verdict of causation.In the meantime, biological plausibility should not be invoked to facilitate publication of epidemiological research of inappropriate quality. Specific recommendations as to how to design, report and interpret epidemiological research into biologically plausible links between shift work and cancer are provided.Epidemiology is certainly a poor toolfor learning about the mechanismby which a disease is produced,but it has the tremendous advantagethat it focuses on the diseases and the deathsthat actually occur,and experience has shown that it continues to be second to none asa means of discovering linksin the chain of causationthat are capable of being broken.-Sir Richard Doll
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Frontiers in Zoology - Latest Articles
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Marked changes in neuropeptide expression accompany broadcast spawnings in the gastropod Haliotis asinina
IntroductionA huge diversity of marine species reproduce by synchronously spawning their gametes into the water column. Although this species-specific event typically occurs in a particular season, the precise time and day of spawning often can not be predicted. There is little understanding of how the environment (e.g. water temperature, day length, tidal and lunar cycle) regulates a population's reproductive physiology to synchronise a spawning event. The Indo-Pacific tropical abalone, Haliotis asinina, has a highly predictable spawning cycle, where individuals release gametes on the evenings of spring high tides on new and full moons during the warmer half of the year. These calculable spawning events uniquely allow for the analysis of the molecular and cellular processes underlying reproduction. Here we characterise neuropeptides produced in H. asinina ganglia that are known in egg-laying molluscs to control vital aspects of reproduction.
Results:
We demonstrate that genes encoding APGWamide, myomodulin, the putative proctolin homologue whitnin, FMRFamide, a schistosomin-like peptide (SLP), a molluscan insulin-related peptide (MIP) and a haliotid growth-associated peptide (HGAP) all are differentially expressed in the anterior ganglia during the two week spawning cycle in both male and female abalone. Each gene has a unique and sex-specific expression profile. Despite these differences, expression levels in most of the genes peak at or within 12 h of the spawning event. In contrast, lowest levels of transcript abundance typically occurs 36 h before and 24 h after spawning, with differences in peak and low expression levels being most pronounced in genes orthologous to known molluscan reproduction neuromodulators.
Conclusions:
Exploiting the predictable semi-lunar spawning cycle of the gastropod H. asinina, we have identified a suite of evolutionarily-conserved, mollusc-specific and rapidly-evolving neuropeptides that appear to contribute to the regulation of spawning. Dramatic increases and decreases in ganglionic neuropeptide expression levels from 36 h before to 24 h after the broadcast spawning event are consistent with these peptides having a regulatory role in translating environmental signals experienced by a population into a synchronous physiological output, in this case, the release of gametes.
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Mismatch between shape changes and ecological shifts during the post-settlement growth of the surgeonfish, Acanthurus triostegus
Background:
Many coral reef fishes undergo habitat and diet shifts during ontogeny. However, studies focusing on the physiological and morphological adaptations that may prepare them for these transitions are relatively scarce. Here, we explored the body shape variation related to ontogenetic shifts in the ecology of the surgeonfish Acanthurus triostegus (Acanthuridae) from new settler to adult stages at Moorea Island (French Polynesia). Specifically, we tested the relationship between diet and habitat shifts and changes in overall body shape during the ontogeny of A. triostegus using a combination of geometric morphometric methods, stomach contents and stable isotope analysis.
Results:
After reef settlement, stable isotope composition of carbon and nitrogen revealed a change from a zooplanktivorous to a benthic algae diet. The large amount of algae (> 75% of stomach contents) found in the digestive tract of small juveniles (25-30 mm SL) suggested the diet shift is rapid. The post-settlement growth of A. triostegus is highly allometric. The allometric shape changes mainly concern cephalic and pectoral regions. The head becomes shorter and more ventrally oriented during growth. Morphological changes are directly related to the diet shift given that a small mouth ventrally oriented is particularly suited for grazing activities at the adult stage. The pectoral fin is more anteriorely and vertically positioned and its basis is larger in adults than in juveniles. This shape variation had implications for swimming performance, manoeuvrability, turning ability and is related to habitat shift. Acanthurus triostegus achieves its main transformation of body shape to an adult-like form at size of 35-40 mm SL.
Conclusion:
Most of the shape changes occurred after the reef colonization but before the transition between juvenile habitat (fringing reef) and adult habitat (barrier reef). A large amount of allometric variation was observed after diet shift from zooplankton to benthic algae. Diet shift could act as an environmental factor favouring or inducing morphological changes. On the other hand, the main shape changes have to be achieved before the recruitment to adult populations and start negotiating the biophysical challenges of locomotion and feeding in wave- and current-swept outer reef habitat.
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Conditional monogyny: female quality predicts male faithfulness
IntroductionMale monogyny in the absence of paternal investment is arguably one of the most puzzling mating systems. Recent evidence suggests that males of monogynous species adjust their life-history and their mating decision to shifting spatial and temporal selection regimes. In the cannibalistic wasp spider Argiope bruennichi males can be either monogynous or mate with a maximum of two females. We studied factors underlying male mating decisions in a natural population over a whole mating season. We documented all matings and categorized the males into single-mated and double-mated monogynous as well as bigynous males.
Results:
We found that all categories were continuously present with relatively stable frequencies despite changes in the operational sex ratio. Males were more likely monogynous when copulating with relatively heavy and old females and otherwise bigynous.
Conclusion:
Our results imply that males make conditional mating decisions based on the quality of the first female they encounter but do not adjust their mating tactic to the local selection regime.
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TINA manual landmarking tool: software for the precise digitization of 3D landmarks
Background:
Interest in the placing of landmarks and subsequent morphometric analyses of shape for 3D data has increased with the increasing accessibility of computed tomography (CT) scanners. However, current computer programs for this task suffer from various practical drawbacks. We present here a free software tool that overcomes many of these problems.
Results:
The TINA Manual Landmarking Tool was developed for the digitization of 3D data sets. It enables the generation of a modifiable 3D volume rendering display plus matching orthogonal 2D cross-sections from DICOM files. The object can be rotated and axes defined and fixed. Predefined lists of landmarks can be loaded and the landmarks identified within any of the representations. Output files are stored in various established formats, depending on the preferred evaluation software.
Conclusions:
The software tool presented here provides several options facilitating the placing of landmarks on 3D objects, including volume rendering from DICOM files, definition and fixation of meaningful axes, easy import, placement, control, and export of landmarks, and handling of large datasets. The TINA Manual Landmark Tool runs under Linux and can be obtained for free from http://www.tina-vision.net/tarballs/.
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Virulence of mixed fungal infections in honey bee brood
IntroductionHoney bees, Apis mellifera, have a diverse community of pathogens. Previous research has mostly focused on bacterial brood diseases of high virulence, but milder diseases caused by fungal pathogens have recently attracted more attention. This interest has been triggered by partial evidence that co-infection with multiple pathogens has the potential to accelerate honey bee mortality. In the present study we tested whether co-infection with closely related fungal brood-pathogen species that are either specialists or non-specialist results in higher host mortality than infections with a single specialist. We used a specially designed laboratory assay to expose honey bee larvae to controlled infections with spores of three Ascosphaera species: A. apis, the specialist pathogen that causes chalkbrood disease in honey bees, A. proliperda, a specialist pathogen that causes chalkbrood disease in solitary bees, and A. atra, a saprophytic fungus growing typically on pollen brood-provision masses of solitary bees.
Results:
We show for the first time that single infection with a pollen fungus A. atra may induce some mortality and that co-infection with A. atra and A. apis resulted in higher mortality of honey bees compared to single infections with A. apis. However, similar single and mixed infections with A. proliperda did not increase brood mortality.
Conclusion:
Our results show that co-infection with a closely related fungal species can either increase or have no effect on host mortality, depending on the identity of the second species. Together with other studies suggesting that multiple interacting pathogens may be contributing to worldwide honey bee health declines. Our results highlight the importance of studying effects of multiple infections, even when all interacting species are not known to be specialist pathogens.
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Ultrastructure of book gill development in embryos and first instars of the horseshoe crab Limulus polyphemus L. (Chelicerata, Xiphosura)
Background:
The transmission electron microscope (TEM) is used for the first time to study the development of book gills in the horseshoe crab. Near the end of the nineteenth century the hypothesis was presented for homology and a common ancestry for horseshoe crab book gills and arachnid book lungs. The present developmental study and the author's recent ones of book gills (SEM) and scorpion book lungs (TEM) are intended to clarify early histological work and provide new ultrastructural details for further research and for hypotheses about evolutionary history and relationships.
Results:
The observations herein are in agreement with earlier reports that the book gill lamellae are formed by proliferation and evagination of epithelial cells posterior to opisthosomal branchial appendages. A cartilage-like endoskeleton is produced in the base of the opisthosomal appendages. The lamellar precursor cells in the appendage base proliferate, migrate outward and secrete the lamellar cuticle from their apical surface. A series of external, posteriorly-directed lamellae is formed, with each lamella having a central channel for hemolymph and pillar-type space holders formed from cells of the opposed walls. This repeated, page-like pattern results also in water channels (without space holders) between the sac-like hemolymph lamellae.
Conclusions:
The developmental observations herein and in an earlier study (TEM) of scorpion book lungs show that the lamellae in book gills and book lungs result from some similar activities and features of the precursor epithelial cells: proliferation, migration, alignment and apical/basal polarity with secretion of cuticle from the apical surface and the basal surface in contact with hemolymph. These cellular similarities and the resulting book-like structure suggest a common ancestry, but there are also substantial developmental differences in producing these organs for gas exchange in the different environments, aqueous and terrestrial. For scorpion book lungs, the invaginated precursor cells align in rows and secrete rows of cell fragments that are the basis for the internal, anterior-directed air sacs. The hemolymph sacs of book gills are formed by epithelial evagination or outfolding from the posterior surface of the branchial appendages. Both book gills and scorpion book lungs have many page-like lamellae, but the lamellae are formed in a different manner and have some structural and functional differences that are apparently adaptive for the different environments.
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Eel osmotic stress transcriptional factor 1 (Ostf1) is highly expressed in gill mitochondria-rich cells, where ERK phosphorylated
Background:
Osmotic stress transcriptional factor 1 (Ostf1) was firstly identified in tilapia in 2005. Then numerous studies have investigated its regulation and expression profile in fish gill tissues in related to osmoregulation. Generally, hyperosmotic stress induced ostf1 mRNA expression level, however there is no report studying the cellular localization of Ostf1 expression in any osmoregulatory tissue. In this study immunohistochemical (IHC) approach was used to study the cellular localization of Ostf1 in gill cells of Japanese eels.FindingsOstf1 protein was found to be localized in branchial mitochondria-rich/chloride cell (MRC/CC) as revealed by Naα5 and CFTR co-localization. The protein was detectable at day 3 after fresh water to seawater transfer and was mainly localized in MRCs. Moreover, elevated levels of extracellular signal regulated kinase (ERK) phosphorylation was observed at day 3 of the transfer and was co-localized with MRCs.
Conclusions:
Our data identified Ostf1 expression in gill MRCs. The observation supports the role of Ostf1 in osmosensing and/or osmoregulation in fish gills, particularly its functional relationship with MRCs. The observation of the co-expression of pERK and Ostf1 in MRCs suggests a cross-talk mechanism between the mitogen-activated protein kinases (MAPKs) and Ostf1 in response to hyperosmotic challenge. To summarize, this report has addressed the cellular localization of Ostf1 and provides evidence to illustrate the involvement of Ostf1 and ERK on osmosensing and osmoregulatory function of gill MRCs.
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Variation in rates of early development in Haliotis asinina generate competent larvae of different ages
IntroductionInter-specific comparisons of metazoan developmental mechanisms have provided a wealth of data concerning the evolution of body form and the generation of morphological novelty. Conversely, studies of intra-specific variation in developmental programs are far fewer. Variation in the rate of development may be an advantage to the many marine invertebrates that posses a biphasic life cycle, where fitness commonly requires the recruitment of planktonically dispersing larvae to patchily distributed benthic environments.
Results:
We have characterised differences in the rate of development between individuals originating from a synchronised fertilisation event in the tropical abalone Haliotis asinina, a broadcast spawning lecithotrophic vetigastropod. We observed significant differences in the time taken to complete early developmental events (time taken to complete third cleavage and to hatch from the vitelline envelope), mid-larval events (variation in larval shell development) and late larval events (the acquisition of competence to respond to a metamorphosis inducing cue). We also provide estimates of the variation in maternally provided energy reserves that suggest maternal provisioning is unlikely to explain the majority of the variation in developmental rate we report here.
Conclusions:
Significant differences in the rates of development exist both within and between cohorts of synchronously fertilised H. asinina gametes. These differences can be detected shortly after fertilisation and generate larvae of increasingly divergent development states. We discuss the significance of our results within an ecological context, the adaptive significance of mechanisms that might maintain this variation, and potential sources of this variation.
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Landscape requirements of a primate population in a human-dominated environment
IntroductionAs urban and rural land development become widespread features of the global landscape so an understanding of the landscape requirements of displaced and isolated wildlife species becomes increasingly important for conservation planning. In the Cape Peninsula, South Africa, rapid human population growth, and the associated urban and rural land transformation, threatens the sustainability of the local chacma baboon population. Here we analyse spatial data collected from nine of the 12 extant troops to determine their population-level landscape requirements. We use hurdle models to ascertain the key landscape features influencing baboon occurrence and abundance patterns on two hierarchical spatial scales.
Results:
Both spatial scales produced similar results that were ecologically reliable and interpretable. The models indicated that baboons were more likely to occur, and be more abundant, at low altitudes, on steep slopes and in human-modified habitats. The combination of these landscape variables provides baboons with access to the best quality natural and anthropogenic food sources in close proximity to one another and suitable sleeping sites. Surface water did not emerge as an influential landscape feature presumably as the area is not water stressed.
Conclusions:
The model results indicate that land development in the Cape Peninsula has pushed baboons into increasingly marginal natural habitat while simultaneously providing them with predictable and easily accessible food sources in human-modified habitats. The resultant spatial competition between humans and baboons explains the high levels of human-baboon conflict and further erosion of the remaining land fragments is predicted to exacerbate competition. This study demonstrates how the quantification of animal landscape requirements can provide a mechanism for identifying priority conservation areas at the human-wildlife interface.
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An Intermediate in the evolution of superfast sonic muscles
Abstract
Background:
Intermediate forms in the evolution of new adaptations such as transitions from water to land and the evolution of flight are often poorly understood. Similarly, the evolution of superfast sonic muscles in fishes, often considered the fastest muscles in vertebrates, has been a mystery because slow bladder movement does not generate sound. Slow muscles that stretch the swimbladder and then produce sound during recoil have recently been discovered in ophidiiform fishes. Here we describe the disturbance call (produced when fish are held) and sonic mechanism in an unrelated perciform pearl perch (Glaucosomatidae) that represents an intermediate condition in the evolution of super-fast sonic muscles.
Results:
The pearl perch disturbance call is a two-part sound produced by a fast sonic muscle that rapidly stretches the bladder and an antagonistic tendon-smooth muscle combination (part 1) causing the tendon and bladder to snap back (part 2) generating a higher-frequency and greater-amplitude pulse. The smooth muscle is confirmed by electron microscopy and protein analysis. To our knowledge smooth muscle attachment to a tendon is unknown in animals.
Conclusion:
The pearl perch, an advanced perciform teleost unrelated to ophidiiform fishes, uses a slow type mechanism to produce the major portion of the sound pulse during recoil, but the swimbladder is stretched by a fast muscle. Similarities between the two unrelated lineages, suggest independent and convergent evolution of sonic muscles and indicate intermediate forms in the evolution of superfast muscles.
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Genetic Vaccines and Therapy - Latest Articles
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Treatment of adult MPSI mouse brains with IDUA-expressing mesenchymal stem cells decreases GAG deposition and improves exploratory behavior
Background:
Mucopolysaccharidosis type I (MPSI) is caused by a deficiency in alpha-L iduronidase (IDUA), which leads to lysosomal accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate. While the currently available therapies have good systemic effects, they only minimally affect the neurodegenerative process. Based on the neuroprotective and tissue regenerative properties of mesenchymal stem cells (MSCs), we hypothesized that the administration of MSCs transduced with a murine leukemia virus (MLV) vector expressing IDUA to IDUA KO mouse brains could reduce GAG deposition in the brain and, as a result, improve neurofunctionality, as measured by exploratory activity.
Methods:
MSCs infected with an MLV vector encoding IDUA were injected into the left ventricle of the brain of 12- or 25-month-old IDUA KO mice. The behavior of the treated mice in the elevated plus maze and open field tests was observed for 1 to 2 months. Following these observations, the brains were removed for biochemical and histological analyses.
Results:
After 1 or 2 months of observation, the presence of the transgene in the brain tissue of almost all of the treated mice was confirmed using PCR, and a significant reduction in GAG deposition was observed. This reduction was directly reflected in an improvement in exploratory activity in the open field and the elevated plus maze tests. Despite these behavioral improvements and the reduction in GAG deposition, IDUA activity was undetectable in these samples. Overall, these results indicate that while the initial level of IDUA was not sustainable for a month, it was enough to reduce and maintain low GAG deposition and improve the exploratory activity for months.
Conclusions:
These data show that gene therapy, via the direct injection of IDUA-expressing MSCs into the brain, is an effective way to treat neurodegeneration in MPSI mice.
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Molecular Relationship between Field and Vaccine Strain of Measles Virus and its Persistence in Pakistan
Background:
Countrywide 5.9 million, 0-11 Month old children are immunized annually by EPI (Expended Program on Immunization) against 8 vaccine preventable diseases including measles and so on. Unfortunately the basic immunity centers are not uniform throughout the country. Each center provides services to about 27000 people which is inadequate. The purpose of this study was to explore the development of EPI Pakistan in terms of immunization of measles.
Methods:
Nucleotide sequences were analyzed by neighbor joining method (bootstrap test) using Bio- edit and MEGA-5 software to find evolutionary relationship between wild type measles strain and vaccine strain (Edmonston strain) used in Pakistan. For statistical analysis of data SPSS 16 was used.
Results:
Currently 1.3 vaccinators are working at each U C (union council) which according to national EPI policy should be at least 2. About 56% and 44% children of age 0-11 months did not received second dose of measles in the last two years respectively. Out of these 4231 cases which were reported last year, 1370 have received their first dose of measles vaccine.
Conclusion:
Seroconversion and seroprevalence study of the vaccine and field strain of measles virus is needed to confirm whether its failure is due to service unavailability or vaccine in-affectivity.
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HCV entry receptor as potential targets for siRNA based inhibition of HCV
Background:
Hepatitis C virus (HCV) is a major health concern with almost 3% of the world's population (350 million individuals) and 10% of the Pakistani population chronically infected with this viral pathogen. The current therapy of interferon-α and ribavirin against HCV has limited efficiency, so alternative options are desperately needed. RNA interference (RNAi), which results in a sequence-specific degradation of HCV RNA has potential as a powerful alternative molecular therapeutic approach. Concerning viral entry, the HCV structural gene E2 is mainly involved in virus attachment to the host cell surface receptors i.e., CD81 tetraspanin, scavenger receptor class B type 1 (SR-B1), low density lipoprotein receptor (LDLR) and claudin1 (CLDN1).
Results:
In this report, we studied the relationship of the HCV receptors CD81, LDL, CLDN1 and SR-B1to HCV infection. The potential of siRNAs to inhibit HCV-3a replication in serum-infected Huh-7 cells was demonstrated by treatment with siRNAs against HCV receptors, which resulted in a significant decrease in HCV viral copy number.
Conclusions:
Our data clearly demonstrate that the RNAi-mediated silencing of HCV receptors is among the first of its type for the development of an effective siRNA-based therapeutic option against HCV-3a. These findings will shed further light on the possible role of receptors in inhibition of HCV-3a viral titre through siRNA mediated silencing.
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Occult HCV or delayed viral clearance from lymphocytes of Chronic HCV genotype 3 patients after interferon therapy
Background:
A recently discovered occult HCV entity reported by various investigators seems to be highly controversial. Especially, the clinical significance of these findings remains uncertain. For optimal outcome of antiviral therapy, investigation of occult HCV needs a broad-based probe in order to investigate the results of viral therapy and its host/viral interaction. The current study was aimed at determining the prevalence of occult HCV in peripheral blood lymphocytes of predominantly genotype 3 HCV-infected patients after completion of antiviral therapy and to investigate long term outcomes in the presence or absence of PBMC positivity.MethodA total of 151 chronic, antiHCV and serum RNA-positive patients were enrolled in the study. Patients with a complete virological response at the end of treatment were screened for the presence of viral RNA in their PBMCs and were followed for up to one year for the presence of serum and PBMC viral genomic RNA.
Results:
Out of 151 patients, 104 (70%) responded to the prescribed interferon treatment and showed viral-clearance from serum. These were screened for the presence of genomic RNA in their PBMCs. Sixteen samples were PBMC-positive for viral RNA at the end of treatment (EOT). All these patients had also cleared the virus from peripheral blood cells after the 6-12 month follow-up study.
Conclusion:
True occult hepatitis C virus does not exist in our cohort. Residual viremia at the EOT stage merely reflects a difference in viral kinetics in various compartments that remains a target of immune response even after the end of antiviral therapy and is eventually cleared out at the sustained viral response (SVR).
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Biodistribution and blood clearance of plasmid DNA administered in arginine peptide complexes
Background:
Peptide/DNA complexes have great potential as non-viral methods for gene delivery. Despite promising results for peptide-mediated gene delivery technology, an effective systemic peptide-based gene delivery system has not yet been developed.
Methods:
This study used pCMV-Luc as a model gene to investigate the biodistribution and the in vivo efficacy of arginine peptide-mediated gene delivery by polymerase chain reaction (PCR).
Results:
Plasmid DNA was detected in all organs tested 1 h after intraperitoneal administration of arginine/DNA complexes, indicating that the arginine/DNA complexes disseminated widely through the body. The plasmid was primarily detected in the spleen, kidney, and diaphragm 24 h post administration. The mRNA expression of plasmid DNA was noted in the spleen, kidney, and diaphragm for up to 2 weeks, and in the other major organs, for at least 1 week. Blood clearance studies showed that injected DNA was found in the blood as long as 6 h after injection.
Conclusions:
Taken together, our results demonstrated that arginine/DNA complexes are stable in blood and are effective for in vivo gene delivery. These findings suggest that intraperitoneal administration of arginine/DNA complexes is a promising tool in gene therapy.
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Establishment of stable Huh-7 cell lines expressing various hepatitis C virus genotype 3a protein: an in-vitro testing system for novel anti-HCV drugs
Background:
Hepatitis C virus (HCV) infection is the leading cause of chronic hepatitis which progresses to hepatocellular carcinoma (HCC) afflicting > 170 million people worldwide. HCV 3a is the most common genotype (about 70% of all genotypes) circulating in Pakistan. Expression of HCV individual gene of 3a would facilitate therapeutic and vaccines strategies against chronic HCV and liver Cirrhosis. The aim of the present study was the establishment of stable Huh-7 cell lines expressing structural and non structural proteins of HCV Genotype 3a Pakistani isolate obtained from chronic HCV patients.
Methods:
Blood samples were obtained from chronic HCV-3a positive patients. HCV individual genes were amplified using PCR with gene specific primers having restriction sites. These gene amplicons were cloned in mammalian expression vector PcDNA3.1+. Huh-7 cell lines were transfected with these constructed plasmids having structural or non-structural HCV genes in confluent cells with lipofectamine. Positive clones were selected with G418 and then confirmed by genome PCR. Subsequently, transcription and expression of the integrated genes were demonstrated by RT-PCR, sequencing and Western blot analysis.
Results:
We successfully cloned and express five HCV-3a genes in PcDNA3.1+ mammalian expression vector. Results of western blot and sequencing PCR confirmed the stable expression of these five genes.
Conclusion:
The stable cell-lines expressing HCV-3a individual genes would be a useful tool to investigate the role of various HCV proteins on HCV disease outcome and testing of new therapeutic strategies against HCV.
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Antiviral drugs against Hepatitis C Virus
Hepatitis C virus (HCV) infection is a major worldwide problem causes acute and chronic HCV infection. Current treatment of HCV includes pegylated interferon-α (PEG IFN- α) plus ribavirin (RBV) which has significant side effects depending upon the type of genotype. Currently, there is a need to develop antiviral agents, both from synthetic chemistry and Herbal sources. In the last decade, various novel HCV replication, helicase and entry inhibitors have been synthesized and some of which have been entered in different phases of clinical trials. Successful results have been acquired by executing combinational therapy of compounds with standard regime in different HCV replicons. Even though, diverse groups of compounds have been described as antiviral targets against HCV via Specifically Targeted Antiviral Therapy for hepatitis C (STAT-C) approach (in which compounds are designed to directly block HCV or host proteins concerned in HCV replication), still there is a need to improve the properties of existing antiviral compounds. In this review, we sum up potent antiviral compounds against entry, unwinding and replication of HCV and discussed their activity in combination with standard therapy. Conclusively, further innovative research on chemical compounds will lead to consistent standard therapy with fewer side effects.
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Comparative analysis of macrophage associated vectors for use in genetic vaccine.
Background:
Antigen presentation by non professional antigen presenting cells (APC) can lead to anergy. In genetic vaccines, targeting the macrophages and APC for efficient antigen presentation might lead to balanced immune response. One such approach is to incorporate APC specific promoter in the vector to be used.
Methods:
Three promoters known to be active in macrophage were selected and cloned in mammalian expressing vector (pAcGFP1-N1) to reconstruct (pAcGFP-MS), (pAcGFP-EMR) and (pAcGFP-B5I) with macrosialin, EmrI and Beta-5 Integrin promoters respectively. As a positive control (pAcGFP-CMV) was used with CMV promoter and promoterless vector (pAcGFP-NIX) which served as a negative control. GFP gene was used as readout under the control of each of the promoter. The expression of GFP was analyzed on macrophage and non-macrophage cell lines using Flow cytometry and qRT-PCR with TaqMan probe chemistries.
Results:
All the promoters in question were dominant to macrophage lineage cell lines as observed by fluorescence, Western blot and quantitative RT-PCR. The activity of macrosialin was significantly higher than other macrophage promoters. CMV promoter showed 1.83 times higher activity in macrophage cell lines. The expression of GFP driven by macrosialin promoter after 24 hours was 4.40 times higher in macrophage derived cell lines in comparison with non macrophage cell lines.
Conclusions:
Based on this study, macrosialin promoter can be utilized for targeting macrophage dominant expression. In vivo study needs to be carried out for its utility as a vaccine candidate.
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A comparison of multiple shRNA expression methods for combinatorial RNAi
RNAi gene therapies for HIV-1 will likely need to employ multiple shRNAs to counter resistant strains. We evaluated 3 shRNA co-expression methods to determine their suitability for present use; multiple expression vectors, multiple expression cassettes and single transcripts comprised of several dsRNA units (aka domains) with each being designed to a different target. Though the multiple vector strategy was effective with 2 shRNAs, the increasing number of vectors required is a major shortcoming. With single transcript configurations we only saw adequate activity from 1 of 10 variants tested, the variants being comprised of 2 - 3 different target domains. Whilst single transcript configurations have the most advantages on paper, these configurations can not yet be rapidly and reliably re-configured for new targets. However, our multiple cassette combinations of 2, 3 and 4 (29 bp) shRNAs were all successful, with suitable activity maintained in all positions and net activities comparable to that of the corresponding single shRNAs. We conclude that the multiple cassette strategy is the most suitably developed for present use as it is easy to design, assemble, is directly compatible with pre-existing shRNA and can be easily expanded.
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Altering alpha-dystroglycan receptor affinity of LCMV pseudotyped lentivirus yields unique cell and tissue tropism
Background:
The envelope glycoprotein of lymphocytic choriomeningitis virus (LCMV) can efficiently pseudotype lentiviral vectors. Some strains of LCMV exploit high affinity interactions with α-dystroglycan (α-DG) to bind to cell surfaces and subsequently fuse in low pH endosomes. LCMV strains with low α-DG affinity utilize an unknown receptor and display unique tissue tropisms. We pseudotyped non-primate feline immunodeficiency virus (FIV) vectors using LCMV derived glycoproteins with high or low affinity to α-DG and evaluated their properties in vitro and in vivo.
Methods:
We pseudotyped FIV with the LCMV WE54 strain envelope glycoprotein and also engineered a point mutation in the WE54 envelope glycoprotein (L260F) to diminish α-DG affinity and direct binding to alternate receptors. We hypothesized that this change would alter in vivo tissue tropism and enhance gene transfer to neonatal animals.
Results:
In mice, hepatic α- and β-DG expression was greatest at the late gestational and neonatal time points. When displayed on the surface of the FIV lentivirus the WE54 L260F mutant glycoprotein bound weakly to immobilized α-DG. Additionally, LCMV WE54 pseudotyped FIV vector transduction was neutralized by pre-incubation with soluble α-DG, while the mutant glycoprotein pseudotyped vector was not. In vivo gene transfer in adult mice with either envelope yielded low transduction efficiencies in hepatocytes following intravenous delivery. In marked contrast, neonatal gene transfer with the LCMV envelopes, and notably with the FIV-L260F vector, conferred abundant liver and lower level cardiomyocyte transduction as detected by luciferase assays, bioluminescent imaging, and β-galactosidase staining.
Conclusions:
These results suggest that a developmentally regulated receptor for LCMV is expressed abundantly in neonatal mice. LCMV pseudotyped vectors may have applications for neonatal gene transfer.AbbreviationsArmstrong 53b (Arm53b); baculovirus Autographa californica GP64 (GP64); charge-coupled device (CCD); dystroglycan (DG); feline immunodeficiency virus (FIV); glycoprotein precursor (GP-C); firefly luciferase (Luc); lymphocytic choriomeningitis virus (LCMV); nuclear targeted β-galactosidase (ntLacZ); optical density (OD); PBS/0.1% (w/v) Tween-20 (PBST); relative light units (RLU); Rous sarcoma virus (RSV); transducing units per milliliter (TU/ml); vesicular stomatitis virus (VSV-G); wheat germ agglutinin (WGA); 50% reduction in binding (C50).
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Geochemical Transactions - Latest Articles
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Quantification of particle-induced inflammatory stress response: a novel approach for toxicity testing of earth materials
Background:
Reactive oxygen species (ROS) are vital regulators of many cellular functions in the body. The intracellular ROS concentration is highly regulated by a balance between pro-oxidants and anti-oxidants. A chronic excess of pro-oxidants leads to elevated ROS concentrations and inflammation, possibly initiating or enhancing disease onset. Mineral-induced generation of ROS, the role of minerals in upregulating cellular ROS, and their role in the development of several occupational diseases are now widely recognized. However, there is no standard protocol to determine changes in ROS production in cells after exposure to mineral dust or earth materials in general. In this study, a new method for determining the degree of cellular toxicity (i.e., cytotoxicity) of particles is described that will help bridge the gap in knowledge.
Results:
By measuring the production of ROS and the viability of cells, an inflammatory stress response (ISR) indicator is defined. This approach normalizes the ROS upregulation with respect to the number of viable cells at the time of measurement. We conducted experiments on a series of minerals and soils that represent materials that are inert (i.e., glass beads, anatase, and a soil with low trace element content), moderately reactive (i.e., soil with high trace element content), and highly reactive (i.e., pyrite). Inert materials generated the lowest ISR, averaging 350% compared to the control. Acid washed pyrite produced the highest ISR (1,100 fold higher than the control). The measurements conducted as a function of time showed a complex response. Most materials showed an increase in ISR with particle loading.
Conclusions:
The amount of cellularly generated ROS and cell viability combined provide a better understanding of particle-induced oxidative stress. The results indicate that some earth materials may solicit an initial burst of ROS, followed by a second phase in which cell viability decreases and ROS production increases, leading to a high ISR value. Hence, measurements conducted over a range of particle loading combined with multiple data measurements up to 24 hours can provide new insights in the possible effect of exposure to earth materials on human health.
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Phenylalanine as a hydroxyl radical-specific probe in pyrite slurries
The abundant iron sulfide mineral pyrite has been shown to catalytically produce hydrogen peroxide (H2O2) and hydroxyl radical (
.
OH) in slurries of oxygenated water. Understanding the formation and fate of these reactive oxygen species is important to biological and ecological systems as exposure can lead to deleterious health effects, but also environmental engineering during the optimization of remediation approaches for possible treatment of contaminated waste streams. This study presents the use of the amino acid phenylalanine (Phe) to monitor the kinetics of pyrite-induced
.
OH formation through rates of hydroxylation forming three isomers of tyrosine (Tyr) - ortho-, meta-, and para-Tyr. Results indicate that about 50% of the Phe loss results in Tyr formation, and that these products further react with
.
OH at rates comparable to Phe. The overall loss of Phe appeared to be pseudo first-order in [Phe] as a function of time, but for the first time it is shown that initial rates were much less than first-order as a function of initial substrate concentration, [Phe]o. These results can be rationalized by considering that the effective concentration of
.
OH in solution is lower at a higher level of reactant and that an increasing fraction of
.
OH is consumed by Phe-degradation products as a function of time. A simplified first-order model was created to describe Phe loss in pyrite slurries which incorporates the [Phe]o, a first-order dependence on pyrite surface area, the assumption that all Phe degradation products compete equally for the limited supply of highly reactive
.
OH, and a flux that is related to the release of H2O2 from the pyrite surface (a result of the incomplete reduction of oxygen at the pyrite surface). An empirically derived rate constant, Kpyr
, was introduced to describe a variable
.
OH-reactivity for different batches of pyrite. Both the simplified first-order kinetic model, and a more detailed numerical simulation, yielded results that compare well to the observed kinetic data describing the effects of variations in concentrations of both initial Phe and pyrite. This work supports the use of Phe as a useful probe to assess the formation of
.
OH in the presence of pyrite, and its possible utility for similar applications with other minerals.
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Geochemically induced shifts in catabolic energy yields explain past ecological changes of diffuse vents in the East Pacific Rise 9 degrees 50'N area
The East Pacific Rise (EPR) at 9°50'N hosts a hydrothermal vent field (Bio9) where the change in fluid chemistry is believed to have caused the demise of a tubeworm colony. We test this hypothesis and expand on it by providing a thermodynamic perspective in calculating free energies for a range of catabolic reactions from published compositional data. The energy calculations show that there was excess H2S in the fluids and that oxygen was the limiting reactant from 1991 to 1997. Energy levels are generally high, although they declined in that time span. In 1997, sulfide availability decreased substantially and H2S was the limiting reactant. Energy availability dropped by a factor of 10 to 20 from what it had been between 1991 and 1995. The perishing of the tubeworm colonies began in 1995 and coincided with the timing of energy decrease for sulfide oxidizers. In the same time interval, energy availability for iron oxidizers increased by a factor of 6 to 8, and, in 1997, there was 25 times more energy per transferred electron in iron oxidation than in sulfide oxidation. This change coincides with a massive spread of red staining (putative colonization by Fe-oxidizing bacteria) between 1995 and 1997.For a different cluster of vents from the EPR 9°50'N area (Tube Worm Pillar), thermodynamic modeling is used to examine changes in subseafloor catabolic metabolism between 1992 and 2000. These reactions are deduced from deviations in diffuse fluid compositions from conservative behavior of redox-sensitive species. We show that hydrogen is significantly reduced relative to values expected from conservative mixing. While H2 concentrations of the hydrothermal endmember fluids were constant between 1992 and 1995, the affinities for hydrogenotrophic reactions in the diffuse fluids decreased by a factor of 15 and then remained constant between 1995 and 2000. Previously, these fluids have been shown to support subseafloor methanogenesis. Our calculation results corroborate these findings and indicate that the 1992-1995 period was one of active growth of hydrogenotrophic communities, while the system was more or less at steady state between 1995 and 2000.
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The Effect of the CO3^(2-) to Ca^(2+) Ion Activity Ratio on Calcite Precipitation Kinetics and Sr^(2+) partitioning
Background:
A proposed strategy for immobilizing trace metals in the subsurface is to stimulate calcium carbonate precipitation and incorporate contaminants by co-precipitation. Such an approach will require injecting chemical amendments into the subsurface to generate supersaturated conditions that promote mineral precipitation. However, the formation of reactant mixing zones will create gradients in both the saturation state and ion activity ratios (i.e.,
a
C
O
3
2
-
/
a
C
a
2
+
). To better understand the effect of ion activity ratios on CaCO3 precipitation kinetics and Sr2+ co-precipitation, experiments were conducted under constant composition conditions where the supersaturation state (Ω) for calcite was held constant at 9.4, but the ion activity ratio
(
r
=
a
C
O
3
2
-
/
a
C
a
2
+
)
was varied between 0.0032 and 4.15.
Results:
Calcite was the only phase observed, by XRD, at the end of the experiments. Precipitation rates increased from 41.3 ± 3.4 μmol m-2 min-1 at r = 0.0315 to a maximum rate of 74.5 ± 4.8 μmol m-2 min-1 at r = 0.306 followed by a decrease to 46.3 ± 9.6 μmol m-2 min-1 at r = 1.822. The trend was simulated using a simple mass transfer model for solute uptake at the calcite surface. However, precipitation rates at fixed saturation states also evolved with time. Precipitation rates accelerated for low r values but slowed for high r values. These trends may be related to changes in effective reactive surface area. The
a
C
O
3
2
-
/
a
C
a
2
+
ratios did not affect the distribution coefficient for Sr in calcite (DP
Sr
2+), apart from the indirect effect associated with the established positive correlation between DP
Sr
2+ and calcite precipitation rate.
Conclusion:
At a constant supersaturation state (Ω = 9.4), varying the ion activity ratio affects the calcite precipitation rate. This behavior is not predicted by affinity-based rate models. Furthermore, at the highest ion ratio tested, no precipitation was observed, while at the lowest ion ratio precipitation occurred immediately and valid rate measurements could not be made. The maximum measured precipitation rate was 2-fold greater than the minima, and occurred at a carbonate to calcium ion activity ratio of 0.306. These findings have implications for predicting the progress and cost of remediation operations involving enhanced calcite precipitation where mineral precipitation rates, and the spatial/temporal distribution of those rates, can have significant impacts on the mobility of contaminants.
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Experimental Study of Cement-Sandstone/Shale-Brine-CO2 Interactions
Background:
Reactive-transport simulation is a tool that is being used to estimate long-term trapping of CO2, and wellbore and cap rock integrity for geologic CO2 storage. We reacted end member components of a heterolithic sandstone and shale unit that forms the upper section of the In Salah Gas Project carbon storage reservoir in Krechba, Algeria with supercritical CO2, brine, and with/without cement at reservoir conditions to develop experimentally constrained geochemical models for use in reactive transport simulations.
Results:
We observe marked changes in solution composition when CO2 reacted with cement, sandstone, and shale components at reservoir conditions. The geochemical model for the reaction of sandstone and shale with CO2 and brine is a simple one in which albite, chlorite, illite and carbonate minerals partially dissolve and boehmite, smectite, and amorphous silica precipitate. The geochemical model for the wellbore environment is also fairly simple, in which alkaline cements and rock react with CO2-rich brines to form an Fe containing calcite, amorphous silica, smectite and boehmite or amorphous Al(OH)3.
Conclusions:
Our research shows that relatively simple geochemical models can describe the dominant reactions that are likely to occur when CO2 is stored in deep saline aquifers sealed with overlying shale cap rocks, as well as the dominant reactions for cement carbonation at the wellbore interface.
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Inducing mineral precipitation in groundwater by addition of phosphate
Background:
Induced precipitation of phosphate minerals to scavenge trace elements from groundwater is a potential remediation approach for contaminated aquifers. The success of engineered precipitation schemes depends on the particular phases generated, their rates of formation, and their long term stability. The purpose of this study was to examine the precipitation of calcium phosphate minerals under conditions representative of a natural groundwater. Because microorganisms are present in groundwater, and because some proposed schemes for phosphate mineral precipitation rely on stimulation of native microbial populations, we also tested the effect of bacterial cells (initial densities of 105 and 107 mL-1) added to the precipitation medium. In addition, we tested the effect of a trace mixture of propionic, isovaleric, formic and butyric acids (total concentration 0.035 mM).
Results:
The general progression of mineral precipitation was similar under all of the study conditions, with initial formation of amorphous calcium phosphate, and transformation to poorly crystalline hydroxylapatite (HAP) within one week. The presence of the bacterial cells appeared to delay precipitation, although by the end of the experiments the overall extent of precipitation was similar for all treatments. The stoichiometry of the final precipitates as well as Rietveld structure refinement using x-ray diffraction data indicated that the presence of organic acids and bacterial cells resulted in an increasing a and decreasing c lattice parameter, with the higher concentration of cells resulting in the greatest distortion. Uptake of Sr into the solids was decreased in the treatments with cells and organic acids, compared to the control.
Conclusions:
Our results suggest that the minerals formed initially during an engineered precipitation application for trace element sequestration may not be the ones that control long-term immobilization of the contaminants. In addition, the presence of bacterial cells appears to be associated with delayed HAP precipitation, changes in the lattice parameters, and reduced incorporation of trace elements as compared to cell-free systems. Schemes to remediate groundwater contaminated with trace metals that are based on enhanced phosphate mineral precipitation may need to account for these phenomena, particularly if the remediation approach relies on enhancement of in situ microbial populations.
