Minor effect of GLUT1 polymorphisms on susceptibility to diabetic nephropathy in type 1 diabetes

Elevation of intracellular glucose in mesangial cells as mediated by GLUT1 may be important in initiating cellular mechanisms that cause diabetic nephropathy. To determine whether DNA sequence differences in GLUT1 confer susceptibility to this complication, single-nucleotide polymorphisms (SNPs) in this gene were examined using a large case-control study. SNPs examined included the known XbaI (intron 2) and HaeIII SNPs (exon 2). Four novel SNPs located in three putative enhancers were also investigated. Homozygosity for the XbaI(-) allele was associated with diabetic nephropathy (odds ratio 1.83 [95% CI 1.01-3.33]). Furthermore, homozygosity for the A allele for a novel SNP (enhancer-2 SNP 1) located in a putative insulin-responsive enhancer-2 was associated with diabetic nephropathy (2.38 [1.16-4.90]). Patients who were homozygous for risk alleles at both XbaI SNP and enhancer-2 SNP 1 [i.e., homozygosity for XbaI(-)/A haplotype] also had an increased risk of diabetic nephropathy (2.40 [1.13-5.07]). Because enhancer-2 SNP 1 may directly control GLUT1 expression, the strong linkage disequilibrium between the two SNPs likely accounts for XbaI SNP being associated with diabetic nephropathy. In conclusion, our study confirms that SNPs at the GLUT1 locus are associated with susceptibility to diabetic nephropathy in type 1 diabetes. Although these SNPs confer a considerable personal risk for diabetic nephropathy, they account for a limited proportion of cases among type 1 diabetic patients.     

Recombinant human interleukin-1 receptor antagonist in severe traumatic brain injury: a phase II randomized control trial

Traumatic brain injury (TBI) is the commonest cause of death and disability in those aged under 40 years. Interleukin-1 receptor antagonist (IL1ra) is an endogenous competitive antagonist at the interleukin-1 type-1 receptor (IL-1R). Antagonism at the IL-1R confers neuroprotection in several rodent models of neuronal injury (i.e., trauma, stroke and excitotoxicity). We describe a single center, phase II, open label, randomized-control study of recombinant human IL1ra (rhIL1ra, anakinra) in severe TBI, at a dose of 100 mg subcutaneously once a day for 5 days in 20 patients randomized 1:1. We provide safety data (primary outcome) in this pathology, utilize cerebral microdialysis to directly determine brain extracellular concentrations of IL1ra and 41 cytokines and chemokines, and use principal component analysis (PCA) to explore the resultant cerebral cytokine profile. Interleukin-1 receptor antagonist was safe, penetrated into plasma and the brain extracellular fluid. The PCA showed a separation in cytokine profiles after IL1ra administration. A candidate cytokine from this analysis, macrophage-derived chemoattractant, was significantly lower in the rhIL1ra-treated group. Our results provide promising data for rhIL1ra as a therapeutic candidate by showing safety, brain penetration and a modification of the neuroinflammatory response to TBI by a putative neuroprotective agent in humans for the first time.     

Cardiopulmonary exercise testing as a predictor of complications in oesophagogastric cancer surgery

Introduction

An anaerobic threshold (AT) of <11ml/min/kg can identify patients at high risk of cardiopulmonary complications after major surgery. The aim of this study was to assess the value of cardiopulmonary exercise testing (CPET) in predicting cardiopulmonary complications in high risk patients undergoing oesophagogastric cancer resection.

Methods

Between March 2008 and October 2010, 108 patients (83 men, 25 women) with a median age of 66 years (range: 38–84 years) underwent CPET before potentially curative resections for oesophagogastric cancers. Measured CPET variables included AT and maximum oxygen uptake at peak exercise (VO₂ peak). Outcome measures were length of high dependency unit stay, length of hospital stay, unplanned intensive care unit (ICU) admission, and postoperative morbidity and mortality.

