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Goodbye, Columbus
{no abstract}.
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Recent Alzheimer's disease research highlights
As co-editors of Alzheimer's Research and Therapy we would like to highlight several of the major translational research advances that have occurred over the last year, during which a tremendous amount of superb science relevant to the study of Alzheimer's disease (AD) has been published. Our selection is, of course, influenced by our own biases, and selecting particular advances to highlight was challenging. Nevertheless, many major scientific questions relevant to developing better therapies and diagnostics for AD remain. The advances we have chosen to highlight represent evolving areas of research in AD that raise as many questions as they answer, but offer some promise that may help us to reach our shared goal of translating research advances into real advances that benefit patients.
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Treatment of one case of cerebral palsy combined with posterior visual pathway injury using autologous bone marrow mesenchymal stem cells
Background:
Cerebral palsy is currently one of the major diseases that cause severe paralysis of the nervous system in children; about 9-30% of cerebral palsy patients also have visual impairment, which has no effective treatment thus far. Bone marrow mesenchymal stem cells (BMSCs) have very strong self-renewal, proliferation, and pluripotent differentiation potentials. Therefore, autologous BMSC transplantation has become a novel method for treating cerebral palsy.
Methods:
An 11-year-old boy had a clear history of dystocia and asphyxia after birth; at the age of 6 months, the family members observed his gaze casting around and noted that he displayed a lack of attention. A brain MRI examination at the age of 7 years showed that the child had cerebral palsy with visual impairment (i.e., posterior visual pathway injury). The patient was hospitalized for 20 days and was given four infusions of intravenous autologous BMSCs. Before transplantation and 1, 6, and 12 months after transplantation, a visual evoked potential test, an electrocardiogram, routine blood tests, and liver and kidney function tests were performed.
Results:
The patient did not have any adverse reactions or abnormal consequences during hospitalization or postoperative follow-up. After discharge, the patient could walk more smoothly than he could before transplantation; his vision significantly improved 6 months after transplantation, which was also supported by the electrophysiological examinations.
Conclusions:
The clinical application of BMSCs is safe and effective for improving vision in the treatment of cerebral palsy combined with visual impairment.
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Inflammation-induced changes in BKCa currents in cutaneous dorsal root ganglion neurons from the adult rat
Background:
Inflammation-induced sensitization of primary afferents is associated with a decrease in K+ current. However, the type of K+ current and basis for the decrease varies as a function of target of innervation. Because glabrous skin of the rat hindpaw is used often to assess changes in nociception in models of persistent pain, the purpose of the present study was to determine the type and extent to which K+ currents contribute to the inflammation-induced sensitization of cutaneous afferents. Acutely dissociated retrogradely labeled cutaneous dorsal root ganglion neurons from naive and inflamed (3 days post complete Freund's adjuvant injection) rats were studied with whole cell and perforated patch techniques.
Results:
Inflammation-induced sensitization of small diameter cutaneous neurons was associated with an increase in action potential duration and rate of decay of the afterhyperpolarization. However, no changes in voltage-gated K+ currents were detected. In contrast, Ca2+ modulated iberiotoxin sensitive and paxilline sensitive K+ (BKCa) currents were significantly smaller in small diameter IB4+ neurons. This decrease in current was not associated with a detectable change in total protein levels of the BKCa channel alpha or beta subunits. Single cell PCR analysis revealed a significant change in the pattern of expression of alpha subunit splice variants and beta subunits that were consistent, at least in part, with inflammation-induced changes in the biophysical properties of BKCa currents in cutaneous neurons.
Conclusions:
Results of this study provide additional support for the conclusion that it may be possible, if not necessary to selectively treat pain arising from specific body regions. Because a decrease in BKCa current appears to contribute to the inflammation-induced sensitization of cutaneous afferents, BKCa channel openers may be effective for the treatment of inflammatory pain.
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Longitudinal study on transmission of MRSA CC398 within pig herds
Background:
Since the detection of MRSA CC398 in pigs in 2004, it has emerged in livestock worldwide. MRSA CC398 has been found in people in contact with livestock and thus has become a public health issue. Data from a large-scale longitudinal study in two Danish and four Dutch pig herds were used to quantify MRSA CC398 transmission rates within pig herds and to identify factors affecting transmission between pigs.