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Geophysical monitoring and reactive transport modeling of ureolytically-driven calcium carbonate precipitation
Ureolytically-driven calcium carbonate precipitation is the basis for a promising in-situ remediation method for sequestration of divalent radionuclide and trace metal ions. It has also been proposed for use in geotechnical engineering for soil strengthening applications. Monitoring the occurrence, spatial distribution, and temporal evolution of calcium carbonate precipitation in the subsurface is critical for evaluating the performance of this technology and for developing the predictive models needed for engineering application. In this study, we conducted laboratory column experiments using natural sediment and groundwater to evaluate the utility of geophysical (complex resistivity and seismic) sensing methods, dynamic synchrotron x-ray computed tomography (micro-CT), and reactive transport modeling for tracking ureolytically-driven calcium carbonate precipitation processes under site relevant conditions. Reactive transport modeling with TOUGHREACT successfully simulated the changes of the major chemical components during urea hydrolysis. Even at the relatively low level of urea hydrolysis observed in the experiments, the simulations predicted an enhanced calcium carbonate precipitation rate that was 3-4 times greater than the baseline level. Reactive transport modeling results, geophysical monitoring data and micro-CT imaging correlated well with reaction processes validated by geochemical data. In particular, increases in ionic strength of the pore fluid during urea hydrolysis predicted by geochemical modeling were successfully captured by electrical conductivity measurements and confirmed by geochemical data. The low level of urea hydrolysis and calcium carbonate precipitation suggested by the model and geochemical data was corroborated by minor changes in seismic P-wave velocity measurements and micro-CT imaging; the latter provided direct evidence of sparsely distributed calcium carbonate precipitation. Ion exchange processes promoted through NH4
+ production during urea hydrolysis were incorporated in the model and captured critical changes in the major metal species. The electrical phase increases were potentially due to ion exchange processes that modified charge structure at mineral/water interfaces. Our study revealed the potential of geophysical monitoring for geochemical changes during urea hydrolysis and the advantages of combining multiple approaches to understand complex biogeochemical processes in the subsurface.
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Formation of H2 and CH4 by weathering of olivine at temperatures between 30 and 70 degrees C
Hydrocarbons such as CH4 are known to be formed through the Fischer-Tropsch or Sabatier type reactions in hydrothermal systems usually at temperatures above 100°C. Weathering of olivine is sometimes suggested to account for abiotic formation of CH4 through its redox lowering and water splitting properties. Knowledge about the CH4 and H2 formation processes at low temperatures is important for the research about the origin and cause of early Earth and Martian CH4 and for CO2 sequestration. We have conducted a series of low temperature, long-term weathering experiments in which we have tested the CH4 and H2 formation potential of forsteritic olivine.The results show low temperature CH4 production that is probably influenced by chromite and magnetite as catalysts. Extensive analyses of a potential CH4 source trapped in the crystal structure of the olivine showed no signs of incorporated CH4. Also, the available sources of organic carbon were not enough to support the total amount of CH4 detected in our experiments. There was also a linear relationship between silica release into solution and the net CH4 accumulation into the incubation bottle headspaces suggesting that CH4 formation under these conditions could be a qualitative indicator of olivine dissolution.It is likely that minerals such as magnetite, chromite and other metal-rich minerals found on the olivine surface catalyze the formation of CH4, because of the low temperature of the system. This may expand the range of environments plausible for abiotic CH4 formation both on Earth and on other terrestrial bodies.
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Chromite oxidation by manganese oxides in subseafloor basalts and the presence of putative fossilized microorganisms
Chromite is a mineral with low solubility and is thus resistant to dissolution. The exception is when manganese oxides are available, since they are the only known naturally occurring oxidants for chromite. In the presence of Mn(IV) oxides, Cr(III) will oxidise to Cr(VI), which is more soluble than Cr(III), and thus easier to be removed. Here we report of chromite phenocrysts that are replaced by rhodochrosite (Mn(II) carbonate) in subseafloor basalts from the Koko Seamount, Pacific Ocean, that were drilled and collected during the Ocean Drilling Program (ODP) Leg 197. The mineral succession chromite-rhodochrosite-saponite in the phenocrysts is interpreted as the result of chromite oxidation by manganese oxides. Putative fossilized microorganisms are abundant in the rhodochrosite and we suggest that the oxidation of chromite has been mediated by microbial activity. It has previously been shown in soils and in laboratory experiments that chromium oxidation is indirectly mediated by microbial formation of manganese oxides. Here we suggest a similar process in subseafloor basalts.
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A 50-year record of NOx and SO2 sources in precipitation in the Northern Rocky Mountains, USA
Ice-core samples from Upper Fremont Glacier (UFG), Wyoming, were used as proxy records for the chemical composition of atmospheric deposition. Results of analysis of the ice-core samples for stable isotopes of nitrogen (δ15N, ) and sulfur (δ34S, ), as well as and deposition rates from the late-1940s thru the early-1990s, were used to enhance and extend existing National Atmospheric Deposition Program/National Trends Network (NADP/NTN) data in western Wyoming. The most enriched δ34S value in the UFG ice-core samples coincided with snow deposited during the 1980 eruption of Mt. St. Helens, Washington. The remaining δ34S values were similar to the isotopic composition of coal from southern Wyoming. The δ15N values in ice-core samples representing a similar period of snow deposition were negative, ranging from -5.9 to -3.2 ‰ and all fall within the δ15N values expected from vehicle emissions. Ice-core nitrate and sulfate deposition data reflect the sharply increasing U.S. emissions data from 1950 to the mid-1970s.
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Globalization and Health - Latest Articles
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The Economic Impact of Non-communicable Diseases on Households in India
Background:
In India, Non Communicable Diseases (NCDs) and injuries account for an estimated 62% of the total age-standardized burden of forgone Disability Adjusted Life Years (DALYs). Public and private financing of clinical services to reduce the NCD burden is a major challenge.
Methods:
We used National Sample Survey Organization (NSSO) survey data from 1995-96 and 2004 covering nearly 200 thousand households to assess healthcare utilization patterns and out of pocket health spending by disease category. For this purpose, self-reported diseases and conditions were categorized into NCDs and non-NCDs. Survey data were used to assess how households financed their overall health expenditures and related this pattern to specific health conditions. We measured catastrophic spending on NCD-related hospitalization, defined as occurring when health expenditures exceeded 40% of a household's ability to pay, that is, household consumption spending less combined survival consumption expenditure; and impoverishment when per capita expenditure within the household decreased to below the poverty line once health spending was netted out.
Results:
The share of NCDs in out of pocket health expenses incurred by households increased over time, from 31.6 percent in 1995-96 to 47.3 percent in 2004. In both years, own savings and income were the most important source of financing for many health conditions, typically between 40-60 percent of all spending, whereas 30-35 percent was from borrowing. The odds of catastrophic hospitalization expenditures for cancer was nearly 170% greater and for CVD and injuries 22 percent greater than the odds due to communicable diseases. Impoverishment patterns were similar.
Conclusions:
Out of pocket expenses for treating NCDs rose sharply over the period from 1995-96 to 2004. When NCDs are present, the financial risks to which Indians households are exposed are significant.
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Global health funding and economic development
The impact of increased national wealth, as measured by Gross Domestic Product (GDP), on public health is widely understood, however an equally important but less well-acclaimed relationship exists between improvements in health and the growth of an economy. Communicable diseases such as HIV, TB, Malaria and the Neglected Tropical Diseases (NTDs) are impacting many of the world's poorest and most vulnerable populations, and depressing economic development. Sickness and disease has decreased the size and capabilities of the workforce through impeding access to education and suppressing foreign direct investment (FDI). There is clear evidence that by investing in health improvements a significant increase in GDP per capita can be attained in four ways: Firstly, healthier populations are more economically productive; secondly, proactive healthcare leads to decrease in many of the additive healthcare costs associated with lack of care (treating opportunistic infections in the case of HIV for example); thirdly, improved health represents a real economic and developmental outcome in-and-of itself and finally, healthcare spending capitalises on the Keynesian 'economic multiplier' effect. Continued under-investment in health and health systems represent an important threat to our future global prosperity. This editorial calls for a recognition of health as a major engine of economic growth and for commensurate investment in public health, particularly in poor countries.
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The politics behind the implementation of the WTO Paragraph 6 Decision in Canada to increase global drug access
Background:
The reform of pharmaceutical policy can often involve trade-offs between competing social and commercial goals. Canada's Access to Medicines Regime (CAMR), a legislative amendment that permits compulsory licensing for the production and export of medicines to developing countries, aimed to reconcile these goals. Since it was passed in 2004, only two orders of antiretroviral drugs, enough for 21,000 HIV/AIDS patients in Rwanda have been exported. Future use of the regime appears unlikely. This research aimed to examine the politics of CAMR.
Methods:
Parliamentary Committee hearing transcripts from CAMR's legislative development (2004) and legislative review (2007) were analysed using a content analysis technique to identify how stakeholders who participated in the debates framed the issues. These findings were subsequently analysed using a framework of framing, institutions and interests to determine how these three dimensions shaped CAMR.
Results:
In 2004, policy debates in Canada were dominated by two themes: intellectual property rights and the TRIPS Agreement. The right to medicines as a basic human right and CAMR's potential impact on innovation were hardly discussed. With the Departments of Industry Canada and International Trade as the lead institutions, the goals of protecting intellectual property and ensuring good trade relations with the United States appear to have taken priority over encouraging generic competition to achieve drug affordability. The result was a more limited interpretation of patent flexibilities under the WTO Paragraph 6 Decision. The most striking finding is the minimal discussion over the potential barriers developing country beneficiaries might face when attempting to use compulsory licensing, including their reluctance to use TRIPS flexibilities, their desire to pursue technological development and the constraints inherent in the WTO Paragraph 6 Decision. Instead, these issues were raised in 2007, which can be partly accounted for by experience in implementing the legislation and hence a greater representation of the interests of potential beneficiary country governments.
Conclusions:
The Canadian government designed CAMR as a last resort measure. Increased input from the developing country beneficiaries and shifting to institutions where the right to health gets prioritized may lead to policies that better achieves affordable drug access.
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Is the Brazilian pharmaceutical policy ensuring population access to essential medicines?
Background:
To evaluate medicine prices, availability and affordability in Brazil, considering the differences across three types of medicines (originator brands, generics and similar medicines) and different types of facilities (private pharmacies, public sector pharmacies and "popular pharmacies").
Methods:
Data on prices and availability of 50 medicines were collected in 56 pharmacies across six cities in Southern Brazil using the World Health Organization / Health Action International methodology. Median prices obtained were divided by international reference prices to derive the median price ratio (MPR).
Results:
In the private sector, prices were 8.6 MPR for similar medicines, 11.3 MRP for generics and 18.7 MRP for originator brands, respectively. Mean availability was 65%, 74% and 48% for originator brands, generics and similar medicines, respectively. In the public sector, mean availability of similar medicines was 2-7 times higher than that of generics. Mean overall availability in the public sector ranged from 68.8% to 81.7%. In "popular pharmacies", mean availability was greater than 90% in all cities.
Conclusions:
Availability of medicines in the public sector does not meet the challenge of supplying essential medicines to the entire population, as stated in the Brazilian constitution. This has unavoidable repercussions for affordability, particularly amongst the lower socio-economic strata.
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Development cooperation for health: reviewing a dynamic concept in a complex global aid environment
The 4th High Level Forum on Aid Effectiveness, held in Busan, South Korea in November 2011 again promised an opportunity for a "new consensus on development cooperation" to emerge. This paper reviews the recent evolution of the concept of coordination for development assistance in health as the basis from which to understand current discourses. The paper reviews peer-reviewed scientific literature and relevant 'grey' literature, revisiting landmark publications and influential authors, examining the transitions in the conceptualisation of coordination, and the related changes in development assistance. Four distinct transitions in the understanding, orientation and application of coordination have been identified: coordination within the sector, involving geographical zoning, sub-sector specialisation, donor consortia, project co-financing, sector aid, harmonisation of procedures, ear-marked budgetary support, donor agency reform and inter-agency intelligence gathering; sector-wide coordination, expressed particularly through the Sector-Wide Approach; coordination across sectors at national level, expressed in the evolution of Poverty Strategy Reduction Papers and the national monitoring of the Millennium Development Goals; and, most recently, global-level coordination, embodied in the Paris Principles, and the emergence of agencies such as the International Health Partnerships Plus. The transitions are largely but not strictly chronological, and each draws on earlier elements, in ways that are redefined in the new context. With the increasing complexity of both the territory of global health and its governance, and increasing stakeholders and networks, current imaginings of coordination are again being challenged. The High Level Forum in Busan may have been successful in recognising a much more complex landscape for development than previously conceived, but the challenges to coordination remain.
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Contextualizing chronicity: A perspective from Malaysia
The increasing prevalence of chronic Non Communicable Disease (NCD) around the world is well documented and projections suggest a frightening increase in prevalence around the world. The majority of new patients with chronic disease are expected to occur in developing countries.Effective management of chronic disease is a complex process that involves a proactive health care team working within an integrated healthcare delivery system supporting a well informed and confident patient skilled in self-management of the condition.There is increasing evidence especially from western countries that methods of implementation that use these principles work.Widespread and not contextualized dissemination of these approaches especially to less developed countries, however, would pose particular challenges. These challenges relate to a number of factors; a lack of resources, poorly functioning healthcare systems and their ability to cope, the rise of private financing for healthcare with increasing out-of-pocket payments for accessing healthcare, rapid industrialization and urbanization with attendant breakdown in support relationships and the general lack of support services including a social support model.We discuss some of these health system issues, using diabetes as the indicator condition, and the relating this to the Malaysian health system to illustrate the challenges of translating evidence from better resourced countries. Malaysia is a middle-income country with a well-functioning public health system designed primarily for control of communicable disease and Maternal and Child health. While a population approach in dealing with NCDs is key, we have highlighted an individual high-risk approach in this commentary.A number of patient support systems by professionals have been tested successfully in developed countries. In most developing countries, individuals especially the elderly depend on families to provide support. This and support from peers may be areas that may require further study especially in the area of self-management.
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Positioning women's and children's health in African Union policy-making: A policy analysis
Background:
With limited time to achieve the Millennium Development Goals, progress towards improving women's and children's health needs to be accelerated. With Africa accounting for over half of the world's maternal and child deaths, the African Union (AU) has a critical role in prioritizing related policies and catalysing required investments and action. In this paper, the authors assess the evolution of African Union policies related to women's and children's health, and analyze how these policies are prioritized and framed.
Methods:
The main method used in this policy analysis was a document review of all African Union policies developed from 1963 to 2010, focusing specifically on policies that explicitly mention health. The findings from this document review were discussed with key actors to identify policy implications.
Results:
With over 220 policies in total, peace and security is the most common AU policy topic. Social affairs and other development issues became more prominent in the 1990s. The number of policies that mentioned health rose steadily over the years (with 1 policy mentioning health in 1963 to 7 in 2010).This change was catalysed by factors such as: a favourable shift in AU priorities and systems towards development issues, spurred by the transition from the Organization of African Unity to the African Union; the mandate of the African Commission on Human and People's Rights; health-related advocacy initiatives, such as the Campaign for the Accelerated Reduction of Maternal Mortality in Africa (CARMMA); action and accountability requirements arising from international human rights treaties, the Millennium Development Goals (MDGs), and new health-funding mechanisms, such as the Global Fund to Fight AIDS, Tuberculosis and Malaria.Prioritization of women's and children's health issues in AU policies has been framed primarily by human rights, advocacy and accountability considerations, more by economic and health frames looking at investments and impact. AU policies related to reproductive, maternal, newborn and child health also use fewer policy frames than do AU policies related to HIV/AIDS, tuberculosis and malaria.
Conclusion:
We suggest that more effective prioritization of women's and children's health in African Union policies would be supported by widening the range of policy frames used (notably health and economic) and strengthening the evidence base of all policy frames used. In addition, we suggest it would be beneficial if the partner groups advocating for women's and children's health were multi-stakeholder, and included, for instance, health care professionals, regional institutions, parliamentarians, the media, academia, NGOs, development partners and the public and private sectors.
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A Comparative Study of Allowable Pesticide Residue Levels on Produce in the United States
Background:
The U.S. imports a substantial and increasing portion of its fruits and vegetables. The U.S. Food and Drug Administration currently inspects less than one percent of import shipments. While countries exporting to the U.S. are expected to comply with U.S. tolerances, including allowable pesticide residue levels, there is a low rate of import inspections and few other incentives for compliance.
Methods:
This analysis estimates the quantity of excess pesticide residue that could enter the U.S. if exporters followed originating country requirements but not U.S. pesticide tolerances, for the top 20 imported produce items based on quantities imported and U.S. consumption levels. Pesticide health effects data are also shown.
Results:
The model estimates that for the identified items, 120 439 kg of pesticides in excess of U.S. tolerances could potentially be imported to the U.S., in cases where U.S. regulations are more protective than those of originating countries. This figure is in addition to residues allowed on domestic produce. In the modeling, the top produce item, market, and pesticide of concern were oranges, Chile, and Zeta-Cypermethrin. Pesticides in this review are associated with health effects on 13 body systems, and some are associated with carcinogenic effects.
Conclusions:
There is a critical information gap regarding pesticide residues on produce imported to the U.S. Without a more thorough sampling program, it is not possible accurately to characterize risks introduced by produce importation. The scenario presented herein relies on assumptions, and should be considered illustrative. The analysis highlights the need for additional investigation and resources for monitoring, enforcement, and other interventions, to improve import food safety and reduce pesticide exposures in originating countries.
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Descriptive Review and Evaluation of the Functioning of the International Health Regulations (IHR) Annex 2
Background:
The International Health Regulations (IHRs) (2005) was developed with the aim of governing international responses to public health risks and emergencies. The document requires all 194 World Health Organization (WHO) Member States to detect, assess, notify and report any potential public health emergency of international concern (PHEIC) under specific timelines. Annex 2 of the IHR outlines decision-making criteria for State-appointed National Focal Points (NFP) to report potential PHEICs to the WHO, and is a critical component to the effective functioning of the IHRs.
Methods:
The aim of the study was to review and evaluate the functioning of Annex 2 across WHO-reporting States Parties. Specific objectives were to ascertain NFP awareness and knowledge of Annex 2, practical use of the tool, activities taken to implement it, its perceived usefulness and user-friendliness. Qualitative telephone interviews, followed by a quantitative online survey, were administered to NFPs between October, 2009 and February, 2010.
Results:
A total of 29 and 133 NFPs participated in the qualitative and quantitative studies, respectively. Qualitative interviews found most NFPs had a strong working knowledge of Annex 2; perceived the tool to be relevant and useful for guiding decisions; and had institutionalized management, legislation and communication systems to support it. NFPs also perceived Annex 2 as human and disease-centric, and emphasized its reduced applicability to potential PHEICs involving bioterrorist attacks, infectious diseases among animals, radio-nuclear and chemical spills, and water- or food-borne contamination. Among quantitative survey respondents, 88% reported having excellent/good knowledge of Annex 2; 77% reported always/usually using Annex 2 for assessing potential PHEICs; 76% indicated their country had some legal, regulatory or administrative provisions for using Annex 2; 95% indicated Annex 2 was always/usually useful for facilitating decisions regarding notifiability of potential PHEICs.
Conclusion:
This evaluation, including a large sample of WHO-reporting States Parties, found that the IHR's Annex 2 is perceived as useful for guiding decisions about notifiability of potential PHEICs. There is scope for the WHO to expand training and guidance on application of the IHR's Annex 2 to specific contexts. Continued monitoring and evaluation of the functioning of the IHR is imperative to promoting global health security.
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Multi-Country Analysis of Palm Oil Consumption and Cardiovascular Disease Mortality for Countries at Different Stages of Economic Development: 1980-1997
Background:
Cardiovascular diseases represent an increasing share of the global disease burden. There is concern that increased consumption of palm oil could exacerbate mortality from ischemic heart disease (IHD) and stroke, particularly in developing countries where it represents a major nutritional source of saturated fat.
Methods:
The study analyzed country-level data from 1980-1997 derived from the World Health Organization's Mortality Database, U.S. Department of Agriculture international estimates, and the World Bank (234 annual observations; 23 countries). Outcomes included mortality from IHD and stroke for adults aged 50 and older. Predictors included per-capita consumption of palm oil and cigarettes and per-capita Gross Domestic Product as well as time trends and an interaction between palm oil consumption and country economic development level. Analyses examined changes in country-level outcomes over time employing linear panel regressions with country-level fixed effects, population weighting, and robust standard errors clustered by country. Sensitivity analyses included further adjustment for other major dietary sources of saturated fat.
Results:
In developing countries, for every additional kilogram of palm oil consumed per-capita annually, IHD mortality rates increased by 68 deaths per 100,000 (95% CI [21-115]), whereas, in similar settings, stroke mortality rates increased by 19 deaths per 100,000 (95% CI [-12-49]) but were not significant. For historically high-income countries, changes in IHD and stroke mortality rates from palm oil consumption were smaller (IHD: 17 deaths per 100,000 (95% CI [5.3-29]); stroke: 5.1 deaths per 100,000 (95% CI [-1.2-11.0])). Inclusion of other major saturated fat sources including beef, pork, chicken, coconut oil, milk cheese, and butter did not substantially change the differentially higher relationship between palm oil and IHD mortality in developing countries.
Conclusions:
Increased palm oil consumption is related to higher IHD mortality rates in developing countries. Palm oil consumption represents a saturated fat source relevant for policies aimed at reducing cardiovascular disease burdens.
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Harm Reduction Journal - Latest Articles
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Harmonizing disease prevention and police practice in the implementation of HIV prevention programs: Up-stream strategies from wilmington, delaware
IntroductionImproving access to sterile injection equipment is a key component in community-based infectious disease prevention. Implementation of syringe access programs has sometimes been complicated by community opposition and police interference.Case descriptionIn 2006, the Delaware legislature authorized a pilot syringe exchange program (SEP). A program designed to prevent, monitor, and respond to possible policing and community barriers before they had a chance to effect program implementation and operation . was planned and implemented by a multidisciplinary team of legal practitioners and public health professionals.DiscussionWe report on an integrated intervention to address structural barriers to syringe exchange program utilization. This intervention employs community, police and client education combined with systematic surveillance of and rapid response to police interference to preempt the kinds of structural barriers to implementation observed elsewhere. The intervention addresses community concerns and stresses the benefits of syringe exchange programs to officer occupational safety.
Conclusions:
A cohesive effort combining collaboration with and educational outreach to police and community members based on the needs and concerns of these groups as well as SEP clients and potential clients helped establish a supportive street environment for the SEP.. Police-driven structural barriers to implementation of public health programs targeting populations engaged in drug use and other illicit behavior can be addressed by up-stream planning, prevention, monitoring and intervention strategies. More research is needed to inform the tailoring of interventions to address police-driven barriers to HIV prevention services, especially among marginalized populations.
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Language acquisition for deaf children: Reducing the harms of zero tolerance to the use of alternative approaches
Children acquire language without instruction as long as they are regularly and meaningfully engaged with an accessible human language. Today, 80% of children born deaf in the developed world are implanted with cochlear devices that allow some of them access to sound in their early years, which helps them to develop speech. However, through early childhood, brain plasticity changes and children who have not acquired a first language in the early years might never be completely fluent in any language. If they miss this critical period for exposure to a natural language, their subsequent development of the cognitive activities that rely on a solid first language might be underdeveloped, such as literacy, memory organization, and number manipulation. An alternative to speech-exclusive approaches to language acquisition exists in the use of sign languages such as American Sign Language (ASL), where acquiring a sign language is subject to the same time constraints of spoken language development. Unfortunately, so far, these alternatives are caught up in an "either - or" dilemma, leading to a highly polarized conflict about which system families should choose for their children, with little tolerance for alternatives by either side of the debate and widespread misinformation about the evidence and implications for or against either approach. The success rate with cochlear implants is highly variable. This issue is still debated, and as far as we know, there are no reliable predictors for success with implants. Yet families are often advised not to expose their child to sign language. Here absolute positions based on ideology create pressures for parents that might jeopardize the real developmental needs of deaf children. What we do know is that cochlear implants do not offer accessible language to many deaf children. By the time it is clear that the deaf child is not acquiring spoken language with cochlear devices, it might already be past the critical period, and the child runs the risk of becoming linguistically deprived. Linguistic deprivation constitutes multiple personal harms as well as harms to society (in terms of costs to our medical systems and in loss of potential productive societal participation).
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Correlates to the variable effects of cannabis in young adults: a preliminary study
Background:
Cannabis use can frequently have adverse affects in those that use it and these can be amplified by various characteristics of an individual, from demographic and environmental variations to familial predisposition for mental illnesses.
Methods:
The current study of 100 individuals, who were cannabis users during their adolescence and may still be users, was a survey of the self perceived effects of cannabis and their correlates. A reliable family member was also interviewed for determination of family history of various major mental illnesses and substance use.
Results:
As many as 40% of cannabis users had paranoid feelings (suspiciousness) when using cannabis, although the most frequent effect was feeling relaxed (46%). Having a familial background for mental illnesses such as depression or schizophrenia did not determine the effects of cannabis nor its pattern of use, although the number of subjects with such a history was small. An age at which an individual began using cannabis did have an effect on how heavily it was used and the heavier the cannabis use, the more likely the individual was also to have had psychotic symptoms after use. There were no sex differences in effects of cannabis. These results are tempered by the reliance on self-report for many of the variables ascertained.
Conclusion:
Cannabis can frequently have negative effects in its users, which can be amplified by certain demographic and/or psychosocial factors. Thus, users with a specific profile may be at a higher risk of unpleasant effects from cannabis use and caution should be noted when cannabis is administered to young people for medicinal purposes.
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Integrated programs for mothers with substance abuse issues: A systematic review of studies reporting on parenting outcomes
Background:
Integrated treatment programs (those that include on-site pregnancy-, parenting-, or child-related services with addiction services) were developed to break the intergenerational cycle of addiction, dysfunctional parenting, and poor outcomes for mothers and children, yet there has been no systematic review of studies of parenting outcomes.ObjectivesAs part of larger systematic review to examine the effectiveness of integrated programs for mothers with substance abuse issues, we performed a systematic review of studies published from 1990 to 2011 with data on parenting outcomes.
Methods:
Literature search strategies included online bibliographic database searches, checking printed sources, and requests to researchers. Studies were included if all participants were mothers with substance abuse problems at baseline, the treatment program included at least one specific substance use treatment and at least one parenting or child service, and there were quantitative data on parenting outcomes. We summarized data on parenting skills and capacity outcomes.
Results:
There were 24 cohort studies, 3 quasi-experimental studies, and 4 randomized trials. In the three randomized trials comparing integrated programs to addiction treatment-as-usual (N = 419), most improvements in parenting skills favored integrated programs and most effect sizes indicated that this advantage was small, ds = -0.02 to 0.94. Results for child protection services involvement did not differ by group. In the three studies that examined factors associated with treatment effects, parenting improvements were associated with attachment-based parenting interventions, children residing in the treatment facility, and improvements in maternal mental health.
Conclusions:
This is the first systematic review of studies evaluating the effectiveness of integrated programs on parenting. The limited available evidence supports integrated programs, as findings suggest that they are associated with improvements in parenting skills. However, more research is required comparing integrated programs to addiction treatment-as-usual. This review highlights the need for improved methodology, study quality, and reporting to improve our understanding of how best to meet the parenting needs of women with substance abuse issues.
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Effects of concurrent intravenous morphine sulfate and naltrexone hydrochloride on end-tidal carbon dioxide
Background:
Respiratory depression, a potentially fatal side-effect of opioid-overdose, may be reversed by timely administration of an opioid antagonist, such as naloxone or naltrexone. Tampering with a formulation of morphine sulfate and sequestered naltrexone hydrochloride extended release capsules (MS-sNT) releases both the opioid morphine and the antagonist naltrexone. A study in recreational opioid-users indicated that morphine and naltrexone injected in the 25:1 ratio (duplicating the ratio of the formulation) found MS-sNT reduced morphine-induced euphoric effects vs intravenous (IV) morphine alone. In the same study, the effects of morphine + naltrexone on end-tidal carbon dioxide (EtCO2), a measure of respiratory-depression, were evaluated and these data are reported here.
Methods:
Single-center, placebo-controlled, double-blind crossover study. Non-dependent male opioid users were randomized to receive single IV doses of placebo, 30 mg morphine alone, and 30 mg morphine + 1.2 mg naltrexone. EtCO2 was measured by noninvasive capnography.
Results:
Significant differences in EtCO2 least-squares means across all treatments for maximal effect (Emax) and area under the effect curve (AUE0-2, AUE0-8, AUE0-24) were detected (all p ≤ 0.0011). EtCO2 Emax values for morphine + naltrexone were significantly reduced vs morphine alone (42.9 mm Hg vs 47.1 mm Hg, p < 0.0001) and were not significantly different vs placebo (41.9 mm Hg). Median time to reach maximal effect (TEmax) was delayed for morphine + naltrexone vs morphine alone (5.0 h vs 1.0 h).
Conclusions:
Results provide preliminary evidence that the naltrexone:morphine ratio within MS-sNT is sufficient to significantly reduce EtCO2 when administered intravenously to non-dependent male recreational opioid-users. Further studies with multiple measures of respiratory-function are warranted to determine if risk of respiratory depression is also reduced by naltrexone in the tampered formulation.
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Clinical Service Desires of Medical Cannabis Patients
Background:
Medical cannabis dispensaries following the social or hybrid model offer supplementary holistic services in addition to dispensing medical cannabis. Historically, alternative physical health services have been the norm for these dispensaries, including services such as yoga, acupuncture, or chiropractor visits. A clinical service dearth remains for medical cannabis patients seeking substance use, misuse, dependence, and mental health services. This study examined patient desires for various clinical services and level of willingness to participate in specific clinical services.
Methods:
Anonymous survey data (N = 303) were collected at Harborside Health Center (HHC), a medical cannabis dispensary in Oakland, CA. The sample was 70% male, 48% Caucasian and 21% African American. The mean male age was 38 years old and female mean age was 30. Sixty two percent of the male participants and 44% of the female participants are single. Sixteen percent of the population reported having a domestic partner. Forty six percent of the participants are employed full time, 41% have completed at least some college, and 49% make less than $40,000 a year.
Results:
A significant portion of the sample, 62%, indicated a desire to participate in free clinical services at HHC, 34% would like more information about substances and use, and 41% want to learn more about reducing harms from substance use. About one quarter of the participants marked "would" or "likely would" participate in individual services such as consultation. Approximately 20% indicated "would" or "likely would" participate in psycho-educational forums, harm reduction information sharing sessions, online support groups, and coping, life, and social skills group. There was little interest in traditional NA/AA 12-step groups or adapted 12-step groups.
Conclusions:
Desired clinical services can be qualified as a combination of harm reduction, educational, skills-based, peer support and therapeutic individual and group services. Results suggest that medical cannabis patients seek more information about various substances, including cannabis. Dispensaries can help to decrease gaps in substance education and clinical services and fulfill unmet clinical desires. More research is necessary in additional medical cannabis dispensaries in different geographic settings with different service delivery models.
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Reaching out and reaching up - developing a low cost drug treatment system in Cambodia
Cambodia, confronted by the spread of drug misuse among young people, requested support from international agencies to develop a drug treatment programme in 2000. The initial plan developed by the United Nations Office on Drugs and Crime was to set up a number of conventional drug treatment centres in urban areas. During the planning phase, however, the project was redesigned as a community based outreach programme. Ten Community Counselling Teams have been formed and trained in pilot areas, and within the first year of operation 462 drug and alcohol users contacted. Comprising former drug users, family members affected by drug use and health care staff, they have drug scene credibility, local knowledge and connectivity, and a rudimentary level of medical competence. Crucially, they enjoy the support of village elders, who are involved in the planning and reporting stages. While the Community Counselling Teams with their basic training in addiction counselling are in no position as yet to either provide or refer clients to treatment, they can provide brief interventions, organise self help groups, and most importantly provide an alternative to law enforcement. By taking a development centred approach, with emphasis on community, empowerment and inclusion, it provides a constructive and inclusive alternative to medical approaches and the compulsory drug treatment centres. The paper is based on an evaluation involving interviews with a range of stakeholders and a review of project documents.
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Contrasting snus and NRT as methods to quit smoking. An observational study
Background:
Snus is considerably less hazardous to health than cigarettes. Recent data from Scandinavia have indicated that many smokers use snus as a method for quitting smoking.
Methods:
Data from five repeated cross-sectional surveys of Norwegian men and women aged 16-74 were pooled (N = 6 262). Respondents were asked about current and former smoking and snus use. Former daily smokers (N = 1219) and current daily smokers who had tried to quit at least once (N = 1118) were asked about the method they had used at their latest quit attempt and how many quit attempts they had made. Former smokers were also requested to report what year they had made their final quit attempt.
Results:
Snus was the most common method used for quitting smoking among men, while NRT was most often used among women. Stratifying the data according to year of quitting smoking (1945-2007) indicated a significant increase in use of the methods for quitting asked about over time. Among men, this was largely due to an increase in the use of snus. Among male quitters under the age of 45 years, 45.8% of those who had used snus on their last attempt to quit were current non-smokers (OR = 1.61, CI 1.04-2.29), while 26,3% of those who had used NRT were current non-smokers. 59.6% of successful quitters and 19.5% of unsuccessful quitters who had used snus as a method for quitting smoking had continued to use snus on a daily basis after quitting.
Conclusion:
Norwegian men frequently use snus as a method for quitting smoking whereas women are more likely to use NRT. The findings indicate that switching to snus can be an effective method for quitting smoking.
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Reducing widespread pipe sharing and risky sex among crystal methamphetamine smokers in Toronto: do safer smoking kits have a potential role to play?
Background:
Crystal methamphetamine smoking is associated with many negative health consequences, including the potential for transmission of hepatitis. We examined whether or not a kit for crystal methamphetamine smoking might have some potential to reduce the negative health effects of crystal methamphetamine smoking.
Methods:
Five focus groups were conducted with crystal methamphetamine smokers recruited by community health agencies and youth shelters in Toronto, Canada. Target groups included homeless/street-involved youth, sex workers, men who have sex with men, and youth in the party scene. Participants (n = 32) were asked questions about motivations for crystal methamphetamine use, the process of smoking, health problems experienced, sharing behaviour, risky sexual practices, and the ideal contents of a harm reduction kit.
Results:
Pipe sharing was widespread among participants and was deemed integral to the social experience of smoking crystal methamphetamine. Heated pipes were unlikely to cause direct injuries, but participants mentioned having dry, cracked lips, which may be a vector for disease transmission. Many reported having sex with multiple partners and being less likely to use condoms while on the drug. Demand for harm reduction kits was mixed.
Conclusions:
Changing pipe sharing behaviours may be difficult because many participants considered sharing to be integral to the social experience of smoking crystal methamphetamine. Within the context of a broader health promotion and prevention program, pilot testing of safer smoking kits to initiate discussion and education on the risks associated with sharing pipes and unprotected sex for some communities (e.g., homeless/street-involved youth) is worth pursuing.
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Sex work involvement among women with long-term opioid injection drug dependence who enter opioid agonist treatment
Background:
Substitution with opioid-agonists (e.g., methadone) has shown to be an effective treatment for chronic long-term opioid dependency. Survival sex work, very common among injection drug users, has been associated with poor Opioid Agonist Treatment (OAT) engagement, retention and response. Therefore, this study was undertaken to determine factors associated with engaging in sex work among long-term opioid dependent women receiving OAT.
Methods:
Data from a randomized controlled trial, the North American Opiate Medication Initiative (NAOMI), conducted in Vancouver and Montreal (Canada) between 2005-2008, was analyzed. The NAOMI study compared the effectiveness of oral methadone to injectable diacetylmorphine or injectable hydromorphone, the last two on a double blind basis, over 12 months. A research team, independent of the clinic services, obtained outcome evaluations at baseline and follow-up (3, 6, 9, 12, 18 and 24 months).
Results:
A total 53.6% of women reported engaging in sex work in at least one of the research visits. At treatment initiation, women who were younger and had fewer years of education were more likely to be engaged in sex work. The multivariate logistic generalized estimating equation regression analysis determined that psychological symptoms, and high illicit heroin and cocaine use correlated with women's involvement in sex work during the study period.
Conclusions:
After entering OAT, women using injection drugs and engaging in sex work represent a particularly vulnerable group showing poorer psychological health and a higher use of heroin and cocaine compared to women not engaging in sex work. These factors must be taken into consideration in the planning and provision of OAT in order to improve treatment outcomes.Trial RegistrationNCT00175357.
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Head & Face Medicine - Latest Articles
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A concept to transfer a therapeutic condyle position into permanent occlusion with a customized lingual appliance
IntroductionThe role of occlusion concerning temporomandibular disorder is still unclear but seems to be the only component of the stomathognathic system dentists are able to change morphologically. The aim of the paper is to describe the orthodontist's approach for transferring and maintaining a therapeutic condyle position into permanent occlusion using the Incognito-System (3M Unitek).
Methods:
Fixed acrylic bite planes on lower molars were used to maintain a symptom-free condyle position prior to orthodontic treatment. Silicone impressions of the arches including the fixed bite planes were used for the Incognito laboratory procedure. Two digital setups were made. One setup represents the target occlusion. A second setup including the bite planes was used to fabricate an additional set of lower molar brackets. In the leveling stage all teeth except the lower molars were settled to maintain the therapeutic condyle position. Finally, the fixed bite planes were stepwise removed and molar brackets were replaced to establish the permanent occlusion planned with the first setup.Results and discussionThe advantage of an individual lingual appliance consists in the high level of congruence between the fabricated setups and the final clinical result. Both the individual scope for design and the precision of the appliance were vitally important in the treatment of a patient with a functional disorder of the masticatory system.
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Do skeletal cephalometric characteristics correlate with condylar volume, surface and shape? A 3D analysis
ObjectiveThe purpose of this study was to determine the condylar volume in subjects with different mandibular divergence and skeletal class using cone-beam computed tomography (CBCT) and analysis software.Materials and methodsFor 94 patients (46 females and 48 males; mean age 24.3 +/- 6.5 years), resultant rendering reconstructions of the left and right temporal mandibular joints (TMJs) were obtained.Subjects were then classified on the base of ANB angle the GoGn-SN angle in three classes (I, II, III) . The data of the different classes were compared.
Results:
No significant difference was observed in the whole sample between the right and the left sides in condylar volume.The analysis of mean volume among low, normal and high mandibular plane angles revealed a significantly higher volume and surface in low angle subjects (p < 0.01) compared to the other groups.Class III subjects also tended to show a higher condylar volume and surface than class I and class II subjects, although the difference was not significant.
Conclusions:
Higher condylar volume was a common characteristic of low angle subjects compared to normal and high mandibular plane angle subjects. Skeletal class also appears to be associated to condylar volume and surface.
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The University Munster model surgery system for Orthognathic surgery. Part I - The idea behind
Background:
We describe a procedure for diagnosis and planning for orthognatic surgery based on international standards. A special 2D planning based on lateral cephalograms (Axis Orbital Marker Lines System) realize a transmission to the SAM 2P articulator (3D) by means of the Axis Orbital Plane.
Methods:
Former intraoperative measurement of the average height of the LeFort I osteotomy plane relative to the molar occlusal plane allow to construct a virtual osteotomy plane in the lateral cephalogram. This is the basis for the development of the Axis Orbital Marker Lines System (AO-MLS).
Results:
The AO-MLS is presented graphically, and in detail, with construction guidelines. The system could be integrated into various lateral cephalometric analysis- and surgical prediction schemes. It forms the basis for a standardized transfer of the 2D planning to the 3D planning in the articulator, and vice versa. This procedure makes it possible to generate surgical planning protocols based on the model surgery, which represent the dislocations in the proximity of the real osteotomy planes.
Conclusions:
The Axis Orbital Marker Lines System (software component) in conjunction with the University Munster Model Surgery System (hardware system) increases the predictability of model operations in orthognathic surgery.
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Semi-open rhinoplasty: a new Maxillofacial technique
Background:
Rhinoplasty "open" represents a surgical technique to access to the internal structures of the nose; it is an alternative to more traditional "closed" rhinoplasty. However, both these techniques have some advantages and some disadvantages. In this work the authors describe a case that shows the steps of a new surgical technique: the "semi-open" rhinoplasty.
Methods:
The "semi-open" technique is performed by making an incision to access on the mucosa of both the nostrils, and through this access we separate the cartilages of the columella from the alar cartilages, debriding them at the domus. With such access we can perform any type of rhinoplasty surgery with functional or aesthetic purposes.DiscussionsTraditional techniques have undoubtedly some advantages and some disadvantages. The "semi-open" technique has the several advantages of the open technique, and it does not involve the presence of post-surgical scars.
Conclusions:
This innovative technique provides great predictability and minimal postoperative discomfort, with no aesthetic damage.
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Comparison between scaling-root-planing (SRP) and SRP/photodynamic therapy: six-month study
IntroductionThe purpose of this long-term clinical study was to examine the additional efficacy of photodynamic therapy (PDT) to scaling and root planing (SRP) in patients with chronic periodontal disease.
Methods:
A total of 22 patients (mean age: 59.3 ± 11.7 years) with chronic periodontal disease and four teeth with probing depth ≥ 5 mm were enrolled in the study. Inclusion criteria were: no systemic disease, no smoking, no pregnancy and no long-term medication. Beside the anamnesis, the following clinical parameters were assessed at baseline (one week before therapy), and one, three and six months after the therapy: bleeding on probing (BOP), plaque index (PI) probing depth (PD), and clinical attachment loss. All measurements were done by the same examiner with a fixed periodontal probe (PCP 12, Hu-Friedy) at six measurements/tooth. In each patient, two teeth were treated with SRP alone and two teeth with SRP and PDT (Periowave, Ondine Biopharma, Vancouver, Canada). The nonparametric Wilcoxon test for paired samples was used for comparison of the effect of the two treatments (p ≤ 0.05).
