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Cardiovascular autonomic function tests in an African population
Background:
Diabetes mellitus is becoming increasingly common in sub-Saharan Africa. Autonomic dysfunction contributes to morbidity and mortality in diabetic patients. Data on autonomic dysfunction in the African population is scarce, and no reference values for standardized autonomic function tests are available. The aim of this study was to establish reference values for five easy-to-use cardiovascular autonomic function tests that may be suitable for resource-poor settings.
Methods:
We recruited 276 healthy African individuals, 156 men and 120 women, aged >20 years. Participants were tested for (1) resting heart rate (HR), (2) HR variation in response to deep breathing, (3) HR response to standing, and (4) postural changes in systolic and diastolic blood pressure (SBP and DBP). Respective cut-off values were calculated according to the 95th or 5th percentile.
Results:
Taking an association of the autonomic test results with gender and age into consideration, we defined the following cut-off values: resting HR (bpm) >89 for men and >97 for women; HR (bpm) in response to deep breathing [less than or equal to]13, [less than or equal to]11, [less than or equal to]9, [less than or equal to]8, and [less than or equal to]7 for age groups 20-29, 30-39, 40-49, 50-59, and 60+ years, respectively; HR (bpm) in response to standing [less than or equal to]14 for 20-29 years, and [less than or equal to]11 for 30+ years; postural decreases in SBP [greater than or equal to]17 mmHg for all age groups; and postural decreases in DBP (mmHg) [greater than or equal to]2 for men and [greater than or equal to]5 for women.
Conclusions:
The test battery revealed cut-off values different from those measured in Caucasians. Further studies are recommended to assess whether these reference values are generally applicable to Africans.
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The Edinburgh Type 2 Diabetes Study: study protocol
Background:
Risk factors underlying the development and progression of some of the less well-recognised complications of type 2 diabetes, including cognitive impairment and non-alcoholic fatty liver disease, are poorly understood. The Edinburgh Type 2 Diabetes study was established in 2006 in order to investigate the role of potential risk factors in these complications, as well as to further investigate mechanisms underlying the development and progression of micro and macrovascular disease in type 2 diabetes.
Methods:
The study is designed as a prospective cohort study. Participants recruited at baseline (2006-2007) constitute 1066 men and women aged 60 to 75 years with established type 2 diabetes, living in the Lothian region of central Scotland. Subjects underwent detailed cognitive and physical examination, the latter including measures of micro- and macro-vascular disease, glycaemic control, body fat composition and plasma inflammatory markers, cortisol, lipids and liver function tests. Participants were re-examined after one year with hepatic ultrasonography and additional measures of vascular disease. This paper reports the methods of recruitment to the study and examinations performed at baseline and one year. Follow-up cognitive, vascular and liver assessments are scheduled for 2010-2011 when subjects will have been in the study for 4 years.DiscussionThis study will provide a wealth of epidemiological and biomarker data that should be invaluable in the identification of potentially modifiable, causal risk factors for diabetes-related cognitive impairment, liver dysfunction and vascular disease, which can be targeted for the development of preventive and therapeutic interventions.
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Association of angiotensin-converting enzyme inhibitor therapy and comorbidity in diabetes: results from the Vermont Diabetes Information System
Background:
Angiotensin converting enzyme inhibitors (ACE inhibitors) reduce peripheral vascular resistance via blockage of angiotensin converting enzyme (ACE). ACE inhibitors are commonly used to treat congestive heart failure and high blood pressure, but other effects have been reported. In this study, we explored the association between ACE inhibitor therapy and the prevalence of comorbid conditions in adults with diabetes
Methods:
We surveyed 1003 adults with diabetes randomly selected from community practices. Patients were interviewed at home and self-reported their personal and clinical characteristics including comorbidity. Current medications were obtained by direct observation of medication containers. We built logistic regression models with the history of comorbidities as the outcome variable and the current use of ACE inhibitors as the primary predictor variable. We adjusted for possible confounding by social (age, sex, alcohol drinking, cigarette smoking) and clinical factors (systolic blood pressure, body mass index (BMI), glycosolated hemoglobin (A1C), number of comorbid conditions, and number of prescription medications).
Results:
ACE users reported a history of any cancer (except the non-life-threatening skin cancers) less frequently than non-users (10% vs. 15%; odd ratio = 0.59; 95% confidence interval [0.39, 0.89]; P=0.01); and a history of stomach ulcers or peptic ulcer disease less frequently than non-users (12% vs. 16%, odd ratio=0.70, [0.49, 1.01], P=0.06). After correcting for potential confounders, ACE inhibitors remained significantly inversely associated with a personal history of cancer (odds ratio=0.59, [0.39, 0.89]; P=0.01) and peptic ulcer disease (odd ratio=0.68, [0.46, 1.00], P=0.05).