Results

The mean AT and VO₂ peak were 10.8ml/min/kg (standard deviation [SD]: 2.8ml/min/kg, range: 4.6–19.3ml/min/kg) and 15.2ml/min/kg (SD: 5.3ml/min/kg, range: 5.4–33.3ml/min/kg) respectively; 57 patients (55%) had an AT of <11ml/min/ kg and 26 (12%) had an AT of <9ml/min/kg. Postoperative complications occurred in 57 patients (29 cardiopulmonary [28%] and 28 non-cardiopulmonary [27%]). Four patients (4%) died in hospital and 21 (20%) required an unplanned ICU admission. Cardiopulmonary complications occurred in 42% of patients with an AT of <9ml/min/kg compared with 29% of patients with an AT of ≥9ml/min/kg but <11ml/min/kg and 20% of patients with an AT of ≥11ml/min/kg (p=0.04). There was a trend that those with an AT of <11ml/min/kg and a low VO₂ peak had a higher rate of unplanned ICU admission.

Conclusions

This study has shown a correlation between AT and the development of cardiopulmonary complications although the discriminatory ability was low.     

Peripheral blood immune response elicited by beta-lactoglobulin in childhood cow's milk allergy

Several studies analyzing the immune responses in patients with cow's milk allergy (CMA) have used T-cell lines or T-cell clones that require prolonged in vitro cell culturing and may result in a switched cell phenotype and function. We investigated immune responses to beta-lactoglobulin (b-LG) in peripheral blood mononuclear cells after a short in vitro antigen stimulation in children with acute CMA (both IgE-mediated and non-IgE-mediated forms) and in those who outgrew an IgE-mediated CMA. Healthy controls were also investigated. Peripheral blood mononuclear cells were assayed for IL-13, IFN-γ, IL-4, and IL-10. Although b-LG induced a cytokine production and/or cell proliferation almost in all children, included healthy controls, differences were observed among the four groups. Children with IgE-mediated CMA had a marked Th2-response, with high IL-13 production and proliferation, but low IFN-γ; by contrast, children with non-IgE-mediated CMA produced no, or very low, IL-13 and cell proliferation. Children, who outgrew CMA, showed a shift to a Th1-response, with reduced IL-13 and increased IFN-γ. IL-10-responses were high in all groups, with the highest level in healthy children; by contrast, IL-4 was undetectable in all children. This study highlights the use of shortly stimulated peripheral blood cells to investigate the food-induced immune responses.     

Evidence for different susceptibility genes for proteinuria and ESRD in type 2 diabetes

Proteinuria and impaired kidney function are 2 major traits of diabetic nephropathy that aggregate (are heritable) in families of diabetic individuals. Although both traits are heritable, they are not genetically correlated. These findings not only support the hypothesis that the development of diabetic nephropathy consists of 2 distinct disease processes (ie, increasing proteinuria and declining kidney function) but also strongly justify searches for the putative genes that separately determine variation in these processes. These searches have used both genome-wide scans and candidate-gene approaches. By use of genome-scan approaches, several research groups have identified genetic regions on chromosomes 7q, 18q, and 22q that harbor genes that determine either variation in urinary albumin excretion or susceptibility to proteinuria in families who have type 2 diabetes. The evidence for linkage in these 3 genetic regions was suggestive or strong, but, except for 7q, the regions did not overlap across studies. Two genome scans performed in families who have type 2 diabetes identified genetic regions on chromosome 3q, 6q, 7p, and 18q that harbor susceptibility genes that determine variation in glomerular filtration rate or susceptibility to the development of end-stage renal disease (ESRD). The region on 7p overlapped in both studies. Optimism is growing that a positional cloning approach applied to these putative genetic regions will lead to the isolation of the susceptibility genes for proteinuria and ESRD. Meanwhile, significant efforts that make use of the candidate-gene approach have been directed to the search for susceptibility genes for diabetic nephropathy. Unfortunately, positive findings have not been consistent.     

Plantar thermography is useful in the early diagnosis of diabetic neuropathy

OBJECTIVES:

This study evaluated plantar thermography sensitivity and specificity in diagnosing diabetic polyneuropathy using cardiac tests (heart rate variability) as a reference standard because autonomic small fibers are affected first by this disease.

METHODS:

Seventy-nine individuals between the ages of 19 and 79 years old (28 males) were evaluated and divided into three groups: control (n = 37), pre-diabetics (n = 13) and type 2 diabetics (n = 29). The plantar images were recorded at baseline and then minutes after a provocative maneuver (Cold Stress Test) using an infrared camera that is appropriate for clinical use. Two thermographic variables were studied: the thermal recovery index and the interdigital anisothermal technique. Heart rate variability was measured in a seven-test battery that included three spectral indexes (in the frequency domain) and four Ewing tests (the Valsalva maneuver, the orthostatic test, a deep breathing test, and the orthostatic hypotension test). Other classically recommended tests were applied, including electromyography (EMG), Michigan inventory, and a clinical interview that included a neurological physical examination.