Results:
After both types of treatment, the number of teeth positive for BOP declined. At baseline, the CAL measured 7.2 ± 1.2 mm (SRP) or 8.1 ± 1.3 mm (SRP/PDT); one, three and six months after both types of treatment an improvement was observed. At baseline, the probing depth was 5.9 ± 0.8 mm (SRP) or 6.4 ± 0.8 mm (SRP/PDT); after six months, an improvement of 2.4 ± 0.6 mm (SRP) or 2.9 ± 0.8 mm (SRP/PDT) was found. The greater reduction of the PD, achieved by a combination of SRP/PDT, was statistically significant after six months (p = 0.007).
Conclusion:
This clinical study demonstrates that SRP in combination with PDT seems to be effective and is therefore suitable as an adjuvant therapy to the mechanical conditioning of the periodontal pockets in patients with chronic periodontal diseases.
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Bilateral multifocal Warthin's tumors in upper neck lymph nodes. Report of a case and brief review of the literature
Cystadenolymphomas (Warthin's tumors) are the second most frequent lesions of the parotid gland. Due to their benign clinical behavior, the low rates of recurrence and malignant transformation they were classified as tumor-like lesions. In addition, a polyclonal growth of the epithelial components of the tumor could be detected. Warthin's tumors occur bilateral in 7-10%, whereas a multifocal appearance is extremely rare. Even if the pathogenesis is still unclear a heterotopia of salivary tissue during embryogenesis is the most likely explanation for the origin of these tumors in the upper neck and periparotideal region. Here we present a rare case of bilateral, multifocal, extraglandular Warthin's tumors in lymph nodes of the upper neck and give a brief review of the literature. If a primary malignancy can be excluded by a careful staging procedure prior to the operation an isolated excision of the lesions of the neck is the adequate treatment.
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Clinical case-study describing the use of skin-perichondrium-cartilage graft from the auricular concha to cover large defects of the nose
Background:
The composite graft from the conchal cartilage is a graft that is often used, especially in surgery on the nose, due to its capacity to resolve problems of cover and tissue deficit, arising from the removal of neoplasms or as the result of trauma, burns or following over-aggressive rhinoplasty. We have started to use skin-perichondrium-cartilage graft from the ear to cover large areas of the nose with very satisfying results as well as we describe in the reported clinical case.
Methods:
The operation consisted of reconstruction of the cartilaginous nasal septum, which had previously been removed, using two vestibular labial mucosa flaps to reconstruct the mucosa, and cartilage from the ear conch for the cartilaginous septum. After this, the skin edges of the fistula were turned to recreate the inner lining of the nose and form a vascular base of wide area to accept the composite graft. The case concerns a female 74-year old patient who had undergone several oncological surgery for a relapsing basal cell carcinoma on the dorsum of the nose. The operation consisted of reconstruction of the cartilaginous nasal septum using two vestibular labial mucosa flaps to reconstruct the mucosa, and cartilage from the ear conch for the cartilaginous septum.
Results:
The perichondrial cutaneous graft has shown in this surgical case very favorable peculiarities that make it usable even in facial plastic surgery.
Conclusions:
We believe that the positive experience that we achieved in the use of composite grafts for the reconstruction of large areas of the nose could be interesting for others surgeons.
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A prospective clinical trial on the influence of a triamcinolone/demeclocycline and a calcium hydroxide based temporary cement on pain perception
IntroductionThe aim of this clinical trial was to compare the degree of short term post-operative irritation after application of a triamcinolone/demeclocycyline based or a calcium hydroxide based provisional cement.
Methods:
A total of 109 patients (55 female and 54 male; mean age: 51 ± 14 years) with primary or secondary dentinal caries were randomly assigned to the two treatment groups of this biomedical clinical trial (phase III). Selection criteria were good systemic health and treated teeth, which were vital and showed no symptoms of pulpitis. Up to three teeth were prepared for indirect metallic restorations, and the provisional restorations were cemented with a triamcinolone/demeclocycyline (Ledermix) or a calcium hydroxide (Provicol) based material. The intensity of post-operative pain experienced was documented according to the VAS (4, 12, 20, 24, and 82 h) and compared to VAS baseline.
Results:
A total of 159 teeth were treated (Ledermix: 83 teeth, Provicol: 76 teeth). The minor irritation of the teeth, experienced prior to treatment, was similar in both groups; however, 4 h after treatment this value was significantly higher in the Provicol group than in the Ledermix group (p < 0.005, t-test). After 12 h, the difference was no longer significant. The number of patients taking analgesics for post-treatment pain was higher in the Provicol group (n = 11/53) than in the Ledermix group (n = 3/56).
Conclusions:
The patients had no long term post-operative pain experience in both groups. However, within the first hours after cementation the sensation of pain was considerably higher in the Provicol group than in the Ledermix group.
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Benign chondroid syringoma of the orbit: a rare cause of exophtalmos
Chondroid syringoma (CS) of the orbit is an extremely rare benign neoplasm. To the best of our knowledege, this is the second case reported in the english literature.We report a case of a 41-year-old woman with orbital CS. This tumor developed slowly over 8 years causing indolor, no axil, exophtalmos of the left eye. Computed tomography demonstrated an isodense intraorbital tumor with homogeneous enhancement without bony erosion. On Magnetic resonance imaging the tumor was isointense on T1-weighted imaging, slightly hyper intense on T2-weighted imaging, and enhanced after Gadolinium administration. The patient was operated via left lateral orbitotomy. At surgery the mass was well circumscribed, extraconal, very firm and did not invade or adhere to other structures. The tumor was removed in toto. The diagnosis was confirmed by histopathological examination, the lesion was nodular, and there was differentiation toward the adnexal ductal epithelium with chondromyxoid and adipocytic differentiation in the stroma. No recurrence was seen with one year follow-up.CS should be included in the differential diagnosis of intra-orbital tumors. Complete resection remains the best therapeutic option to prevent recurrence. Close followup is recommended because malignant transformation, although rare, is possible.
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Prospective Blind Comparative clinical study of two point fixation of zygomatic complex fracture using wire and mini plates
Background:
The zygomatic maxillary complex (ZMC) fractures are one of the most frequent injuries of the facial skeleton due to its position and facial contour. Assaults, road traffic accidents and falls are the principal etiologic factors that may cause fractures of zygomatic bone. The different fixation methods are applied to treat the zygomatic bone fractures, with many more classifications which have been described in the literature for the ease of management. The type of the fracture, its severity and associated facial fractures usually interferes the treatment modality.Purpose of studyThe aim of this paper is to show the results of 18yrs prospective blind comparative study using wire and plate osteosynthesis which needed open reduction and internal fixation involving Type II to Type IV Spissel and Schroll ZMC fractures.Materials and methodsTotal 80 cases included in the study out of 1780 ZMC cases which were treated using wire and plate osteosynthesis over a period of 18 yrs, involving only Type II to Type IV Spissel and Schroll ZMC fractures. Other types excluded from study to prevent observer bias. All the fixations carried out through Standard Dingman's incision using stainless steel 26 gauze wire and titanium 1.5 mm mini plate system under general anesthesia by single maxillofacial surgeon and evaluated by another maxillofacial surgeon who is blinded for surgical procedure after 2 and 4 wks of follow-up for facial symmetry, wound healing, functional assessment (mouth opening, diplopia), and sensory disturbance. All the data tabulated in Excel software (Microsoft) for statistical analysis. P-value calculated to know the Significance of treatment modality in all aspects.
Results:
Result shows no significant p-values indicating both the operating techniques are equally efficient in the surgical management of ZMC fracture.
Conclusion:
Osteosynthesis by mini plates is simple, logical and effective treatment compared to wire osteosynthesis in regard to stability of fracture fragments. Wire osteosynthesis will be helpful in emergency surgeries or where the mini plates are not available. Even though the wire osteosynthesis is economical compared to mini plate fixation; but the time and skill is required for fixation of wires.
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Health and Quality of Life Outcomes - Latest Articles
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Rasch analysis of the Mini-Mental Adjustment to
Cancer Scale (mini-MAC) among a heterogeneous
sample of long-term cancer survivors: A crosssectional
study
Background:
The mini-Mental Adjustment to Cancer Scale (mini-MAC) is a well-recognised, popular measure of coping in psycho-oncology and assesses five cancer-specific coping strategies. It has been suggested that these five subscales could be grouped to form the over-arching adaptive and maladptive coping subscales to facilitate the interpretation and clinical application of the scale. Despite the popularity of the mini-MAC, few studies have examined its psychometric properties among long-term cancer survivors, and further validation of the mini-MAC is needed to substantiate its use with the growing population of survivors. Therefore, this study examined the psychometric properties and dimensionality of the mini-MAC in a sample of long-term cancer survivors using Rasch analysis.
Methods:
RUMM 2030 was used to analyse the mini-MAC data (n=851). Separate Rasch analyses were conducted for each of the original mini-MAC subscales as well as the over-arching adaptive and maladaptive coping subscales to examine summary and individual model fit statistics, person separation index (PSI), response format, local dependency, targeting, item bias (or differential item functioning -DIF), and dimensionality.
Results:
For the fighting spirit, fatalism, and helplessness-hopelessness subscales, a revised three-point response format seemed more optimal than the original four-point response. To achieve model fit, items were deleted from four of the five subscales - Anxious Preoccupation items 7, 25, and 29; Cognitive Avoidance items 11 and 17; Fighting Spirit item 18; and Helplessness-Hopelessness items 16 and 20. For those subscales with sufficient items, analyses supported unidimensionality. Combining items to form the adaptive and maladaptive subscales was partially supported.
Conclusions:
The original five subscales required item deletion and/or rescaling to improve goodness of fit to the Rasch model. While evidence was found for overarching subscales of adaptive and maladaptive coping, extensive modifications were necessary to achieve this result. Further exploration and validation of over-arching subscales assessing adaptive and maladaptive coping is necessary with cancer survivors.
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Translation and validation of the EORTC brain cancer module
(EORTC QLQ-BN20) for use in Iran
Background:
The aim of this study was to translate the EORTC quality of life questionnaire for braincancer, the QLQ-BN20, into Persian, and to evaluate its psychometric properties when usedamong brain cancer patients in Iran.
Methods:
A standard backward and forward translation procedure was used to generate the Persianlanguage version of the QLQ-BN20. The QLQ-BN20 was administered together with theQLQ-C30 to 194 patients diagnosed with primary brain cancer. Multitrait scaling andconfirmatory factor analysis (CFA) were used to evaluate the hypothesized scale structure ofthe questionnaire. Internal consistency reliability was estimated with Cronbach's alpha. Theability of the QLQ-BN20 to distinguish between patient subgroups formed on the basis ofperformance status and cognitive status was evaluated, as was the responsiveness of thequestionnaire to changes in performance status over time.
Results:
Multitrait scaling and CFA results confirmed the hypothesized scale structure. Themeasurement model was consistent across men and women. Internal consistency reliability ofthe multi-item scales ranged from 0.74 to 0.89. The QLQ-BN20 distinguished clearlybetween patients with relatively good versus poor performance and cognitive status, andchanges in scores over time reflected changes observed in performance status ratings.
Conclusions:
These results support the validity and reliability of the QLQ-BN20 for use among Iranianpatients diagnosed with primary brain cancer. Future studies should examine thepsychometrics of the questionnaire when used in patients with brain metastasis.
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Peer support and improved quality of life among persons living with HIV on antiretroviral treatment: A randomised controlled trial from north-eastern Vietnam
Background:
Among people living with HIV (PLHIV) on antiretroviral therapy (ART), it is important to determine how quality of life (QOL) may be improved and HIV-related stigma can be lessened over time. This study assessed the effect of peer support on QOL and internal stigma during the first year after initiating ART among a cohort of PLHIV in north-eastern Vietnam.
Methods:
A sub-sample study of a randomised controlled trial was implemented between October 2008 and November 2010 in Quang Ninh, Vietnam. In the intervention group, participants (n=119) received adherence support from trained peer supporters who visited participants' houses biweekly during the first two months, thereafter weekly. In the control group, participants (n=109) were treated according to standard guidelines, including adherence counselling, monthly health check and drug refills. Basic demographics were measured at baseline. QOL and internal stigma were measured using a Vietnamese version of the WHOQOL-HIVBREF and Internal AIDS-related Stigma Scale instruments at baseline and 12 months. T-tests were used to detect the differences between mean values, multilevel linear regressions to determine factors influencing QOL.
Results:
Overall, QOL improved significantly in the intervention group compared to the control group. Among participants initiating ART at clinical stages 3 and 4, education at high school level or above and having experiences of a family member dying from HIV were also associated with higher reported QOL. Among participants at clinical stage 1 and 2, there was no significant effect of peer support, whereas having children was associated with an increased QOL. Viral hepatitis was associated with a decreased QOL in both groups. Lower perceived stigma correlated significantly but weakly with improved QOL, however, there was no significant relation to peer support.
Conclusion:
The peer support intervention improved QOL after 12 months among ART patients presenting at clinical stages 3 and 4 at baseline, but it had no impact on QOL among ART patients enrolled at clinical stages 1 and 2. The intervention did not have an effect on Internal AIDS-related stigma. To improve QOL for PLHIV on ART, measures to support adherence should be contextualized in accordance with individual clinical and social needs.KeywordsQuality of life, Peer support, HIV, ART, Quang Ninh, Vietnam, randomised controlled trial
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Health related quality of life assessment in Pakistani
paediatric cancer patients using PedsQLTM 4.0
generic core scale and PedsQLTM cancer module
Background:
The purpose of the study was to evaluate and compare the HRQOL of paediatric cancer incomparison to the healthy children across age groups, using PedsQLTM 4.0 Generic CoreScales and the PedsQLTM Cancer Module.MethodThe PedsQLTM 4.0 Generic Core Scales and PedsQL Cancer Module 3.0 were administeredon 56 children including 26 cancer patients and 30 healthy children while employing self andproxy report forms. Furthermore, the results were compared with their healthy comparisongroup.
Results:
The results indicated a significant relationship between HRQOL reports of cancer patientsand their parents. However, the mean of paediatric cancer patients is significantly lower ascompare to their healthy comparison group. The mean of proxy report is lower overall onboth PedsQL and PedsQL cancer module reports.
Conclusion:
Conclusively, overall HRQOL of cancer patients was lower than healthy children but it isquite similar to their parents' perception. Whereas, the parental mean on PedsQL and PedsQL3.0 Cancer Module are significantly low. The study indicated a marked difference betweencancer patients and healthy children's HRQOL perception and unfortunately in country likePakistan where cancer is on increase, no significant work has yet been done to explore this area of research. The present study highlighted the need to focus on the particularpsychological health services required to serve the physically challenged population.
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Validation of the Neurological Fatigue Index for Stroke (NFI-Stroke)
Background Fatigue is a common symptom in Stroke. Several self-report scales are available to measure this debilitating symptom but concern has been expressed about their construct validity.Objective To examine the reliability and validity of a recently developed scale for multiple sclerosis (MS) fatigue, the Neurological Fatigue Index (NFI-MS), in a sample of stroke patients.Method Six patients with stroke participated in qualitative interviews which were analysed and the themes compared for equivalence to those derived from existing data on MS fatigue. 999 questionnaire packs were sent to those with a stroke within the past four years. Data from the four subscales, and the Summary scale of the NFI-MS were fitted to the Rasch measurement model.Results Themes identified by stroke patients were consistent with those identified by those with MS. 282 questionnaires were returned and respondents had a mean age of 67.3 years; 62% were male, and were on average 17.2 (SD 11.4, range 2-50) months post stroke. The Physical, Cognitive and Summary scales all showed good fit to the model, were unidimensional, and free of differential item functioning by age, sex and time. The sleep scales failed to show adequate fit in their current format.Conclusion Post stroke fatigue appears to be represented by a combination of physical and cognitive components, confirmed by both qualitative and quantitative processes. The NFI-Stroke, comprising a Physical and Cognitive subscale, and a 10-item Summary scale, meets the strictest measurement requirements. Fit to the Rasch model allows conversion of ordinal raw scores to a linear metric.
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Oral health-related quality of life in an aging Canadian population
Background:
The purpose of the study is to describe the impact of oral health-related quality of life (OHRQoL) on the lives of pre-seniors and seniors living in Nova Scotia, Canada.
Methods:
This cross-sectional study involved 1461 participants, grouped by age (pre-seniors [45-64] and seniors [65+]) and residential status (long-term care facility [LTC] or community). OHRQoL was measured using the 14-item Oral Health Impact Profile questionnaire (OHIP-14) in a random digit dialing telephone survey (for community residents) or a face-to-face interview (for LTC residents). Intra-oral examinations were performed by one of six dentists calibrated to W.H.O. standards.
Results:
Approximately one in four pre-seniors and seniors reported at least one OHRQoL impact 'fairly/very often'. The most commonly reported impacts were within the dimensions 'physical pain' and 'psychological discomfort'. It was found that 12.2% of LTC residents found it uncomfortable to eat any foods 'fairly/very' often compared to 7.7% in the community, and 11.6% of LTC residents reported being self-conscious 'fairly/very often' compared to 8.2% in the community. Of those residing in the community, pre-seniors (28.8%) reported significantly more impacts than seniors (22.0%); but there were no significant differences in OHRQoL between pre-seniors (21.2%) and seniors (25.3%) in LTC. Pre-seniors living in the community scored significantly higher than community dwelling seniors on prevalence, extent and severity of OHIP-14 scores. Logistic regression revealed that for the community dwelling sample, individuals living in rural areas in addition to those being born outside of Canada were approximately 2.0 times more likely to report an impact 'fairly/very often', whereas among the LTC sample, those having a high school education or less were 2.3 times more likely to report an impact.
Conclusions:
Findings indicate that the oral health and OHRQoL of both pre-seniors and seniors in LTC residents is poor. Community dwelling pre-seniors have the highest prevalence rate of oral impacts.
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Long term follow-up of health-related quality of life
in young adults born very preterm or with a very
low birth weight
Background:
The purpose was, first, to evaluate changes in health-related quality of life (HRQL) in acohort of very low birth weight (VLBW; <1500 g.) or very preterm (< 32 weeks of gestation)children between ages 14 and 19, and second, to identify correlates of HRQL at age 19.
Methods:
HRQL was assessed using the Health Utilities Index Mark 3 (HUI3). In order to explorecorrelates of HRQL, we performed a hierarchical regression analysis.
Results:
Surviving VLBW children (n = 959) from a 1983 Dutch nation-wide cohort were eligible;630 participated both at age 14 and 19; 54 at age 19 only. The mean HRQL score decreasedfrom 0.87 to 0.86. The HRQL of 45% was stable, 25% were better and 30% were worse. Aregression model showed internalizing problems were related most strongly to HRQL.
Conclusions:
In the transition from adolescence to young adulthood, HRQL in Dutch VLBW children wasstable at the group level but varied at the individual level. HRQL was negatively associatedwith internalizing problems and also with physical handicaps. Long-term follow-up studieson the impact of VLBW on HRQL are all the more called for, given the growing number ofvulnerable infants surviving the neonatal period.
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Hemoglobin A1c
improvements and better diabetesspecific quality of life among participants
completing diabetes self-management programs: A
nested cohort study
Background:
Numerous primary care innovations emphasize patient-centered processes of care. Within thecontext of these innovations, greater understanding is needed of the relationship betweenimprovements in clinical endpoints and patient-centered outcomes. To address this gap, we evaluated the association between glycosylated hemoglobin (HbA1c) and diabetes-specificquality of life among patients completing diabetes self-management programs.
Methods:
We conducted a retrospective cohort study nested within a randomized comparativeeffectiveness trial of diabetes self-management interventions in 75 diabetic patients. Multiplelinear regression models were developed to examine the relationship between change inHbA1c from baseline to one-year follow-up and Diabetes-39 (a diabetes-specific quality oflife measure) at one year.
Results:
HbA1c levels improved for the overall cohort from baseline to one-year follow-up (t(74) = 3.09, p = .0029). One-year follow up HbA1c was correlated with worse overall qualityof life (r = 0.33, p = 0.004). Improvements in HbA1c from baseline to one-year follow-up wereassociated with greater D-39 diabetes control (beta = 0.23, p = .04) and D-39 sexual functioning(beta = 0.25, p = .03) quality of life subscales.
Conclusions:
Improvements in HbA1c among participants completing a diabetes self-management programwere associated with better diabetes-specific quality of life. Innovations in primary care thatengage patients in self-management and improve clinical biomarkers, such as HbA1c, mayalso be associated with better quality of life, a key outcome from the patient perspective.
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Comparison of the burden of illness for adults with ADHD across seven countries: a qualitative study
Background:
The purpose of this study was to expand the understanding of the burden of illness experienced by adults with Attention Deficit-Hyperactivity Disorder (ADHD) living in different countries and treated through different health care systems.
Methods:
Fourteen focus groups and five telephone interviews were conducted in seven countries in North America and Europe, comprised of adults who had received a diagnosis of ADHD. The countries included Canada, France, Germany, Italy, The Netherlands, United Kingdom, and United States (two focus groups in each country). There were 108 participants. The focus groups were designed to elicit narratives of the experience of ADHD in key domains of symptoms, daily life, and social relationships. Consonant with grounded theory, the transcripts were analyzed using descriptive coding and then themed into larger domains.
Results:
Participants' statements regarding the presentation of symptoms, childhood experience, impact of ADHD across the life course, addictive and risk-taking behavior, work and productivity, finances, relationships and psychological health impacts were similarly themed across all seven countries. These similarities were expressed through the domains of symptom presentation, childhood experience, medication treatment issues, impacts in adult life and across the life cycle, addictive and risk-taking behavior, work and productivity, finances, psychological and social impacts.
Conclusions:
These data suggest that symptoms associated with adult ADHD affect individuals similarly in different countries and that the relevance of the diagnostic category for adults is not necessarily limited to certain countries and sociocultural milieus.
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Mortality and health-related quality of life in
prevalent dialysis patients: comparison between 12-
items and 36-items short-form health survey
Background:
To assess health- related quality of life (HRQOL) with SF-12 and SF-36 and compare theirabilities to predict mortality in chronic dialysis patients, after adjusting for traditional riskfactors.
Methods:
The Short-Form Health Survey (SF-36) with the embedded SF-12 was applied in 301 dialysispatients cross-sectionally. Physical and mental component summary (PCS-36, MCS-36, PCS-12, and MCS-12) scores were calculated. Clinical and demographic data were collected.Mortality (followed for up to 4.5 years) was analyzed with Kaplan Meier plots and Coxproportional hazards, after censoring for renal transplantation. Exclusion factors wereobservation time <2 months (n = 21) and missing component summary scores (n = 10 for SF-36; n = 28 for SF-12), thus 252 patient were included in the analyses.
Results:
In 252 patients (60.2 +/- 15.5 years, 65.9% males, dialysis vintage 9.0, IQR 5.0-23.0 months),mortality during follow-up was 33.7%(85 deaths). Significant correlations were observedbetween PCS-36 and PCS-12 (rho = 0.93, p < 0.001) and between MCS-36 and MCS-12(rho = 0.95, p < 0.001). Mortality rate was highest in patients in the lowest quartile of PCS-12(chi2 = 15.3, p = 0.002) and PCS-36 (chi2 = 16.7, p = 0.001). MCS was not associated withmortality. Adjusted hazard ratios for mortality were 2.5 (95% CI 1.0-6.3, PCS-12) and 2.7(1.1 - 6.4, PCS-36) for the lowest compared with the highest ("best perceived") quartile ofPCS.
Conclusion:
Compromised HRQOL is an independent predictor of poor outcome in dialysis patients. TheSF-12 provided similar predictions of mortality as SF-36, and may serve as an applicableclinical tool because it requires less time to complete.
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Health Research Policy and Systems - Latest Articles
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Empowering communities in combating river blindness and the role of NGOs: case studies from Cameroon, Mali, Nigeria and Uganda
The control of onchocerciasis is not only a major success story in global health, but also one of the best examples of the power of public-private partnership at the international level as well as at the national level. The onchocerciasis story is also a leading example of the contribution of a group of Non- Governmental Organizations (NGO) called Non-Governmental Development Organizations (NGDO) to operational research which resulted in important changes in treatment strategies and policies.The four case studies presented here illustrate some key contributions the NGDOs made to the development of "community directed treatment with ivermectin" -CDTI, in Africa, which became the approved methodology within the African Programme for Onchocerciasis Control (APOC). The partnership between the international, multilateral, government institutions and the NGDO Coordination Group was the backbone of the APOC programme's structure and facilitated progress and scale-up of treatment programmes. Contributions included piloting community-based methodology in Mali and Nigeria; research, collaboration and coordination on treatment strategies and policies, coalition building, capacity building of national health workforce and advocacy at the national and international level. While the Onchocerciasis Control Programme (OCP) and APOC provided leadership, the NGDOs working with the national health authorities played a major role in advocacy evolving the community methodology which led to achieving and maintaining- treatments with ivermectin for at least 20 years and strengthening community health systems.
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A multi-faceted approach to promote knowledge translation platforms in eastern Mediterranean countries: climate for evidence-informed policy
Objectives:Limited work has been done to promote knowledge translation (KT) in the Eastern Mediterranean Region (EMR). The objectives of this study are to: 1.assess the climate for evidence use in policy; 2.explore views and practices about current processes and weaknesses of health policymaking; 3.identify priorities including short-term requirements for policy briefs; and 4.identify country-specific requirements for establishing KT platforms.
Methods:
Senior policymakers, stakeholders and researchers from Algeria, Bahrain, Egypt, Iran, Jordan, Lebanon, Oman, Sudan, Syria, Tunisia, and Yemen participated in this study. Questionnaires were used to assess the climate for use of evidence and identify windows of opportunity and requirements for policy briefs and for establishing KT platforms. Current processes and weaknesses of policymaking were appraised using case study scenarios. Closed-ended questions were analyzed descriptively. Qualitative data was analyzed using thematic analysis.
Results:
KT activities were not frequently undertaken by policymakers and researchers in EMR countries, research evidence about high priority policy issues was rarely made available, and interaction between policymakers and researchers was limited, and policymakers rarely identified or created places for utilizing research evidence in decision-making processes. Findings emphasized the complexity of policymaking. Donors, political regimes, economic goals and outdated laws were identified as key drivers. Lack of policymakers' abilities to think strategically, constant need to make quick decisions, limited financial resources, and lack of competent and trained human resources were suggested as main weaknesses.
Conclusion:
Despite the complexity of policymaking processes in countries from this region, the absence of a structured process for decision making, and the limited engagement of policymakers and researchers in KT activities, there are windows of opportunity for moving towards more evidence informed policymaking.
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Policy assessment and policy development for physical activity promotion: results of an exploratory intervention study in 15 European Nations
Background:
Purpose of the study was to test a theoretical model to assess and develop policies for the promotion of physical activity among older people as part of an international intervention study.
Methods:
248 semi-standardized interviews with policy-makers were conducted in 15 European nations. The questionnaire assessed policy-makers' perceptions of organizational goals, resources, obligations, as well as organizational, political and public opportunities in the area of physical activity promotion among older people. In order to develop policies, workshops with policy-makers were conducted. Workshop outputs and outcomes were assessed for four nations nine months after the workshops.
Results:
Policy assessment: Results of the policy assessment were diverse across nations and policy sectors. For example, organizational goals regarding actions for physical activity promotion were perceived as being most favorably by the sports sector. Organizational obligations for the development of such policies were perceived as being most favorably by the health sector.Policy development: The workshops resulted in different outputs: a national intersectoral action plan (United Kingdom), a national alliance (Sweden), an integrated policy (the Netherlands), and a continuing dialogue (Germany).
Conclusions:
Theory-driven policy assessment and policy-maker workshops might be an important means of scientific engagement in policy development for health promotion.
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Striving for better health through health research in post-conflict Timor-Leste
The Cabinet of Health Research and Development (CHRD) has recently been established as the first health research institute in one of the world's newest nations, Timor-Leste. We discuss the development of this initiative to build health research capacity within the context of Timor-Leste's health system, history and future goals.
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Public health research support through the European structural funds in central and eastern Europe and the Mediterranean
Background:
Public health research provides evidence for practice across fields including health care, health promotion and health surveillance. Levels of public health research vary markedly across European Union (EU) countries, and are lowest in the EU's new member states (in Central and Eastern Europe and the Mediterranean). However, these countries now receive most of the EU's Structural Funds, some of which are allocated to research.
Methods:
STEPS, an EU-funded study, sought to assess support for public health research at national and European levels. To identify support through the Structural funds, STEPS drew information from country respondents and internet searches for all twelve EU new member states.
Results:
The EU allocates annually around €7 billion through the Structural Funds for member states' own use on research. These funds can cover infrastructure, academic employment, and direct research grants. The programmes emphasise links to business. Support for health research includes major projects in biosciences, but direct support for public health research was found in only three countries - Cyprus, Latvia and Lithuania.
Conclusions:
Public health research is not prioritised in the EU's Structural Funds programme in comparison with biomedicine. For the research dimension of the new European programme for Structural Funds 2014-2002, ministries of health should propose public health research to strengthen the evidence-base for European public health policy and practice.
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Investing in African research training institutions creates sustainable capacity for Africa: the case of the University of the Witwatersrand School of Public Health Masters programme in epidemiology and biostatistics
Background:
Improving health in Africa is a high priority internationally. Inadequate research capacity to produce local, relevant research has been identified as a limitation to improved population health. Increasing attention is being paid to the higher education sector in Africa as a method of addressing this; evidence that such investment is having the desired impact is required. A 1998 3-year investment by the Special Programme for Research and Training in Tropical Diseases (TDR) in research training at the School of Public Health, University of the Witwatersrand, South Africa was reviewed to assess its' impact.
Methods:
A descriptive cross-sectional survey of the 70 students registered for the Masters programme in epidemiology & biostatistics from 2000-2005 was conducted. Data were collected from self-administered questionnaires.
Results:
Sixty percent (42/70) of students responded. At the time of the survey 19% of respondents changed their country of residence after completion of the Masters course, 14% migrated within Africa and 5% migrated out of Africa. Approximately half (47%) were employed as researchers and 38% worked in research institutions. Sixty percent reported research output, and four graduates were pursuing PhD studies. Government subsidy to higher education institutions, investments of the University of the Witwatersrand in successful programmes and ongoing bursaries for students to cover tuition fees were important for sustainability.
Conclusions:
Investing in African institutions to improve research training capacity resulted in the retention of graduates in Africa in research positions and produced research output. Training programmes can be sustained when national governments invest in higher education and where that funding is judiciously applied. Challenges remain if funding for students bursaries is not available.
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Knowledge mobilization in the context of health technology assessment: an exploratory case study
Background:
Finding measures to enhance the dissemination and implementation of their recommendations has become part of most health technology assessment (HTA) bodies' preoccupations. The Quebec government HTA organization in Canada observed that some of its projects relied on innovative practices in knowledge production and dissemination. A research was commissioned in order to identify what characterized these practices and to establish whether they could be systematized.
Methods:
An exploratory case study was conducted during summer and fall 2010 in the HTA agency in order to determine what made the specificity of its context, and to conceptualize an approach to knowledge production and dissemination that was adapted to the mandate and nature of this form of HTA organization. Six projects were selected. For each, the HTA report and complementary documents were analyzed, and semi-structured interviews were carried out. A narrative literature review of the most recent literature reviews of the principal knowledge into practice frameworks (2005-2010) and of articles describing such frameworks (2000-2010) was undertaken.Results and discussionOur observations highlighted an inherent difficulty as regards applying the dominant knowledge translation models to HTA and clinical guidance practices. For the latter, the whole process starts with an evaluation question asked in a problematic situation for which an actionable answer is expected. The objective is to produce the evidence necessary to respond to the decision-maker's request. The practices we have analyzed revealed an approach to knowledge production and dissemination, which was multidimensional, organic, multidirectional, dynamic, and dependent on interactions with stakeholders. Thus, HTA could be considered as a knowledge mobilization process per se.
Conclusions:
HTA's purpose is to solve a problem by mobilizing the types of evidence required and the concerned actors, in order to support political, organizational or clinical decision-making. HTA relies on the mediation between contextual, colloquial and scientific evidence, as well as on interactions with stakeholders for recommendation making. Defining HTA as a knowledge mobilization process might contribute to consider the different orders of knowledge, the social, political and ethical dimensions, and the interactions with stakeholders, among the essential components required to respond to the preoccupations, needs and contexts of all actors concerned with the evaluation question's issues.
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Looking for interaction: quantitative measurement of research utilization by Dutch local health officials
Background:
In the Netherlands, local authorities are required by law to develop local health memoranda, based on epidemiological analyses. The purpose of this study was to assess the actual use of these epidemiological reports by municipal health officials and associated factors that affect this use.MethodBased on a conceptual framework, we designed a questionnaire in which we operationalized instrumental, conceptual, and symbolic use, the interaction between researchers and local health officials, and four clusters of barriers in this interaction process. We conducted an internet survey among 155 Dutch local health officials representing 35% of all Dutch municipalities. By means of multiple regression analyses, we gained insight into the related factors for each of the three types of research utilization.
Results:
The results show that local health officials use epidemiological research more often in a conceptual than an instrumental or symbolic way. This can be explained by the complexity of the local policy process which is often linked to policies in other areas, and the various policy actors involved. Conceptual use was statistically associated with a presentation given by the epidemiologist during the policy process, the presence of obstructions regarding the report's accessibility, and the local official's personal belief systems and interests originating from different professional values and responsibilities. Instrumental and symbolic use increased with the involvement of local officials in the research process.
Conclusions:
The results of this study provide a partial solution to understanding and influencing research utilization. The quantitative approach underpins earlier qualitative findings on this topic. The outcomes suggest that RPHS epidemiologists can use different strategies to improve research utilization. 'Blurring the boundaries', and the enhancement of interfaces between epidemiologists and local health officials, like direct interactions into each other's work processes, is expected to create better possibilities for optimizing research use.
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Developing lay health worker policy in South Africa: a qualitative study
Background:
Over the past half decade South Africa has been developing, implementing and redeveloping its Lay Health Worker (LHW) policies. Research during this period has highlighted challenges with LHW programme implementation. These challenges have included an increased burden of care for female LHWs. The aim of this study was to explore contemporary LHW policy development processes and the extent to which issues of gender are taken up within this process.
Methods:
The study adopted a qualitative approach to exploring policy development from the perspective of policy actors. Eleven policy actors (policy makers and policy commentators) were interviewed individually. Data from the interviews were analysed thematically.
Results:
Considerations of LHW working conditions drove policy redevelopment. From the interviews it seems that gender as an issue never reached the policy making agenda. Although there was strong recognition that the working conditions of LHWs needed to be improved, poor working conditions were not necessarily seen as a gender concern. Our data suggests that in the process of defining the problem which the redeveloped policy had to address, gender was not included. There was no group or body who brought the issue of gender to the attention of policy developers. As such the issue of gender never entered the policy debates. These debates focused on whether it was appropriate to have LHWs, what LHW programme model should be adopted and whether or not LHWs should be incorporated into the formal health system.
Conclusion:
LHW policy redevelopment focused on resolving issues of LHW working conditions through an active process involving many actors and strong debates. Within this process the issue of gender had no champion and never reached the LHW policy agenda. Future research may consider how to incorporate the voices of ordinary women into the policy making process.
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Approaches to developing the capacity of health policy analysis institutes: a comparative case study
ObjectivesTo review and assess (i) the factors that facilitate the development of sustainable health policy analysis institutes in low and middle income countries and (ii) the nature of external support for capacity development provided to such institutes.
Methods:
Comparative case studies of six health policy analysis institutes (3 from Asia and 3 from Africa) were conducted. In each region an NGO institute, an institute linked to government and a university based institute were included. Data collection comprised document review, semi-structured interviews with stakeholders and discussion of preliminary findings with institute staff.FindingsThe findings are organized around four key themes: (i) Financial resources: three of the institutes had received substantial external grants at start-up, however two of these institutes subsequently collapsed. At all but one institute, reliance upon short term, donor funding, created high administrative costs and unpredictability. (ii) Human resources: the retention of skilled human resources was perceived to be key to institute success but was problematic at all but one institute. In particular staff often moved to better paid positions elsewhere once having acquired necessary skills and experience, leaving remaining senior staff with heavy workloads. (iii) Governance and management: board structures and roles varied according to the nature of institute ownership. Boards made important contributions to organizational capacity through promoting continuity, independence and fund raising. Routine management systems were typically perceived to be strong. (iv) Networks: linkages to policy makers helped promote policy influences. External networks with other research organizations, particularly where these were longer term institutional collaborations helped promote capacity.
Conclusions:
The development of strong in-country analytical and research capacity to guide health policy development is critical, yet many health policy analysis institutes remain very fragile. A combination of more strategic planning, active recruitment and retention strategies, and longer term, flexible funding, for example through endowments, needs to be promoted. Specific recommendations to funders and institutes are provided.
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Human Resources for Health - Latest Articles
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Analysis of policy implications and challenges of the Cuban health assistance program related to human resources for health in the Pacific
Background:
Cuba has extended its medical cooperation to Pacific Island Countries (PICs) by supplying doctors to boost service delivery and offering scholarships for Pacific Islanders to study medicine in Cuba. Given the small populations of PICs, the Cuban engagement could prove particularly significant for health systems development in the region. This paper reviews the magnitude and form of Cuban medical cooperation in the Pacific and analyses its implications for health policy, human resource capacity and overall development assistance for health in the region.
Methods:
We reviewed both published and grey literature on health workforce in the Pacific including health workforce plans and human resource policy documents. Further information was gathered through discussions with key stakeholders involved in health workforce development in the region.
Results:
Cuba formalised its relationship with PICs in September 2008 following the first Cuba-Pacific Islands ministerial meeting. Some 33 Cuban health personnel work in Pacific Island Countries and 177 Pacific island students are studying medicine in Cuba in 2010 with the most extensive engagement in Kiribati, the Solomon Islands, Tuvalu and Vanuatu. The cost of the Cuban medical cooperation to PICs comes in the form of countries providing benefits and paying allowances to in-country Cuban health workers and return airfares for their students in Cuba. This has been seen by some PICs as a cheaper alternative to training doctors in other countries.
Conclusions:
The Cuban engagement with PICs, while smaller than engagement with other countries, presents several opportunities and challenges for health system strengthening in the region. In particular, it allows PICs to increase their health workforce numbers at relatively low cost and extends delivery of health services to remote areas. A key challenge is that with the potential increase in the number of medical doctors, once the local students return from Cuba, some PICs may face substantial rises in salary expenditure which could significantly strain already stretched government budgets. Finally, the Cuban engagement in the Pacific has implications for the wider geo-political and health sector support environment as the relatively few major bilateral donors, notably Australia (through AusAID) and New Zealand (through NZAID), and multilaterals such as the World Bank will need to accommodate an additional player with whom existing links are limited.
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The effects of midwives' job satisfaction on burnout, intention to quit and turnover: a longitudinal study in Senegal
Background:
Despite working in a challenging environment plagued by persistent personnel shortages, public sector midwives in Senegal play a key role in tackling maternal mortality. A better understanding of how they are experiencing their work and how it is affecting them is needed in order to better address their needs and incite them to remain in their posts. This study aims to explore their job satisfaction and its effects on their burnout, intention to quit and professional mobility.
Methods:
A cohort of 226 midwives from 22 hospitals across Senegal participated in this longitudinal study. Their job satisfaction was measured from December 2007 to February 2008 using a multifaceted instrument developed in West Africa. Three expected effects were measured two years later: burnout, intention to quit and turnover. Descriptive statistics were reported for the midwives who stayed and left their posts during the study period. A series of multiple regressions investigated the correlations between the nine facets of job satisfaction and each effect variable, while controlling for individual and institutional characteristics.
Results:
Despite nearly two thirds (58.9%) of midwives reporting the intention to quit within a year (mainly to pursue new professional training), only 9% annual turnover was found in the study (41/226 over 2 years). Departures were largely voluntary (92%) and entirely domestic. Overall the midwives reported themselves moderately satisfied; least contented with their "remuneration" and "work environment" and most satisfied with the "morale" and "job security" facets of their work. On the three dimensions of the Maslach Burnout Inventory, very high levels of emotional exhaustion (80.0%) and depersonalization (57.8%) were reported, while levels of diminished personal accomplishment were low (12.4%). Burnout was identified in more than half of the sample (55%). Experiencing emotional exhaustion was inversely associated with "remuneration" and "task" satisfaction, actively job searching was associated with being dissatisfied with job "security" and voluntary quitting was associated with dissatisfaction with "continuing education".
Conclusions:
This study found that although midwives seem to be experiencing burnout and unhappiness with their working conditions, they retain a strong sense of confidence and accomplishment in their work. It also suggests that strategies to retain them in their positions and in the profession should emphasize continuing education.
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Emigration preferences and plans among medical students in Poland
Background:
Migration and ethical recruitment of health care workers is receiving increased attention worldwide. Europe's aging population is creating new opportunities for medical doctors for finding employment in other countries, particularly those of a better standard of living.
Methods:
We conducted a survey among 1214 medical students in five out of eleven universities in Poland with medical schools in October 2008. A series of statistical tests was applied to analyse the characteristics of potential migrants. Projections were obtained using statistical analyses: descriptive, multifactorial logistic regression and other statistical methods .