Conclusions:
ACE inhibitor use is associated with a lower likelihood of a history of cancer and peptic ulcers in patients with diabetes. These findings are limited by the cross sectional study design, self-report of comorbid diagnoses, and lack of information on the timing and duration of ACE inhibitor use. Further research is needed to confirm these associations and understand their mechanisms.
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Prediction of peak pressure from clinical and radiological measurements in patients with diabetes
Background:
Various structural and functional factors of foot function have been associated with high local plantar pressures. The therapist focuses on these features which are thought to be responsible for plantar ulceration in patients with diabetes. Risk assessment of the diabetic foot would be made easier if locally elevated plantar pressure could be indicated with a minimum set of clinical measures.
Methods:
Ninety three patients were evaluated through vascular, orthopaedic, neurological and radiological assessment. A pressure platform was used to quantify the barefoot peak pressure for six forefoot regions: big toe (BT) and metatarsals one (MT-1) to five (MT-5). Stepwise regression modelling was performed to determine which set of the clinical and radiological measures explained most variability in local barefoot plantar peak pressure in each of the six forefoot regions. Comprehensive models were computed with independent variables from the clinical and radiological measurements. The difference between the actual plantar pressure and the predicted value was examined through Bland-Altman analysis.
Results:
Forefoot pressures were significant higher in patients with neuropathy, compared to patients without neuropathy for the whole forefoot, the MT-1 region and the MT-5 region (respectively 138 kPa, 173 kPa and 88 kPa higher: mean difference). The clinical models explained up to 34 percent of the variance in local peak pressures. Callus formation and toe deformity were identified as relevant clinical predictors for all forefoot regions. Regression models with radiological variables explained about 22 percent of the variance in local peak pressures. For most regions the combination of clinical and radiological variables resulted in a higher explained variance. The Bland and Altman analysis showed a major discrepancy between the predicted and the actual peak pressure values.
Conclusions:
At best, clinical and radiological measurements could only explain about 34 percent of the variance in local barefoot peak pressure in this population of diabetic patients. The prediction models constructed with linear regression are not useful in clinical practice because of considerable underestimation of high plantar pressure values. Identification of elevated plantar pressure without equipment for quantification of plantar pressure is inadequate. The use of quantitative plantar pressure measurement for diabetic foot screening is therefore advocated.
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Pediatric reference intervals for thyroid hormone levels from birth to adulthood: a retrospective study
Background:
Age- and sex-specific reference intervals are an important prerequisite for interpreting thyroid hormone measurements in children. However, only few studies have reported age- and sex-specific pediatric reference values for TSHbasal (TSH), free T3 (fT3), and free T4 (fT4) so far. Reference intervals are known to be method- and population-dependent. The aim of our study was to establish reference intervals for serum TSH, fT3, and fT4 from birth to 18 years and to assess sex differences.
Methods:
2,194 thyroid hormone tests obtained from a hospital-based pediatric population were included into our retrospective analysis. Individuals with diagnoses or medications likely to affect thyroid function were primarily excluded, as well as the diagnostic groups, if different from the purely healthy subgroup (n = 414). Age groups were ranging from 1 day to 1 month, 1 - 12 months, and 1 - 5, 6 - 10, 11 - 14, and 15 - 18 years, respectively. Levels of fT3, fT4 and TSH were measured on Advia(R) CentaurTM automated immunoassay system.
Results:
The final sample size for reference data creation was 1,209 for TSH, 1,395 for fT3, and 1,229 for fT4. Median and 2.5/10/25/75/90/97.5 percentiles were calculated for each age group. Males had greater mean fT3 concentrations than females (p < 0.001). No sex-differences were found for TSH and fT4 between age-matched serum samples. Median concentrations of fT3, fT4 and TSH were greatest during the first month of life, followed by a continuous decline with age.
Conclusions:
Our results corroborate those of previous studies showing that thyroid hormone levels change markedly during childhood, and that adult reference intervals are not universally applicable to children. Moreover, differences of our reference intervals compared to previous studies were observed, likely caused by different antibody characteristics of various analytical methods, different populations or undefined geographic covariates, e.g. iodine and selenium status.
