Citations

Patients with irritable bowel syndrome (IBS) with diarrhea (IBS-D) carrying human leukocyte antigen (HLA)-DQ2/8 genotypes benefit from gluten withdrawal. Our objective was to compare gastrointestinal barrier function, mucosal inflammation, and transit in nonceliac IBS-D patients and assess association with HLA-DQ2/8 status. In 45 IBS-D patients who were naive to prior exclusion of dietary gluten, we measured small bowel (SB) and colonic mucosal permeability by cumulative urinary lactulose and mannitol excretion (0–2 h for SB and 8–24 h for colon), inflammation on duodenal and rectosigmoid mucosal biopsies (obtained in 28 of 45 patients), tight junction (TJ) protein mRNA and protein expression in SB and rectosigmoid mucosa, and gastrointestinal and colonic transit by validated scintigraphy. SB mucosal biopsies were stained with hematoxylin-eosin to assess villi and intraepithelial lymphocytes, and immunohistochemistry was used to assess CD3, CD8, tryptase, and zonula occludens 1 (ZO-1); colonic biopsy intraepithelial lymphocytes were quantitated. Associations of HLA-DQ were assessed using Wilcoxon's rank-sum test. Relative to healthy control data, we observed a significant increase in SB permeability ( P < 0.001), a borderline increase in colonic permeability ( P = 0.10), and a decrease in TJ mRNA expression in rectosigmoid mucosa in IBS-D. In HLA-DQ2/8-positive patients, ZO-1 protein expression in the rectosigmoid mucosa was reduced compared with that in HLA-DQ2/8-negative patients and colonic transit was slower than in HLA-DQ2/8-negative patients. No other associations with HLA genotype were identified. There is abnormal barrier function (increased SB permeability and reduced mRNA expression of TJ proteins) in IBS-D relative to health that may be, in part, related to immunogenotype, given reduced ZO-1 protein expression in rectosigmoid mucosa in HLA-DQ2/8-positive relative to HLA-DQ2/8-negative patients.

Aim Postprandial insulin pulsatility is impaired in patients with type 2 diabetes, but the effects of exogenous insulin therapy on pulsatile insulin secretion are not known. We addressed, whether pulsatile insulin secretion is related to glycaemic control, whether basal insulin supplementation increases postprandial insulin secretion, and if so, is this accomplished by a specific improvement in pulsatile insulin secretion? Methods Fourteen patients with type 2 diabetes underwent a mixed meal test before and after an 8‐week treatment period with insulin glargine. Glucose, insulin and C‐peptide levels were measured, and insulin pulsatility was determined by deconvolution analysis. Results Insulin treatment lowered fasting glycaemia from 179.6 ± 7.5 mg/dl to 117.6 ± 6.5 mg/dl (p < 0.001). Postprandial insulin and C‐peptide levels increased significantly after the treatment period (p < 0.0001). The total calculated insulin secretion rate increased with insulin treatment (p = 0.0039), with non‐significant increases in both pulsatile and non‐pulsatile insulin secretion. Insulin pulse frequency was unchanged by the intervention. There was an inverse relationship between fasting and postprandial glycaemia and insulin pulse mass ( r 2 = 0.51 and 0.56, respectively), whereas non‐pulsatile insulin secretion was unrelated to either fasting or postprandial glucose concentrations ( r 2 = 0.0073 and 0.031). Conclusions Hyperglycaemia in type 2 diabetes is associated with a reduction in postprandial insulin secretion, specifically through a reduction in insulin pulsatility. Reducing chronic hyperglycaemia by basal insulin therapy enhances endogenous β‐cell function in the postprandial state. These data support the use of basal insulin regimens in the pharmacotherapy of overtly hyperglycaemic patients with type 2 diabetes.

Frontotemporal degeneration (FTD) is a common cause of dementia for which there are currently no approved therapies. Over the past decade, there has been an explosion of knowledge about the biology and clinical features of FTD that has identified a number of promising therapeutic targets as well as animal models in which to develop drugs. The close association of some forms of FTD with neuropathological accumulation of tau protein or increased neuroinflammation due to progranulin protein deficiency suggests that a drug's success in treating FTD may predict efficacy in more common diseases such as Alzheimer's disease. A variety of regulatory incentives, clinical features of FTD such as rapid disease progression, and relatively pure molecular pathology suggest that there are advantages to developing drugs for FTD as compared with other more common neurodegenerative diseases such as Alzheimer's disease. In March 2011, the Frontotemporal Degeneration Treatment Study Group sponsored a conference entitled “FTD, the Next Therapeutic Frontier,” which focused on preclinical aspects of FTD drug development. The goal of the meeting was to promote collaborations between academic researchers and biotechnology and pharmaceutical researchers to accelerate the development of new treatments for FTD. Here we report the key findings from the conference, including the rationale for FTD drug development; epidemiological, genetic, and neuropathological features of FTD; FTD animal models and how best to use them; and examples of successful drug development collaborations in other neurodegenerative diseases.