Results:
We can forecast that 26-36% of Polish medical students will emigrate over the next few years; 62% of respondents estimated the likelihood of emigration at 50%. Students in their penultimate year of study declared a stronger desire to migrate than those in the final year. At the same time, many students were optimistic about career opportunities in Poland. Also noted among students were: the decline in interest in leaving among final year students, their moderate elaboration of departure plans, and their generally optimistic views about the opportunities for professional development in Poland.
Conclusions:
The majority of Polish students see the emigration as a serious alternative to the continuation of their professional training. This trend can pose a serious threat to the Polish health care system, however the observed decline of the interest in leaving among final year students, the moderate involvement in concrete departure plans and the optimistic views about the opportunities for professional development in Poland suggest that the actual scale of brain drain of young Polish doctors due to emigration will be more limited than previously feared.
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Information systems on human resources for health:
a global review
Background:
Although attainment of the health-related Millennium Development Goals relies on countrieshaving adequate numbers of human resources for health (HRH) and their appropriatedistribution, global understanding of the systems used to generate information for monitoringHRH stock and flows, known as human resources information systems (HRIS), is minimal.While HRIS are increasingly recognized as integral to health system performance assessment,baseline information regarding their scope and capability around the world has been limited.We conducted a review of the available literature on HRIS implementation processes in orderto draw this baseline.
Methods:
Our systemic search initially retrieved 11 923 articles in four languages published in peerreviewedand grey literature. Following the selection of those articles which detailed HRISimplementation processes, reviews of their contents were conducted using two-person teams,each assigned to a national system. A data abstraction tool was developed and used tofacilitate objective assessment.
Results:
Ninety-five articles with relevant HRIS information were reviewed, mostly from the greyliterature, which comprised 84 % of all documents. The articles represented 63 national HRISand two regionally integrated systems. Whereas a high percentage of countries reported thecapability to generate workforce supply and deployment data, few systems were documentedas being used for HRH planning and decision-making. Of the systems examined, only 23 %explicitly stated they collect data on workforce attrition. The majority of countriesexperiencing crisis levels of HRH shortages (56 %) did not report data on health workerqualifications or professional credentialing as part of their HRIS.
Conclusion:
Although HRIS are critical for evidence-based human resource policy and practice, there is adearth of information about these systems, including their current capabilities. The absence ofstandardized HRIS profiles (including documented processes for data collection,management, and use) limits understanding of the availability and quality of information thatcan be used to support effective and efficient HRH strategies and investments at the national,regional, and global levels.
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Non-physician providers of obstetric care in Mexico:
Perspectives of physicians, obstetric nurses and
professional midwives
Background:
In Mexico 87% of births are attended by physicians. However, the decline in the nationalmaternal mortality rate has been slower than expected. The Mexican Ministry of Health's2009 strategy to reduce maternal mortality gives a role to two non-physician models thatmeet criteria for skilled attendants: obstetric nurses and professional midwives. This studycompares and contrasts these two provider types with the medical model, analyzingperspectives on their respective training, scope of practice, and also their perception and/orexperiences with integration into the public system as skilled birth attendants.MethodologyThis paper synthesizes qualitative research that was obtained as a component of thequantitative and qualitative study that evaluated three models of obstetric care: professionalmidwives (PM), obstetric nurses (ON) and general physicians (GP). A total of 27 individualinterviews using a semi-structured guide were carried out with PMs, ONs, GPs andspecialists. Interviews were transcribed following the principles of grounded theory, codesand categories were created as they emerged from the data. We analyzed data in ATLAS.ti.
Results:
All provider types interviewed expressed confidence in their professional training andacknowledge that both professional midwives and obstetric nurses have the necessary skillsand knowledge to care for women during normal pregnancy and childbirth. The three types ofproviders recognize limits to their practice, namely in the area of managing complications.We found differences in how each type of practitioner perceived the concept and process ofbirth and their role in this process. The barriers to incorporation as a model to attend birthfaced by PMs and ONs are at the individual, hospital and system level. GPs question theirability and training to handle deliveries, in particular those that become complicated, and theprofessional midwifery model particularly as it relates to a clinical setting, is also questioned.
Conclusions:
Hospitals in the Mexican public health sector have a heavy obstetric workload; physicianscarry the additional burden of non-obstetric cases. The incorporation of a non- physicianmodel at the primary health center level to attend low-risk, normal deliveries wouldcontribute to the reduction of non-necessary referrals. There is also a role for these providersat the hospital level.
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Exploring professionalization among Brazilian oral
health technicians
Professional dental auxiliaries emerged in the early 20th century in the United States ofAmerica and quickly spread to Europe and other regions of the world. In Brazil, however,oral health technicians (OHTs), who occupy a similar role as dental hygienists, had a longjourney before the occupation achieved legal recognition: Brazilian Law 11.889, whichregulates this occupation in the country, was only enacted in 2008. The aim of this paper is toreview the literature on the professionalization of OHTs, highlighting the triggering, limitingand conflicting aspects that exerted an influence on the historical progress of theseprofessionals in Brazil. We have tested Abbott's and Larson's theory on professionalization,against the history of OHTs. A number of different dental corporative interests exerted aninfluence over professionalization, especially in discussions regarding the permissibleactivities of these professionals in the oral cavity of patients. With primary health careadvances in Brazil, the importance of these professionals has once again come to theforefront. This seems to be a key point in the consolidation of OHTs in the area of humanresources for health in Brazil.
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A survey of Sub-Saharan African medical schools
Background:
Sub-Saharan Africa suffers a disproportionate share of the world's burden of disease while having some of the world's greatest health care workforce shortages. Doctors are an important component of any high functioning health care system. However, efforts to strengthen the doctor workforce in the region have been limited by a small number of medical schools with limited enrolments, international migration of graduates, poor geographic distribution of doctors, and insufficient data on medical schools. The goal of the Sub-Saharan African Medical Schools Study (SAMSS) is to increase the level of understanding and expand the baseline data on medical schools in the region.
Methods:
The SAMSS survey is a descriptive survey study of Sub-Saharan African medical schools. The survey instrument included quantitative and qualitative questions focused on institutional characteristics, student profiles, curricula, post-graduate medical education, teaching staff, resources, barriers to capacity expansion, educational innovations, and external relationships with government and non-governmental organizations. Surveys were sent via e-mail to medical school deans or officials designated by the dean. Analysis is both descriptive and multivariable.
Results:
Surveys were distributed to 146 medical schools in 40 of 48 Sub-Saharan African countries. One hundred and five responses were received (72% response rate). An additional 23 schools were identified after the close of the survey period. Fifty-eight respondents have been founded since 1990, including 22 private schools. Enrolments for medical schools range from 2 to 1800 and graduates range from 4 to 384. Seventy-three percent of respondents (n = 64) increased first year enrolments in the past five years. On average, 26% of respondents' graduates were reported to migrate out of the country within five years of graduation (n = 68). The most significant reported barriers to increasing the number of graduates, and improving quality, related to infrastructure and faculty limitations, respectively. Significant correlations were seen between schools implementing increased faculty salaries and bonuses, and lower percentage loss of faculty over the previous five years (P = 0.018); strengthened institutional research tools (P = 0.00015) and funded faculty research time (P = 0.045) and greater faculty involvement in research; and country compulsory service requirements (P = 0.039), a moderate number (1-5) of post-graduate medical education programs (P = 0.016) and francophone schools (P = 0.016) and greater rural general practice after graduation.
Conclusions:
The results of the SAMSS survey increases the level of data and understanding of medical schools in Sub-Saharan Africa. This data serves as a baseline for future research, policies and investment in the health care workforce in the region which will be necessary for improving health.
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Human resources for health care delivery in Tanzania: a multifaceted problem
Background:
Recent years have seen an unprecedented increase in funds for procurement of health commodities in developing countries. A major challenge now is the efficient delivery of commodities and services to improve population health. With this in mind, we documented staffing levels and productivity in peripheral health facilities in southern Tanzania.MethodA health facility survey was conducted to collect data on staff employed, their main tasks, availability on the day of the survey, reasons for absenteeism, and experience of supervisory visits from District Health Teams. In-depth interview with health workers was done to explore their perception of work load. A time and motion study of nurses in the Reproductive and Child Health (RCH) clinics documented their time use by task.
Results:
We found that only 14% (122/854) of the recommended number of nurses and 20% (90/441) of the clinical staff had been employed at the facilities. Furthermore, 44% of clinical staff was not available on the day of the survey. Various reasons were given for this. Amongst the clinical staff, 38% were absent because of attendance to seminar sessions, 8% because of long-training, 25% were on official travel and 20% were on leave. RCH clinic nurses were present for 7 hours a day, but only worked productively for 57% of time present at facility. Almost two-third of facilities had received less than 3 visits from district health teams during the 6 months preceding the survey.
Conclusion:
This study documented inadequate staffing of health facilities, a high degree of absenteeism, low productivity of the staff who were present and inadequate supervision in peripheral Tanzanian health facilities. The implications of these findings are discussed in the context of decentralized health care in Tanzania.
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Using staffing ratios for workforce planning: evidence on nine allied health professions
Background:
Modern healthcare managers are faced with pressure to deliver effective, efficient services within the context of fixed budget constraints. Managers are required to make decisions regarding the skill mix of the workforce particularly when staffing new services. One measure used to identify numbers and mix of staff in healthcare settings is workforce ratio. The aim of this study was to identify workforce ratios in nine allied health professions and to identify whether these measures are useful for planning allied health workforce requirements.
Methods:
A systematic literature search using relevant MeSH headings of business, medical and allied health databases and relevant grey literature for the period 2000-2008 was undertaken.
Results:
Twelve articles were identified which described the use of workforce ratios in allied health services. Only one of these was a staffing ratio linked to clinical outcomes. The most comprehensive measures were identified in rehabilitation medicine.
Conclusion:
The evidence for use of staffing ratios for allied health practitioners is scarce and lags behind the fields of nursing and medicine.
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Access to general practitioner services amongst underserved Australians: a microsimulation study
Background:
One group often identified as having low socioeconomic status, those living in remote or rural areas, are often recognised as bearing an unequal burden of illness in society. This paper aims to examine equity of utilisation of general practitioner services in Australia.
Methods:
Using the 2005 National Health Survey undertaken by the Australian Bureau of Statistics, a microsimulation model was developed to determine the distribution of GP services that would occur if all Australians had equal utilisation of health services relative to need.
Results:
It was estimated that those who are unemployed would experience a 19% increase in GP services. Persons residing in regional areas would receive about 5.7 million additional GP visits per year if they had the same access to care as Australians residing in major cities. This would be a 18% increase. There would be a 20% increase for inner regional residents and a 14% increase for residents of more remote regional areas. Overall there would be a 5% increase in GP visits nationally if those in regional areas had the same access to care as those in major cities.
Conclusion:
Parity is an insufficient goal and disadvantaged persons and underserved areas require greater access to health services than the well served metropolitan areas due to their greater poverty and poorer health status. Currently underserved Australians suffer a double disadvantage: poorer health and poorer access to health services.
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AIDS Research and Therapy - Latest Articles
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Dual role of autophagy in HIV-1 replication and pathogenesis
Autophagy, the major mechanism for degrading long-lived intracellular proteins and organelles, is essential for eukaryotic cell homeostasis. Autophagy also defends the cell against invasion by microorganisms and has important roles in innate and adaptive immunity. Increasingly evident is that HIV-1 replication is dependent on select components of autophagy. Fittingly, HIV-1 proteins are able to modulate autophagy to maximize virus production. At the same time, HIV-1 proteins appear to disrupt autophagy in uninfected cells, thereby contributing to CD4+ cell death and HIV-1 pathogenesis. These observations allow for new approaches for the treatment and possibly the prevention of HIV-1 infection. This review focuses on the relationship between autophagy and HIV-1 infection. Discussed is how autophagy plays dual roles in HIV-1 replication and HIV-1 disease progression.
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Predictors of mortality among HIV infected patients taking antiretroviral treatment in Ethiopia: a retrospective cohort study
Background:
Studies indicate that there is high early mortality among patients starting antiretroviraltreatment in sub-Saharan Africa. However, there is paucity of evidence on long term survivalof patients on anti-retroviral treatment in the region. The objective of this study is to examinemortality and its predictors among a cohort of HIV infected patients on anti-retroviraltreatment retrospectively followed for five years.
Methods:
A retrospective cohort study was conducted among HIV infected patients on ART in easternEthiopia. Cox regression and Kaplan-Meier analyses were performed to investigate factorsthat influence time to death and survival over time.
Results:
A total of 1540 study participants were included in the study. From the registered patients inthe cohort, the outcome of patients as active, deceased, lost to follow up and transfer out was1005 (67.2%), 86 (5.9%), 210 (14.0%) and 192 (12.8%) respectively. The overall mortalityrate provides an incidence density of 2.03 deaths per 100 person years (95% CI 1.64 - 2.50).Out of a total of 86 deaths over 60 month period; 63 (73.3%) died during the first 12 months, 10 (11.6%) during the second year, and 10 (11.6%) in the third year of follow up. Inmultivariate analysis, the independent predictors for mortality were loss of more than 10%weight loss, bedridden functional status at baseline, [less than or equal to]200 CD4 cell count/ml, and advancedWHO stage patients.
Conclusion:
A lower level of mortality was detected among the cohort of patients on antiretroviraltreatment in eastern Ethiopia. Previous history of weight loss, bedridden functional status atbaseline, low CD4 cell count and advanced WHO status patients had a higher risk of death.Early initiation of ART, provision of nutritional support and strengthening of the food byprescription initiative, and counseling of patients for early presentation to treatment isrecommended.
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Is the Sexual Behaviour of HIV Patients on Antiretroviral therapy safe or risky in Sub-Saharan Africa? Meta-Analysis and Meta-Regression
Background:
Reports on the sexual behavior of people on antiretroviral therapy (ART) are inconsistent. We selected 14 articles that compared the sexual behavior of people with and without ART for this analysis.
Methods:
We included both cross-sectional studies that compared different ART-naive and ART-experienced participants and longitudinal studies examining the behavior of the same individuals pre- and post-ART start. Meta-analyses were performed both stratified by type of study and combined. Outcome variables assessed for association with ART experience were any sexual activity, unprotected sex and having multiple sexual partners. Random-effect models were applied to determine the overall odds ratios. Sub-group analyses and meta-regression analyses were performed to examine sources of heterogeneity among the studies. Sensitivity analysis was also conducted to evaluate the stability of the overall odds ratio in the presence of outliers.
Results:
: The meta-analysis failed to show a statistically significant association of any sexual activity with ART experience. It did, however, show an overall statistically significant reduction of any unprotected sex, having multiple sexual partners and unprotected sex with HIV negative or unknown HIV status with ART experience. Meta-regression showed no interaction between duration of ART use or recall period of sexual behavior with the sexual activity variables. However, there was an association between the percentage of married or cohabiting participants included in a study and reductions in the practice of unprotected sex with ART.
Conclusion:
In general, this meta-analysis demonstrated a significant reduction in risky sexual behavior among people on ART in sub-Saharan Africa. Future studies should investigate the reproducibility and continuity of the observed positive behavioural changes as the duration of ART lasts a decade or more.
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Standardized representation, visualization and searchable repository of antiretroviral treatment-change episodes
Background:
To identify the determinants of successful antiretroviral (ARV) therapy, researchers study the virological responses to treatment-change episodes (TCEs) accompanied by baseline plasma HIV-1 RNA levels, CD4+ T lymphocyte counts, and genotypic resistance data. Such studies, however, often differ in their inclusion and virological response criteria making direct comparisons of study results problematic. Moreover, the absence of a standard method for representing the data comprising a TCE makes it difficult to apply uniform criteria in the analysis of published studies of TCEs.
Results:
To facilitate data sharing for TCE analyses, we developed an XML (Extensible Markup Language) Schema that represents the temporal relationship between plasma HIV-1 RNA levels, CD4 counts and genotypic drug resistance data surrounding an ARV treatment change. To demonstrate the adaptability of the TCE XML Schema to different clinical environments, we collaborate with four clinics to create a public repository of about 1,500 TCEs. Despite the nascent state of this TCE XML Repository, we were able to perform an analysis that generated a novel hypothesis pertaining to the optimal use of second-line therapies in resource-limited settings. We also developed an online program (TCE Finder) for searching the TCE XML Repository and another program (TCE Viewer) for generating a graphical depiction of a TCE from a TCE XML Schema document.
Conclusions:
The TCE Suite of applications - the XML Schema, Viewer, Finder, and Repository - addresses several major needs in the analysis of the predictors of virological response to ARV therapy. The TCE XML Schema and Viewer facilitate sharing data comprising a TCE. The TCE Repository, the only publicly available collection of TCEs, and the TCE Finder can be used for testing the predictive value of genotypic resistance interpretation systems and potentially for generating and testing novel hypotheses pertaining to the optimal use of salvage ARV therapy.
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A home-based approach to managing multi-drug resistant tuberculosis in Uganda: A case report
This case report describes an HIV-positive patient with recurrent tuberculosis in Uganda. After several failed courses of treatment, the patient was diagnosed with multi-drug resistant tuberculosis (MDR-TB). As adequate in-patient facilities were unavailable, we advised the patient to remain at home, and he received treatment at home via his family and a community nurse. The patient had a successful clearance of tuberculosis. This strategy of home-based care represents an important opportunity for treatment of patients in East Africa, where human resource constraints and inadequate hospital facilities exist for complex patients at high risk of infection to others.
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The pattern and predictors of mortality of HIV/AIDS patients with neurologic manifestation in Ethiopia: a retrospective study
Background:
Even though the prevalence of HIV infection among the adult population in Ethiopia was estimated to be 2.2% in 2008, the studies on the pattern of neurological manifestations are rare. The aim of this retrospective study was to assess the pattern and predictors of mortality of HIV/AIDS patients with neurologic manifestations.
Methods:
Medical records of 347 patients (age ≥13 years) admitted to Tikur Anbesa Hospital from September 2002 to August 2009 were reviewed and demographic and clinical data were collected.
Results:
Data from 347 patients were analysed. The mean age was 34.6 years. The diagnosis of HIV was made before current admission in 33.7% and 15.6% were on antiretroviral therapy (ART). Causes of neurological manifestation were: cerebral toxoplasmosis (36.6%), tuberculous meningitis (22.5%), cryptococcal meningitis (22.2%) and bacterial meningitis (6.9%). HIV-encephalopathy, primary central nervous system (CNS) lymphoma and progressive multifocal leukoencephalopathy were rare in our patients. CD4 count was done in 64.6% and 89.7% had count below 200/mm3[mean = 95.8, median = 57] and 95.7% were stage IV. Neuroimaging was done in 38% and 56.8% had mass lesion. The overall mortality was 45% and the case-fatality rates were: tuberculous meningitis (53.8%), cryptococcal meningitis (48.1%), cerebral toxoplasmosiss (44.1%) and bacterial meningitis (33.3%). Change in sensorium and seizure were predictors of mortality.
Conclusions:
CNS opportunistic infections were the major causes of neurological manifestations of HIV/AIDS and were associated with high mortality and morbidity. Almost all patients had advanced HIV disease at presentation. Early diagnosis of HIV, prophylaxis and treatment of opportunistic infections, timely ART, and improving laboratory services are recommended. Mortality was related to change in sensorium and seizure.
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Spontaneous virologic suppression in HIV controllers is independent of delayed-type hypersensitivity test responsiveness
Background:
Delayed-type hypersensitivity (DTH) testing, an in vivo assessment of cell-mediated immunity, is a predictor of HIV disease progression beyond CD4 cell count. We investigated whether preserved DTH responsiveness was characteristic of HIV controllers compared to non-controllers and individuals on suppressive HAART.FindingsDTH testing consisted of ≥ 3 recall antigens applied approximately every 6 months. DTH responses were classified by the number of positive skin tests: anergic (0), partial anergic (1), or non-anergic (≥ 2). HIV controllers were compared to treatment naïve non-controllers (n = 3822) and a subgroup of non-controllers with VL < 400 copies/mL on their initial HAART regimen (n = 491). The proportion of non-anergic results at first DTH testing was similar for HIV controllers compared to non-controllers (81.9% vs. 77.6%; P = 0.22), but tended to be greater in HIV controllers compared to the HAART subgroup (81.9% vs. 74.5%; P = 0.07). Complete anergy was observed in 14 (10.1%) HIV controllers with CD4 counts ≥ 400 cells/uL. For longitudinal testing, the average percentage of non-anergic DTH determinations per participant was higher in HIV controllers compared to non-controllers (81.2 ± 31.9% vs. 70.7 ± 36.8%; P = 0.0002), however this difference was eliminated with stratification by CD4 count: 200-399 (83.4 ± 35.6% vs. 71.9 ± 40.9%; P = 0.15) and > 400 cells/uL (81.2 ± 31.5% vs. 80.4 ± 32.7%; P = 0.76).
Conclusions:
Spontaneous virologic control was not associated with DTH responsiveness, and several HIV controllers were anergic despite having elevated CD4 counts. These findings suggest that cellular immunity assessed by DTH is not a principal factor contributing to spontaneous virologic suppression in HIV controllers.
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Sexual behavior of HIV-positive adults not accessing HIV treatment in Mombasa, Kenya: Defining their prevention needs
Background:
HIV spread continues at high rates from infected persons to their sexual partners. In 2009, an estimated 2.6 million new infections occurred globally. People living with HIV (PLHIV) receiving treatment are in contact with health workers and therefore exposed to prevention messages. By contrast, PLHIV not receiving ART often fall outside the ambit of prevention programs. There is little information on their sexual risk behaviors. This study in Mombasa Kenya therefore explored sexual behaviors of PLHIV not receiving any HIV treatment.
Results:
Using modified targeted snowball sampling, 698 PLHIV were recruited through community health workers and HIV-positive peer counsellors. Of the 59.2% sexually-active PLHIV, 24.5% reported multiple sexual partners. Of all sexual partners, 10.2% were HIV negative, while 74.5% were of unknown HIV status. Overall, unprotected sex occurred in 52% of sexual partnerships; notably with 32% of HIV-negative partners and 54% of partners of unknown HIV status in the last 6 months. Multivariate analysis, controlling for intra-client clustering, showed non-disclosure of HIV status (AOR: 2.38, 95%CI: 1.47-3.84, p < 0.001); experiencing moderate levels of perceived stigma (AOR: 2.94, 95%CI: 1.50-5.75, p = 0.002); and believing condoms reduce sexual pleasure (AOR: 2.81, 95%CI: 1.60-4.91, p < 0.001) were independently associated with unsafe sex. Unsafe sex was also higher in those using contraceptive methods other than condoms (AOR: 5.47, 95%CI: 2.57-11.65, p < 0.001); or no method (AOR: 3.99, 95%CI: 2.06-7.75, p < 0.001), compared to condom users.
Conclusions:
High-risk sexual behaviors are common among PLHIV not accessing treatment services, raising the risk of HIV transmission to discordant partners. This population can be identified and reached in the community. Prevention programs need to urgently bring this population into the ambit of prevention and care services. Moreover, beginning HIV treatment earlier might assist in bringing this group into contact with providers and HIV prevention services, and in reducing risk behaviors.
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Long-term treatment outcomes of ritonavir-boosted lopinavir monotherapy among HIV-infected patients who experienced NRTI and NNRTI failure
Background:
We continue the previously described prospective cohort study of ritonovir-boosted lopinavir (LPV/r) monotherapy for second-line therapy in HIV-infected patients with prior failure and extensive resistance to nucleoside reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), with the objective being to determine the three-year treatment responses.FindingsThere were 40 patients with a mean ± SD age of 37 ± 8 years. Median (IQR) baseline CD4 was 123 (37-245) cells/mm3 and median (IQR) HIV-1 RNA was 55,800 (9,670-100,000) copies/mL. All patients received twice daily LPV/r 400/100 mg and recycled lamivudine 150 mg. By intend-to-treat analysis at 144 weeks, 26 (65%) and 22 (56%) patients achieved HIV-1 RNA at < 400 and < 50 copies/mL, respectively. In as-treated analysis, the corresponding rates were 26 of 28 (93%) and 22 of 28 (78%), respectively. Low-level viral rebound (HIV-1 RNA 50-400 copies/mL) was found in 6 (15%), 6 (15%), and 4 (10%) patients at week 48, 96 and week 144, respectively. Medians CD4 at week 48, 96, and 144 were 351, 481, and 584 cells/mm3 and significantly changed from baseline (all, P < 0.05). There were increments of mean triglycerides at 48 weeks and 144 weeks from baseline (P < 0.05). No major protease resistance-associated mutations emerged after virologic failure.
Conclusion:
LPV/r monotherapy with recycled lamivudine can maintain long-term virologic suppression in a relatively small proportion of patients failing NNRTI-based regimen and having limit option for active NRTI. More antiretroviral classes are needed be accessible in resource-limited countries.
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Conference highlights of the 5th international workshop on HIV persistence during therapy, 6-9 December 2011, St. Maartin, West Indies
The December 2011 5th International Workshop on HIV Persistence during Therapy addressed the issue of HIV persistence among 210 scientists from 10 countries involved in the study of HIV reservoirs and the search of an HIV cure. High quality abstracts were selected and discussed as oral or poster presentations. The aim of this review is to distribute the scientific highlights of this workshop outside the group as analyzed and represented by experts in retrovirology, immunology and clinical research.
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Algorithms for Molecular Biology - Latest Articles
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Ubiquity of synonymity: almost all large binary trees are not uniquely identified by their spectra or their immanantal polynomials
Background:
There are several common ways to encode a tree as a matrix, such as the adjacency matrix, the Laplacian matrix (that is, the infinitesimal generator of the natural random walk), and the matrix of pairwise distances between leaves. Such representations involve a specific labeling of the vertices or at least the leaves, and so it is natural to attempt to identify trees by some feature of the associated matrices that is invariant under relabeling. An obvious candidate is the spectrum of eigenvalues (or, equivalently, the characteristic polynomial).
Results:
We show for any of these choices of matrix that the fraction of binary trees with a unique spectrum goes to zero as the number of leaves goes to infinity. We investigate the rate of convergence of the above fraction to zero using numerical methods. For the adjacency and Laplacian matrices, we show that the a priori more informative immanantal polynomials have no greater power to distinguish between trees.
Conclusion:
Our results show that a generic large binary tree is highly unlikely to be identified uniquely by common spectral invariants.
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Tree-average distances on certain phylogenetic networks have their weights uniquely determined
A phylogenetic network N has vertices corresponding to species and arcs corresponding to direct genetic inheritance from the species at the tail to the species at the head. Measurements of DNA are often made on species in the leaf set, and one seeks to infer properties of the network, possibly including the graph itself. In the case of phylogenetic trees, distances between extant species are frequently used to infer the phylogenetic trees by methods such as neighbor-joining.This paper proposes a "tree-average" distance for networks more general than trees. The notion requires a "weight" on each arc measuring the genetic change along the arc. For each displayed tree the distance between two leaves is the sum of the weights along the path joining them. At a hybrid vertex, each character is inherited from one of its parents. We will assume that for each hybrid there is a probability that the inheritance of a character is from a specified parent. Assume that the inheritance events at different hybrids are independent. Then for each displayed tree there will be a probability that the inheritance of a given character follows the tree; this probability may be interpreted as the probability of the tree. The "tree-average" distance between the leaves is defined to be the expected value of their distance in the displayed trees.For a class of rooted networks that includes rooted trees, it is shown that the weights and the probabilities at each hybrid vertex can be calculated given the network and the tree-average distances between the leaves. Hence these weights and probabilities are uniquely determined. The hypotheses on the networks include that hybrid vertices have indegree exactly 2 and that vertices that are not leaves have a tree-child.
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Fractal MapReduce decomposition of sequence alignment
The dramatic fall in the cost of genomic sequencing, and the increasing convenience of distributed cloud computing resources, positions the MapReduce coding pattern as a cornerstone of scalable bioinformatics algorithm development. In some cases an algorithm will find a natural distribution via use of map functions to process vectorized components, followed by a reduce of aggregate intermediate results. However, for some data analysis procedures such as sequence analysis, a more fundamental reformulation may be required. Results - In this report we describe a solution to sequence comparison that can be thoroughly decomposed into multiple rounds of map and reduce operations. The route taken makes use of iterated maps, a fractal analysis technique, that has been found to provide a "alignment-free" solution to sequence analysis and comparison. That is, a solution that does not require dynamic programming, relying on a numeric Chaos Game Representation (CGR) data structure. This claim is demonstrated in this report by calculating the length of the longest similar segment by inspecting only the USM coordinates of two analogous units: with no resort to dynamic programming. Conclusions - The procedure described is an attempt at extreme decomposition and parallelization of sequence alignment in anticipation of a volume of genomic sequence data that cannot be met by current algorithmic frameworks. The solution found is delivered with a browser-based application (webApp), highlighting the browser's emergence as an environment for high performance distributed computing.
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Wrapper-based selection of genetic features in genome-wide association studies through fast matrix operations
Background:
Through the wealth of information contained within them, genome-wide association studies (GWAS) have the potential to provide researchers with a systematic means of associating genetic variants with a wide variety of disease phenotypes. Due to the limitations of approaches that have analyzed single variants one at a time, it has been proposed that the genetic basis of these disorders could be determined through detailed analysis of the genetic variants themselves and in conjunction with one another. The construction of models that account for these subsets of variants requires methodologies that generate predictions based on the total risk of a particular group of polymorphisms. However, due to the excessive number of variants, constructing these types of models has so far been computationally infeasible.
Results:
We have implemented an algorithm, known as greedy RLS, that we use to perform the first known wrapper-based feature selection on the genome-wide level. The running time of greedy RLS grows linearly in the number of training examples, the number of features in the original data set, and the number of selected features. This speed is achieved through computational short-cuts based on matrix calculus. Since the memory consumption in present-day computers can form an even tighter bottleneck than running time, we also developed a space efficient variation of greedy RLS which trades running time for memory. These approaches are then compared to traditional wrapper-based feature selection implementations based on support vector machines (SVM) to reveal the relative speed-up and to assess the feasibility of the new algorithm. As a proof of concept, we apply greedy RLS to the Hypertension - UK National Blood Service WTCCC dataset and select the most predictive variants using 3-fold external cross-validation in less than 26 minutes on a high end desktop. On this dataset, we also show that greedy RLS has a better classification performance on independent test data than a classifier trained using features selected by a statistical p-value-based filter, which is currently the most popular approach for constructing predictive models in GWAS.
Conclusions:
Greedy RLS is the first known implementation of a machine learning based method with the capability to conduct a wrapper-based feature selection on an entire GWAS containing several thousand examples and over 400,000 variants. In our experiments, greedy RLS selected a highly predictive subset of genetic variants in a fraction of the time spent by wrapper-based selection methods used together with SVM classifiers. The proposed algorithms are freely available as part of the RLScore software library at http://users.utu.fi/aatapa/RLScore/.
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Pattern matching through Chaos Game Representation: bridging numerical and discrete data structures for biological sequence analysis
Background:
Chaos Game Representation (CGR) is an iterated function that bijectively maps discrete sequences into a continuous domain. As a result, discrete sequences can be object of statistical and topological analyses otherwise reserved to numerical systems. Characteristically, CGR coordinates of substrings sharing an L-long suffix will be located within 2^-L distance of each other. In the two decades since its original proposal, CGR has been generalized beyond its original focus on genomic sequences and has been successfully applied to a wide range of problems in bioinformatics. This report explores the possibility that it can be further extended to approach algorithms that rely on discrete, graph-based representations.
Results:
The exploratory analysis described here consisted of selecting foundational string problems and refactoring them using CGR-based algorithms. We found that CGR can take the role of suffix trees and emulate sophisticated string algorithms, efficiently solving exact and approximate string matching problems such as finding all palindromes and tandem repeats, and matching with mismatches. The common feature of these problems is that they use longest common extension (LCE) queries as subtasks of their procedures, which we show to have a constant time solution with CGR. Additionally, we show that CGR can be used as a rolling hash function within the Rabin-Karp algorithm.
Conclusions:
The analysis of biological sequences relies on algorithmic foundations facing mounting challenges, both logistic (performance) and analytical (lack of unifying mathematical framework). CGR is found to provide the latter and to promise the former: graph-based data structures for sequence analysis operations are entailed by numerical-based data structures produced by CGR maps, providing a unifying analytical framework for a diversity of pattern matching problems.
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Maximum Parsimony on Phylogenetic Networks
Background:
Phylogenetic networks are generalizations of phylogenetic trees, that are used to model evolutionary events in various contexts. Several different methods and criteria have been introduced for reconstructing phylogenetic trees. Maximum Parsimony is a character-based approach that infers a phylogenetic tree by minimizing the total number of evolutionary steps required to explain a given set of data assigned on the leaves. Exact solutions for optimizing parsimony scores on phylogenetic trees have been introduced in the past.
Results:
In this paper, we define the parsimony score on networks as the sum of the substitution costs along all the edges of the network; and show that certain well-known algorithms that calculate the optimum parsimony score on trees, such as Sankoff and Fitch algorithms extend naturally for networks, barring conflicting assignments at the reticulate vertices. We provide heuristics for finding the optimum parsimony scores on networks. Our algorithms can be applied for any cost matrix that may contain unequal substitution costs of transforming between different characters along different edges of the network. We analyzed this for experimental data on 10 leaves or fewer with at most 2 reticulations and found that for almost all networks, the bounds returned by the heuristics matched with the exhaustively determined optimum parsimony scores.
Conclusion:
The parsimony score we define here does not directly reflect the cost of the best tree in the network that displays the evolution of the character. However, when searching for the most parsimonious network that describes a collection of characters, it becomes necessary to add additional cost considerations to prefer simpler structures, such as trees over networks. The parsimony score on a network that we describe here takes into account the substitution costs along the additional edges incident on each reticulate vertex, in addition to the substitution costs along the other edges which are common to all the branching patterns introduced by the reticulate vertices. Thus the score contains an in-built cost for the number of reticulate vertices in the network, and would provide a criterion that is comparable among all networks. Although the problem of finding the parsimony score on the network is believed to be computationally hard to solve, heuristics such as the ones described here would be beneficial in our efforts to find a most parsimonious network.
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Reconciling taxonomy and phylogenetic inference: formalism and algorithms for describing discord and inferring taxonomic roots
Background:
Although taxonomy is often used informally to evaluate the results of phylogenetic inference and find the root of phylogenetic trees, algorithmic methods to do so are lacking.
Results:
In this paper we formalize these procedures and develop algorithms to solve the relevant problems. In particular, we introduce a new algorithm that solves a "subcoloring" problem to express the difference between a taxonomy and a phylogeny at a given rank. This algorithm improves upon the current best algorithm in terms of asymptotic complexity for the parameter regime of interest; we also describe a branch-and-bound algorithm that saves orders of magnitude in computation on real data sets. We also develop a formalism and an algorithm for rooting phylogenetic trees according to a taxonomy.
Conclusions:
The algorithms in this paper, and the associated freely available software, will help biologists better use and understand taxonomically labeled phylogenetic trees.
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A polynomial time algorithm for calculating the probability of a ranked gene tree given a species tree
Background:
The ancestries of genes form gene trees which do not necessarily have the same topology as the species tree due to incomplete lineage sorting. Available algorithms determining the probability of a gene tree given a species tree require exponential computational runtime.
Results:
In this paper, we provide a polynomial time algorithm to calculate the probability of a ranked gene tree topology for a given species tree, where a ranked tree topology is a tree topology with the internal vertices being ordered. The probability of a gene tree topology can thus be calculated in polynomial time if the number of orderings of the internal vertices is a polynomial number. However, the complexity of calculating the probability of a gene tree topology with an exponential number of rankings for a given species tree remains unknown.
Conclusions:
Polynomial algorithms for calculating ranked gene tree probabilities may become useful in developing methodology to infer species trees based on a collection of gene trees, leading to a more accurate reconstruction of ancestral species relationships.
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Computing evolutionary distinctiveness indices in large scale analysis
We present optimal linear time algorithms for computing the Shapley values and 'heightened evolutionary distinctiveness' (HED) scores for the set of taxa in a phylogenetic tree. We demonstrate the efficiency of these new algorithms by applying them to a set of 10,000 reasonable 5139-species mammal trees. This is the first time these indices have been computed on such a large taxon and we contrast our finding with an ad-hoc index for mammals, fair proportion (FP), used by the Zoological Society of London's EDGE programme. Our empirical results follow expectations. In particular, the Shapley values are very strongly correlated with the FP scores, but provide a higher weight to the few monotremes that comprise the sister to all other mammals. We also find that the HED score, which measures a species' unique contribution to future subsets as function of the probability that close relatives will go extinct, is very sensitive to the estimated probabilities. When they are low, HED scores are less than FP scores, and approach the simple measure of a species' age. Deviations (like the Solendon genus of the West Indies) occur when sister species are both at high risk of extinction and their clade roots deep in the tree. Conversely, when endangered species have higher probabilities of being lost, HED scores can be greater than FP scores and species like the African elephant Loxondonta africana, the two solendons and the thumbless bat Furipterus horrens can move up the rankings. We suggest that conservation attention be applied to such species that carry genetic responsibility for imperiled close relatives. We also briefly discuss extensions of Shapley values and HED scores that are possible with the algorithms presented here.
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A normalization strategy for comparing tag count data
Background:
High-throughput sequencing, such as ribonucleic acid sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) analyses, enables various features of organisms to be compared through tag counts. Recent studies have demonstrated that the normalization step for RNA-seq data is critical for a more accurate subsequent analysis of differential gene expression. Development of a more robust normalization method is desirable for identifying the true difference in tag count data.
Results:
We describe a strategy for normalizing tag count data, focusing on RNA-seq. The key concept is to remove data assigned as potential differentially expressed genes (DEGs) before calculating the normalization factor. Several R packages for identifying DEGs are currently available, and each package uses its own normalization method and gene ranking algorithm. We compared a total of eight package combinations: four R packages (edgeR, DESeq, baySeq, and NBPSeq) with their default normalization settings and with our normalization strategy. Many synthetic datasets under various scenarios were evaluated on the basis of the area under the curve (AUC) as a measure for both sensitivity and specificity. We found that packages using our strategy in the data normalization step overall performed well. This result was also observed for a real experimental dataset.
Conclusion:
Our results showed that the elimination of potential DEGs is essential for more accurate normalization of RNA-seq data. The concept of this normalization strategy can widely be applied to other types of tag count data and to microarray data.
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Annals of Clinical Microbiology and Antimicrobials - Latest Articles
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Unusual manifestations of acute Q fever:
autoimmune hemolytic anemia and tubulointerstitial
nephritis
Q fever is a worldwide zoonotic infection that caused by Coxiella burnetii, a strictintracellular bacterium. It may be manifested by some of the autoimmune events and isclassified into acute and chronic forms. The most frequent clinical manifestation of acuteform is a self-limited febrile illness which is associated with severe headache, muscle ache,arthralgia and cough. Meningoencephalitis, thyroiditis, pericarditis, myocarditis, mesentericlymphadenopathy, hemolytic anemia, and nephritis are rare manifestations. Here we present acase of acute Q fever together with Coombs' positive autoimmune hemolytic anemia (AIHA)and tubulointerstitial nephritis treated with chlarithromycin, steroids and hemodialysis.Clinicians should be aware of such rare manifestations of the disease.
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Antibacterial activity of statins: a comparative study of Atorvastatin, Simvastatin, and Rosuvastatin
Background:
Statins have several effects beyond their well-known antihyperlipidemic activity, whichinclude immunomodulatory, antioxidative and anticoagulant effects. In this study, we havetested the possible antimicrobial activity of statins against a range of standard bacterial strainsand bacterial clinical isolates.
Methods:
Minimum inhibitory concentrations (MIC) values were evaluated and compared among threemembers of the statins drug (atorvastatin, simvastatin, and rosuvastatin).
Results:
It was revealed that statins are able to induce variable degrees of antibacterial activity withatorvastatin, and simvastatin being the more potent than rosuvastatin. Methicillin-sensitivestaphylococcus aureus (MSSA), methicillin-resistant staphylococcus aureus (MRSA),vancomycin-susceptible enterococci (VSE), vancomycin-resistant enterococcus (VRE),acinetobacter baumannii, staphylococcus epidermidis, and enterobacter aerogenes, weremore sensitive to both atorvastatin, and simvastatin compared to rosuvastatin. On the otherhand, escherichia coli, proteus mirabilis, and enterobacter cloacae were more sensitive toatorvastatin compared to both simvastatin and rosuvastatin. Furthermore, most clinicalisolates were less sensitive to statins compared to their corresponding standard strains.
Conclusion:
Our findings might raise the possibility of a potentially important antibacterial class effect forstatins especially, atorvastatin and simvastatin.
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Miliary tuberculosis occurred after immunosuppressive
drug in PNH patient with completely cured tuberculosis; a
case report
Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder that presents with hemolytic anemia, marrow failure and thrombophilia. During acute attacks, corticosteroid can alleviate the hemolytic paroxysm, but the prolonged administration induces serious toxicity including immunosupporession. So American thoracic society (ATS) for tuberculosis (TB) recommends prophylactic anti-TB medication in patients with a long-term steroid therapy. However, in the patient who was treated for active TB in the past, there are no guidelines of the test for determining patients who have latent TB infection (LTBI) and no recommendations of TB prophylaxis if there is no evidence of reactivation at present. A 40-year-old male patient presented with fever and aggravated weakness for a week. He was diagnosed with PNH a month ago and took corticosteroid for 3 weeks. In the past, he was diagnosed with pulmonary TB and completely cured after treatment. According to guideline, he was not indicated with TB prophylaxis. However, he caught miliary TB, progressed to acute respiratory distress syndrome. We experience this embarrassing case, and emphasize the need to investigate multicentral TB prevalence and to make the guidelines of anti-TB medication in subgroups of hematologic diseases including PNH.