Results:
Sows and their offspring were sampled at varying intervals during a production cycle. Overall MRSA prevalence of sows increased from 33% before farrowing to 77% before weaning. Overall MRSA prevalence of piglets was > 60% during the entire study period. The recurrent finding of MRSA in the majority of individuals indicates true colonization or might be the result of contamination. Transmission rates were estimated using a Susceptible-Infectious-Susceptible (SIS-)model, which resulted in values of the reproduction ratio (R0) varying from 0.24 to 8.08. Transmission rates were higher in pigs treated with tetracyclins and beta-lactams compared to untreated pigs implying a selective advantage of MRSA CC398 when these antimicrobials are used. Furthermore, transmission rates were higher in pre-weaning pigs compared to post-weaning pigs which might be explained by an age-related susceptibility or the presence of the sow as a primary source of MRSA CC398. Finally, transmission rates increased with the relative increase of the infection pressure within the pen compared to the total infection pressure, implying that within-pen transmission is a more important route compared to between-pen transmission and transmission through environmental exposure.
Conclusions:
Our results indicate that MRSA CC398 is able to spread and persist in pig herds, resulting in an endemic situation. Transmission rates are affected by the use of selective antimicrobials and by the age of pigs.
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Determinants of uncontrolled hypertension in adult type 2 diabetes mellitus: an analysis of the Malaysian diabetes registry 2009
Background:
Uncontrolled blood pressure (BP) is a significant contributor of morbidity and even mortality in type 2 diabetes (T2D) patients. This study was done to determine the significant determinants of uncontrolled blood pressure in T2D patients in Malaysia.
Methods:
Between 1st January 2009 to 31st December 2009, data from 70 889 patients with Type 2 diabetes was obtained from the Adult Diabetes Control and Management Registry for analysis; 303 centers participated in the study. Their demographic characteristics, the nature of their diabetes, their state of hypertension, treatment modalities, risk factors, and complications are described. Based on their most recent BP values, subjects were divided into controlled BP and uncontrolled BP and their clinical determinants compared. Independent determinants were identified using multivariate logistic regression.
Results:
The mean age of patients at diagnosis of diabetes was 52.3 +/- 11.1 years old. Most were women (59.0%) and of Malay ethnicity (61.9%). The mean duration of diabetes was 5.9 +/- 5.6 years. A total of 57.4% were hypertensive. Of the 56 503 blood pressure (BP) measured, 13 280 (23.5%) patients had BP <130/80 mmHg. Eighteen percent was on > two anti-hypertensive agents. Health clinics without doctor, older age ([greater than or equal to] 50 years old), shorter duration of diabetes (< 5 years), Malay, overweight were determinants for uncontrolled blood pressure (BP [greater than or equal to]130/80mmHg). Patients who were on anti-hypertensive agent/s were 2.7 times more likely to have BP [greater than or equal to]130/80mmHg. Type 2 diabetes patients who had ischaemic heart disease or nephropathy were about 20% and 15% more likely to have their blood pressure treated to target respectively.
Conclusions:
Major independent determinants of uncontrolled BP in our group of T2D patients were Malay ethnicity, older age, recent diagnosis of diabetes, overweight and follow-up at health clinics without a doctor and possibly the improper use of anti hypertensive agent. More effort, education and resources, especially in the primary health care centres are needed to improve hypertensive care among our patients with diabetes.