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Safety and tolerability of sitagliptin in patients with type 2 diabetes: a pooled analysis
Background:
Sitagliptin, a highly selective dipeptidyl peptidase-4 inhibitor, is the first in a new class of oral antihyperglycemic agents (AHAs) for the treatment of patients with type 2 diabetes. Type 2 diabetes is a life-long disease requiring chronic treatment and management. Therefore, robust assessment of the long-term safety and tolerability of newer therapeutic agents is of importance. The purpose of this analysis was to assess the safety and tolerability of sitagliptin by pooling 12 large, double-blind, Phase IIb and III studies up to 2 years in duration. Methods: This analysis included 6139 patients with type 2 diabetes receiving either sitagliptin 100 mg/day (N = 3415) or a comparator agent (placebo or an active comparator) (N = 2724; non-exposed group). The 12 studies from which this pooled population was drawn represent the double-blind, randomized, Phase IIB and III studies that included patients treated with the clinical dose of sitagliptin (100 mg/day) for at least 18 weeks up to 2 years and that were available in a single safety database as of November 2007. These 12 studies assessed sitagliptin as monotherapy, initial combination therapy with metformin, or add-on combination therapy with other oral AHAs (metformin, pioglitazone, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone). Patients in the non-exposed group were taking placebo, pioglitazone, metformin, sulfonylurea, sulfonylurea + metformin, or metformin + rosiglitazone. This safety analysis used patient-level data from each study to evaluate clinical and laboratory adverse experiences.
Results:
For clinical adverse experiences, the incidence rates of adverse experiences overall, serious adverse experiences, and discontinuations due to adverse experiences were similar in the sitagliptin and non-exposed groups. The incidence rates of specific adverse experiences were also generally similar in the two groups, with the exception of an increased incidence rate of hypoglycemia observed in the non-exposed group. The incidence rates of drug-related adverse experiences overall and discontinuations due to drug-related adverse experiences were higher in the non-exposed group, primarily due to the increased incidence rate of hypoglycemia in this group. For cardiac- and ischemia-related adverse experiences (including serious events), there were no meaningful between-group differences. No meaningful differences between groups in laboratory adverse experiences, either summary measures or specific adverse experiences, were observed.
Conclusion:
In patients with type 2 diabetes, sitagliptin 100 mg/day was well tolerated in clinical trials up to 2 years in duration.
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The AQUA-FONTIS study: protocol of a multidisciplinary, cross-sectional and prospective longitudinal study for developing standardized diagnostics and classification of non-thyroidal illness syndrome
Background:
Non-thyroidal illness syndrome (NTIS) is a characteristic functional constellation of thyrotropic feedback control that frequently occurs in critically ill patients. Although this condition is associated with significantly increased morbidity and mortality, there is still controversy on whether NTIS is caused by artefacts, is a form of beneficial adaptation, or is a disorder requiring treatment. Trials investigating substitution therapy of NTIS revealed contradictory results. The comparison of heterogeneous patient cohorts may be the cause for those inconsistencies.ObjectivesPrimary objective of this study is the identification and differentiation of different functional states of thyrotropic feedback control in order to define relevant evaluation criteria for the prognosis of affected patients. Furthermore, we intend to assess the significance of an innovative physiological index approach (SPINA) in differential diagnosis between NTIS and latent (so-called "sub-clinical") thyrotoxicosis.Secondary objective is observation of variables that quantify distinct components of NTIS in the context of independent predictors of evolution, survival or pathophysiological condition and influencing or disturbing factors like medication.DesignThe approach to a quantitative follow-up of non-thyroidal illness syndrome (AQUA FONTIS study) is designed as both a cross-sectional and prospective longitudinal observation trial in critically ill patients. Patients are observed in at least two evaluation points with consecutive assessments of thyroid status, physiological and clinical data in additional weekly observations up to discharge. A second part of the study investigates the neuropsychological impact of NTIS and medium-term outcomes.The study design incorporates a two-module structure that covers a reduced protocol in form of an observation trial before patients give informed consent. Additional investigations are performed if and after patients agree in participation.Trial RegistrationClinicalTrials.gov NCT00591032
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Lack of association of colonic epithelium telomere length and oxidative DNA damage in Type 2 diabetes under good metabolic control
Background:
Telomeres are DNA repeat sequences necessary for DNA replication which shorten at cell division at a rate directly related to levels of oxidative stress. Critical telomere shortening predisposes to cell senescence and to epithelial malignancies. Type 2 diabetes is characterised by increased oxidative DNA damage, telomere attrition, and an increased risk of colonic malignancy. We hypothesised that the colonic mucosa in Type 2 diabetes would be characterised by increased DNA damage and telomere shortening.