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Isolation of antibacterial compounds from Quercus
dilatata L. through bioassay guided fractionation
Background:
Four medicinal plants (Chrozophora hierosolymitana Spreng, Chrysanthemum leucanthemumL., Ephedra gerardiana Wall. ex Stapf, and Quercus dilatata L.) used by indigenous healersto treat various infectious diseases were selected for the present study. The major objective ofthe present study was isolation and characterization of antimicrobial components from thecrude plant extracts using bioassay guided fractionation.
Methods:
Seven methanolic extracts of the four plants were screened to identify any antimicrobialagents present in them. The active crude plant extract was fractionated first by solventpartitioning and then by HPLC. Characterization of the active fractions was done by usingspectrophotometer.
Results:
All the seven methanolic extracts showed low antifungal activity, however, when theseextracts were tested for antibacterial activity, significant activity was exhibited by twoextracts. The extract of aerial parts of Q. dilatata was most active and therefore, was selectedfor further analysis. Initially fractionation was done by solvent-solvent partitioning and out ofsix partitioned fractions, ethanol fraction was selected on the basis of results of antibacterialactivity and phytochemical analysis. Further, fractionation was carried out by RP- HPLC andpurified active subfractions were characterized by comparing their absorption spectra withthat of the known natural products isolated from the plants of Quercus genus.Discussion and conclusionThe results suggest that this is the first report of the isolated antibacterial compounds fromthis genus.
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Bioassay-guided discovery of antibacterial agents: in
vitro screening of Peperomia vulcanica, Peperomia
fernandopoioana and Scleria striatinux
Background:
The global burden of bacterial infections is high and has been further aggravated byincreasing resistance to antibiotics. In the search for novel antibacterials, three medicinalplants: Peperomia vulcanica, Peperomia fernandopoioana (Piperaceae) and Scleria striatinux(Cyperaceae), were investigated for antibacterial activity and toxicity.
Methods:
Crude extracts of these plants were tested by the disc diffusion method against six bacterialtest organisms followed by bio-assay guided fractionation, isolation and testing of purecompounds. The minimum inhibitory (MIC) and minimum bactericidal (MBC)concentrations were measured by the microdilution method. The acute toxicity of the activeextracts and cytotoxicity of the active compound were performed in mice and mammaliancells, respectively.
Results:
The diameter of the zones of inhibition (DZI) of the extracts ranged from 7-13 mm onEscherichia coli and Staphylococcus aureus of which the methylene chloride:methanol [1:1]extract of Scleria striatinux recorded the highest activity (DZI = 13 mm). Twenty-nine purecompounds were screened and one, Okundoperoxide, isolated from S. striatinux, recorded aDZI ranging from 10-19 mm on S. aureus. The MICs and MBCs indicated that thePeperomias had broad-spectrum bacteriostatic activity. Toxicity tests showed thatOkundoperoxide may have a low risk of toxicity with an LC50 of 46.88 mug/mL.
Conclusions:
The antibacterial activity of these plants supports their use in traditional medicine. The purecompound, Okundoperoxide, may yield new antibacterial lead compounds followingmedicinal chemistry exploration.
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A rapid low-cost real-time PCR for the detection of
Klebsiella pneumonia carbapenemase genes
Background:
Klebsiella pneumonia carbapenemases (KPCs) are able to hydrolyze the carbapenems, whichcause many bacteria resistance to multiple classes of antibiotics, so the rapid dissemination ofKPCs is worrisome. Laboratory identification of KPCs-harboring clinical isolates would be akey to limit the spread of the bacteria. This study would evaluate a rapid low-cost real-timePCR assay to detect KPCs.
Methods:
Real-time PCR assay based on SYBR GreenIwas designed to amplify a 106 bp product of theblaKPC gene from the159 clinical Gram-negative isolates resistant to several classes of beta-lactam antibiotics through antimicrobial susceptibility testing. We confirmed the results ofreal-time PCR assay by the conventional PCR-sequencing. At the same time, KPCs of theseclinical isolates were detected by the modified Hodge test (MHT). Then we compared theresults of real-time PCR assay with those of MHT from the sensitivity and specificity.Moreover, we evaluated the sensitivity of the real-time PCR assay.
Results:
The sensitivity and specificity of the results of the real-time PCR assay compared with thoseof MHT was 29/29(100 %) and 130/130(100 %), respectively. The results of the real-timePCR and the MHT were strongly consistent (Exact Sig. (2-tailed) =1. 000; McNemar test).The real-time PCR detection limit was about 0.8 cfu using clinical isolates.
Conclusion:
The real-time PCR assay could rapidly and accurately detect KPCs -harboring strains withhigh analytical sensitivity and specificity.
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Inhibitory effect of Allium sativum and Zingiber
officinale extracts on clinically important drug
resistant pathogenic bacteria
Background:
Herbs and spices are very important and useful as therapeutic agent against manypathological infections. Increasing multidrug resistance of pathogens forces to findalternative compounds for treatment of infectious diseases.
Methods:
In the present study the antimicrobial potency of garlic and ginger has been investigatedagainst eight local clinical bacterial isolates. Three types of extracts of each garlic and gingerincluding aqueous extract, methanol extract and ethanol extract had been assayed separatelyagainst drug resistant Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis,Staphylococcus aureus, Klebsiella pneumoniae, Shigella sonnei, Staphylococcus epidermidisand Salmonella typhi. The antibacterial activity was determined by disc diffusion method.
Results:
All tested bacterial strains were most susceptible to the garlic aqueous extract and showedpoor susceptibility to the ginger aqueous extract. The (minimum inhibitory concentration)MIC of different bacterial species varied from 0.05 mg/ml to 1.0 mg/ml.
Conclusion:
In the light of several socioeconomic factors of Pakistan mainly poverty and poor hygieniccondition, present study encourages the use of spices as alternative or supplementarymedicine to reduce the burden of high cost, side effects and progressively increasing drugresistance of pathogens.
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Sensitivity pattern among bacterial isolates in neonatal septicaemia in Port Harcourt, Nigeria.
Background:
The organisms responsible for neonatal sepsis vary across geographical boundaries and with the time of illness thus periodic bacteriologic surveillance is a neccessity. The present study was therefore carried out to determine the common bacterial pathogens in Port Harcourt and their sensitivity pattern.
Methods:
Four hundred and six neonates were prospectively screened for sepsis over a 6 month period. Sensitivity of the bacterial isolates to different antibiotics was determined using Kirby-Bauer diffusion method.
Results:
Gram negative organisms predominated (75.1%) with Klebsiella pneumonia (58.2%) being the commonest. The quinolones were the most sensitive antibiotics to the commonly isolated organisms.
Conclusion:
Klebsiella pneumonia is the commonest organism responsible for neonatal sepsis in Port Harcourt. There is an overall decline in the antibiotic susceptibility to the commonly isolated bacterial pathogens.
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Successful salvage therapy with Daptomycin for osteomyelitis caused by methicillin-resistant Staphylococcus aureus in a renal transplant recipient with Fabry-Anderson disease
Daptomycin is licensed in adults for the management of Staphylococcus aureus methicillin-resistant infections, including bone and skin complicated infections. We describe for the first time its use in a renal transplant recipient for Fabry-Anderson Disease with right heel osteomyelitis. The patient was unresponsive to first-line Teicoplanin and second-line Tigecycline, whereas he was successfully treated with third-line Daptomycin monotherapy at 4 mg/Kg/qd for 4 weeks. Local debridement was performed in advance of each line of treatment.
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Antimicrobial activity of polyphenol-rich fractions from Sida alba L. (Malvaceae) against co-trimoxazol-resistant bacteria strains
Background:
The increased resistance of microorganisms to the currently used antimicrobials has lead to the evaluation of other agents that might have antimicrobial activity. Medicinal plants are sources of phytochemicals which are able to initiate different biological activities including antimicrobialsMaterials and methodsIn vitro antibacterial (MIC, MBC and time-kill studies) of polyphenol-rich fractions from Sida alba L. (Malvaceae) was assessed using ten bacteria strains (Gram-negative and Gram-positive).
Results:
All test bacteria were susceptible to the polyphenol-rich fractions. Time-kill results showed that after 5 h exposition there was no viable microorganism in the initial inoculum and the effect of polyphenol-rich fractions was faster on Enterococcus faecalis (Gram-positive bacterium) comparatively to the other bacteria strains.
Conclusion:
The data analysis indicates that the tested of polyphenol-rich fractions has significant effects when compared with the standard antibiotic. These results therefore justify the traditional use of sida alba L., alone or in combination with other herbs to treat bacterial infections.
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Annals of General Psychiatry - Latest Articles
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Development of the Global Disability Scale (GloDiS): preliminary results
Background:
The assessment of functioning and disability is an important part of clinical evaluation, since it measures disease burden and reflects the effectiveness of therapeutic planning and interventions. The aim of the current study was to develop a self-report instrument on the basis of a review of the literature, compatible with the World Health Organization (WHO) approach.
Methods:
The review of the literature led to the development of the Global Disability Scale (GloDiS), with 25 items assessing different aspects of disability. The study sample included 728 persons from vulnerable populations (homeless, jobless, very low income, single parent families and so on (29.12% males and 70.88% females; age 55.96 +/- 15.22 years). The protocol also included the State-Trait Anxiety Inventory (STAI) and the Center for Epidemiologic Studies Depression Scale (CES-D). The statistical analysis included factor analysis, item analysis and analysis of covariance (ANCOVA).
Results:
The factor analysis revealed the presence of four factors explaining 71% of total variance (everyday functioning, social and interpersonal functioning, severity and mental disability). The Cronbach alpha value for the whole scale was 0.95 and for subscales the range of values was 0.74 to 0.94.DiscussionThe results of the current study suggest that the GloDiS has the potential to serve as a reliable and valid tool for assessing functioning and disability. Further research is needed to prove that it could be useful across countries, populations and diseases, and on whether it provides data that are culturally meaningful and comparable. It can be used in surveys and in clinical research settings and it can generate information of use in evaluating health needs and the effectiveness of interventions to reduce disability and improve health.
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Deep transcranial magnetic stimulation add-on for the treatment of auditory hallucinations: a double-blind study
Background:
About 25% of schizophrenia patients with auditory hallucinations are refractory to pharmacotherapy and electroconvulsive therapy. We conducted a deep transcranial magnetic stimulation (TMS) pilot study in order to evaluate the potential clinical benefit of repeated left temporoparietal cortex stimulation in these patients. The results were encouraging, but a sham-controlled study was needed to rule out a placebo effect.
Methods:
A total of 18 schizophrenic patients with refractory auditory hallucinations were recruited, from Beer Yaakov MHC and other hospitals outpatient populations. Patients received 10 daily treatment sessions with low-frequency (1 Hz for 10 min) deep TMS applied over the left temporoparietal cortex, using the H1 coil at the intensity of 110% of the motor threshold. Procedure was either real or sham according to patient randomization. Patients were evaluated via the Auditory Hallucinations Rating Scale, Scale for the Assessment of Positive Symptoms-Negative Symptoms, Clinical Global Impressions, and Quality of Life Questionnaire.
Results:
In all, 10 patients completed the treatment (10 TMS sessions). Auditory hallucination scores of both groups improved; however, there was no statistical difference in any of the scales between the active and the sham treated groups.
Conclusions:
Low-frequency deep TMS to the left temporoparietal cortex using the protocol mentioned above has no statistically significant effect on auditory hallucinations or the other clinical scales measured in schizophrenic patients.Trial RegistrationClinicaltrials.gov identifier: NCT00564096.
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Treatment of refractory catatonic schizophrenia with low dose aripiprazole
This case report concerns a 54-year-old woman with catatonic schizophrenia, characterized by treatment resistance to pharmacotherapy with olanzapine, risperidone and flunitrazepam, and electroconvulsive therapy (ECT). In this case, olanzapine and risperidone and flunitrazepam did not improve her catatonic and psychotic symptoms, and induced extrapyramidal symptoms. The effects of ECT did not continue even for a month. However, treatment with low-dose aripiprazole dramatically improved the patient's psychotic symptoms and extrapyramidal symptoms. The mechanisms underlying the effects of low-dose aripiprazole in this case remain unclear, but unlike other antipsychotics aripiprazole is a dopamine D2 partial agonist. In this regard, our results suggest that aripiprazole has numerous advantages, especially in cases of stuporous catatonia and a defective general status such as the present case.
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Body composition in patients with schizophrenia: comparison with healthy controls
Background:
Recently, a relationship between obesity and schizophrenia has been reported. Although fat mass and fat-free mass have been shown to be more predictive of health risk than body mass index, there are limited findings about body composition among patients suffering from schizophrenia. The aim of this study was to compare the body composition of schizophrenia patients with that of healthy subjects in Japan.
Methods:
We recruited patients (n = 204), aged 41.3 +/- 13.8 (mean +/- SD) years old with a Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) diagnosis of schizophrenia who were admitted to psychiatric hospital using a cross-sectional design. Subjects' anthropometric measurements including weight, height, body mass index (BMI), and medications were also collected. Body fat, percentage (%) body fat, fat-free mass, muscle mass, and body water were measured using the bioelectrical impedance analysis (BIA) method. A comparative analysis was performed with schizophrenic subjects and 204 healthy control individuals.
Results:
In a multiple regression model with age, body mass index, and dose in chlorpromazine equivalents, schizophrenia was significantly linked with more body fat, higher percentage body fat, lower fat-free mass, lower muscle mass, and lower body water among males. In females, schizophrenia had a significant association with lower percentage body fat, higher fat-free mass, higher muscle mass, and higher body water.
Conclusions:
Our data demonstrate gender differences with regard to changes in body composition in association with schizophrenia. These results indicate that intervention programs designed to fight obesity among schizophrenic patients should be individualized according to gender.
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Treatment received, satisfaction with health care services, and psychiatric symptoms 3 months after hospitalization for self-poisoning
Background:
Patients who self-poison have high repetition and high mortality rates. Therefore, appropriate follow-up is important. The aims of the present work were to study treatment received, satisfaction with health care services, and psychiatric symptoms after hospitalization for self-poisoning.
Methods:
A cohort of patients who self-poisoned (n = 867) over a period of 1 year received a questionnaire 3 months after discharge. The Beck Depression Inventory (BDI), Beck Hopelessness Scale (BHS), and Generalized Self-Efficacy Scale (GSE) were used. The participation rate was 28% (n = 242); mean age, 41 years; 66% females.
Results:
Although only 14% of patients were registered without follow-up referrals at discharge, 41% reported no such measures. Overall, satisfaction with treatment was fairly good, although 29% of patients waited more than 3 weeks for their first appointment. A total of 22% reported repeated self-poisoning and 17% cutting. The mean BDI and BHS scores were 23.3 and 10.1, respectively (both moderate to severe). The GSE score was 25.2. BDI score was 25.6 among patients with suicide attempts, 24.9 for appeals, and 20.1 for substance-use-related poisonings.
Conclusions:
Despite plans for follow-up, many patients reported that they did not receive any. The reported frequency of psychiatric symptoms and self-harm behavior indicate that a more active follow-up is needed.
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The role of cytokines and hot flashes in perimenopausal depression
Background:
An imbalance in the production of proinflammatory and anti-inflammatory cytokines may play a role in the pathophysiology of perimenopausal depression. The aim of this study was to examine serum levels of the proinflammatory cytokines interleukin 6 (IL-6) and tumor necrosis factor α (TNFα), and the anti-inflammatory cytokine IL-10, in perimenopausal women suffering from depression. Furthermore, to assess whether serum cytokine levels are associated with the presence of hot flashes or the use of selective serotonin reuptake inhibitors (SSRIs). We also evaluated the possible association of hot flashes and perimenopausal depression.
Methods:
Serum samples from 65 perimenopausal women, 41 with depression and 24 without depression, were assessed for serum IL-6, TNFα and IL-10 by conventional enzyme-linked immunosorbent assays. Depression was evaluated by the 17-item Hamilton Depression Rating Scale (HAM-D 17) and a psychiatric interview. The presence and severity of hot flashes were examined using the Menopause Rating Scale (MRS).
Results:
Serum levels cytokines did not differ between depressed women and normal controls. Serum levels of cytokines did not change significantly in depressed women with hot flashes or in depressed women treated with SSRIs. Hot flashes were strongly associated (P < 0.0001) with perimenopausal depression.
Conclusion:
The study supports the hypothesis that perimenopausal depression is not characterized by increased proinflammatory cytokines and decreased anti-inflammatory cytokines. Women with perimenopausal depression suffer from more severe and more frequent hot flashes than women without perimenopausal depression.
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Caregiving in severe mental illness: the psychometric properties of the Involvement Evaluation Questionnaire in Portugal
Background:
Despite the achievements of previous research, caregiving assessments in severe mental illness should be crossculturally validated in order to define risk groups or to evaluate family work. This study reports on the psychometric properties of the European version of the Involvement Evaluation Questionnaire (IEQ-EU) in Portugal.
Methods:
A Portuguese translation of the IEQ-EU was developed according to the 'European Psychiatric Services: Inputs Linked to Outcome Domains and Needs' (EPSILON) group guidelines. We then studied 194 caregivers who were related to patients with schizophrenia spectrum disorders in psychiatric outpatient services. All relatives were assessed using the IEQ-EU. In order to describe the corresponding patients' sample, the majority (n = 162) was evaluated with the World Health Organization Disability Assessment Schedule (WHO-DAS II); 108 patients were also assessed with the Brief Psychiatric Rating Scale (BPRS) and the Global Assessment of Functioning (GAF).
Results:
The factor structure of the Portuguese version of the questionnaire was similar to the original; internal consistency was good, with Cronbach's alpha ranging from 0.71 to 0.87 in the IEQ-EU scales (total score and domains: tension, supervision, worrying, urging); test-retest reliability yielded intraclass correlation coefficients (ICCs) from 0.80 to 0.94, concerning the same scores. Ecological validity was confirmed. Most caregiving consequences were reported on the worrying domain of the IEQ-EU.
Conclusions:
Validity and reliability of the Portuguese IEQ-EU translation were established. Specifically the four IEQ-EU subscale domains seem to be valid in Portugal.
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Number of prior episodes and the presence of depressive symptoms are associated with longer length of stay for patients with acute manic episodes
Background:
Few studies have analyzed predictors of length of stay (LOS) in patients admitted due to acute bipolar manic episodes. The purpose of the present study was to estimate LOS and to determine the potential sociodemographic and clinical risk factors associated with a longer hospitalization. Such information could be useful to identify those patients at high risk for long LOS and to allocate them to special treatments, with the aim of optimizing their hospital management.
Methods:
This was a cross-sectional study recruiting adult patients with a diagnosis of bipolar disorder (Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) criteria) who had been hospitalized due to an acute manic episode with a Young Mania Rating Scale total score greater than 20. Bivariate correlational and multiple linear regression analyses were performed to identify independent predictors of LOS.
Results:
A total of 235 patients from 44 centers were included in the study. The only factors that were significantly associated to LOS in the regression model were the number of previous episodes and the Montgomery-Åsberg Depression Rating Scale (MADRS) total score at admission (P < 0.05).
Conclusions:
Patients with a high number of previous episodes and those with depressive symptoms during mania are more likely to stay longer in hospital. Patients with severe depressive symptoms may have a more severe or treatment-resistant course of the acute bipolar manic episode.
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Atomoxetine treatment for nicotine withdrawal: a pilot double-blind, placebo-controlled, fixed-dose study in adult smokers
Background:
Many effective treatments for nicotine addiction inhibit noradrenaline reuptake. Three recent studies have suggested that another noradrenaline reuptake inhibitor, atomoxetine, may reduce smoking behaviors.
Methods:
The present double-blind, placebo-controlled, fixed-dose study was carried out over 21 days during which administration of 40 mg atomoxetine was compared to placebo in 17 individuals. Of these, nine were randomized to atomoxetine and eight to placebo. Baseline and weekly measurements were made using the Cigarette Dependence Scale (CDS), Cigarette Withdrawal Scale (CWS), Questionnaire of Smoking Urges (QSU), reported number of cigarettes smoked, and salivary cotinine levels.
Results:
The study results showed that all those on placebo completed the study. In marked contrast, of the nine individuals who started on atomoxetine, five dropped out due to side effects. In a completer analysis there were statistically significant differences at 14 and 21 days in several measures between the atomoxetine and placebo groups, including CDS, CWS, QSU, number of cigarettes smoked (decreasing to less than two per day in the treatment group who completed the study), and a trend towards lower mean salivary cotinine levels. However, these differences were not seen in a last observation carried forward (LOCF) analysis.
Conclusions:
In summary, this is the first study to examine the use of atomoxetine in non-psychiatric adult smokers for a period of more than 7 days, and the findings suggest that atomoxetine might be a useful treatment for nicotine addiction. However, the dose used in the current study was too high to be tolerated by many adults, and a dose-finding study is required to determine the most appropriate dose for future studies of this potential treatment for smoking cessation.
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Effect of age and disease on bone mass in Japanese patients with schizophrenia
Background:
There have been a limited number of studies comparing bone mass between patients with schizophrenia and the general population. The aim of this study was to compare the bone mass of schizophrenia patients with that of healthy subjects in Japan.
Methods:
We recruited patients (n = 362), aged 48.8 ± 15.4 (mean ± SD) years who were diagnosed with schizophrenia or schizoaffective disorder based on the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV). Bone mass was measured using quantitative ultrasound densitometry of the calcaneus. The osteosono-assessment index (OSI) was calculated as a function of the speed of sound and the transmission index. For comparative analysis, OSI data from 832 adults who participated in the Iwaki Health Promotion Project 2009 was used as representative of the general community.
Results:
Mean OSI values among male schizophrenic patients were lower than those in the general population in the case of individuals aged 40 and older. In females, mean OSI values among schizophrenic patients were lower than those in the general community in those aged 60 and older. In an analysis using the general linear model, a significant interaction was observed between subject groups and age in males.
Conclusions:
Older schizophrenic patients exhibit lower bone mass than that observed in the general population. Our data also demonstrate gender and group differences among schizophrenic patients and controls with regard to changes in bone mass associated with aging. These results indicate that intervention programs designed to delay or prevent decreased bone mass in schizophrenic patients might be tailored according to gender.
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Annals of Surgical Innovation and Research - Latest Articles
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Three dimensional socket preservation: A technique for soft tissue augmentation along with socket grafting.
Background:
A cursory review of the current socket preservation literatures well depicts the necessity of further esthetic considerations through the corrective procedures of the alveolar ridge upon and post extraction. A new technique has been described here is a rotational pedicle combined epithelialized and connective tissue graft (RPC graft) adjunct with immediate guided tissue regeneration (GBR) procedure. Results: We reviewed this technique through a case report and discuss it`s benefit in compare to other socket preservation procedures. Conclusion: The main advantages of RPC graft would be summarized as follows: stable primary closure during bone remodeling, saving or crating sufficient vestibular depth, making adequate keratinized gingiva on the buccal surface, and being esthetically pleasant.Keywordsbone, dental implant, esthetic.
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Emergency treatment of a ruptured huge omphalocele by simple suture of its membrane
Background:
The rupture of a huge omphalocele is an emergency that threatens the newborn baby's life. It constitutes a therapeutical concern in the absence of prosthesis especially in developing countries.
Methods:
We are reporting herein the case of a newborn baby that we managed in emergency successfully thanks to a simple treatment.
Results:
It was a huge omphalocele, ruptured during delivery, in a male newborn baby. We conducted a simple and conservative surgical treatment without prosthesis, which consisted of reconstruction of the omphalocele's membrane by closing it with absorbable suture materials. The suture of the omphalocele's membrane was followed by treatment with the Grob's method. This treatment saved the newborn baby's life. The total skinning was obtained after 3 months.
Conclusions:
In case of rupture of huge omphalocele in absence of prosthesis, it is better to suture the membrane, and continue the treatment according to the Grob's method; the residual disembowelment can be repaired later.
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Emergency incisional hernia repair: A difficult problem waiting for a solution
Background:
Emergency repair of incarcerated incisional hernia with associated bowel obstruction in potentially or contaminated field is technically challenging due to edematous, inflamed and friable tissues with occasional need for concurrent bowel resection and carries high rates of post-operative infectious complications. The aim of this study was to retrospectively assess the wound related morbidity of use of permanent prosthetic mesh in emergency repair of incarcerated incisional hernia with associated bowel obstruction. We also describe a new technique of leaving the mesh exposed to heal by secondary intention with granulation tissue.
Methods:
Between 2000 and 2010 a total of 60 patients underwent emergency surgery for incarcerated incisional hernia with associated bowel obstruction with placement of permanent prosthetic mesh. The wound was closed after hernia repair in 55 patients while it was left open to granulate in 5 patients.
Results:
In the group of patients with primary wound closure, 11 patients developed superficial surgical site infection, 5 developed deep wound infection and one patient had cellulitis. These patients were treated with wound debridement and antibiotics. Mesh removal was required in one patient. There were no infections in the group of patients who had their surgical wounds left open. One patient in this group died on the fifth postoperative day from septicemia.
Conclusion:
Use of permanent prosthetic mesh in emergency repair of incarcerated incisional hernia with associated bowel obstruction. in contaminated field is associated with high risk of wound infection.
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At times, myomectomy is mandatory to effect delivery
Background:
Excision of a leiomyoma has never been a choice during caesarean section.MethodMyomectomy of a massive fibroid was necessitated prior to delivering the baby.
Results:
Delivery of a healthy was effected by Classical caesarean section.
Conclusion:
Leiomyoma in pregnancy is not an unknown entity and is a cause of concern for being a source of excruciating pain, at times, during the ongoing gestation.Although performed rarely, it is sometimes necessary to remove a large myoma to effect delivery of the baby during Cesarean section as is depicted in the case being presented hereunder.
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Novel technique for biliary reconstruction using an isolated gastric tube with a vascularized pedicle: a live animal experimental study and the first clinical case.
Background:
Biliary tract reconstruction continues to be a challenging surgical problem. Multiple experimental attempts have been reported to reconstruct biliary defects with different materials and variable outcome. Our aim was to evaluate a new method for biliary reconstruction using an isolated pedicled gastric tube in a live animal trial and also to present the first clinical case.
Methods:
Seven mongrel dogs underwent biliary reconstruction using gastric tube harvested, completely separated from the greater curvature, and based on a vascularized pedicle with the right gastroepiploic vessels. The tube was interposed between the common bile duct (CBD) and the duodenum. Postoperative mortality, morbidity, liver functions, gross and microscopic histological picture were assessed. The first clinical case was also presented where, in a patient with post-cholecystectomy biliary injury, an isolated pedicled gastric tube was interposed between the proximal and distal ends of the CBD.
Results:
One dog did not recover from anesthesia and another one died postoperatively from septic peritonitis. Five dogs survived the procedure and showed uneventful course and no cholestasis. The mean anastomotic circumference was 4.8 mm (range 4-6) for CBD anastomosis and 6.2 mm (range 5-7) for duodenal anastomosis. Histologically, anastomotic sites showed good evidence of healing. In the first clinical case, the patient showed clinical and biochemical improvement. Endoscopic retrograde cholangiography was feasible and assured patent biliary anastomoses.
Conclusion:
In mongrel dogs, biliary reconstruction using pedicled gastric tube interposition between CBD and duodenum is feasible with satisfactory clinical results, anastomotic circumference and histological evidence of healing. The technique is also feasible in human and seems to be promising.
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Stapler Access and Visibility in the Deep Pelvis: A Comparative Human Cadaver Study between a Computerized Right Angle Linear Cutter versus a Curved Cutting Stapler
PurposeDistal rectal stapling is often challenging because of limited space and visibility. We compared two stapling devices in the distal rectum in a cadaver study: the iDrive™ right angle linear cutter (RALC) (Covidien, New Haven, CT) and the CONTOUR® curved cutter (CC) (Ethicon Endo-Surgery, Cincinnati, OH).
Methods:
Twelve male cadavers underwent pelvic dissection by 4 surgeons. After rectal mobilization as in a total mesorectal excision, the staplers were applied to the rectum as deep as possible in both the coronal and sagittal positions. The distance from the pelvic floor was measured for each application. A questionnaire rated the visibility and access of the stapling devices. Measurements were taken between pelvic landmarks to see what anatomic factors hinder the placement of a distal rectal stapler.
Results:
The median (range) distance of the stapler from the pelvic floor in the coronal position for the RALC was 1.0 cm (0-4.0) vs. 2.0 cm (0-5.0) for the CC, p = 0.003. In the sagittal position, the median distance was 1.6 cm (0-3.5) for the RALC and 3.3 cm (0-5.0) for the CC, p < 0.0001. The RALC scored better than the CC in respect to: 1. interference by the symphysis pubis, 2. number of stapler readjustments, 3. ease of placement in the pelvis, 4. impediment of visibility, 5. ability to hold and retain tissue, 6. visibility rating, and 7. access in the pelvis. A shorter distance between the tip of the coccyx and the pubic symphysis correlated with a longer distance of the stapler from the pelvic floor (p = 0.002).
Conclusions:
The RALC is superior to the CC in terms of access, visibility, and ease of placement in the deep pelvis. This could provide important clinical benefit to both patient and surgeon during difficult rectal surgery.
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Use of a radiopaque localizer grid to reduce radiation exposure
Background:
Minimally invasive spine surgery requires placement of the skin incision at an ideal location in the patient's back by the surgeon. However, numerous fluoroscopic x-ray images are sometimes required to find the site of entry, thereby exposing patients and Operating Room personnel to additional radiation. To minimize this exposure, a radiopaque localizer grid was devised to increase planning efficiency and reduce radiation exposure.
Results:
The radiopaque localizer grid was utilized to plan the point of entry for minimally invasive spine surgery. Use of the grid allowed the surgeon to accurately pinpoint the ideal entry point for the procedure with just one or two fluoroscopic X-ray images.
Conclusions:
The reusable localizer grid is a simple and practical device that may be utilized to more efficiently plan an entry site on the skin, thus reducing radiation exposure. This device or a modified version may be utilized for any procedure involving the spine.
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Odontostomatologic Management of Patients Receiving Oral Anticoagulant Therapy: A Retrospective Multicentric Study.
IntroductionToday, we frequently find patients taking oral anticoagulant therapy (OAT), a prophylaxis against the occurrence of thromboembolic events. An oral surgeon needs to know how to better manage such patients, in order to avoid hemorrhagic and thromboembolic complications.Materials and methodsA group of 193 patients (119 men aged between 46 and 82 and 74 women aged between 54 and 76) undergoing OAT for more than 5 years were managed with a standardized management protocol and a 2-months follow-up. The aim of the present study was to apply a protocol, which could provide a safe intra- and postoperative management of patients on OAT.
Results:
Among the 193 patients, only 2 had postoperative complications.
Conclusions:
We think that the protocol used in the present study can be used for complete safety in the treatment of this type of patients.
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Comparing ambient, air-convection, and fluid-convection heating techniques in treating hypothermic burn patients, a clinical RCT
Background:
Hypothermia in burns is common and increases morbidity and mortality. Several methods are available to reach and maintain normal core body temperature, but have not yet been evaluated in critical care for burned patients. Our unit's ordinary technique for controlling body temperature (Bair Hugger®+ radiator ceiling + bed warmer + Hotline®) has many drawbacks e.g.; slow and the working environment is hampered.The aim of this study was to compare our ordinary heating technique with newly-developed methods: the Allon™2001 Thermowrap (a temperature regulating water-mattress), and Warmcloud (a temperature regulating air-mattress).
Methods:
Ten consecutive burned patients (> 20% total burned surface area and a core temperature < 36.0°C) were included in this prospective, randomised, comparative study. Patients were randomly exposed to 3 heating methods. Each treatment/measuring-cycle lasted for 6 hours. Each heating method was assessed for 2 hours according to a randomised timetable. Core temperature was measured using an indwelling (bladder) thermistor. Paired t-tests were used to assess the significance of differences between the treatments within the patients. ANOVA was used to assess the differences in temperature from the first to the last measurement among all treatments. Three-way ANOVA with the Tukey HSD post hoc test and a repeated measures ANOVA was used in the same manner, but included information about patients and treatment/measuring-cycles to control for potential confounding. Data are presented as mean (SD) and (range). Probabilities of less than 0.05 were accepted as significant.
Results:
The mean increase, 1.4 (SD 0.6°C; range 0.6-2.6°C) in core temperature/treatment/measuring-cycle highly significantly favoured the Allon™2001 Thermowrap in contrast to the conventional method 0.2 (0.6)°C (range -1.2 to 1.5°C) and the Warmcloud 0.3 (0.4)°C (range -0.4 to 0.9°C). The procedures for using the Allon™2001 Thermowrap were experienced to be more comfortable and straightforward than the conventional method or the Warmcloud.
Conclusions:
The Allon™2001 Thermowrap was more effective than the Warmcloud or the conventional method in controlling patients' temperatures.
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Minimally Invasive Surgery - Maximal Exposure To Research
Annals of Surgical Innovation and Research enters its fourth year as an open access, fully on-line journal. In the last few years we witnessed dramatic changes in the world of science, clinically and from a research point of view. Social media and the ever growing world wide web became an integral part of science groups and discussion forums. These new technologies allow for a wide and fast dissemination of cutting edge research, clinical findings and are capable of incorporating audio-visual content unlike any other form of scientific publication, in our fast paced environment an important point not to underestimate. Its big advantage is the open access policy which allows everyone to see your research and dynamic manuscript immediately upon acceptance. With incorporating an unlimited number of dynamic manuscripts we take the forefront in 'multimedia-publishing'. This new concept is especially useful in the field of minimally invasive surgery, robotic surgery and newer technologies, like NOTES, involving endoscopic devices where visual content is more important than a plain manuscript. Scientists still fear to publish open access because of its costs and still not wide acceptance.
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BMC Anesthesiology - Latest Articles
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Endotracheal intubation with Airtraq versus Storz videolaryngoscope in children younger than two years - a randomized pilot-study
Background:
New laryngoscopes have become available for use in small children. The aim of the study was to compare the Storz videolaryngoscope (SVL) to the Airtraq Optical laryngoscope (AOL) for tracheal intubation in children younger than two years of age who had a normal airway assessment. Our hypothesis was that the SVL would have a better success rate than the AOL.
Methods:
Ten children aged 2 years or younger scheduled for elective cleft lip/palate surgery were included. The anesthesia was standardized and a Cormack-Lehane (CL)-score was obtained using a Macintosh laryngoscope. After randomization CL-score and endotracheal tube positioning in front of the glottis was performed with one device, followed by the same procedure and intubation with the other device. The video-feed was recorded along with real-time audio. The primary endpoint was the success rate, defined as intubation in first attempt. Secondary endpoints were the time from start of laryngoscopy to CL-score, tube positioning in front of the glottis, and intubation.
Results:
Two intubation attempts were needed in two of five patients randomized to the SVL. The difference in time (SVL vs. AOL) to CL-score was 4.5 sec (p = 0.0449). The difference in time (SVL vs. AOL) to tube positioning was 11.6 sec (p = 0.0015). Time to intubation was 29.0 sec for SVL and 15.8 sec for AOL.
Conclusion:
No difference in the success rate of endotracheal intubation could be established in this ten patient sample of children younger than two years with a normal airway assessment scheduled for elective cleft lip/palate surgery. However, the Airtraq Optical videolaryngoscope showed a number of time related advantages over the Storz videolaryngoscope. Because of the small sample size a larger trial is needed to confirm these findings. Both devices were considered safe in all intubations.
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The effect of initial local anesthetic dose with continuous interscalene analgesia on postoperative pain and diaphragmatic function in patients undergoing arthroscopic shoulder surgery: a double-blind, randomized controlled trial
Background:
Interscalene block (ISB) is commonly performed using 20-40 mL of local anesthetic. Spread to adjacent structures and consequent adverse effects including paralysis of the ipsilateral hemidiaphragm are frequent. Pain ratings, analgesic requirements, adverse events, satisfaction, function and diaphragmatic excursion were compared following interscalene block (ISB) with reduced initial bolus volumes.
Methods:
Subjects undergoing arthroscopic rotator cuff repair were randomized to receive 5, 10, or 20 mL ropivacaine 0.75% for ISB in a double-blind fashion (N = 36). Continuous infusion with ropivacaine 0.2% was maintained for 48 h. Pain and diaphragmatic excursion were assessed before block and in the recovery unit.
Results:
Pain ratings in the recovery room were generally less than 4 (0-10 NRS) for all treatment groups, but a statistically significant difference was noted between the 5 and 20 mL groups (NRS: 2.67 vs. 0.62 respectively; p = 0.04). Pain ratings and supplemental analgesic use were similar among the groups at 24 h, 48 h and 12 weeks. There were no differences in the quality of block for surgical anesthesia. Dyspnea was significantly greater in the 20 mL group (p = 0.041). Subjects with dyspnea had significant diaphragmatic impairment more frequently (Relative risk: 2.5; 95%CI: 1.3-4.8; p = 0.042). Increased contralateral diaphragmatic motion was measured in 29 of the 36 subjects. Physical shoulder function at 12 weeks improved over baseline in all groups (baseline mean SST: 6.3, SEM: 0.6; 95%CI: 5.1-7.5; 12 week mean SST: 8.2, SEM: 0.46; 95%CI: 7.3-9.2; p = 0.0035).
Conclusions:
ISB provided reliable surgical analgesia with 5 mL, 10 mL or 20 mL ropivacaine (0.75%). The 20 mL volume was associated with increased complaints of dyspnea. The 5 mL volume was associated with statistically higher pain scores in the immediate postoperative period. Lower volumes resulted in a reduced incidence of dyspnea compared to 20 mL, however diaphragmatic impairment was not eliminated. Compensatory increases in contralateral diaphragmatic movement may explain tolerance for ipsilateral paresis.Trial Registrationclinicaltrials.gov. identifier: NCT00672100
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Recent trends in publication of basic science and clinical research by United States investigators in anesthesia journals
Background:
United States anesthesia research production declined sharply from 1980-2005. Whether this trend has continued despite recent calls to improve output is unknown. We conducted an observational internet analysis to quantify American basic science and clinical anesthesia research output in 14 anesthesia journals with impact factors greater than one at three-year intervals during the past decade.
Results:
American investigators published 1,486 (21.7%) of the total of 6,845 research articles identified in anesthesia journals in 2001, 2004, 2007, and 2010. Approximately two-thirds of all US articles were published in Anesthesiology and Anesthesia and Analgesia. There was a significant correlation (r2 = 0.316; P = 0.036) between the number of articles published by American authors in each anesthesia journal and the corresponding journal's impact factor in 2010. Significantly (P < 0.05; Pearson's Chi-square) fewer basic science articles were published in 2007 and 2010 compared with 2001. US clinical research output also declined in 2007 (201; 15.7%) compared with 2001 (266; 19.1%) and 2004, but an increase occurred in 2010 (279; 21.8%, P < 0.05 versus 2007).
Conclusions:
The results indicate that US anesthesia research output continued to decrease from 2001 to 2007. An increase in clinical but not basic science research was observed in 2010 compared with 2007, suggesting that a modest recovery in clinical research production may have begun.
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Does using a femoral nerve block for total knee replacement decrease postoperative delirium?
Background:
The effect of peripheral nerve blocks on postoperative delirium in older patients has not been studied. Peripheral nerve blocks may reduce the incidence of postoperative opioid use and its side effects such as delirium via opioid-sparing effect.
Methods:
A prospective cohort study was conducted in patients who underwent total knee replacement. Baseline cognitive function was assessed using the Telephone Interview for Cognitive Status. Postoperative delirium was measured using the Confusion Assessment Method postoperatively. Incidence of postoperative delirium was compared in two postoperative management groups: femoral nerve block +/- patient-controlled analgesia and patient-controlled analgesia only. In addition, pain levels (using numeric rating scales) and opioid use were compared in two groups.
Results:
85 patients were studied. The overall incidence of postoperative delirium either on postoperative day one or day two was 48.1%. Incidence of postoperative delirium in the femoral nerve block group was lower than patient controlled analgesia only group (25% vs. 61%, P = 0.002). However, there was no significant difference between the groups with respect to postoperative pain level or the amount of intravenous opioid use.
Conclusions:
Femoral nerve block reduces the incidence of postoperative delirium. These results suggest that a larger randomized control trial is necessary to confirm these preliminary findings.
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Prediction of arterial pressure increase after fluid challenge.
Background:
Mean arterial pressure above 65 mmHg is recommended for critically ill hypotensive patients whereas they do not benefit from supranormal cardiac output values. In this study we investigated if the increase of mean arterial pressure after volume expansion could be predicted by cardiovascular and renal variables. This is a relevant topic because unnecessary positive fluid balance increases mortality, organ dysfunction and Intensive Care Unit length of stay.
Methods:
Thirty-six hypotensive patients (mean arterial pressure < 65 mmH) received a fluid challenge with hydroxyethyl starch. Patients were excluded if they had active bleeding and/or required changes in vasoactive agents infusion rate in the previous 30 minutes. Responders were defined by the increase of mean arterial pressure value to over 65 mmHg or by more than 20% with respect to the value recorded before fluid challenge. Measurements were performed before and at one hour after the end of fluid challenge.