RESULTS:

Among the diabetic patients, the interdigital anisothermal technique alone performed better than the thermal recovery index alone, with a better sensitivity (81.3%) and specificity (46.2%). For the pre-diabetic patients, the three tests performed equally well. None of the control subjects displayed abnormal interdigital anisothermal readouts or thermal recovery indices, which precluded the sensitivity estimation in this sample of subjects. However, the specificity (70.6%) was higher in this group.

CONCLUSION:

In this study, plantar thermography, which predominately considers the small and autonomic fibers that are commonly associated with a sub-clinical condition, proved useful in diagnosing diabetic neuropathy early. The interdigital anisothermal test, when used alone, performed best.     

Diabetic retinopathy predicts all-cause mortality and cardiovascular events in both type 1 and 2 diabetes: meta-analysis of observational studies

OBJECTIVE

The prognostic significance of diabetic retinopathy (DR) for death and cardiovascular (CV) outcomes is debated. We investigated the association of DR with all-cause mortality and CV events in patients with diabetes by a systematic review and meta-analysis.

RESEARCH DESIGN AND METHODS

The electronic databases Medline and Embase were searched for cohort studies that evaluated DR in type 2 or type 1 diabetic patients and reported total mortality and/or fatal and nonfatal CV events, including myocardial infarction, angina pectoris, coronary artery bypass graft, ischemic changes on a conventional 12-lead electrocardiogram, transient ischemic attack, nonfatal stroke, or lower leg amputation. Data extraction was performed by two reviewers independently. Pooled effect estimates were obtained by using random-effects meta-analysis.

RESULTS

The analysis included 20 studies that fulfilled the inclusion criteria, providing data from 19,234 patients. In patients with type 2 diabetes (n = 14,896), the presence of any degree of DR increased the chance for all-cause mortality and/or CV events by 2.34 (95% CI 1.96–2.80) compared with patients without DR. In patients with type 1 diabetes (n = 4,438), the corresponding odds ratio was 4.10 (1.50–11.18). These associations remained after adjusting for traditional CV risk factors. DR was also predictive of all-cause mortality in type 2 diabetes (odds ratio 2.41 [1.87–3.10]) and type 1 diabetes (3.65 [1.05–12.66]).

CONCLUSIONS

The presence of DR was associated with an increased risk of all-cause mortality and CV events in both type 2 and type 1 diabetic patients.Diabetic retinopathy (DR) is a common chronic microvascular diabetes complication. Approximately 29% of U.S. adults with type 2 diabetes have DR (1), whereas DR will develop in 95% of type 1 diabetic individuals during their lifetime (2). DR has been associated with increased all-cause and cardiovascular (CV) mortality risk in both type 2 and type 1 diabetes (3–7). Associations with DR have been more extensively evaluated in type 2 diabetes, whereas studies in type 1 diabetes are scarce.Considering these data, identification of DR could possibly add to the diabetic patient’s CV risk stratification. Furthermore, the fundus examination is inexpensive and is routinely performed for the screening of chronic diabetes complications. Therefore, it is worthwhile to comprehensively review data on the predictive role of DR. The aim of the current study was to investigate the association of DR with all-cause mortality and CV events (fatal and nonfatal) in type 2 and type 1 diabetic patients by a systematic review and meta-analysis of cohort studies.     

Saccharomyces boulardii: a summary of the evidence for gastroenterology clinical practice in adults and children

Probiotics are viable, nonpathogenic microorganisms (bacteria or yeast) which when administered in adequate amounts, confer a health benefit on the host. At this time, Saccharomyces boulardii is the only yeast commonly used in clinical practice. Literature on this probiotic is wide and even more data become available each year. Thus, it could be problematic for a physician summarize all the best information deriving from basic research and clinical studies. With the aim to help physicians in the use of Saccharomyces boulardii, this paper focuses on the available evidences for its efficacy and safety in different diseases in adult and pediatric patients in order to provide a practical guidance for gastroenterology clinical practice. Indications and dosage for several gastrointestinal diseases for a correct use of this probiotic are provided, and recent insights on its mechanisms of action and possible future clinical application are also discussed.