Methods:
We examined telomere length (by flow fluorescent in situ hybridization) and oxidative DNA damage (flow cytometry of 8 – oxoguanosine) in the colonic mucosal cells of subjects with type 2 diabetes (n = 10; mean age 62.2 years, mean HbA1c 6.9%) and 22 matched control subjects. No colonic pathology was apparent in these subjects at routine gastrointestinal investigations.
Results:
Mean colonic epithelial telomere length in the diabetes group was not significantly different from controls (10.6 [3.6] vs. 12.1 [3.4] Molecular Equivalent of Soluble Fluorochrome Units [MESF]; P = 0.5). Levels of oxidative DNA damage were similar in both T2DM and control groups (2.6 [0.6] vs. 2.5 [0.6] Mean Fluorescent Intensity [MFI]; P = 0.7). There was no significant relationship between oxidative DNA damage and telomere length in either group (both p > 0.1).
Conclusion:
Colonic epithelium in Type 2 diabetes does not differ significantly from control colonic epithelium in oxidative DNA damage or telomere length. There is no evidence in this study for increased oxidative DNA damage or significant telomere attrition in colonic mucosa as a carcinogenic mechanism.
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Exercise training in the aerobic/anaerobic metabolic transition prevents glucose intolerance in alloxan-treated rats
Background:
Ninety percent of cases of diabetes are of the slowly evolving non-insulin-dependent type, or Type 2 diabetes. Lack of exercise is regarded as one of the main causes of this disorder. In this study we analyzed the effects of physical exercise on glucose homeostasis in adult rats with type 2 diabetes induced by a neonatal injection of alloxan.
Methods:
Female Wistar rats aged 6 days were injected with either 250 mg/kg of body weight of alloxan or citrate buffer 0.01 M (controls). After weaning, half of the animals in each group were subjected to physical training adjusted to meet the aerobic-anaerobic metabolic transition by swimming 1 h/day for 5 days a week with weight overloads. The necessary overload used was set and periodically readjusted for each rat through effort tests based on the maximal lactate steady state procedure. When aged 28, 60, 90, and 120 days, the rats underwent glucose tolerance tests (GTT) and their peripheral insulin sensitivity was evaluated using the HOMA index.
Results:
The area under the serum glucose curve obtained through GTT was always higher in alloxan-treated animals than in controls. A decrease in this area was observed in trained alloxan-treated rats at 90 and 120 days old compared with non-trained animals. At 90 days old the trained controls showed lower HOMA indices than the non-trained controls.
Conclusion:
Neonatal administration of alloxan induced a persistent glucose intolerance in all injected rats, which was successfully counteracted by physical training in the aerobic/anaerobic metabolic transition.
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Twenty-four hours secretion pattern of serum estradiol in healthy prepubertal and pubertal boys as determined by a validated ultra-sensitive extraction RIA
Background:
The role of estrogens in male physiology has become evident. However, clinically useful normative data for estradiol secretion in boys has not previously been established due to the insensitivity of current methods used in clinical routine. By use of a validated ultra-sensitive extraction RIA, our aim was to establish normative data from a group consisting of healthy boys in prepuberty and during pubertal development.
Methods:
Sixty-two 24-hours serum profiles (6 samples/24 hours) were obtained from 44 healthy boys (ages; 7.2–18.6 years) during their pubertal development, classified into five stages: prepuberty (testis, 1–2 mL), early (testis, 3–6 mL), mid (testis, 8–12 mL), late-1 (testis,15–25 mL, not reached final height) and late-2 (testis,15–25 mL, reached final height). Serum estradiol was determined by an ultra- sensitive extraction radioimmunoassay with detection limit 4 pmol/L and functional sensitivity 6 pmol/L.
Results:
Mean estradiol concentrations during 24-hours secretion increased from prepuberty (median: <4 (5–95 percentiles: <4 – 7) pmol/L) to early puberty (6 (<4 – 12 pmol/L) but then remained relatively constant until a marked increase between mid-puberty (8 (4 – 17) pmol/L) and late-1 (21 (12 – 37) pmol/L) puberty, followed by a slower increase until late-2 puberty (32 (20 – 47) pmol/L). The diurnal rhythm of serum estradiol was non-measurable in pre- and early puberty, but discerned in mid-puberty, and become evident in late pubertal stages with peak values at 0600 to 1000 h.
Conclusion:
With the use of an ultra-sensitive extraction RIA, we have provided clinically useful normative data for estradiol secretion in boys.
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