Results:
Twenty-two patients (61%) increased arterial pressure after volume expansion. Baseline heart rate, arterial pressure, central venous pressure, central venous saturation, central venous to arterial PCO2 difference, lactate, urinary output, fractional excretion of sodium and urinary sodium/potassium ratio were similar between responder and non-responder. Only 7 out of 36 patients had valuable dynamic indices and then we excluded them from analysis. When the variables were tested as predictors of responders, they showed values of areas under the ROC curve ranging between 0.502 and 0.604. Logistic regression did not reveal any association between variables and responder definition.
Conclusions:
Fluid challenge did not improve arterial pressure in about one third of hypotensive critically ill patients. Cardiovascular and renal variables did not enable us to predict the individual response to volume administration.
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Sciatic lateral popliteal block with clonidine alone or clonidine plus 0.2% ropivacaine : effect on the intra- and postoperative analgesia for lower extremity surgery in children: a randomized prospective controlled study
Background:
The effect of adding clonidine to local anesthetics for nerve or plexus blocks remains unclear. Most of the studies in adults have demonstrated the positive effects of clonidine on intra- and postoperative analgesia when used as an adjunctive agent or in some cases as a single to regional techniques. In the pediatric population, there are only few trials involving clonidine as an adjunct to regional anesthesia, and the analgesic benefits are not definite in this group of patients. The evidence concerning perineural administration of clonidine is so far inconclusive in children, as different types and volume of local anesthetic agents have been used in these studies. Moreover, the efficacy of regional anesthesia is largely affected by the operator's technique, accuracy and severity of operation.
Methods:
The use of clonidine alone or combined with 0.2% ropivacaine for effective analgesia after mild to moderate painful foot surgery was assessed in 66 children, after combined sciatic lateral popliteal block (SLPB) plus femoral block. The patients were randomly assigned into three groups to receive placebo, clonidine, and clonidine plus ropivacaine. Time to first analgesic request in the groups was analyzed by using Kaplan-Meier and the log-rank test (mean time, median time, 95% CI).
Results:
In our study, clonidine administered alone in the SLPB seems promising, maintaining intraoperatively the hemodynamic parameters SAP, DAP, HR to the lower normal values so that no patient needed nalbuphine under 0.6 MAC sevoflurane anesthesia, and postoperatively without analgesic request for a median time of 6 hours. In addition, clonidine administered as adjuvant enhances ropivacaine's analgesic effect for the first postoperative day in the majority of children (p = 0.001). Clonidine and clonidine plus ropivacaine groups also didn’t demonstrate PONV, motor blockade, and moreover, the parents of children expressed their satisfaction with the excellent perioperative management of their children, with satisfaction score 9.74 ± 0.45 and 9.73 ± 0.70 respectively. On the contrary all the patients in the control group required rescue nalbuphine in the recovery room, and postoperatively, along with high incidence of PONV, and the parents of children reported a low satisfaction score (7.50 ± 0.70).
Conclusions:
Clonidine appears promising more as an adjuvant in 0.2% ropivacaine and less than alone in the SLPB plus femoral block in children undergoing mild to moderate painful foot surgery, with no side effects.Trial registrationClinicalTrials.gov, ISRCTN90832436, (ref: CCT-NAPN-20886).
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Preoperative muscle weakness as defined by handgrip strength and postoperative outcomes: a systematic review.
Background:
Reduced muscle strength- commonly characterized by decreased handgrip strength compared to population norms- is associated with numerous untoward outcomes. Preoperative handgrip strength is a potentially attractive real-time, non-invasive, cheap and easy-to-perform "bedside" assessment tool. Using systematic review procedure, we investigated whether preoperative handgrip strength was associated with postoperative outcomes in adults undergoing surgery.
Methods:
PRISMA and MOOSE consensus guidelines for reporting systematic reviews were followed. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials (1980-2010) were systematically searched by two independent reviewers. The selection criteria were limited to include studies of preoperative handgrip strength in human adults undergoing non-emergency, cardiac and non-cardiac surgery. Study procedural quality was analysed using the Newcastle-Ottawa Quality Assessment score. The outcomes assessed were postoperative morbidity, mortality and hospital stay.
Results:
Nineteen clinical studies (17 prospective; 4 in urgent surgery) comprising 2194 patients were identified between1980-2010. Impaired handgrip strength and postoperative morbidity were defined inconsistently between studies. Only 2 studies explicitly ensured investigators collecting postoperative outcomes data were blinded to preoperative handgrip strength test results. The heterogeneity of study design used and the diversity of surgical procedures precluded formal meta-analysis. Despite the moderate quality of these observational studies, lower handgrip strength was associated with increased morbidity (n = 10 studies), mortality (n = 2/5 studies) and length of hospital stay (n = 3/7 studies).
Conclusions:
Impaired preoperative handgrip strength may be associated with poorer postoperative outcomes, but further work exploring its predictive power is warranted using prospectively acquired, objectively defined measures of postoperative morbidity.
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High tidal volume mechanical ventilation-induced lung injury in rats is greater after acid instillation than after sepsis-induced acute lung injury, but does not increase systemic inflammation: an experimental study.
Background:
To examine whether acute lung injury from direct and indirect origins differ in susceptibility to ventilator-induced lung injury (VILI) and resultant systemic inflammatory responses.
Methods:
Rats were challenged by acid instillation or 24 h of sepsis induced by cecal ligation and puncture, followed by mechanical ventilation (MV) with either a low tidal volume (Vt) of 6 mL/kg and 5 cm H2O positive end-expiratory pressure (PEEP; LVt acid, LVt sepsis) or with a high Vt of 15 mL/kg and no PEEP (HVt acid, HVt sepsis). Rats sacrificed immediately after acid instillation and non-ventilated septic animals served as controls. Hemodynamic and respiratory variables were monitored. After 4 h, lung wet to dry (W/D) weight ratios, histological lung injury and plasma mediator concentrations were measured.
Results:
Oxygenation and lung compliance decreased after acid instillation as compared to sepsis. Additionally, W/D weight ratios and histological lung injury scores increased after acid instillation as compared to sepsis. MV increased W/D weight ratio and lung injury score, however this effect was mainly attributable to HVt ventilation after acid instillation. Similarly, effects of HVt on oxygenation were only observed after acid instillation. HVt during sepsis did not further affect oxygenation, compliance, W/D weight ratio or lung injury score. Plasma interleukin-6 and tumour necrosis factor-α concentrations were increased after acid instillation as compared to sepsis, but plasma intercellular adhesion molecule-1 concentration increased during sepsis only. In contrast to lung injury parameters, no additional effects of HVt MV after acid instillation on plasma mediator concentrations were observed.
Conclusions:
During MV more severe lung injury develops after acid instillation as compared to sepsis. HVt causes VILI after acid instillation, but not during sepsis. However, this differential effect was not observed in the systemic release of mediators.
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Tolerability of NGX-4010, a capsaicin 8% dermal patch, following pretreatment with lidocaine 2.5%/prilocaine 2.5% cream in patients with post-herpetic neuralgia
Background:
Post-herpetic neuralgia (PHN) is a common type of neuropathic pain that can severely affect quality of life. NGX-4010, a capsaicin 8% dermal patch, is a localized treatment that can provide patients with significant pain relief for up to 3 months following a single 60-minute application. The NGX-4010 application can be associated with application-site pain and in previous clinical trials pretreatment with a topical 4% lidocaine anesthetic was used to enhance tolerability. The aim of the current investigation was to evaluate tolerability of NGX-4010 after pretreatment with lidocaine 2.5%/prilocaine 2.5% anesthetic cream.
Methods:
Twenty-four patients with PHN were pretreated with lidocaine 2.5%/prilocaine 2.5% cream for 60 minutes before receiving a single 60-minute application of NGX-4010. Tolerability was assessed by measuring patch application duration, the proportion of patients completing over 90% of the intended treatment duration, application site-related pain using the Numeric Pain Rating Scale (NPRS), and analgesic medication use to relieve such pain. Safety was assessed by monitoring adverse events (AEs) and dermal irritation using dermal assessment scores.
Results:
The mean treatment duration of NGX-4010 was 60.2 minutes and all patients completed over 90% of the intended patch application duration. Pain during application was transient. A maximum mean change in NPRS score of +3.0 was observed at 55 minutes post-patch application; pain scores gradually declined to near pre-anesthetic levels (+0.71) within 85 minutes of patch removal. Half of the patients received analgesic medication on the day of treatment; by Day 7, no patients required medication. The most common AEs were application site-related pain, erythema, edema, and pruritus. All patients experienced mild dermal irritation 5 minutes after patch removal, which subsequently decreased; at Day 7, no irritation was evident. The maximum recorded dermal assessment score was 2.
Conclusion:
NGX-4010 was well tolerated following pretreatment with lidocaine 2.5%/prilocaine 2.5% cream in patients with PHN. The tolerability of the patch application appeared comparable with that seen in other studies that used 4% lidocaine cream as the pretreatment anesthetic. This study is registered at http://www.clinicaltrials.gov as number NCT00916942.
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A bibliometric search of citation classics in anesthesiology
Background:
Articles cited counts are catalogued and help identify landmark papers. This study provides a citation classics of anesthesiology literature using the framework of subspecialties to provide a review of well-developed areas of research in anesthesiology.
Methods:
A comprehensive list of the most-cited articles in anesthesia was compiled using a bibliometric database and general search terms such as "anesthesia" as well as subspecialty-specific search terms. Queries were reviewed for relevance to anesthesiology practice, categorized by subspecialty, and ranked according to their citation counts.
Results:
The database resulted in 2519 articles published between 1945 and 2008. The specialty areas most represented were chronic pain medicine (11%), pharmacology (9%), and pain sciences (9%).
Conclusions:
This citations classic allows for advances in anesthesiology and its subspecialties to be highlighted as well to provide useful manuscripts to guide patient care, direct future research, and serve as sources for future academic pursuit.
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BMC Biochemistry - Latest Articles
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The ORF2 glycoprotein of hepatitis E virus inhibits
cellular NF-kappaB activity by blocking ubiquitination
mediated proteasomal degradation of IkappaBalpha in human
hepatoma cells
Background:
Nuclear factor kappa B (NF-kappaB) is a key transcription factor that plays a crucial role in hostsurvival during infection by pathogens. Therefore, it has been a priority of many pathogens tomanipulate the cellular NF-kappaB activity in order to create a favorable environment for theirsurvival inside the host.
Results:
We observed that heterologous expression of the open reading frame 2 (ORF2) protein inhuman hepatoma cells led to stabilization of the cellular I kappa B alpha (IkappaBalpha) pool, with aconcomitant reduction in the nuclear localization of the p65 subunit of NF-kappaB and inhibitionof NF-kappaB activity. Although basal or TPA induced phosphorylation of IkappaBalpha was not altered,its ubiquitination was markedly reduced in ORF2 expressing cells. Further analysis revealedthat ORF2 protein could directly associate with the F-box protein, beta transducin repeatcontaining protein (betaTRCP) and ORF2 over expression resulted in reduced association ofIkappaBalpha with the SKP1 and CUL1 components of the SCFbetaTRCP complex. Chromatinimmunoprecipitation (ChIP) assay of the proximal promoter regions of MHC-I heavy chainand IL-8 genes using p65 antibody and LPS stimulated ORF2 expressing cell extract revealeddecreased association of p65 with the above regions, indicating that ORF2 inhibited p65binding at endogenous promoters.
Conclusions:
In this report we suggest a mechanism by which ORF2 protein of HEV may inhibit host cellNF-kappaB activity during the course of a viral infection.
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Alternative splicing produces structural and functional changes in CUGBP2
Background:
CELF/Bruno-like proteins play multiple roles, including the regulation of alternative splicing and translation. These RNA-binding proteins contain two RNA recognition motif (RRM) domains at the N-terminus and another RRM at the C-terminus. CUGBP2 is a member of this family of proteins that possesses several alternatively spliced exons.
Results:
The present study investigated the expression of exon 14, which is an alternatively spliced exon and encodes the first half of the third RRM of CUGBP2. The ratio of exon 14 skipping product (R3delta) to its inclusion was reduced in neuronal cells induced from P19 cells and in the brain. Although full length CUGBP2 and the CUGBP2 R3delta isoforms showed a similar effect on the inclusion of the smooth muscle (SM) exon of the ACTN1 gene, these isoforms showed an opposite effect on the skipping of exon 11 in the insulin receptor gene. In addition, examination of structural changes in these isoforms by molecular dynamics simulation and NMR spectrometry suggested that the third RRM of R3delta isoform was flexible and did not form an RRM structure.
Conclusion:
Our results suggest that CUGBP2 regulates the splicing of ACTN1 and insulin receptor by different mechanisms. Alternative splicing of CUGBP2 exon 14 contributes to the regulation of the splicing of the insulin receptor. The present findings specifically show how alternative splicing events that result in three-dimensional structural changes in CUGBP2 can lead to changes in its biological activity.
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A proteomic view on the developmental transfer of homologous 30 kDa lipoproteins from peripheral fat body to perivisceral fat body via hemolymph in silkworm, Bombyx mori
Background:
A group of abundant proteins of ~30 kDa is synthesized in silkworm larval peripheral fat body (PPFB) tissues and transported into the open circulatory system (hemolymph) in a time-depended fashion to be eventually stored as granules in the pupal perivisceral fat body (PVFB) tissues for adult development during the non-feeding stage. These proteins have been shown to act anti-apoptotic besides being assigned roles in embryogenesis and defense. However, detailed protein structural information for individual PPFB and PVFB tissues during larval and pupal developmental stages is still missing. Gel electrophoresis and chromatography were used to separate the 30 kDa proteins from both PPFB and PVFB as well as hemolymph total proteomes. Mass spectrometry (MS) was employed to elucidate individual protein sequences. Furthermore, 30 kDa proteins were purified and biochemically characterized.
Results:
One- and two-dimensional gel electrophoresis (1/2D-PAGE) was used to visualize the relative changes of abundance of the 30 kDa proteins in PPFB and PVFB as well as hemolymph from day 1 of V instar larval stage to day 6 of pupal stage. Their concentrations were markedly increased in hemolymph and PVFB up to the first two days of pupal development and these proteins were consumed during development of the adult insect. Typically, three protein bands were observed (~29, 30, 31 kDa) in 1D-PAGE, which were subjected to MS-based protein identification along with spots excised from 2D-gels run for those proteomes. Gas phase fragmentation was used to generate peptide sequence information, which was matched to the available nucleotide data pool of more than ten highly homologous insect 30 kDa lipoproteins. Phylogenetic and similarity analyses of those sequences were performed to assist in the assignment of experimentally identified peptides to known sequences. Lipoproteins LP1 to LP5 and L301/302 could be matched to peptides extracted from all bands suggesting the presence of full length and truncated or modified protein forms in all of them. The individual variants could not be easily separated by classical means of purification such as 2D-PAGE because of their high similarity. They even seemed to aggregate as was indicated by native gel electrophoresis. Multistep chromatographic procedures eventually allowed purification of an LP3-like protein. The protein responded to lipoprotein-specific staining.
Conclusions:
In B. mori larvae and pupae, 30 kDa lipoproteins LP1 to LP5 and L301/302 were detected in PPFB and PVFB tissue as well as in hemolymph. The concentration of these proteins changed progressively during development from their synthesis in PPFB, transport in hemolymph to storage in PVFB. While the 30 kDa proteins could be reproducibly separated in three bands electrophoretically, the exact nature of the individual protein forms present in those bands remained partially ambiguous. The amino acid sequences of all known 30 kDa proteins showed very high homology. High-resolution separation techniques will be necessary before MS and other structural analysis can shed more light on the complexity of the 30 kDa subproteome in B. mori. A first attempt to that end allowed isolation of a B. mori LP3-like protein, the complete structure, properties and function of which will now be elucidated in detail.
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Identification of Avian Wax Synthases
Background:
Bird species show a high degree of variation in the composition of their preen gland waxes. For instance, galliform birds like chicken contain fatty acid esters of 2,3-alkanediols, while Anseriformes like goose or Strigiformes like barn owl contain wax monoesters in their preen gland secretions. The final biosynthetic step is catalyzed by wax synthases (WS) which have been identified in pro- and eukaryotic organisms.
Results:
Sequence similarities enabled us to identify six cDNAs encoding putative wax synthesizing proteins in chicken and two from barn owl and goose. Expression studies in yeast under in vivo and in vitro conditions showed that three proteins from chicken performed WS activity while a sequence from chicken, goose and barn owl encoded a bifunctional enzyme catalyzing both wax ester and triacylglycerol synthesis. Mono- and bifunctional WS were found to differ in their substrate specificities especially with regard to branched-chain alcohols and acyl-CoA thioesters. According to the expression patterns of their transcripts and the properties of the enzymes, avian WS proteins might not be confined to preen glands.
Conclusions:
We provide direct evidence that avian preen glands possess both monofunctional and bifunctional WS proteins which have different expression patterns and WS activities with different substrate specificities.
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Enzymatic activity and immunoreactivity of Aca s 4, an alpha-amylase allergen from the storage mite Acarus siro
Background:
Enzymatic allergens of storage mites that contaminate stored food products are poorly characterized. We describe biochemical and immunological properties of the native alpha-amylase allergen Aca s 4 from Acarus siro, a medically important storage mite.
Results:
A. siro produced a high level of alpha-amylase activity attributed to Aca s 4. This enzyme was purified and identified by protein sequencing and LC-MS/MS analysis. Aca s 4 showed a distinct inhibition pattern and an unusual alpha-amylolytic activity with low sensitivity to activation by chloride ions. Homology modeling of Aca s 4 revealed a structural change in the chloride-binding site that may account for this activation pattern. Aca s 4 was recognized by IgE from house dust mite-sensitive patients, and potential epitopes for cross-reactivity with house dust mite group 4 allergens were found.
Conclusions:
We present the first protein-level characterization of a group 4 allergen from storage mites. Due to its high production and IgE reactivity, Aca s 4 is potentially relevant to allergic hypersensitivity.
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Hyaluronan synthase mediates dye translocation across liposomal membranes
Background:
Hyaluronan (HA) is made at the plasma membrane and secreted into the extracellular medium or matrix by phospolipid-dependent hyaluronan synthase (HAS), which is active as a monomer. Since the mechanism by which HA is translocated across membranes is still unresolved, we assessed the presence of an intraprotein pore within HAS by adding purified Streptococcus equisimilis HAS (SeHAS) to liposomes preloaded with the fluorophore Cascade Blue (CB).
Results:
CB translocation (efflux) was not observed with mock-purified material from empty vector control E. coli membranes, but was induced by SeHAS, purified from membranes, in a time- and dose-dependent manner. CB efflux was eliminated or greatly reduced when purified SeHAS was first treated under conditions that inhibit enzyme activity: heating, oxidization or cysteine modification with N-ethylmaleimide. Reduced CB efflux also occurred with SeHAS K48E or K48F mutants, in which alteration of K48 within membrane domain 2 causes decreased activity and HA product size. The above results used liposomes containing bovine cardiolipin (BCL). An earlier study testing many synthetic lipids found that the best activating lipid for SeHAS is tetraoleoyl cardiolipin (TO-CL) and that, in contrast, tetramyristoyl cardiolipin (TM-CL) is an inactivating lipid (Weigel et al, J. Biol. Chem. 281, 36542, 2006). Consistent with the effects of these CL species on SeHAS activity, CB efflux was more than 2-fold greater in liposomes made with TO-CL compared to TM-CL.
Conclusions:
The results indicate the presence of an intraprotein pore in HAS and support a model in which HA is translocated to the exterior by HAS itself.
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Lipid-bound apolipoproteins in tyrosyl radical-oxidized HDL stabilize ABCA1 like lipid-free apolipoprotein A-I
Background:
ATP-binding cassette transporter A1 (ABCA1) mediates the lipidation of exchangeable apolipoproteins, the rate-limiting step in the formation of high density lipoproteins (HDL). We previously demonstrated that HDL oxidized ex vivo by peroxidase-generated tyrosyl radical (tyrosylated HDL, tyrHDL) increases the availability of cellular cholesterol for efflux and reduces the development of atherosclerosis when administered to apolipoprotein E-deficient mice as compared to treatment with control HDL.
Results:
In the current study we determined that tyrHDL requires functional ABCA1 for this enhanced activity. Like lipid-free apolipoprotein A-I (apoA-I), tyrHDL increases total and cell surface ABCA1, inhibits calpain-dependent and -independent proteolysis of ABCA1, and can be bound by cell surface ABCA1 in human skin fibroblasts. Additionally, tyrHDL apoproteins are susceptible to digestion by enteropeptidase like lipid-free apoA-I, but unlike lipid-bound apoA-I on HDL, which is resistant to proteolysis.
Conclusions:
These results provide the first evidence that lipid-bound apolipoproteins on the surface of spherical HDL particles can behave like lipid-free apoA-I to increase ABCA1 protein levels and activity.
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Topological characterisation and identification of critical domains within glucosyltransferase IV (GtrIV) of Shigella flexneri
Background:
The three bacteriophage genes gtrA, gtrB and gtr(type) are responsible for O-antigen glucosylation in Shigella flexneri. Both gtrA and gtrB have been demonstrated to be highly conserved and interchangeable among serotypes while gtr(type) was found to be specific to each serotype, leading to the hypothesis that the Gtr(type) proteins are responsible for attaching glucosyl groups to the O-antigen in a site- and serotype- specific manner. Based on the confirmed topologies of GtrI, GtrII and GtrV, such interaction and attachment of the glucosyl groups to the O-antigen has been postulated to occur in the periplasm.
Results:
In this study, the topology of GtrIV was experimentally determined by creating different fusions between GtrIV and a dual-reporter protein, PhoA/LacZ. This study shows that GtrIV consists of 8 transmembrane helices, 2 large periplasmic loops, 2 small cytoplasmic N- and C- terminal ends and a re-entrant loop that occurs between transmembrane helices III and IV. Though this topology differs from that of GtrI, GtrII, GtrV and GtrX, it is very similar to that of GtrIc. Furthermore, both the N-terminal periplasmic and the C-terminal periplasmic loops are important for GtrIV function as shown via a series of loop deletion experiments and the creation of chimeric proteins between GtrIV and its closest structural homologue, GtrIc.
Conclusion:
The current study provides the basis for elucidating the structure and mechanism of action of this important O-antigen modifying glucosyltransferase.
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Low affinity PEGylated hemoglobin from Trematomus bernacchii, a model for hemoglobin-based blood substitutes
Background:
Conjugation of human and animal hemoglobins with polyethylene glycol has been widely explored as a means to develop blood substitutes, a novel pharmaceutical class to be used in surgery or emergency medicine. However, PEGylation of human hemoglobin led to products with significantly different oxygen binding properties with respect to the unmodified tetramer and high NO dioxygenase reactivity, known causes of toxicity. These recent findings call for the biotechnological development of stable, low-affinity PEGylated hemoglobins with low NO dioxygenase reactivity.
Results:
To investigate the effects of PEGylation on protein structure and function, we compared the PEGylation products of human hemoglobin and Trematomus bernacchii hemoglobin, a natural variant endowed with a remarkably low oxygen affinity and high tetramer stability. We show that extension arm facilitated PEGylation chemistry based on the reaction of T. bernacchii hemoglobin with 2-iminothiolane and maleimido-functionalyzed polyethylene glycol (MW 5000 Da) leads to a tetraPEGylated product, more homogeneous than the corresponding derivative of human hemoglobin. PEGylated T. bernacchii hemoglobin largely retains the low affinity of the unmodified tetramer, with a p50 50 times higher than PEGylated human hemoglobin. Moreover, it is still sensitive to protons and the allosteric effector ATP, indicating the retention of allosteric regulation. It is also 10-fold less reactive towards nitrogen monoxide than PEGylated human hemoglobin.
Conclusions:
These results indicate that PEGylated hemoglobins, provided that a suitable starting hemoglobin variant is chosen, can cover a wide range of oxygen-binding properties, potentially meeting the functional requirements of blood substitutes in terms of oxygen affinity, tetramer stability and NO dioxygenase reactivity.
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Computational Identification and Experimental Characterization of Substrate Binding Determinants of Nucleotide Pyrophosphatase/Phosphodiesterase 7
Background:
Nucleotide pyrophosphatase/phosphodiesterase 7 (NPP7) is the only member of the mammalian NPP enzyme family that has been confirmed to act as a sphingomyelinase, hydrolyzing sphingomyelin (SM) to form phosphocholine and ceramide. NPP7 additionally hydrolyzes lysophosphatidylcholine (LPC), a substrate preference shared with the NPP2/autotaxin(ATX) and NPP6 mammalian family members. This study utilizes a synergistic combination of molecular modeling validated by experimental site-directed mutagenesis to explore the molecular basis for the unique ability of NPP7 to hydrolyze SM.
Results:
The catalytic function of NPP7 against SM, LPC, platelet activating factor (PAF) and para-nitrophenylphosphorylcholine (pNPPC) is impaired in the F275A mutant relative to wild type NPP7, but different impacts are noted for mutations at other sites. These results are consistent with a previously described role of F275 to interact with the choline headgroup, where all substrates share a common functionality. The L107F mutation showed enhanced hydrolysis of LPC, PAF and pNPPC but reduced hydrolysis of SM. Modeling suggests this difference can be explained by the gain of cation-pi interactions with the choline headgroups of all four substrates, opposed by increased steric crowding against the sphingoid tail of SM. Modeling also revealed that the long and flexible hydrophobic tails of substrates exhibit considerable dynamic flexibility in the binding pocket, reducing the entropic penalty that might otherwise be incurred upon substrate binding.
Conclusions:
Substrate recognition by NPP7 includes several important contributions, ranging from cation-pi interactions between F275 and the choline headgroup of all substrates, to tail-group binding pockets that accommodate the inherent flexibility of the lipid hydrophobic tails. Two contributions to the unique ability of NPP7 to hydrolyze SM were identified. First, the second hydrophobic tail of SM occupies a second hydrophobic binding pocket. Second, the leucine residue present at position 107 contrasts with a conserved phenylalanine in NPP enzymes that do not utilize SM as a substrate, consistent with the observed reduction in SM hydrolysis by the NPP7-L107F mutant.
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BMC Bioinformatics - Latest Articles
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Natural product-likeness score revisited: an open-source,
open-data implementation
Background:
Natural product-likeness of a molecule, i.e. similarity of this molecule to the structure space covered by natural products, is a useful criterion in screening compound libraries and in designing new lead compounds. A closed source implementation of a natural product-likeness score, that finds its application in virtual screening, library design and compound selection, has been previously reported by one of us. In this note, we report an open-source and open-data re-implementation of this scoring system, illustrate its efficiency in ranking small molecules for natural product likeness and discuss its potential applications.
Results:
The Natural-Product-Likeness scoring system is implemented as Taverna 2.2 workflows, and is available under Creative Commons Attribution-Share Alike 3.0 Unported License at http://www.myexperiment.org/packs/183.html. It is also available for download as executable standalone java package from http://sourceforge.net/projects/np-likeness/ under Academic Free License.
Conclusions:
Our open-source, open-data Natural-Product-Likeness scoring system can be used as a filter for metabolites in Computer Assisted Structure Elucidation or to select natural-product-like molecules from molecular libraries for the use as leads in drug discovery.
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Multiple structure alignment with msTALI
Background:
Multiple structure alignments have received increasing attention in recent years as an alternative to multiple sequence alignments. Although multiple structure alignment algorithms can potentially be applied to a number of problems, they have primarily been used for protein core identification. A method that is capable of solving a variety of problems using structure comparison is still absent. Here we introduce a program msTALI for aligning multiple protein structures. Our algorithm uses several informative features to guide its alignments: torsion angles, backbone Calpha atom positions, secondary structure, residue type, surface accessibility, and properties of nearby atoms. The algorithm allows the user to weight the types of information used to generate the alignment, which expands its utility to a wide variety of problems.
Results:
msTALI exhibits competitive results on 824 families from the Homstrad and SABmark databases when compared to Matt and Mustang. We also demonstrate success at building a database of protein cores using 341 randomly selected CATH domains and highlight the contribution of msTALI compared to the CATH classifications. Finally, we present an example applying msTALI to the problem of detecting hinges in a protein undergoing rigid-body motion.
Conclusions:
msTALI is an effective algorithm for multiple structure alignment. In addition to its performance on standard comparison databases, it utilizes clear, informative features, allowing further customization for domain-specific applications. The C++ source code for msTALI is available for Linux on the web at http://ifestos.cse.sc.edu/mstali.
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Profile-based short linear protein motif discovery.
Background:
Short linear protein motifs are attracting increasing attention as functionally independent sites, typically 3-10 amino acids in length that are enriched in disordered regions of proteins. Multiple methods have recently been proposed to discover over-represented motifs within a set of proteins based on simple regular expressions. Here, we extend these approaches to profile-based methods, which provide a richer motif representation.
Results:
The profile motif discovery method MEME performed relatively poorly for motifs in disordered regions of proteins. However, when we applied evolutionary weighting to account for redundancy amongst homologous proteins, and masked out poorly conserved regions of disordered proteins, the performance of MEME is equivalent to that of regular expression methods. However, the two approaches returned different subsets within both a benchmark dataset, and a more realistic discovery dataset.
Conclusions:
Profile-based motif discovery methods complement regular expression based methods. Whilst profile-based methods are computationally more intensive, they are likely to discover motifs currently overlooked by regular expression methods.
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rCUR:an R package for CUR matrix
decomposition
Background:
Many methods for dimensionality reduction of large data sets such as those generated inmicroarray studies boil down to the Singular Value Decomposition (SVD). Althoughsingular vectors associated with the largest singular values have strong optimalityproperties and can often be quite useful as a tool to summarize the data, they are linearcombinations of up to all of the data points, and thus it is typically quite hard to interpretthose vectors in terms of the application domain from which the data are drawn. Recently,an alternative dimensionality reduction paradigm, CUR matrix decompositions, has beenproposed to address this problem and has been applied to genetic and internet data. CURdecompositions are low-rank matrix decompositions that are explicitly expressed in termsof a small number of actual columns and/or actual rows of the data matrix. Since they areconstructed from actual data elements, CUR decompositions are interpretable bypractitioners of the eld from which the data are drawn.
Results:
We present an implementation to perform CUR matrix decompositions, in the form of afreely available, open source R-package called rCUR. This package will help users to perform CUR-based analysis on large-scale data, such as those obtained from differenthigh-throughput technologies, in an interactive and exploratory manner. We show twoexamples that illustrate how CUR-based techniques make it possible to reducesignicantly the number of probes, while at the same time maintaining major trends indata and keeping the same classication accuracy.
Conclusions:
The package rCUR provides functions for the users to perform CUR-based matrixdecompositions in the R environment. In gene expression studies, it gives an additionalway of analysis of differential expression and discriminant gene selection based on the useof statistical leverage scores. These scores, which have been used historically indiagnostic regression analysis to identify outliers, can be used by rCUR to identify themost informative data points with respect to which to express the remaining data points.
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Workflows for microarray data processing in the Kepler
environment
Background:
Microarray data analysis has been the subject of extensive and ongoing pipeline developmentdue to its complexity, the availability of several options at each analysis step, and thedevelopment of new analysis demands, including integration with new data sources.Bioinformatics pipelines are usually custom built for different applications, making themtypically difficult to modify, extend and repurpose. Scientific workflow systems are intendedto address these issues by providing general-purpose frameworks in which to develop andexecute such pipelines. The Kepler workflow environment is a well-established system undercontinual development that is employed in several areas of scientific research. Keplerprovides a flexible graphical interface, featuring clear display of parameter values, for designand modification of workflows. It has capabilities for developing novel computationalcomponents in the R, Python, and Java programming languages, all of which are widely usedfor bioinformatics algorithm development, along with capabilities for invoking externalapplications and using web services.
Results:
We developed a series of fully functional bioinformatics pipelines addressing common tasksin microarray processing in the Kepler workflow environment. These pipelines consist of aset of tools for GFF file processing of NimbleGen chromatin immunoprecipitation onmicroarray (ChIP-chip) datasets and more comprehensive workflows for Affymetrix geneexpression microarray bioinformatics and basic primer design for PCR experiments, whichare often used to validate microarray results. Although functional in themselves, theseworkflows can be easily customized, extended, or repurposed to match the needs of specific projects and are designed to be a toolkit and starting point for specific applications. Theseworkflows illustrate a workflow programming paradigm focusing on local resources(programs and data) and therefore are close to traditional shell scripting or R/BioConductorscripting approaches to pipeline design. Finally, we suggest that microarray data processingtask workflows may provide a basis for future example-based comparison of differentworkflow systems.
Conclusions:
We provide a set of tools and complete workflows for microarray data analysis in the Keplerenvironment, which has the advantages of offering graphical, clear display of conceptualsteps and parameters and the ability to easily integrate other resources such as remote dataand web services.
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MELTING, a flexible platform to predict the melting temperatures
of nucleic acids
Background:
Computing accurate nucleic acid melting temperatures has become a crucial step for the efficiency and theoptimisation of numerous molecular biology techniques such as in situ hybridisation, PCR, antigenetargeting, and microarrays. MELTING is a free open source software which computes the enthalpy, entropyand melting temperature of nucleic acids. MELTING 4.2 was able to handle several types of hybridisationsuch as DNA/DNA, RNA/RNA, DNA/RNA and provided corrections to melting temperatures due to thepresence of sodium. The program can use either an approximative approach or a more accurateNearest-Neighbour approach.
Results:
Two new versions of the MELTING software have been released. MELTING 4.3 is a direct update ofversion 4.2, integrating newly available thermodynamic parameters for inosine, a modified adenine basewith an universal base capacity, and incorporates a correction for magnesium. MELTING 5 is a completereimplementation wich allows much greater flexibility and extensibility. It incorporates all thethermodynamic parameters and corrections provided in MELTING 4.x and introduces a large set ofthermodynamic formulae and parameters, to facilitate the calculation of melting temperatures for perfectlymatching sequences, mismatches, bulge loops, CNG repeats, dangling ends, inosines, locked nucleic acids,2-hydroxyadenines and azobenzenes. It also includes temperature corrections for monovalent ions (sodium,potassium, tris), magnesium ions and commonly used denaturing agents such as formamide and DMSO.
Conclusions:
MELTING is a useful and very flexible tool for predicting melting temperatures using approximativeformulae or Nearest-Neighbour approaches, where one can select different sets of Nearest-Neighbourparameters, corrections and formulae. Both versions are freely available athttp://sourceforge.net/projects/melting/ and at http://www.ebi.ac.uk/compneur-srv/melting/ under the termsof the GPL license.
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Handling the data management needs of high-throughput sequencing data: SpeedGene, a compression algorithm for the efficient storage of genetic data
Background:
As Next-Generation Sequencing data becomes available, existing hardware environments do not provide sufficient storage space and computational power to store and process the data due to their enormous size. This is and will be a frequent problem that is encountered everyday by researchers who are working on genetic data. There are some options available for compressing and storing such data, such as general-purpose compression software, PBAT/PLINK binary format, etc. However, these currently available methods either do not offer sufficient compression rates, or require a great amount of CPU time for decompression and loading every time the data is accessed.
Results:
Here, we propose a novel and simple algorithm for storing such sequencing data. We show that the compression factor of the algorithm ranges from 16 to several hundreds, which potentially allows SNP data of hundreds of Gigabytes to be stored in hundreds of Megabytes. We provide a C++ implementation of the algorithm, which supports direct loading and parallel loading of the compressed format without requiring extra time for decompression. By applying the algorithm to simulated and real datasets, we show that the algorithm gives greater compression rate than the commonly used compression methods, and the data-loading process takes less time. Also, The C++ library provides direct-data-retrieving functions, which allows the compressed information to be easily accessed by other C++ programs.
Conclusions:
The SpeedGene algorithm enables the storage and the analysis of next generation sequencing data in current hardware environment, making system upgrades unnecessary.
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MetaMapp: mapping and visualizing metabolomic
data by integrating information from biochemical
pathways and chemical and mass spectral similarity
Background:
Exposure to environmental tobacco smoke (ETS) leads to higher rates of pulmonary diseases and infections in children. To study the biochemical changes that may precede lung diseases, metabolomic effects on fetal and maternal lungs and plasma from rats exposed to ETS were compared to filtered air control animals. Genome-reconstructed metabolic pathways may be used to map and interpret dysregulation in metabolic networks. However, mass spectrometry-based non-targeted metabolomics datasets often comprise many metabolites for which links to enzymatic reactions have not yet been reported. Hence, network visualizations that rely on current biochemical databases are incomplete and also fail to visualize novel, structurally unidentified metabolites.
Results:
We present a novel approach to integrate biochemical pathway and chemical relationships to map all detected metabolites in network graphs (MetaMapp) using KEGG reactant pair database, Tanimoto chemical and NIST mass spectral similarity scores. In fetal and maternal lungs, and in maternal blood plasma from pregnant rats exposed to environmental tobacco smoke (ETS), 459 unique metabolites comprising 179 structurally identified compounds were detected by gas chromatography time of flight mass spectrometry (GC-TOF MS) and BinBase data processing. MetaMapp graphs in Cytoscape showed much clearer metabolic modularity and complete content visualization compared to conventional biochemical mapping approaches. Cytoscape visualization of differential statistics results using these graphs showed that overall, fetal lung metabolism was more impaired than lungs and blood metabolism in dams. Fetuses from ETS-exposed dams expressed lower lipid and nucleotide levels and higher amounts of energy metabolism intermediates than control animals, indicating lower biosynthetic rates of metabolites for cell division, structural proteins and lipids that are critical for in lung development.
Conclusion:
MetaMapp graphs efficiently visualizes mass spectrometry based metabolomics datasets as network graphs in Cytoscape, and highlights metabolic alterations that can be associated with higher rate of pulmonary diseases and infections in children prenatally exposed to ETS. The MetaMapp scripts can be accessed at http://metamapp.fiehnlab.ucdavis.edu.
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The Partitioned LASSO-Patternsearch Algorithm with Application
to Gene Expression Data
Background:
In systems biology, the task of reverse engineering gene pathways from data has been limited not just by the curse of dimensionality (the interaction space is huge) but also by systematic error in the data. The gene expression barcode reduces spurious association driven by batch effects and probe effects. The binary nature of the resulting expression calls lends itself perfectly for modern regularization approaches that thrive with dimensionality.
Results:
The Partitioned LASSO-Patternsearch algorithm is proposed to identify patterns of multiple dichotomous risk factors for outcomes of interest in genomic studies. A partitioning scheme is used to identify promising patterns by solving many LASSO-Patternsearch subproblems in parallel. All variables that survive this stage proceed to an aggregation stage where the most significant patterns are identified by solving a reduced LASSO-Patternsearch problem in just these variables. This approach was applied to genetic data sets with expression levels dichotomized by gene expression bar code. Most of the genes and second-order interactions thus selected and are known to be related to the outcomes.
Conclusions:
We demonstrate with simulations and data analyses that the proposed method not only selects variables and patterns more accurately, but also provides smaller models with better prediction accuracy, in comparison to several competing methodologies.
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3DMolNavi: A web-based retrieval and navigation tool for flexible molecular shape comparison
Background:
Many molecules of interest are flexible and undergo significant shape deformation as part of their function,but most existing methods of molecular shape comparison treat them as rigid shapes, which may lead toincorrect measure of the shape similarity of flexible molecules. Currently, there still is a limited effort inretrieval and navigation for flexible molecular shape comparison, which would improve data retrieval byhelping users locate the desirable molecule in a convenient way.
Results:
To address this issue, we develop a web-based retrieval and navigation tool, named 3DMolNavi, for flexiblemolecular shape comparison. This tool is based on the histogram of Inner Distance Shape Signature (IDSS)for fast retrieving molecules that are similar to a query molecule, and uses dimensionality reduction tonavigate the retrieved results in 2D and 3D spaces. We tested 3DMolNavi in the Database ofMacromolecular Movements (MolMovDB) and CATH. Compared to other shape descriptors, it achievesgood performance and retrieval results for different classes of flexible molecules.
Conclusions:
The advantages of 3DMolNavi, over other existing softwares, are to integrate retrieval for flexible molecularshape comparison and enhance navigation for user's interaction. 3DMolNavi can be accessed viahttps://engineering.purdue.edu/PRECISE/3dmolnavi/index.html.
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BMC Biology - Latest Articles
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Constrained evolution drives limited influenza diversity
H3N2 influenza A viruses have been widely circulating in human populations since the pandemic of 1968. A striking feature of the evolutionary development of this strain has been its 'canalized' nature, with narrow evolutionary trees dominated by long trunks with few branching, or bifurcation events and a consequent lack of standing diversity at any single point. This is puzzling, as one might expect that the strong human immune response against the virus would create an environment encouraging more diversity, not less. Previous models have used various assumptions in order to account for this finding. A new analysis published in BMC Biology suggests that this processive evolution down a single path can be recapitulated by a relatively simple model incorporating only two primary parameters - the mutation rate of the virus, and the immunological distance created by each mutation - so long as these parameters are within a particular narrow but biologically plausible range.See research article: http://www.biomedcentral.com/1741-7007/10/38
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"Toxic" effects of sugar: should we be afraid of fructose?