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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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An eQTL biological data visualization challenge and approaches from the visualization community
In 2011, the IEEE VisWeek conferences inaugurated a symposium on Biological Data Visualization. Like other domain-oriented Vis symposia, this symposium's purpose was to explore the unique characteristics and requirements of visualization within the domain, and to enhance both the Visualization and Bio/Life-Sciences communities by pushing Biological data sets and domain understanding into the Visualization community, and well-informed Visualization solutions back to the Biological community. Amongst several other activities, the BioVis symposium created a data analysis and visualization contest. Unlike many contests in other venues, where the purpose is primarily to allow entrants to demonstrate tour-de-force programming skills on sample problems with known solutions, the BioVis contest was intended to whet the participants' appetites for a tremendously challenging biological domain, and simultaneously produce viable tools for a biological grand challenge domain with no extant solutions. For this purpose expression Quantitative Trait Locus (eQTL) data analysis was selected. In the BioVis 2011 contest, we provided contestants with a synthetic eQTL data set containing real biological variation, as well as a spiked-in gene expression interaction network influenced by single nucleotide polymorphism (SNP) DNA variation and a hypothetical disease model. Contestants were asked to elucidate the pattern of SNPs and interactions that predicted an individual's disease state. 9 teams competed in the contest using a mixture of methods, some analytical and others through visual exploratory methods. Independent panels of visualization and biological experts judged entries. Awards were given for each panel's favorite entry, and an overall best entry agreed upon by both panels. Three special mention awards were given for particularly innovative and useful aspects of those entries. And further recognition was given to entries that correctly answered a bonus question about how a proposed "gene therapy" change to a SNP might change an individual's disease status, which served as a calibration for each approaches' applicability to a typical domain question. In the future, BioVis will continue the data analysis and visualization contest, maintaining the philosophy of providing new challenging questions in open-ended and dramatically underserved Bio/Life Sciences domains.
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RCDB: Renal Cancer Gene Database
Background:
Renal cell carcinoma or RCC is one of the common and most lethal urological cancers, with 40% of the patients succumbing to death because of metastatic progression of the disease. Treatment of metastatic RCC remains highly challenging because of its resistance to chemotherapy as well as radiotherapy, besides surgical resection. Whereas RCC comprises tumors with differing histological types, clear cell RCC remains the most common. A major problem in the clinical management of patients presenting with localized ccRCC is the inability to determine tumor aggressiveness and accurately predict the risk of metastasis following surgery. As a measure to improve the diagnosis and prognosis of RCC, researchers have identified several molecular markers through a number of techniques. However the wealth of information available is scattered in literature and not easily amenable to data-mining. To reduce this gap, this work describes a comprehensive repository called Renal Cancer Gene Database, as an integrated gateway to study renal cancer related data.FindingsRenal Cancer Gene Database is a manually curated compendium of 240 protein-coding and 269 miRNA genes contributing to the etiology and pathogenesis of various forms of renal cell carcinomas. The protein coding genes have been classified according to the kind of gene alteration observed in RCC. RCDB also includes the miRNAs dysregulated in RCC, along with the corresponding information regarding the type of RCC and/or metastatic or prognostic significance. While some of the miRNA genes showed an association with other types of cancers few were unique to RCC. Users can query the database using keywords, category and chromosomal location of the genes. The knowledgebase can be freely accessed via a user-friendly web interface at http://www.juit.ac.in/attachments/jsr/rcdb/homenew.html.
Conclusions:
It is hoped that this database would serve as a useful complement to the existing public resources and as a good starting point for researchers and physicians interested in RCC genetics.
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DNA hypomethylation of the COX-2 gene promoter is associated with up-regulation of its mRNA expression in eutopic endometrium of endometriosis
Background:
Accumulated evidence reveals that cyclooxygenase-2 (COX-2) was overexpressed in eutopic endometrium of endometriosis, which may play a critical role in the pathogenesis of endometriosis. However, few studies have been performed to explore the molecular mechanisms underlying the abnormal high expression of COX-2 in endometriosis. Considering the fact that a number of recent studies have shown DNA methylation affecting some genes in endometriosis, the present study was therefore aimed to determine whether the observed high expression COX-2 in endometriosis is caused by the hypomethylation of CpG island within the promoter of this gene.
Methods:
The endometrial tissues were collected from 60 women with endometriosis (endometriosis group) and 20 women without endometriosis (control group). The methylation status of COX-2 was examined by methylation specific PCR. Quantitative real-time RT-PCR was performed to measure COX-2 mRNA level in endometrial tissues.
Results:
The frequency of promoter hypermethylation of COX-2 was lower in eutopic endometrium of the endometriosis group (41.7%) than that in the control group (75.0%), P < 0.05. COX-2 mRNA level in the eutopic endometrium of the endometriosis group was 2.61-fold higher than that in the control group (P < 0.01). COX-2 mRNA level in unmethylated endometrium of the endometriosis group or the control group was 2.39-fold and 2.66-fold, respectively, higher than that in the methylated endometrium of the same group (P < 0.01).
Conclusions:
The hypomethylation within the promoter of COX-2 may be responsible for the elevated gene expression in eutopic endometrium of endometriosis.
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