Objectives To perform a systematic review and meta-analysis including all the current studies to assess the accuracy of pulmonary embolism rule-out criteria (PERC) in ruling out pulmonary embolism (PE). Methods We conducted a comprehensive search of the major databases (Ovid Medline In-Process & Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid PsycInfo, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews and Scopus) and references of potentially eligible articles and conference proceedings of major emergency medicine organisations through May 2012. We included all original research studies conducted in emergency departments on diagnostic performance of PERC. Two reviewers independently identified the eligible studies and extracted data. Sensitivity, specificity and likelihood ratios were calculated using contingency tables. Results 12 studies including 13 cohorts (three retrospective, 10 prospective) were included, comprising of 14 844 patients from six countries. 12 cohorts were urban and one was rural. Pooled (95% CI) sensitivity, specificity, positive and negative likelihood ratio were 0.97 (0.96 to 0.98), 0.22 (0.22 to 0.23), 1.22 (1.16 to 1.29) and 0.17 (0.13 to 0.23), respectively. The pooled (95% CI) diagnostic OR was 7.4 (5.5–9.8). On meta-regression analysis, there was no significant difference between PE prevalence and PERC diagnostic performance (coefficient (SE) of −0.032 (0.022), p=0.173) or on relative diagnostic OR (0.97, 95% CI 0.92 to 1.02). Significant heterogeneity was observed in specificity (I2=97.4%) and positive likelihood ratio (I2=89.1%). Conclusions Because of the high sensitivity and low negative likelihood ratio, PERC rule can be used confidently in clinically low probability population settings.

Background: Chronic migraine (CM) is a debilitating neurological disorder with few treatment options. Peripheral nerve stimulation (PNS) of the occipital nerves is a potentially promising therapy for CM patients. Methods: In this randomized, controlled multicenter study, patients diagnosed with CM were implanted with a neurostimulation device near the occipital nerves and randomized 2:1 to active ( n = 105) or sham ( n = 52) stimulation. The primary endpoint was a difference in the percentage of responders (defined as patients that achieved a ≥50% reduction in mean daily visual analog scale scores) in each group at 12 weeks. Results: There was not a significant difference in the percentage of responders in the Active compared with the Control group (95% lower confidence bound (LCB) of −0.06; p = 0.55). However, there was a significant difference in the percentage of patients that achieved a 30% reduction ( p = 0.01). Importantly, compared with sham-treated patients, there were also significant differences in reduction of number of headache days (Active Group = 6.1, baseline = 22.4; Control Group = 3.0, baseline = 20.1; p = 0.008), migraine-related disability ( p = 0.001) and direct reports of pain relief ( p = 0.001). The most common adverse event was persistent implant site pain. Conclusion: Although this study failed to meet its primary endpoint, this is the first large-scale study of PNS of the occipital nerves in CM patients that showed significant reductions in pain, headache days, and migraine-related disability. Additional controlled studies using endpoints that have recently been identified and accepted as clinically meaningful are warranted in this highly disabled patient population with a large unmet medical need. Trial registration: Clinical trials.gov (NCT00615342).

AbstractHemodialysis (HD) exposes end‐stage renal disease patients to significantly higher risks for Hepatitis B Virus (HBV) infection, a major public health scourge. Therefore, current US CDC guidelines, last revised in 2001, call for monthly HbsAg tests. The charge to Medicare per HbsAg test is $100. In an economic analysis, we hypothesized that in the new environment of Medicare Fee Bundling, this is unwise and wasteful if de novo HBV infection rate among HD patients is <1%. We determined de novo HBV infection rate among a Mayo Clinic HD cohort, July 2000–July 2010. A retrospective analysis of all relevant medical records of the cohort was completed to identify de novo HBV infection. Nine hundred sixty‐five HD patients were analyzed. One case of de novo HBV infection was identified in a 54‐year old known IV drug user, a previous Hepatitis C carrier. This translates to a de novo HBV case incidence rate of 0.1%. De novo HBV infection among HD patients in the US, 2000–2010, is only 0.1%. In the early 1970s, rates were as high as 30%. We recommend 3‐monthly HbsAg testing, but to continue current monthly testing for IV drug users and other high‐risk groups. Huge cost savings would result, without any compromise of quality outcomes. With over 500,000 HD patients, this represents a mind‐boggling $40 billion savings in Medicare charges over 10 years. The US CDC should revise these outdated guidelines, last revised in 2001, to fall in line with current clinical realities on the ground.

In a mouse model of the human disease pulmonary lymphangioleiomyomatosis, treatment with rapamycin plus simvastatin prevented alveolar space enlargement and growth of TSC2-null lesions.