No abstract. First Paragraph:Carbohydrate is an essential component of our diet. What about fructose? Can we live without any fructose intake?Glucose is unequivocally a central component of human energy metabolism. It constitutes the nearly exclusive energy fuel for the brain, since neurons lack the enzymes required for fatty acid oxidation. The only exception to this exclusive glucose metabolism in the brain is starvation, when the expression of monocarboxylate transporters increases in brain cells, which then become able to use the ketone bodies (beta-hydroxybutyric acid and aceto-acetic acid) produced by the liver. As a consequence of this exclusive reliance on glucose for brain metabolism, intricate hormonal and neural mechanisms have evolved to maintain a constant level of glucose in the blood.
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Mending walls
First paragraph (this article has no abstract)Before I built a wall I'd ask to knowWhat I was walling in or walling out- Robert Frost, 'Mending Wall'In rural New England, as in much of the rest of the world, people mark their territory, like some race of architecturally-adept spaniels, by building a wall around its borders. In some cases this is done for defensive purposes. In others, it is meant to keep in something that should not be allowed to roam freely (spaniels again, perhaps). But much of the time it is simply there to say, 'this is mine, not yours.'
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Macondo crude oil from the Deepwater Horizon oil spill disrupts specific developmental processes during zebrafish embryogenesis
Background:
The Deepwater Horizon disaster was the largest marine oil spill in history, and total vertical exposure of oil to the water column suggests it could impact an enormous diversity of ecosystems. The most vulnerable organisms are those encountering these pollutants during their early life stages. Water-soluble components of crude oil and specific polycyclic aromatic hydrocarbons have been shown to cause defects in cardiovascular and craniofacial development in a variety of teleost species, but the developmental origins of these defects have yet to be determined. We have adopted zebrafish, Danio rerio, as a model to test whether water accumulated fractions (WAF) of the Deepwater Horizon oil could impact specific embryonic developmental processes. While not a native species to the Gulf waters, the developmental biology of zebrafish has been well characterized and makes it a powerful model system to reveal the cellular and molecular mechanisms behind Macondo crude toxicity.
Results:
WAF of Macondo crude oil sampled during the oil spill was used to treat zebrafish throughout embryonic and larval development. Our results indicate that the Macondo crude oil causes a variety of significant defects in zebrafish embryogenesis, but these defects have specific developmental origins. WAF treatments caused defects in craniofacial development and circulatory function similar to previous reports, but we extend these results to show they are likely derived from an earlier defect in neural crest cell development. Moreover, we demonstrate that exposure to WAFs causes a variety of novel deformations in specific developmental processes, including programmed cell death, locomotor behavior, sensory and motor axon pathfinding, somitogenesis and muscle patterning. Interestingly, the severity of cell death and muscle phenotypes decreased over several months of repeated analysis, which was correlated with a rapid drop-off in the aromatic and alkane hydrocarbon components of the oil.
Conclusions:
Whether these teratogenic effects are unique to the oil from the Deepwater Horizon oil spill or generalizable for most crude oil types remains to be determined. This work establishes a model for further investigation into the molecular mechanisms behind crude oil mediated deformations. In addition, due to the high conservation of genetic and cellular processes between zebrafish and other vertebrates, our work also provides a platform for more focused assessment of the impact that the Deepwater Horizon oil spill has had on the early life stages of native fish species in the Gulf of Mexico and the Atlantic Ocean.
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A never ending race for new and improved fluorescent proteins
Bioluminescent and fluorescent proteins are now used as tools for research in all organisms. There has been massive progress over the past 15 years in creating a palette of fluorescent proteins with a wide spectrum of specific properties. One of the big challenges is to decide which variant may be best for a certain application. A recent article by Mann et al. in BMC Biotechnology describes a new orange fluorescent protein in plants.See research article http://www.biomedcentral.com/1472-6750/12/17
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Canalization of the evolutionary trajectory of the human influenza virus
Background:
Since its emergence in 1968, influenza A (H3N2) has evolved extensively in genotype and antigenic phenotype. However, despite strong pressure to evolve away from human immunity and to diversify in antigenic phenotype, H3N2 influenza shows paradoxically limited genetic and antigenic diversity present at any one time. Here, we propose a simple model of antigenic evolution in the influenza virus that accounts for this apparent discrepancy.
Results:
This model displays rapid evolution but low standing diversity and simultaneously accounts for the epidemiological, genetic, antigenic and geographical patterns displayed by the virus. In this model, antigenic phenotype is represented by a N-dimensional vector and virus mutations perturb phenotype within this continuous Euclidean space. We implement this model in a large-scale individual-based simulation, and in doing so, find a remarkable correspondence between model behavior and observed influenza dynamics. We find that evolution away from existing human immunity results in rapid population turnover in the influenza virus and that this population turnover occurs primarily along a single antigenic axis.
Conclusions:
Selective dynamics induce a canalized evolutionary trajectory, in which the evolutionary fate of the influenza population is surprisingly repeatable. In the model, the influenza population shows a 1-2 year timescale of repeatability, suggesting a window in which evolutionary dynamics could be, in theory, predictable.
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BMP2 and mechanical loading cooperatively regulate immediate early signalling events in the BMP pathway
Background:
Efficient osteogenic differentiation is highly dependent on coordinated signals arising from growth factor signalling and mechanical forces. Bone morphogenetic proteins (BMPs) are secreted proteins, which trigger Smad and non-Smad pathways and thereby influence transcriptional and non-transcriptional differentiation cues. Crosstalk at multiple levels allows for promotion or attenuation of signalling intensity and specificity. Similar to BMPs, mechanical stimulation enhances bone formation. However, the molecular mechanism by which mechanical forces crosstalk to biochemical signals is still unclear.
Results:
Here we describe, using a 3D bioreactor system, how mechanical forces are integrated into the BMP pathway. Time dependent phosphorylation of Smad, MAPK and Akt in human fetal osteoblasts was investigated under loading and/or BMP2 stimulation conditions. The phosphorylation of R-Smads is increased both in intensity and duration under BMP2 stimulation with concurrent mechanical loading. Interestingly, the synergistic effect of both stimuli on immediate early Smad phosphorylation is reflected on the transcription of only a subset of BMP target genes, while others are differently affected. Together this results in a cooperative regulation of osteogenesis that is guided by both signalling pathways.
Conclusions:
Mechanical signals are integrated into the BMP signalling pathway by enhancing immediate early steps within the Smad pathway, independent of autocrine ligand secretion. This suggests a direct crosstalk of both mechanotransduction and BMP signalling, most likely at the level of the cell surface receptors. Furthermore, the crosstalk of both pathways over longer time periods might occur on several signalling levels.
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UBXN7 docks on neddylated cullin complexes using its UIM motif and causes HIF1alpha accumulation
Background:
The proteins from the UBA-UBX family interact with ubiquitylated proteins via their UBA domain and with p97 via their UBX domain, thereby acting as substrate-binding adaptors for the p97 ATPase. In particular, human UBXN7 (also known as UBXD7) mediates p97 interaction with the transcription factor HIF1α that is actively ubiquitylated in normoxic cells by a CUL2-based E3 ligase, CRL2. Mass spectrometry analysis of UBA-UBX protein immunoprecipitates showed that they interact with a multitude of E3 ubiquitin-ligases. Conspicuously, UBXN7 was most proficient in interacting with cullin-RING ligase subunits. We therefore set out to determine whether UBXN7 interaction with cullins was direct or mediated by its ubiquitylated targets bound to the UBA domain.
Results:
We show that UBXN7 interaction with cullins is independent of ubiquitin- and substrate-binding. Instead, it relies on the UIM motif in UBXN7 that directly engages the NEDD8 modification on cullins. To understand the functional consequences of UBXN7 interaction with neddylated cullins, we focused on HIF1α, a CUL2 substrate that uses UBXD7/p97 as a ubiquitin-receptor on its way to proteasome-mediated degradation. We find that UBXN7 over-expression converts CUL2 to its neddylated form and causes the accumulation of non-ubiquitylated HIF1α. Both of these effects are strictly UIM-dependent and occur only when UBXN7 contains an intact UIM motif. We also show that HIF1α carrying long ubiquitin-chains can recruit alternative ubiquitin-receptors, lacking p97's ATP-dependent segregase activity.
Conclusions:
Our study shows that independently of its function as a ubiquitin-binding adaptor for p97, UBXN7 directly interacts with neddylated cullins and causes the accumulation of the CUL2 substrate HIF1α. We propose that by sequestering CUL2 in its neddylated form, UBXN7 negatively regulates the ubiquitin-ligase activity of CRL2 and this might prevent recruitment of ubiquitin-receptors other than p97 to nuclear HIF1α.
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Evolving a photosynthetic organelle
The evolution of plastids from cyanobacteria is believed to represent a singularity in the history of life. The enigmatic amoeba Paulinella and its 'recently' acquired photosynthetic inclusions provide a fascinating system through which to gain fresh insight into how endosymbionts become organelles.The plastids, or chloroplasts, of algae and plants evolved from cyanobacteria by endosymbiosis. This landmark event conferred on eukaryotes the benefits of photosynthesis - the conversion of solar energy into chemical energy - and in so doing had a huge impact on the course of evolution and the climate of Earth
1
. From the present state of plastids, however, it is difficult to trace the evolutionary steps involved in this momentous development, because all modern-day plastids have fully integrated into their hosts. Paulinella chromatophora is a unicellular eukaryote that bears photosynthetic entities called chromatophores that are derived from cyanobacteria and has thus received much attention as a possible example of an organism in the early stages of organellogenesis. Recent studies have unlocked the genomic secrets of its chromatophore
2
3
and provided concrete evidence that the Paulinella chromatophore is a bona fide photosynthetic organelle
4
. The question is how Paulinella can help us to understand the process by which an endosymbiont is converted into an organelle.
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Clamp loader ATPases and the evolution of DNA replication machinery
Clamp loaders are pentameric ATPases of the AAA+ family that operate to ensure processive DNA replication. They do so by loading onto DNA the ring-shaped sliding clamps that tether the polymerase to the DNA. Structural and biochemical analysis of clamp loaders has shown how, despite differences in composition across different branches of life, all clamp loaders undergo the same concerted conformational transformations, which generate a binding surface for the open clamp and an internal spiral chamber into which the DNA at the replication fork can slide, triggering ATP hydrolysis, release of the clamp loader, and closure of the clamp round the DNA. We review here the current understanding of the clamp loader mechanism and discuss the implications of the differences between clamp loaders from the different branches of life.
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BMC Cell Biology - Latest Articles
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Regulation of ROCK1 via Notch1 during
breast cancer cell migration into dense
matrices
Background:
The behaviour of tumour cells depends on factors such as genetics and the tumourmicroenvironment. The latter plays a crucial role in normal mammary gland development andalso in breast cancer initiation and progression. Breast cancer tissues tend to be highlydesmoplastic and dense matrix as a pre-existing condition poses one of the highest riskfactors for cancer development. However, matrix influence on tumour cell gene expressionand behaviour such as cell migration is not fully elucidated.
Results:
We generated high-density (HD) matrices that mimicked tumour collagen content of 20mg/cm3 that were ~14-fold stiffer than low-density (LD) matrix of 1 mg/cm3. Live-cellimaging showed breast cancer cells utilizing cytoplasmic streaming and cell bodycontractility for migration within HD matrix. Cell migration was blocked in the presence ofboth the ROCK inhibitor, Y-27632, and the MMP inhibitor, GM6001, but not by the drugsindividually. This suggests roles for ROCK1 and MMP in cell migration are complicated bycompensatory mechanisms. ROCK1 expression and protein activity, were significantlyupregulated in HD matrix but these were blocked by treatment with a histone deacetylase(HDAC) inhibitor, MS-275. In HD matrix, the inhibition of ROCK1 by MS-275 was indirectand relied upon protein synthesis and Notch1. Inhibition of Notch1 using pooled siRNA orDAPT abrogated the inhibition of ROCK1 by MS-275.
Conclusion:
Increased matrix density elevates ROCK1 activity, which aids in cell migration via cellcontractility. The upregulation of ROCK1 is epigenetically regulated in an indirect mannerinvolving the repression of Notch1. This is demonstrated from inhibition of HDACs by MS-275, which caused an upregulation of Notch1 levels leading to blockade of ROCK1expression.
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Correction: Analysis of the Role of Ser1/Ser2/Thr9
Phosphorylation on Myosin II Assembly and
Function in Live Cells
In the Methods section of our original manuscript [J.R.Beach et al. BMC.Cell Biol. 12, (2011)52] under the subheading "Creation of RLC mutants" the third sentence reads "MRLC2 cDNA (gene MYL12B; gene ID 103910) was purchased from ATCC". This sentence is incorrect. The manuscript should read "MRLC1 cDNA (gene MYL9; gene ID 10398) was purchased from ATCC". This correction does not in any way change the conclusions or any of the data in the manuscript. These two redundant genes produce essentially identical proteins, we simply listed the wrong one in the methods section.
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Ubiquitination is involved in secondary growth, not initial formation of polyglutamine protein aggregates in C. elegans
Background:
Protein misfolding and subsequent aggregation are hallmarks of several human diseases. The cell has a variety of mechanisms for coping with misfolded protein stress, including ubiquitin-mediated protein degradation. In fact, the presence of ubiquitin at protein aggregates is a common feature of protein misfolding diseases. Ubiquitin conjugating enzymes (UBCs) are part of the cascade of enzymes responsible for the regulated attachment of ubiquitin to protein substrates. The specific UBC used during ubiquitination can determine the type of polyubiquitin chain linkage, which in turn plays an important role in determining the fate of the ubiquitinated protein. Thus, UBCs may serve an important role in the cellular response to misfolded proteins and the fate of protein aggregates.
Results:
The Q82 strain of C. elegans harbors a transgene encoding an aggregation prone tract of 82 glutamine residues fused to green fluorescent protein (Q82::GFP) that is expressed in the body wall muscle. When measured with time-lapse microscopy in young larvae, the initial formation of individual Q82::GFP aggregates occurs in approximately 58 minutes. This process is largely unaffected by a mutation in the C. elegans E1 ubiquitin activating enzyme. RNAi of ubc-22, a nematode homolog of E2-25 K, resulted in higher pre-aggregation levels of Q82::GFP and a faster initial aggregation rate relative to control. Knockdown of ubc-1 (RAD6 homolog), ubc-13, and uev-1 did not affect the kinetics of initial aggregation. However, RNAi of ubc-13 decreases the rate of secondary growth of the aggregate. This result is consistent with previous findings that aggregates in young adult worms are smaller after ubc-13 RNAi. mCherry::ubiquitin becomes localized to Q82::GFP aggregates during the fourth larval (L4) stage of life, a time point long after most aggregates have formed. FLIP and FRAP analysis indicate that mCherry::ubiquitin is considerably more mobile than Q82::GFP within aggregates.
Conclusions:
These data indicate that initial formation of Q82::GFP aggregates in C. elegans is not directly dependent on ubiquitination, but is more likely a spontaneous process driven by biophysical properties in the cytosol such as the concentration of the aggregating species. The effect of ubiquitination appears to be most significant in later, secondary aggregate growth.
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DNp73 improves generation efficiency of human induced pluripotent stem cells
Background:
Recent studies have found that p53 and its' associated cell cycle pathways are major inhibitors of human induced pluripotent stem (iPS) cell generation. In the same family as p53 is p73, which shares sequence similarities with p53. However, p73 also has distinct properties of its own, such as two alternative promoters to express transactivation of p73 (TAp73) and N terminal deleted p73 (DNp73). Functionally, TAp73 acts similarly to p53 in tumor suppression. However, DNp73, on the other hand acts as an oncogene to suppress p53 and p73 induced apoptosis. Therefore, how can p73 have opposing roles in human iPS cell generation?
Results:
Transcription factors, Oct4, Sox2, Klf4 and cMyc (4TF, Yamanaka factors) are used as basal conditions to generate iPS cells. In addition, the factor of DNp73(actually alpha splicing DNp73, DNp73α) is used to generate iPS cells. The experiment found that the addition of DNp73 gene increases human iPS cell generation efficiency by 12.6 folds in comparison to human fibroblast cells transduced with only the basal conditions. Also, iPS cells generated with DNp73 expression are more resistant to in vitro and in vivo differentiation.
Conclusions:
This study found DNp73, a family member of p53, is also involved in the human iPS cell generation. Specifically, that the involvement of DNp73 generates iPS cells that are more resistant to in vitro and in vivo differentiation. Therefore, this data may prove to be useful in future developmental studies and cancer researches.
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Aurora kinase-C-T191D is constitutively active mutant
Background:
Aurora kinases (Aurora-A, B and C) belong to a family of conserved serine/threonine kinases which are key regulators of cell cycle progression. Aurora-A and Aurora-B are expressed in somatic cells and involved in cell cycle regulation while aurora-C is meiotic chromosome passenger protein. As Aurora kinase C is rarely expressed in normal somatic cells and has been found over expressed in many cancer lines. It is suggested that Aurora-C-T191D is not hyperactive mutant.ResultAurora-C-T191D variant form was investigated and compared with wild type. The overexpression of Aurora-C-T191D was observed that it behaves like Aurora-C wild type (aurC-WT). Both Aurora-C-T191D and aurC-WT induce abnormal cell division resulting in centrosome amplification and multinucleation in transiently transfected cells as well as in stable cell lines. Similarly, Aurora-C-T191D and aurC-WT formed foci of colonies when grown on soft agar, indicating that a gain of Aurora-C activity is sufficient to transform cells. Furthermore, we reported that NIH-3 T3 stable cell lines overexpressing Aurora-C-T191D and its wild type partner induced tumour formation when injected into nude mice, demonstrating the oncogenic activity of enzymatically active Aurora kinase C. Interestingly enough tumour aggressiveness was positively correlated with the rate of kinase activity, making Aurora-C a potential anti-cancer therapeutic target.
Conclusion:
These findings proved that Aurora C-T191D is not hyperactive but is constitutively active mutant.
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PKC-delta mediates interferon-alpha-induced apoptosis through c-Jun NH2-terminal kinase activation
Background:
Interferon-α (IFN-α) exerts an anti-tumor effect at least through induction of apoptosis in a variety of types including B lymphoma cells. We recently found that IFN-α induced a sustained activation of c-Jun NH2-terminal kinase1 (JNK1), which is implicated in activation of the tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) promoter. In the present study, we explored upstream component(s) of the prolonged IFN-α-initiated activation of JNK1.
Results:
IFN-α caused activation of PKC-δ in Daudi B lymphoma cells and myeloma U266 cells, as detected by Western blotting using a monoclonal antibody specific for the phosphorylated form of PKC-δ. The dominant-negative form of mutant PKC-δ (dnPKC-δ) reduced the IFN-α-induced JNK1 activation, TRAIL promoter activity, loss of mitochondrial membrane potential (ΔΨm), and increase in propidium iodide (PI) positive cells. The IFN-α-induced activation of JNK1 and the TRAIL promoter was also attenuated by the PKC-δ inhibitor rottlerin. Moreover, a constitutively active form of mutant PKC-δ enhanced the IFN-α-induced TRAIL promoter activity and loss of ΔΨm in Daudi B lymphoma cells. In addition, IFN-α-induced Ser727 phosphorylation of Stat1 was also abrogated by dnPKC-δ.
Conclusions:
IFN-α induced JNK1 activation via PKC-δ, leading to upregulation of TRAIL. The interaction of the consequent enhanced TRAIL expression with TRAIL-receptor results in a loss of ΔΨm and increase in PI positive cells. The IFN-α-induced apoptotic events may also be affected by the Ser727-Stat1 induced by PKC-δ-mediated signaling component(s).
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Palmitoylation and Membrane Cholesterol Stabilize mu-Opioid Receptor Homodimerization and G Protein Coupling
Background:
A cholesterol-palmitoyl interaction has been reported to occur in the dimeric interface of the β2-adrenergic receptor crystal structure. We sought to investigate whether a similar phenomenon could be observed with μ-opioid receptor (OPRM1), and if so, to assess the role of cholesterol in this class of G protein-coupled receptor (GPCR) signaling.
Results:
C3.55(170) was determined to be the palmitoylation site of OPRM1. Mutation of this Cys to Ala did not affect the binding of agonists, but attenuated receptor signaling and decreased cholesterol associated with the receptor signaling complex. In addition, both attenuation of receptor palmitoylation (by mutation of C3.55[170] to Ala) and inhibition of cholesterol synthesis (by treating the cells with simvastatin, a HMG-CoA reductase inhibitor) impaired receptor signaling, possibly by decreasing receptor homodimerization and Gαi2 coupling; this was demonstrated by co-immunoprecipitation, immunofluorescence colocalization and fluorescence resonance energy transfer (FRET) analyses. A computational model of the OPRM1 homodimer structure indicated that a specific cholesterol-palmitoyl interaction can facilitate OPRM1 homodimerization at the TMH4-TMH4 interface.
Conclusions:
We demonstrate that C3.55(170) is the palmitoylation site of OPRM1 and identify a cholesterol-palmitoyl interaction in the OPRM1 complex. Our findings suggest that this interaction contributes to OPRM1 signaling by facilitating receptor homodimerization and G protein coupling. This conclusion is supported by computational modeling of the OPRM1 homodimer.
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beta3-integrin is required for differentiation in OC-2 cells derived from mammalian embryonic inner ear
Background:
The mammalian inner ear contains the organ of Corti which is responsible for the conversion of sound into neuronal signals. This specialised epithelial tissue is the product of a complex developmental process where a common precursor cell type differentiates into the sound transducing hair cells and the non-innervated supporting cells. We hypothesised that integrin proteins, which are involved in cell attachment to extracellular matrix proteins and cellular signalling, play a role in the differentiation process of the precursor inner ear epithelial cells. To test our hypothesis we have utilised a cell line (OC-2) derived from E13 embryonic immortomouse inner ears. In vitro, by switching the incubation temperature from 33°C to 39°C, the OC-2 cells can be induced to differentiate and express hair cells markers, such as Myosin VIIa. The OC-2 cells are thus a useful model system for testing mechanism of hair cells differentiation.
Results:
We have identified 4 integrin subunits which are expressed in OC-2 cells: α6, αv, β1 and β3. Among these, the relative level of expression of the αv, β1 and β3 subunits increased in a time dependent manner when the cells were exposed to the differentiating temperature of 39°C, most notably so for β3 which was not detectable at 33°C. Treatment of fully differentiated OC-2 cells with siRNA against the four integrin subunits reduced the expression of not only the respective integrin proteins but also of the hair cell marker Myosin VIIa. Conversely over-expression of β3 was sufficient to induce the expression of Myosin VIIa at 33°C.
Conclusions:
Our data demonstrate that modulation of integrin expression is associated with the differentiation process of the OC-2 cells. This suggests that the maturation of the organ of Corti, from where OC-2 cells are derived, may also depend on changes of gene expression associated with integrin expression.
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Rab11-FIP3 is a cell cycle-regulated phosphoprotein.
Background:
Rab11 and its effector molecule, Rab11-FIP3 (FIP3), associate with recycling endosomes and traffic into the furrow and midbody of cells during cytokinesis. FIP3 also controls recycling endosome distribution during interphase. Here, we examine whether phosphorylation of FIP3 is involved in these activities.
Results:
We identify four sites of phosphorylation of FIP3 in vivo, S-102, S-280, S-347 and S-450 and identify S-102 as a target for Cdk1-cyclin B in vitro. Of these, we show that S-102 is phosphorylated in metaphase and is dephosphorylated as cells enter telophase. Over-expression of FIP3-S102D increased the frequency of binucleate cells consistent with a role for this phospho-acceptor site in cytokinesis. Mutation of S-280, S-347 or S-450 or other previously identified phospho-acceptor sites (S-488, S-538, S-647 and S-648) was without effect on binucleate cell formation and did not modulate the distribution of FIP3 during the cell cycle. In an attempt to identify a functional role for FIP3 phosphorylation, we report that the change in FIP3 distribution from cytosolic to membrane-associated observed during progression from anaphase to telophase is accompanied by a concomitant dephosphorylation of FIP3. However, the phospho-acceptor sites identified here did not control this change in distribution.
Conclusions:
Our data thus identify FIP3 as a cell cycle regulated phosphoprotein and suggest dephosphorylation of FIP3 accompanies its translocation from the cytosol to membranes during telophase. S102 is dephosphorylated during telophase; mutation of S102 exerts a modest effect on cytokinesis. Finally, we show that de/phosphorylation of the phospho-acceptor sites identified here (S-102, S-280, S-347 and S-450) is not required for the spatial control of recycling endosome distribution or function.
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Tunicate cytostatic factor TC14-3 induces a polycomb group gene and histone modification through Ca2+ binding and protein dimerization
Background:
As many invertebrate species have multipotent cells that undergo cell growth and differentiation during regeneration and budding, many unique and interesting homeostatic factors are expected to exist in those animals. However, our understanding of such factors and global mechanisms remains very poor. Single zooids of the tunicate, Polyandrocarpa
misakiensis, can give off as many as 40 buds during the life span. Bud development proceeds by means of transdifferentiation of very limited number of cells and tissues. TC14-3 is one of several different but closely related polypeptides isolated from P. misakiensis. It acts as a cytostatic factor that regulates proliferation, adhesion, and differentiation of multipotent cells, although the molecular mechanism remains uncertain. The Polycomb group (PcG) genes are involved in epigenetic control of genomic activity in mammals. In invertebrates except Drosophila, PcG and histone methylation have not been studied so extensively, and genome-wide gene regulation is poorly understood.
Results:
When Phe65 of TC14-3 was mutated to an acidic amino acid, the resultant mutant protein failed to dimerize. The replacement of Thr69 with Arg69 made dimers unstable. When Glu106 was changed to Gly106, the resultant mutant protein completely lost Ca2+ binding. All these mutant proteins lacked cytostatic activity, indicating the requirement of protein dimerization and calcium for the activity. Polyandrocarpa
Eed, a component of PcG, is highly expressed during budding, like TC14-3. When wild-type and mutant TC14-3s were applied in vivo and in vitro to Polyandrocarpa cells, only wild-type TC14-3 could induce Eed without affecting histone methyltransferase gene expression. Eed-expressing cells underwent trimethylation of histone H3 lysine27. PmEed knockdown by RNA interference rescued cultured cells from the growth-inhibitory effects of TC14-3.
Conclusion:
These results show that in P. misakiensis, the cytostatic activity of TC14-3 is mediated by PmEed and resultant histone modification, and that the gene expression requires both the protein dimerization and Ca2+-binding of TC14-3. This system consisting of a humoral factor, PcG, and histone methylation would contribute to the homeostatic regulation of cell growth and terminal differentiation of invertebrate multipotent cells.
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BMC Biotechnology - Latest Articles
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New cell line development for antibody-producing Chinese hamster ovary cells using split green fluorescent protein
Background:
The establishment of high producer is an important issue in Chinese hamster ovary (CHO) cell culture considering increased heterogeneity by the random integration of a transfected foreign gene and the altered position of the integrated gene. Fluorescence-activated cell sorting (FACS)-based cell line development is an efficient strategy for the selection of CHO cells in high therapeutic protein production.
Results:
An internal ribosome entry site (IRES) was introduced for using two green fluorescence protein (GFP) fragments as a reporter to both antibody chains, the heavy chain and the light chain. The cells co-transfected with two GFP fragments showed the emission of green fluorescence by the reconstitution of split GFP. The FACS-sorted pool with GFP expression had a higher specific antibody productivity (qAb) than that of the unsorted pool. The qAb was highly correlated with the fluorescence intensity with a high correlation coefficient, evidenced from the analysis of median GFP and qAb in individual selected clones.
Conclusions:
This study proved that the fragment complementation for split GFP could be an efficient indication for antibody production on the basis of high correlation of qAb with reconstitution of GFP. Taken together, we developed an efficient FACS-based screening method for high antibody-producing CHO cells with the benefits of the split GFP system.
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Validation of glypican-3-specific scFv isolated from paired display/secretory yeast display library
Background:
Glypican-3 (GPC3) is a heparan-sulfate proteoglycan frequently expressed on the cell membrane of malignant hepatocytes in hepatocellular carcinoma. The capacity for screening potential antibodies in vitro using human hepatocellular lines is critical to ensure binding to this highly post-translationally modified glycophosphatidylinositiol-linked protein. We hypothesized that we could utilize a recently described paired display/secretory yeast library to isolate human-derived scFv against glypican-3 for potential diagnostic and/or therapeutic application.
Methods:
Using two different biotinylated antigen targets, a synthesized 29mer fragment GPC3550-558 and a truncated GPC3368-548 fused with glutathione S-transferase (GST) we enriched the yeast display library to greater than 30% target-specific yeast with both positive selection and depletion of streptavidin- and GST-specific clones. After cloning of scFv cDNA from the enriched sub-library, scFv specificity was validated by ELISA for binding to recombinant protein from prokaryotic and eukaryotic sources and ultimately naturally presented human protein on the cell membrane of human hepatocellular cell lines. Specificity was confirmed using non-expressing cell lines and shRNA knockdown.
Results:
Ultimately, five unique scFv with affinity EC50 ranging from 5.0-110.9nM were identified.
Conclusions:
Using a paired display/secretory yeast library, five novel and unique scFvs for potential humoral or chimeric therapeutic development in human hepatocellular carcinoma were isolated and characterized.
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Untranslated regions of diverse plant viral RNAs vary greatly in translation enhancement efficiency
Background:
Whole plants or plant cell cultures can serve as low cost bioreactors to produce massive amounts of a specific protein for pharmacological or industrial use. To maximize protein expression, translation of mRNA must be optimized. Many plant viral RNAs harbor extremely efficient translation enhancers. However, few of these different translation elements have been compared side-by-side. Thus, it is unclear which are the most efficient translation enhancers. Here, we compare the effects of untranslated regions (UTRs) containing translation elements from six plant viruses on translation in wheat germ extract and in monocotyledenous and dicotyledenous plant cells.
Results:
The highest expressing uncapped mRNAs contained viral UTRs harboring Barley yellow dwarf virus (BYDV)-like cap-independent translation elements (BTEs). The BYDV BTE conferred the most efficient translation of a luciferase reporter in wheat germ extract and oat protoplasts, while uncapped mRNA containing the BTE from Tobacco necrosis virus-D translated most efficiently in tobacco cells. Capped mRNA containing the Tobacco mosaic virus omega sequence was the most efficient mRNA in tobacco cells. UTRs from Satellite tobacco necrosis virus, Tomato bushy stunt virus, and Crucifer-infecting tobamovirus (crTMV) did not stimulate translation efficiently. mRNA with the crTMV 5' UTR was unstable in tobacco protoplasts.
Conclusions:
BTEs confer the highest levels of translation of uncapped mRNAs in vitro and in vivo, while the capped omega sequence is most efficient in tobacco cells. These results provide a basis for understanding mechanisms of translation enhancement, and for maximizing protein synthesis in cell-free systems, transgenic plants, or in viral expression vectors.
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RNA viral vectors for improved Agrobacterium-mediated transient expression of heterologous proteins in Nicotiana benthamiana cell suspensions and hairy roots
Background:
Plant cell suspensions and hairy root cultures represent scalable protein expression platforms. Low protein product titers have thus far limited the application of transient protein expression in these hosts. The objective of this work was to overcome this limitation by harnessing A. tumefaciens to deliver replicating and non-replicating RNA viral vectors in plant tissue co-cultures.
Results:
Replicating vectors derived from Potato virus X (PVX) and Tobacco rattle virus (TRV) were modified to contain the reporter gene beta-glucuronidase (GUS) with a plant intron to prevent bacterial expression. In cell suspensions, a minimal PVX vector retaining only the viral RNA polymerase gene yielded 6.6-fold more GUS than an analogous full-length PVX vector. Transient co-expression of the minimal PVX vector with P19 of Tomato bushy stunt virus or HC-Pro of Tobacco etch virus to suppress post-transcriptional gene silencing increased GUS expression by 44 and 83%, respectively. A non-replicating vector containing a leader sequence from Cowpea mosaic virus (CPMV-HT) modified for enhanced translation led to 70% higher transient GUS expression than a control treatment. In hairy roots, a TRV vector capable of systemic movement increased GUS accumulation by 150-fold relative to the analogous PVX vector. Histochemical staining for GUS in TRV-infected hairy roots revealed the capacity for achieving even higher productivity per unit biomass.
Conclusions:
For the first time, replicating PVX vectors and a non-replicating CPMV-HT vector were successfully applied toward transient heterologous protein expression in cell suspensions. A replicating TRV vector achieved transient GUS expression levels in hairy roots more than an order of magnitude higher than the highest level previously reported with a viral vector delivered by A. tumefaciens.
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Solution-based targeted genomic enrichment for precious DNA samples
Background:
Solution-based targeted genomic enrichment (TGE) protocols permit selective sequencing of genomic regions of interest on a massively parallel scale. These protocols could be improved by: 1) modifying or eliminating time consuming steps; 2) increasing yield to reduce input DNA and excessive PCR cycling; and 3) enhancing reproducible.
Results:
We developed a solution-based TGE method for downstream Illumina sequencing in a non-automated workflow, adding standard Illumina barcode indexes during the post-hybridization amplification to allow for sample pooling prior to sequencing. The method utilizes Agilent SureSelect baits, primers and hybridization reagents for the capture, off-the-shelf reagents for the library preparation steps, and adaptor oligonucleotides for Illumina paired-end sequencing purchased directly from an oligonucleotide manufacturing company.
Conclusions:
This solution-based TGE method for Illumina sequencing is optimized for small- or medium-sized laboratories and addresses the weaknesses of standard protocols by reducing the amount of input DNA required, increasing capture yield, optimizing efficiency, and improving reproducibility.
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Development of a diagnostic method for neosporosis in cattle using recombinant Neospora caninum proteins
Background:
Neosporosis is an infectious disease primarily of cattle and dogs, caused by intracellular parasite, Neospora caninum. Neosporosis appears to be a major cause of abortion in dairy cattle worldwide and causes to huge economic loss to dairy industry.
Results:
Recombinant surface associated antigen 1 (NcSAG1), NcSAG1 related sequence 2 (NcSRS2) and the dense granule antigen 2 (NcGRA2) of N. caninum were expressed either in silkworm or in Escherichia coli and purified. The purified recombinant proteins bound to the N. caninum-specific antibodies in serum samples from infected cattle as revealed by an enzyme-linked immunosorbent assay (ELISA). By co-immobilizing these recombinant proteins, a novel indirect ELISA was developed for detection of neosporosis. With the use of 32 serum samples, comprising 12 positive serum samples and 20 negative serum samples, the sensitivity and specificity of the assay were found to be 91.7 and 100%, respectively. Seventy-two serum samples from dairy farms were also tested and one was diagnosed with neosporasis with both this method and a commercial assay.
Conclusions:
A diagnostic method employing recombinant proteins of N. caninum was developed. The method showed high sensitivity and specificity. Diagnostic test with field serum samples suggested its applicability to the practical diagnosis of neosporosis.
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Isolation and characterization of wharton's jellyderived
multipotent mesenchymal stromal cells
obtained from bovine umbilical cord and maintained
in a defined serum-free three-dimensional system
Background:
The possibility for isolating bovine mesenchymal multipotent cells (MSCs) from fetal adnexais an interesting prospect because of the potential for these cells to be used forbiotechnological applications. Bone marrow and adipose tissue are the most common sourcesof MSCs derived from adult animals. However, little knowledge exists about thecharacteristics of these progenitors cells in the bovine species. Traditionally most cellcultures are developed in two dimensional (2D) environments. In mammalian tissue, cellsconnect not only to each other, but also support structures called the extracellular matrix(ECM). The three-dimensional (3D) cultures may play a potential role in cell biotechnology,especially in tissue therapy. In this study, bovine-derived umbilical cord Wharton's jelly(UC-WJ) cells were isolated, characterized and maintained under 3D-free serum condition asan alternative of stem cell source for future cell banking.
Results:
Bovine-derived UC-WJ cells, collected individually from 5 different umbilical cords sources,were successfully cultured under serum-free conditions and were capable to support 60consecutive passages using commercial Stemline(R) mesenchymal stem cells expansionmedium. Moreover, the UC-WJ cells were differentiated into osteocytes, chondrocytes,adipocytes and neural-like cells and cultured separately. Additionally, the genes that areconsidered important embryonic, POU5F1 and ITSN1, and mesenchymal cell markers,CD105+, CD29+, CD73+ and CD90+ in MSCs were also expressed in five bovine-derivedUC-WJ cultures. Morphology of proliferating cells typically appeared fibroblast-like spindleshape presenting the same viability and number. These characteristics were not affectedduring passages. There were 60 chromosomes at the metaphase, with acrocentric morphologyand intense telomerase activity. Moreover, the proliferative capacity of T cells in response toa mitogen stimulus was suppressed when bovine-derived UC-WJ cells was included in theculture which demonstrated the immunossupression profile typically observed amongisolated mesenchymal cells from other species. After classified the UC-WJ cells asmesenchymal stromal phenotype the in vitro 3D cultures was performed using theAlgiMatrix(R) protocol. Based on the size of spheroids (283,07 mum +/- 43,10 mum) we found thatthree weeks of culture was the best period to growth the UC-WJ cells on 3D dimension. Theinitial cell density was measured and the best value was 1.5 x 106 cells/well.
Conclusions:
We described for the first time the isolation and characterization of UC-WJ cells in a serumfreecondition and maintenance of primitive mesenchymal phenotype. The culture was stableunder 60 consecutive passages with no genetic abnormalities and proliferating ratios. Takentogether all results, it was possible to demonstrate an easy way to isolate and culture ofbovine-derived UC-WJ cells under 2D and 3D serum-free condition, from fetal adnexa with agreat potential in cell therapy and biotechnology.
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Very bright orange fluorescent plants: endoplasmic reticulum targeting of orange fluorescent proteins as visual reporters in transgenic plants
Background:
The expression of fluorescent protein (FP) genes as real-time visual markers, both transiently and stably, has revolutionized plant biotechnology. A palette of colors of FPs is now available for use, but the diversity has generally been underutilized in plant biotechnology. Because of the green and far-red autofluorescent properties of many plant tissues and the FPs themselves, red and orange FPs (RFPs, and OFPs, respectfully) appear to be the colors with maximum utility in plant biotechnology. Within the color palette OFPs have emerged as the brightest FP markers in the visible spectra. This study compares several native, near-native and modified OFPs for their "brightness" and fluorescence, therefore, their usability as marker genes in transgenic plant tissues.
Results:
The OFPs DsRed2, tdTomato, mOrange and pporRFP were all expressed under the control of the CaMV 35S promoter in agroinfiltration-mediated transient assays in Nicotiana benthamiana. Each of these, as well as endoplasmic reticulum (ER)-targeted versions, were stably expressed in transgenic Nicotiana tabacum and Arabidopsis thaliana. Congruent results were observed between transient and stable assays. Our results demonstrated that there are several adequate OFP genes available for plant transformation, including the new pporRFP, an unaltered tetramer from the hard coral Porites porites. When the tandem dimer tdTomato and the monomeric mOrange were targeted to the ER, dramatic, ca. 3-fold, increase in plant fluorescence was observed.
Conclusions:
From our empirical data, and a search of the literature, it appears that tdTomato-ER and mOrange-ER are the two highest fluorescing FPs available as reporters for transgenic plants. The pporRFP is a brightly fluorescing tetramer, but all tetramer FPs are far less bright than the ER-targeted monomers we report here.
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Pattern analysis approach reveals restriction enzyme cutting abnormalities and other cDNA library construction artifacts using raw EST data
Background:
Expressed Sequence Tag (EST) sequences are widely used in applications such as genome annotation, gene discovery and gene expression studies. However, some of GenBank dbEST sequences have proven to be "unclean". Identification of cDNA termini/ends and their structures in raw ESTs not only facilitates data quality control and accurate delineation of transcription ends, but also furthers our understanding of the potential sources of data abnormalities/errors present in the wet-lab procedures for cDNA library construction.
Results:
After analyzing a total of 309,976 raw Pinus taeda ESTs, we uncovered many distinct variations of cDNA termini, some of which prove to be good indicators of wet-lab artifacts, and characterized each raw EST by its cDNA terminus structure patterns. In contrast to the expected patterns, many ESTs displayed complex and/or abnormal patterns that represent potential wet-lab errors such as: a failure of one or both of the restriction enzymes to cut the plasmid vector; a failure of the restriction enzymes to cut the vector at the correct positions; the insertion of two cDNA inserts into a single vector; the insertion of multiple and/or concatenated adapters/linkers; the presence of 3' -end terminal structures in designated 5' -end sequences or vice versa; and so on. With a close examination of these artifacts, many problematic ESTs that have been deposited into public databases by conventional bioinformatics pipelines or tools could be cleaned or filtered by our methodology. We developed a software tool for Abnormality Filtering and Sequence Trimming for ESTs (AFST, http://code.google.com/p/afst/) using a pattern analysis approach. To compare AFST with other pipelines that submitted ESTs into dbEST, we reprocessed 230,783 Pinus taeda and 38,709 Arachis hypogaea GenBank ESTs. We found 7.4% of Pinus taeda and 29.2% of Arachis hypogaea GenBank ESTs are "unclean" or abnormal, all of which could be cleaned or filtered by AFST.
Conclusions:
cDNA terminal pattern analysis, as implemented in the AFST software tool, can be utilized to reveal wet-lab errors such as restriction enzyme cutting abnormities and chimeric EST sequences, detect various data abnormalities embedded in existing Sanger EST datasets, improve the accuracy of identifying and extracting bona fide cDNA inserts from raw ESTs, and therefore greatly benefit downstream EST-based applications.
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GMO detection using a bioluminescent real time reporter (BART) of loop mediated isothermal amplification (LAMP) suitable for field use
Background:
There is an increasing need for quantitative technologies suitable for molecular detection in a variety of settings for applications including food traceability and monitoring of genetically modified (GM) crops and their products through the food processing chain. Conventional molecular diagnostics utilising real-time polymerase chain reaction (RT-PCR) and fluorescence-based determination of amplification require temperature cycling and relatively complex optics. In contrast, isothermal amplification coupled to a bioluminescent output produced in real-time (BART) occurs at a constant temperature and only requires a simple light detection and integration device.
Results:
Loop mediated isothermal amplification (LAMP) shows robustness to sample-derived inhibitors. Here we show the applicability of coupled LAMP and BART reactions (LAMP-BART) for determination of genetically modified (GM) maize target DNA at low levels of contamination (0.1-5.0% GM) using certified reference material, and compare this to RT-PCR. Results show that conventional DNA extraction methods developed for PCR may not be optimal for LAMP-BART quantification. Additionally, we demonstrate that LAMP is more tolerant to plant sample-derived inhibitors, and show this can be exploited to develop rapid extraction techniques suitable for simple field-based qualitative tests for GM status determination. We also assess the effect of total DNA assay load on LAMP-BART quantitation.
Conclusions:
LAMP-BART is an effective and sensitive technique for GM detection with significant potential for quantification even at low levels of contamination and in samples derived from crops such as maize with a large genome size. The resilience of LAMP-BART to acidic polysaccharides makes it well suited to rapid sample preparation techniques and hence to both high throughput laboratory settings and to portable GM detection applications. The impact of the plant sample matrix and genome loading within a reaction must be controlled to ensure quantification at low target concentrations.
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BMC Blood Disorders - Latest Articles
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Zinc finger nucleases for targeted mutagenesis and
repair of the sickle-cell disease mutation: An insilico
study
Background:
Sickle cell disease (or simply, SCD) is an inherited hemoglobinopathy which is mostlyprevalent among persons of African descent. SCD results from a monogenic (Hemoglobin,beta) point-mutation (substitution of the base Adenine with Thymine at position six) thatleads to replacement of the amino acid glutamic acid (E) with valine (V). Management ofSCD within resource-poor settings is largely syndromic, since the option of cure offered bybone-marrow transplantation (BMT) is risky and unaffordable by most affected individuals.Despite previous reports of repair and inhibition of the sickle beta-globin gene and messengerribonucleic acids (mRNAs), respectively in erythrocyte precursor cells via gene-targetingusing an oligomer-restriction enzyme construct and either ribozyme- or RNA-DNA chimericoligonucleotides (or simply third strand binding), gene-therapy to treat SCD still remainslargely preclinical. In the wake of the advances in target- gene- mutagenesis and repairwrought by zinc finger nuclease (ZFN) technology, it was hypothesized that SCD may becured by the same. The goal of this study thus, was constructing a database of zinc fingerarrays (ZFAs) and engineering ZFNs, that respectively bind and cleave within or aroundspecific sequences in the sickle hemoglobin, beta (betaS) gene.Methods and resultsFirst, using the complete 1606 genomic DNA base pair (bp) sequences of the normalhemoglobin-beta (betaA) chain gene, and the ZiFiT-CoDA-ZFA software preset at default, 57three-finger arrays (ZFAs) that specifically bind 9 base-pair sequences within the normalhemoglobin-beta chain, were computationally assembled. Second, by serial linkage of theseZFAs to the Flavobacterium okeanokoites endonuclease Fok Ifour ZFNs with uniquespecificity to >24 bp target-sequences at the genomic contextual positions 82, 1333, 1334,and 1413 of the betaA chain-gene were constructed in-silico. Third, localizing the pointmutationof SCD at genomic contextual position 69-70-71- bp (a position corresponding tothe 6th codon) of the betaA chain-gene, inspired the final design of five more ZFNs specific to>24 bp target-sequences within the 8,954 bp that are genomically adjacent to the 5' end of thebetaA chain-gene.
Conclusions:
This set of 57 ZFAs and 9 ZFNs offers us gene-therapeutic precursors for the targetedmutagenesis and repair of the SCD mutation or genotype.
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Molecular characterization of glucose-6-phosphate dehydrogenase deficient variants in Baghdad city - Iraq
Background:
Although G6PD deficiency is the most common genetically determined blood disorder among Iraqis, its molecular basis has only recently been studied among the Kurds in North Iraq, while studies focusing on Arabs in other parts of Iraq are still absent.
Methods:
A total of 1810 apparently healthy adult male blood donors were randomly recruited from the national blood transfusion center in Baghdad. They were classified into G6PD deficient and non-deficient individuals based on the results of methemoglobin reduction test (MHRT), with confirmation of deficiency by subsequent enzyme assays. DNA from deficient individuals was studied using a polymerase chain reaction-Restriction fragment length polymorphism (PCR-RFLP) for four deficient molecular variants, namely G6PD Mediterranean (563 C→T), Chatham (1003 G→A), A- (202 G→A) and Aures (143 T→C). A subset of those with the Mediterranean variant, were further investigated for the 1311 (C→T) silent mutation.
Results:
G6PD deficiency was detected in 109 of the 1810 screened male individuals (6.0%). Among 101 G6PD deficient males molecularly studied, the Mediterranean mutation was detected in 75 cases (74.3%), G6PD Chatham in 5 cases (5.0%), G6PD A- in two cases (2.0%), and G6PD Aures in none. The 1311 silent mutation was detected in 48 out of the 51 G6PD deficient males with the Mediterranean variant studied (94.1%).
Conclusions:
Three polymorphic variants namely: the Mediterranean, Chatham and A-, constituted more than 80% of G6PD deficient variants among males in Baghdad. Iraq. This observation is to some extent comparable to other Asian Arab countries, neighboring Turkey and Iran.
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Hemoglobin E syndromes in Pakistani population
Background:
Hemoglobin E is an important hemoglobin variant with a worldwide distribution. A number of hemoglobinopathies have been reported from Pakistan. However a comprehensive description of hemoglobin E syndromes for the country was never made. This study aimed to describe various hemoglobin E disorders based on hematological parameters and chromatography. The sub-aim was to characterize hemoglobin E at molecular level.
Methods:
This was a hospital based study conducted prospectively for a period of one year extending from January 1 to December 31, 2008. EDTA blood samples were analyzed for completed blood counts and hemoglobin variants through automated hematology analyzer and Bio-Rad beta thalassaemia short program respectively. Six samples were randomly selected to characterize HbE at molecular level through RFLP-PCR utilizing MnlI restriction enzyme.
Results:
During the study period, 11403 chromatograms were analyzed and Hb E was detected in 41 (or 0.36%) samples. Different hemoglobin E syndromes identified were HbEA (n = 20 or 49%), HbE/β-thalassemia (n = 14 or 34%), HbEE (n = 6 or 15%) and HbE/HbS (n = 1 or 2%). Compound heterozygosity for HbE and beta thalassaemia was found to be the most severely affected phenotype. RFLP-PCR utilizing MnlI successfully characterized HbE at molecular level in six randomly selected samples.
Conclusions:
Various HbE phenotypes are prevalent in Pakistan with HbEA and HbE/β thalassaemia representing the most common syndromes. Chromatography cannot only successfully identify hemoglobin E but also assist in further characterization into its phenotype including compound heterozygosity. Definitive diagnosis of HbE can easily be achieved through RFLP-PCR.
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Patient-reported treatment burden of chronic immune thrombocytopenia therapies
Background:
Chronic immune thrombocytopenia (ITP) is a debilitating autoimmune disorder that causes a reduction in blood platelets and increased risk of bleeding. ITP is currently managed with various pharmacologic therapies and splenectomy.This study was conducted to assess patient perceived and reported treatment side effects, as well as the perceived burden or bother, and need to reduce or stop treatment, associated with these side effects among adult patients with chronic ITP.
Methods:
A Web-enabled survey was administered to members of a US-based ITP patient support group. Patients reported demographic and clinical characteristics, ITP treatments' side effects for treatments received since diagnosed, level of bother (or distress), and need to reduce or stop treatment, associated with side effects. Current and past exposure was assessed for five specific treatment types: corticosteroids (CS), intravenous immunoglobulin (IVIg), anti-D immunoglobulin (anti-D), rituximab (RT), and splenectomy (SPL), as well as for other patient-referenced therapies (captured as "other").
Results:
The survey was completed by 589 patients; 78% female, 89% white, mean age 48 years (SD = 14.71), and 68% reported a typical low platelet count of < 50,000/μL. Current or past treatment with CS was reported by 92% (n = 542) of patients, 56% (n = 322) for IVIg, 36% (n = 209) for anti-D, 36% (n = 213) for RT, and 39% (n = 227) for SPL. A substantial proportion of CS-treated patients reported side effects (98%, P < 0.05), were highly bothered by their side effects (53.1%, P < 0.05), and reported the need to stop or reduce treatment due to side effects (37.8%, P < 0.05). Among patients reporting side effects of treatment, significant associations were noted for the number of side effects, aggregate bother of reported side effects, and the need to stop or reduce treatment (all P < 0.05).
Conclusions:
Current ITP treatments, particularly corticosteroids, are associated with multiple bothersome side effects that may lead to patients stopping or reducing therapy. Open, informed and complete communication between clinician and patient regarding both the benefits and the side effects of ITP treatment may better prepare patients for their prescribed regimens.
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Fanconi anaemia with bilateral diffuse pulmonary arterio venous fistulae: a case report
Background:
We report a patient with cytogenetically confirmed Fanconi anaemia with associated diffuse bilateral pulmonary arterio-venous fistulae. This is only the second reported case of diffuse pulmonary arterio-venous fistulae with Fanconi anaemia.Case PresentationA 16 year old Sri Lankan boy, with a cytogenetically confirmed Fanconi anaemia was admitted to University Medical Unit, National Hospital of Sri Lanka for further assessment and treatment. Both central and peripheral cyanosis plus clubbing were noted on examination. The peripheral saturation was persistently low on room air and did not improve with supplementary Oxygen. Contrast echocardiography failed to demonstrate an intra cardiac shunt but showed early crossover of contrast, suggesting the possibility of pulmonary arterio-venous fistulae. Computed tomography pulmonary angiogram was inconclusive. Subsequent right heart catheterisation revealed bilateral diffuse arterio-venous fistulae not amenable for device closure or surgical intervention.
Conclusion:
To our knowledge, this is the second reported patient with diffuse pulmonary arterio-venous fistulae associated with Fanconi anaemia. We report this case to create awareness among clinicians regarding this elusive association. We recommend screening patients with Fanconi anaemia using contrast echocardiography at the time of assessment with transthoracic echocardiogram. Though universal screening may be impossible given the cost constraints, such screening should at least be performed in patients with clinical evidence of desaturation or when a therapeutic option such as haematopoietic stem cell transplantation is considered. Treatment of pulmonary arteriovenous fistulae would improve patient outcome as desaturation by shunting worsens the anaemic symptoms by reducing the oxygen carrying capacity of blood.
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Meta-analysis of efficacy and safety of intravenous ferric carboxymaltose (Ferinject) from clinical trial reports and published trial data
Background:
Recommendations given for intravenous iron treatment are typically not supported by a high level of evidence. This meta-analysis addressed this by summarising the available date from clinical trials of ferric carboxymaltose using clinical trial reports and published reports.
Methods:
Clinical trial reports were supplemented by electronic literature searches comparing ferric carboxymaltose with active comparators or placebo. Various outcomes were sought for efficacy (attainment of normal haemoglobin (Hb), increase of Hb by a defined amount, for example), together with measures of harm, including serious adverse events and deaths.
Results:
Fourteen studies were identified with 2,348 randomised patients exposed to ferric carboxymaltose, 832 to oral iron, 762 to placebo, and 384 to intravenous iron sucrose. Additional data were available from cohort studies. Intravenous ferric carboxymaltose was given up to the calculated iron deficit (up to 1,000 mg in one week) for iron deficiency anaemia secondary to chronic kidney disease, blood loss in obstetric and gynaecological conditions, gastrointestinal disease, and other conditions like heart failure. The most common comparator was oral iron, and trials lasted 1 to 24 weeks. Intravenous ferric carboxymaltose improved mean Hb, serum ferritin, and transferrin saturation levels; the mean end-of-trial increase over oral iron was, for Hb 4.8 (95% confidence interval 3.3 to 6.3) g/L, for ferritin 163 (153 to 173) μg/L, and for transferrin saturation 5.3% (3.7 to 6.8%). Ferric carboxymaltose was significantly better than comparator in achievement of target Hb increase (number needed to treat (NNT) 6.8; 5.3 to 9.7) and target Hb NNT (5.9; 4.7 to 8.1). Serious adverse events and deaths were similar in incidence in ferric carboxymaltose and comparators; rates of constipation, diarrhoea, and nausea or vomiting were lower than with oral iron.
Conclusions:
This review examined the available trials of intravenous ferric carboxymaltose using details from published papers and unpublished clinical trial reports. It increases the evidence available to support recommendations given for intravenous iron treatment, but there are limited trial data comparing different intravenous iron preparations.
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Lung Transplantation for Pulmonary Fibrosis in Dyskeratosis Congenita: Case Report and Systematic Literature Review
Background:
Dyskeratosis congenita (DC) is a progressive, multi-system, inherited disorder of telomere biology with high risks of morbidity and mortality from bone marrow failure, hematologic malignancy, solid tumors and pulmonary fibrosis. Hematopoietic stem cell transplantation (HSCT) can cure the bone marrow failure, but it does not eliminate the risks of other complications, for which life-long surveillance is required. Pulmonary fibrosis is a progressive and lethal complication of DC.Case presentationIn this report, we describe a patient with DC who developed pulmonary fibrosis seven years after HSCT for severe aplastic anemia, and was successfully treated with bilateral lung transplantation. We also performed a systematic literature review to understand the burden of pulmonary disease in patients with DC who did or did not receive an HSCT. Including our patient, we identified 49 DC patients with pulmonary disease (12 after HSCT and 37 without HSCT), and 509 with no reported pulmonary complications.
Conclusion:
Our current case and literature review indicate that pulmonary morbidity is one of the major contributors to poor quality of life and reduced long-term survival in DC. We suggest that lung transplantation be considered for patients with DC who develop pulmonary fibrosis with no concurrent evidence of multi-organ failure.
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Serum levels of leptin in Nigerian patients with sickle cell anaemia
Background:
Several studies have shown that the pathophysiology of homozygous sickle cell anaemia (SCA) results in a myriad of metabolic, nutritional, haematological and clinical effects that interact with other co-morbid factors to determine the quality of life and life expectancy of afflicted patients. Because of its critical roles in nutrition and metabolism, inflammation, haematopoiesis and cellular immunity, this study determined the plasma levels of leptin in steady and unsteady states of HbSS in Nigerian patients.
Methods:
A total of 51 SCA patients aged 5 - 35 years with 34 (61.8%) being females who were either on admission or visiting four medical centres in Lagos, Nigeria together with 22 non-SCD controls aged 5 -30 years comprising 12 (54.5%) females were enrolled after obtaining their informed consent and ethical approval. Patients were further stratified into steady and unsteady cases of SCA based on clinical presentations, while blood samples collected by venipuncture from each of the study participants were analyzed haematologically for full blood count and HbF level and microscopically for malaria, while plasma leptin was assayed using ELISA method. Body composition defined by weight, fat mass and body mass index (BMI) was determined using standard methods. Data obtained for cases and controls were analyzed statistically.
Results:
Twenty - one patients had unsteady HbSS and elicited greater and significant (P < 0.05) reduction in fat mass, BMI, HbF and eosinophil count but elevated mean total leukocyte, count, level of irreversibly sickled cells and P. falciparum parasitaemia (4613.7 vs. 749.6 - 1078.4 parasites/uL), pyrexia rate (58.3 vs. 25.8%) when compared with steady state patients or non-SCD controls. Compared to the control, significant decreases in plasma leptin before and after controlling for body fat that was worsened by crisis were observed among the SCD patients. Unlike the non-SCD controls, leptin correlated non-significantly (P > 0.05) with all body composition indices measured in the patients except for fat mass in unsteady cases. Multivariate regression analysis identified ESR and RC as independent predictor of low plasma leptin concentration in the SCA patients.
Conclusions:
Base on these findings, we conclude that plasma level of leptin is further decreased in the unsteady state of HbSS, shows poor correlation with adiposity and malarial infection but has inflammation and poor reticulocyte response as independent predictors among Nigerian patients.
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Erythrocyte Reference Values in Emirati People with and without
alpha+ Thalassemia
Background:
Interpreting the erythroid lineage in populations with high frequency of α+ thalassemia allele is challenging due to the high prevalence of α+ thalassemia homozygotes. For such populations, separate reference values for normal and α+ thalassemia homozygotes are needed.
Methods:
We studied the erythroid lineage in 1,079 citizens of United Arab Emirates (UAE). Subjects with abnormal hemoglobin (39), iron deficiency (136) or erroneous entries (8) were excluded. MCV distribution in the remaining individuals (896) was visibly bimodal. Statistical mixture analysis with Normix program was used to separate subpopulations with normal and small red cells. Hardy-Weinberg equation was used to estimate genotype frequencies.
Results:
MCV of 78.0 fl separated phenotype-derived normal homozygotes (715) from phenotype-derived α+ thalassemia homozygotes (181). The erythrocyte indices were significantly different between the two groups (p < 0.0001). The overall prevalence of phenotype-derived α+ thalassemia homozygotes (-α/-α) was 0.20 and markedly varied among tribes, 0 to 0.31 (Mean = 0.15). The frequency of phenotype-derived α+ thalassemia allele was 0.44; when accounting for tribal population structure and inbreeding, the calculated frequency was 0.34. These values were very similar to those found in the same population by genotyping and other phenotyping methods. The erythrocyte reference values for phenotype-derived normal homozygotes in Emiratis closely overlapped with those for Caucasians and normal homozygotes defined by genotyping. The reference values for phenotype-derived α+ thalassemia homozygotes in Emiratis also closely overlapped with those for α+ thalassemia homozygotes defined by genotyping.
Conclusion:
In populations with frequent α+ thalassemia mutations, two sets of erythrocyte reference values could be determined without genotyping.
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Pica associated with iron deficiency or depletion: clinical and laboratory correlates in 262 non-pregnant adult outpatients
Background:
There are many descriptions of the association of pica with iron deficiency in adults, but there are few reports in which observations available at diagnosis of iron deficiency were analyzed using multivariable techniques to identify significant predictors of pica. We sought to identify clinical and laboratory correlates of pica in adults with iron deficiency or depletion using univariable and stepwise forward logistic regression analyses.
Methods:
We reviewed charts of 262 non-pregnant adult outpatients (ages ≥18 y) who required treatment with intravenous iron dextran. We tabulated their sex, age, race/ethnicity, body mass index, symptoms and causes of iron deficiency or depletion, serum iron and complete blood count measures, and other conditions at diagnosis before intravenous iron dextran was administered. We excluded patients with serum creatinine >133 μmol/L or disorders that could affect erythrocyte or iron measures. Iron deficiency was defined as both SF <45 pmol/L and TS <10%. Iron depletion was defined as serum ferritin (SF) <112 pmol/L. We performed univariable comparisons and stepwise forward logistic regression analyses to identify significant correlates of pica.
Results:
There were 230 women (184 white, 46 black; ages 19-91 y) and 32 men (31 white, 1 black; ages 24-81 y). 118 patients (45.0%) reported pica; of these, 87.3% reported ice pica (pagophagia). In univariable analyses, patients with pica had lower mean age, black race/ethnicity, and higher prevalences of cardiopulmonary and epithelial manifestations. The prevalence of iron deficiency, with or without anemia, did not differ significantly between patients with and without pica reports. Mean hemoglobin and mean corpuscular volume (MCV) were lower and mean red blood cell distribution width (RDW) and platelet count were higher in patients with pica. Thrombocytosis occurred only in women and was more prevalent in those with pica (20.4% vs. 8.3%; p = 0.0050). Mean total iron-binding capacity was higher and mean serum ferritin was lower in patients with pica. Nineteen patients developed a second episode of iron deficiency or depletion; concordance of recurrent pica (or absence of pica) was 95%. Predictors of pica in logistic regression analyses were age and MCV (negative associations; p = 0.0250 and 0.0018, respectively) and RDW and platelet count (positive associations; p = 0.0009 and 0.02215, respectively); the odds ratios of these predictors were low.
Conclusions:
In non-pregnant adult patients with iron deficiency or depletion, lower age is a significant predictor of pica. Patients with pica have lower MCV, higher RDW, and higher platelet counts than patients without pica.
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BMC Cancer - Latest Articles
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Imatinib-induced liver cirrhosis in a patient with advanced gastrointestinal stroma tumor (GIST)
Background:
The use of imatinib mesylate is associated with a progression free survival of 41 months in first line treatment of metastatic or locally advanced gastrointestinal stromal tumors (GIST) and other studies approved that adjuvant imatinib treatment improves the recurrence-free survival in patients with GIST. Current recommendations include 1 year adjuvant treatment in GIST patients at risk but active studies explore different durations of treatment with an interval of up to 5 years. While the most frequent adverse events (AEs) are blood count alterations, abdominal discomfort and edema, the occurrence of grade 3 or 4 increase of AST or ALT is specified with 2.1% and 2.7% respectively.Case presentationWe report a 49-year old male with a gastrointestinal stromal tumor (GIST) of the small bowel who developed liver cirrhosis under adjuvant imatinib treatment.
Conclusions:
Our report supports the notion that imatinib-induced hepatotoxicity may lead to acute liver damage with subsequent cirrhotic remodelling. Patients developing grade 3 or 4 hepatotoxicity during imatinib treatment should therefore be carefully evaluated for chronic liver disease.
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Customized chemotherapy based on epidermal growth factor receptor mutation status for elderly patients with advanced non-small-cell lung cancer: a phase II trial
Background:
Elderly patients are more vulnerable to toxicity from chemotherapy. Activating epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) are associated with enhanced response to EGFR tyrosine-kinase inhibitors. We studied patients with advanced NSCLC for whom treatment was customized based on EGFR mutation status.
Methods:
We screened 57 chemotherapy-naive patients with histologically or cytologically confirmed NSCLC, stage IIIB or IV, aged 70 years or older, and with an Eastern Cooperative Oncology Group performance status 0 or 1, for EGFR exon 19 codon 746-750 deletion and exon 21 L858R mutation. Twenty-two patients with EGFR mutations received gefitinib; 32 patients without mutations received vinorelbine or gemcitabine. The primary endpoint was the response rate.
Results:
The response rate was 45.5% (95% confidence interval [CI]: 24.4%, 67.8%) in patients with EGFR mutations and 18.8% (95% CI: 7.2%, 36.4%) in patients without EGFR mutations. The median overall survival was 27.9 months (95%CI: 24.4 months, undeterminable months) in patients with EGFR mutations and 14.9 months (95%CI: 11.0 months, 22.4 months) in patients without EGFR mutations. In the gefitinib group, grade 3/4 hepatic dysfunction and dermatitis occurred in 23% and 5% of patients, respectively. In patients treated with vinorelbine or gemcitabine, the most common grade 3 or 4 adverse events were neutropenia (47%; four had febrile neutropenia), anemia (13%), and anorexia (9%). No treatment-related deaths occurred.
Conclusions:
Treatment customization based on EGFR mutation status deserves consideration, particularly for elderly patients who often cannot receive second-line chemotherapy due to poor organ function or comorbidities.Trial registration:This trial is registered at University hospital Medical Information Network-clinical trial registration (www.umin.ac.jp/ctr/index/htm) with the registration identification number C000000436.
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A Systematic Review of the Impact of Stigma and Nihilism on Lung Cancer Outcomes
Background:
This study systematically review the evidence on the influence of stigma and nihilism on lung cancer patterns of care; patients' psychosocial and quality of life (QOL) outcomes; and how this may link to public health programs.
Methods:
Medline, EMBASE, ProQuest, CINAHL and PsycINFO databases were searched. The inclusion criteria were: included lung cancer patients and/or partners or caregivers and/or health professionals (either at least 80% of participants had lung cancer or were partners or caregivers of lung cancer patients, or there was a lung cancer specific sub-group focus or analysis), assessed stigma or nihilism with respect to lung cancer and published in English between 1st January 1999 and 31st January 2011. Trial quality and levels of evidence were assessed.
Results:
Eighteen articles describing 15 studies met inclusion criteria. The seven qualitative studies were high quality with regard to data collection, analysis and reporting; however most lacked a clear theoretical framework; did not address interviewer bias; or provide a rationale for sample size. The eight quantitative studies were generally of low quality with highly selected samples, non-comparable groups and low participation rates and employed divergent theoretical and measurement approaches. Stigma about lung cancer was reported by patients and health professionals and was related to poorer QOL and higher psychological distress in patients. Clear empirical explorations of nihilism were not evident. There is qualitative evidence that from the patients' perspectives public health programs contribute to stigma about lung cancer and this was supported by published commentary.
Conclusions:
Health-related stigma presents as a part of the lung cancer experience however there are clear limitations in the research to date. Future longitudinal and multi-level research is needed and this should be more clearly linked to relevant theory.
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Interaction between interleukin-10 (IL-10) polymorphisms and dietary fibre in relation to risk of colorectal cancer in a Danish case-cohort study
Background:
More than 50% of the colorectal cancer (CRC) etiology has been attributed to diet. Established or suspected dietary factors modifying risk of CRC are red meat, cereals, fish, and fibre. Diet and lifestyle may be linked to cancer through inflammation. Interleukin-10 (IL-10) is an anti-inflammatory cytokine. We wanted to test if dietary factors and IL10 polymorphisms interact in relation to colorectal carcinogenesis.
Methods:
The functional IL10 polymorphism C-592A (rs1800872) and the marker rs3024505 were assessed in relation to diet and lifestyle in a nested case-cohort study of 378 CRC cases and 775 randomly selected participants from a prospective study of 57,053 persons. Genotyping data on the IL10 polymorphism C-592A, smoking and non-steroidal anti-inflammatory drugs (NSAID) was retrieved from Vogel et al (Mutat Res, 2007; 624:88). Incidence rate ratios (IRR) and 95% Confidence Interval (95% CI) were calculated.
Results:
No associations were found between the IL10 rs3024505 polymorphism and risk of CRC. There was interaction between rs3024505 and dietary fibre (P-value for interaction=0.01). IL10 rs3024505 homozygous wildtype carriers were at 27% reduced risk of CRC per 10 g fibre per day (95% CI: 0.60-0.88) whereas variant carriers had no risk reduction by fibre intake. Also, interaction between IL10 C-592A and intake of fibre was found (P-value for interaction=0.02). Among those eating <17.0 grams of fibre per day, carriers of an C-592A variant allele had a statistically significantly higher risk of colorectal cancer compared to homozygous wildtypes. No significant differences in colorectal cancer risk were observed between the reference group (CC and <17.0 g/day) and carriers of one C-592A variant allele eating 17.0 or more grams of dietary fibre per day. This suggests that the increased risk due to carrying the variant allele can be overcome by higher fibre intake. No interactions between IL10 polymorphisms and dietary meat, cereal, or fish intake, or between IL10 rs3024505 and smoking or NSAID use were found.
Conclusions:
In this northern Caucasian cohort we found interaction between IL10 and dietary fibre in CRC carcinogenesis. High intake of fibre seems to protect against CRC among individuals with IL10 related genetic susceptibility to CRC. This finding should be evaluated in other prospective and population-based cohorts with different ethnic groups.
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Does access to a colorectal cancer screening website and/or a nurse-managed telephone help line provided to patients by their family physician increase fecal occult blood test uptake?: A pragmatic cluster randomized controlled trial study protocol
Background:
Fecal occult blood test screening in Canada is sub-optimal. Family physicians play a central role in screening are limited by the time constraints of clinical practice. Patients face multiple barriers that further reduce completion rates. Tools that support family physicians in providing their patients with colorectal cancer information and that support uptake may prove useful. The primary objective of the study is to evaluate the efficacy of a patient decision aid (nurse-managed telephone support line and/or colorectal cancer screening website) distributed by community-based family physicians, in improving colorectal cancer screening rates. Secondary objectives include evaluation of (dis)incentives to patient FOBT uptake and internet use among for health-related questions. Challenges faced by family physicians in engaging in collaborative partnerships with primary healthcare researchers will be documented.
Methods:
A pragmatic, two-arm, randomized cluster controlled trial conducted in 22 community-based family practice clinics (36 clusters) with 76 fee-for-service family physicians in Winnipeg, Manitoba, Canada. Each physician will enroll 30 patients attending their periodic health examination and at average risk for colorectal cancer. All physicians will follow their standard clinical practice for screening. Intervention group physicians will provide a fridge magnet to each patient that contains information facilitating access to the study-specific colorectal cancer screening decision aids (telephone help-line and website). The primary endpoint is patient Fecal occult blood test completion rate after four months (intention to treat model). Multi-level analysis will include clinic, physician and patient level variables. Patient Personal Health Identification Numbers will be collected from those providing consent to facilitate analysis of repeat screening behavior. Secondary outcome data will be obtained through the Clinic Characterization Form, Patient Tracking Form, In-Clinic Patient Survey, Post-Study Follow-Up Patient Survey, and Family Physician Survey. Study protocol approved by The University of Manitoba Health Research Ethics Board.DiscussionThe study intervention has the potential to increase patient fecal occult blood test uptake, decrease colorectal cancer mortality and morbidity, and improve the health of Manitobans. If utilization of the website and/or telephone support line result in clinically significant increases in colorectal cancer screening uptake, changes in screening at the policy- and system-level may be warranted. Trial Registration: clinicaltrials.gov identifier NCT01026753.
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EnROL: A multicentre randomised trial of conventional versus laparoscopic surgery for colorectal cancer within an enhanced recovery programme
Background:
During the last two decades the use of laparoscopic resection and a multimodal approach known as an enhanced recovery programme, have been major changes in colorectal perioperative care. Clinical outcome improves using laparoscopic surgery to resect colorectal cancer but until recently no multicentre trial evidence had been reported regarding whether the benefits of laparoscopy still exist when open surgery is optimized within an enhanced recovery programme. The EnROL trial (Enhanced Recovery Open versus Laparoscopic) examines the hypothesis that laparoscopic surgery within an enhanced recovery programme will provide superior postoperative outcomes when compared to conventional open resection of colorectal cancer within the same programme.
Methods:
EnROL is a phase III, multicentre, randomised trial of laparoscopic versus open resection of colon and rectal cancer with blinding of patients and outcome observers to the treatment allocation for the first 7 days post-operatively, or until discharge if earlier. 202 patients will be recruited at approximately 12 UK hospitals and randomised using minimization at a central computer system in a 1:1 ratio. Recruiting surgeons will previously have performed >100 laparoscopic colorectal resections and >50 open total mesorectal excisions to minimize conversion. Eligible patients are those suitable for elective resection using either technique. Excluded patients include: those with acute intestinal obstruction and patients in whom conversion from laparoscopic to open procedure is likely. The primary outcome is physical fatigue as measured by the physical fatigue domain of the multidimensional fatigue inventory 20 (MFI-20) with secondary outcomes including postoperative hospital stay; complications; reoperation and readmission; quality of life indicators; cosmetic assessments; standardized performance indicators; health economic analysis; the other four domains of the MFI-20. Pathological assessment of surgical quality will also be undertaken and compliance with the enhanced recovery programme will be recorded for all patients.DiscussionShould this trial demonstrate that laparoscopic surgery confers a significant clinical and/or health economic benefit this will further support the transition to this type of surgery, with implications for the training of surgeons and resource allocation.
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Plant HDAC inhibitor chrysin arrest cell growth and induce p21WAF-1 by altering chromatin of STAT response element in A375 cells
Background:
Chrysin and its analogues, belongs to flavonoid family and possess potential anti-tumour activity. The aim of this study is to determine the molecular mechanism by which chrysin controls cell growth and induce apoptosis in A375 cells.
Methods:
Effect of chrysin and its analogues on cell viability and cell cycle analysis was determined by MTT assay and flowcytometry. A series of Western blots was performed to determine the effect of chrysin on important cell cycle regulatory proteins (Cdk2, cyclin D1, p53, p21, p27). The fluorimetry and calorimetry based assays was conducted for characterization of chrysin as HDAC inhibitor. The changes in histone tail modification such as acetylation and methylation was studied after chrysin treatment was estimated by immuno-fluorescence and western blot analysis. The expression of Bcl-xL, survivin and caspase-3 was estimated in chrysin treated cells. The effect of chrysin on p21 promoter activity was studied by luciferase and ChIP assays.
Results:
Chrysin cause G1 cell cycle arrest and found to inhibit HDAC-2 and HDAC-8. Chrysin treated cells have shown increase in the levels of H3acK14, H4acK12, H4acK16 and decrease in H3me2K9 methylation. The p21 induction by chrysin treatment was found to be independent of p53 status. The chromatin remodelling at p21WAF1 promoter induces p21 activity, increased STAT-1 expression and epigenetic modifications that are responsible for ultimate cell cycle arrest and apoptosis.
Conclusion:
Chrysin shows in vitro anti-cancer activity that is correlated with induction of histone hyperacetylation and possible recruitment of STAT-1, 3, 5 proteins at STAT (-692 to -684) region of p21 promoter. Our results also support an unexpected action of chrysin on the chromatin organization of p21WAF1 promoter through histone methylation and hyper-acetylation. It proposes previously unknown sequence specific chromatin modulations in the STAT responsive elements for regulating cell cycle progression negatively via the induction of the CDK inhibitor p21WAF1.
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Impaired degradation followed by enhanced recycling of epidermal growth factor receptor caused by hypo-phosphorylation of tyrosine 1045 in RBE cells
Background:
Since cholangiocarcinoma has a poor prognosis, several epidermal growth factor receptor (EGFR)-targeted therapies with antibody or small molecule inhibitor treatment have been proposed. However, their effect remains limited. The present study sought to understand the molecular genetic characteristics of cholangiocarcinoma related to EGFR, with emphasis on its degradation and recycling.
Methods:
We evaluated EGFR expression and colocalization by immunoblotting and immunofluorescence, cell surface EGFR expression by fluorescence-activated cell sorting (FACS), and EGFR ubiquitination and protein binding by immunoprecipitation in the human cholangiocarcinoma RBE and immortalized cholangiocyte MMNK-1 cell lines. Monensin treatment and Rab11a depletion by siRNA were adopted for inhibition of EGFR recycling.
Results:
Upon stimulation with EGF, ligand-induced EGFR degradation was impaired and the expression of phospho-tyrosine 1068 and phospho-p44/42 MAPK was sustained in RBE cells as compared with MMNK-1 cells. In RBE cells, the process of EGFR sorting for lysosomal degradation was blocked at the early endosome stage, and non-degradated EGFR was recycled to the cell surface. A disrupted association between EGFR and the E3 ubiquitin ligase c-Cbl, as well as hypo-phosphorylation of EGFR at tyrosine 1045 (Tyr1045), were also observed in RBE cells.
Conclusion:
In RBE cells, up-regulation of EGFR Tyr1045 phosphorylation is a potentially useful molecular alteration in EGFR-targeted therapy. The combination of molecular-targeted therapy determined by the characteristics of individual EGFR phosphorylation events and EGFR recycling inhibition show promise in future treatments of cholangiocarcinoma.
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Circulating tumour cells escape from EpCAM-based detection due to epithelial-to-mesenchymal transition
Background:
Circulating tumour cells (CTCs) have shown prognostic relevance in metastatic breast, prostate, colon and pancreatic cancer. For further development of CTCs as a biomarker, we compared the performance of different protocols for CTC detection in murine breast cancer xenograft models (MDA-MB-231, MDA-MB-468 and KPL-4). Blood samples were taken from tumour bearing animals (20 to 200 mm2) and analysed for CTCs using 1. an epithelial marker based enrichment method (AdnaTest), 2. an antibody independent technique, targeting human gene transcripts (qualitative PCR), and 3. an antibody-independent approach, targeting human DNA-sequences (quantitative PCR). Further, gene expression changes associated with epithelial-to-mesenchymal transition (EMT) were determined with an EMT-specific PCR assay.
Methods:
We used the commercially available Adna Test, RT-PCR on human housekeeping genes and a PCR on AluJ sequences to detect CTCs in xenografts models. Phenotypic changes in CTCs were tested with the commercially available "Human Epithelial to Mesenchymal Transition RT-Profiler PCR Array".
Results:
Although the AdnaTest detects as few as 1 tumour cell in 1 ml of mouse blood spiking experiments, no CTCs were detectable with this approach in vivo despite visible metastasis formation. The presence of CTCs could, however, be demonstrated by PCR targeting human transcripts or DNA-sequences - without epithelial pre-enrichment. The failure of CTC detection by the AdnaTest resulted from downregulation of EpCAM, whereas mesenchymal markers like Twist and EGFR were upregulated on CTCs. Such a change in the expression profile during metastatic spread of tumour cells has already been reported and was linked to a biological program termed epithelial-mesenchymal transition (EMT).
Conclusions:
The use of EpCAM-based enrichment techniques leads to the failure to detect CTC populations that have undergone EMT. Our findings may explain clinical results where low CTC numbers have been reported even in patients with late metastatic cancers. These results are a starting point for the identification of new markers for detection or capture of CTCs, including the mesenchymal-like subpopulations.
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Oxidative dna damage correlates with cell immortalization and mir-92 expression in hepatocelllular carcinoma
Background:
MicroRNAs expression has been extensively studied in hepatocellular carcinoma but little is known regarding the relationship, if any, with inflammation, production of reactive oxygenspecies (ROS), host's repair mechanisms and cell immortalization. This study aimed at assessing the extent of oxidative DNA damage (8-hydroxydeoxyguanosine - 8-OHdG) in different phases of the carcinogenetic process, in relation to DNA repair gene polymorphism, telomeric dysfunction and to the expression of several microRNAs, non-coding genes involved in post-transcriptional regulation, cell proliferation, differentiation and death.
Methods:
Tissue samples obtained either at surgery, [neoplastic (HCC) and adjacent non-cancerous cirrhotic tissues (NCCT)] at percutaneous or laparoscopic biopsy (patients with HCV or HBV-related hepatitis or patients undergoing cholecystectomy) were analysed for 8-OHdG (HPCL-ED), OGG1 (a DNA repair gene) polymorphism (PCR-RFLP), telomerase activity, telomere length (T/S, by RT-PCR), Taqman microRNA assay and Bad/Bax mRNA (RTPCR). Twenty-nine samples from 29 HCC patients (obtained in both neoplastic and peritumoral tissues), 22 from chronic hepatitis (CH) and 10 controls (cholecystectomy patients - CON) were examined.
Results:
Eight-OHdG levels were significantly higher in HCC and NCCT than in CH and CON (p=0.001). Telomerase activity was significantly higher in HCC than in the remaining subgroups (p=0.002); conversely T/S was significantly lower in HCC p=0.05). MiR-199a-b, -195, -122, -92a and 145 were down-regulated in the majority of HCCs while miR-222 was up-regulated. A positive correlation was observed among 8-OHdG levels, disease stage, telomerase activity, OGG1 polymorphisms and ALT/GGT levels. In HCC, miR-92expression correlated positively with telomerase activity, 8-OHdG levels and Bad/Bax mRNA.
Conclusions:
The above findings confirm the accumulation in the progression of chronic liver damage to HCC of a ROS-mediated oxidative DNA damage, and suggest that this correlates with induction of telomerase activity and, as a novel finding, with over-expression of miR-92, a microRNA that plays a role in both the apoptotic process and in cellular proliferation pathways.
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BMC Cardiovascular Disorders - Latest Articles
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Local electrogram delay recorded from left ventricular lead at implant predicts response to cardiac resynchronization therapy: Retrospective study with 1 year follow up
Background:
Considerable proportion of patients does not respond to the cardiac resynchronization therapy(CRT). This study investigated clinical relevance of left ventricular electrode localelectrogram delay from the beginning of QRS (QLV). We hypothesized that longer QLVindicating more optimal lead placement in the late activated regions is associated with thehigher probability of positive CRT response.
Methods:
We conducted a retrospective, single-centre analysis of 161 consecutive patients with heartfailure and LBBB or nonspecific intraventricular conduction delay (IVCD) treated with CRT.We routinely intend to implant the LV lead in a region with long QLV. Clinical response toCRT, left ventricular (LV) reverse remodelling (i.e. decrease in LV end-systolic diameter -LVESD [greater than or equal to]10%) and reduction in plasma level of NT-proBNP >30% at 12-month post-implantwere the study endpoints. We analyzed association between pre-implant variables and thestudy endpoints.
Results:
Clinical CRT response rate reached 58%, 84% and 92% in the lowest ([less than or equal to]105 ms), middle(106-130 ms) and the highest (>130 ms) QLV tertile (p < 0.0001), respectively. Longer QRSduration (p = 0.002), smaller LVESD and a non-ischemic cardiomyopathy (both p = 0.02)were also univariately associated with positive clinical CRT response. In a multivariateanalysis, QLV remained the strongest predictor of clinical CRT response (p < 0.00001),followed by LVESD (p = 0.01) and etiology of LV dysfunction (p = 0.04). Comparablepredictive power of QLV for LV reverse remodelling and NT-proBNP response rates wasobserved.
Conclusion:
LV lead position assessed by duration of the QLV interval was found the strongestindependent predictor of beneficial clinical response to CRT.
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Effectiveness of two intensive treatment methods for
smoking cessation and relapse prevention in patients
with coronary heart disease: study protocol and
baseline description
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