Non Celiac Gluten sensitivity (NCGS) was originally described in the 1980s and recently a “re-discovered” disorder characterized by intestinal and extra-intestinal symptoms related to the ingestion of gluten-containing food, in subjects that are not affected with either celiac disease (CD) or wheat allergy (WA). Although NCGS frequency is still unclear, epidemiological data have been generated that can help establishing the magnitude of the problem. Clinical studies further defined the identity of NCGS and its implications in human disease. An overlap between the irritable bowel syndrome (IBS) and NCGS has been detected, requiring even more stringent diagnostic criteria. Several studies suggested a relationship between NCGS and neuropsychiatric disorders, particularly autism and schizophrenia. The first case reports of NCGS in children have been described. Lack of biomarkers is still a major limitation of clinical studies, making it difficult to differentiate NCGS from other gluten related disorders. Recent studies raised the possibility that, beside gluten, wheat amylase-trypsin inhibitors and low-fermentable, poorly-absorbed, short-chain carbohydrates can contribute to symptoms (at least those related to IBS) experienced by NCGS patients. In this paper we report the major advances and current trends on NCGS.

Diabetes mellitus type 1 and 2 (T1DM and T2DM) are complex multifactorial diseases. Loss of beta-cell function caused by reduced secretory capacity and enhanced apoptosis is a key event in the pathogenesis of both diabetes types. Oxidative stress induced by reactive oxygen and nitrogen species is critically involved in the impairment of beta-cell function during the development of diabetes. Because of their low antioxidant capacity, beta-cells are extremely sensitive towards oxidative stress. In beta-cells, important targets for an oxidant insult are cell metabolism and K(ATP) channels. The oxidant-evoked alterations of K(ATP) channel activity seem to be critical for oxidant-induced dysfunction because genetic ablation of K(ATP) channels attenuates the effects of oxidative stress on beta-cell function. Besides the effects on metabolism, interference of oxidants with mitochondria induces key events in apoptosis. Consequently, increasing antioxidant defence is a promising strategy to delay beta cell failure in (pre)-diabetic patients or during islet transplantation. Knock-out of K(ATP) channels has beneficial effects on oxidant-induced inhibition of insulin secretion and cell death. Interestingly, these effects can be mimicked by sulfonylureas that have been used in the treatment of T2DM for many years. Loss of functional K(ATP) channels leads to up-regulation of antioxidant enzymes, a process that depends on cytosolic Ca(2+). These observations are of great importance for clinical intervention because they show a possibility to protect beta-cells at an early stage before dramatic changes of the secretory capacity and loss of cell mass become manifest and lead to glucose intolerance or even overt diabetes.

Background-Abnormally elevated blood pressure is the most prevalent risk factor for cardiovascular disease. The large-conductance, voltage-and Ca 2ϩ -dependent K ϩ (BK) channel has been proposed as an important effector in the control of vascular tone by linking membrane depolarization and local increases in cytosolic Ca 2ϩ to hyperpolarizing K ϩ outward currents. However, the BK channel may also affect blood pressure by regulating salt and fluid homeostasis, particularly by adjusting the renin-angiotensin-aldosterone system. Methods and Results-Here we report that deletion of the pore-forming BK channel ␣ subunit leads to a significant blood pressure elevation resulting from hyperaldosteronism accompanied by decreased serum K ϩ levels as well as increased vascular tone in small arteries. In smooth muscle from small arteries, deletion of the BK channel leads to a depolarized membrane potential, a complete lack of membrane hyperpolarizing spontaneous K ϩ outward currents, and an attenuated cGMP vasorelaxation associated with a reduced suppression of Ca 2ϩ transients by cGMP. The high level of BK channel expression observed in wild-type adrenal glomerulosa cells, together with unaltered serum renin activities and corticotropin levels in mutant mice, suggests that the hyperaldosteronism results from abnormal adrenal cortical function in BK Ϫ/Ϫ mice. Conclusions-These results identify previously unknown roles of BK channels in blood pressure regulation and raise the possibility that BK channel dysfunction may underlie specific forms of hyperaldosteronism. 6,7 Recent studies raise the possibility that changes in ␤1 subunit expression contribute to the development of hypertension in rat 8 and that gain of function mutation in the same subunit decreases the prevalence of diastolic hypertension in humans. 9 However, even in the absence of functional ␤1 subunits, the ␣ subunit can still form functional channels, which might be activated at physiological potentials if their voltage and Ca 2ϩ sensitivity are increased by other factors such as endothelial factors 10,11 and/or phosphorylation. 12,13 Thus, functional BK channels may be operative in blood vessels even when the ␤1 subunit is lacking. In addition, BK channels in tissues other than vasculature, such as the adrenal gland, 14 may also influence blood pressure regulation. Therefore, we used mice lacking the BK channel ␣ subunit (BK Ϫ/Ϫ 15 to evaluate the global impact of BK channels on blood pressure regulation. MethodsDetails are given in the online-only Data Supplement. Mice BKϪ/Ϫ mice were generated as described. 15 Wild type (WT) and BK Ϫ/Ϫ mice with the hybrid SV129/C57BL6 background (always F2 generation) were used. Either litter-or age-matched animals were randomly assigned to the experimental procedures undertaken in accordance with the German legislation on protection of animals. Immunohistochemistry of Adrenal GlandFor immunofluorescence, on-slide 5-m cryostat slices from nonfixed WT and BK Ϫ/Ϫ adrenal glands were incubated with anti-BK␣ (674 -1115) . BK...

for the Karolinska Schizophrenia Project Consortium IMPORTANCE Between-individual variability in brain structure is determined by gene-environment interactions, possibly reflecting differential sensitivity to environmental and genetic perturbations. Magnetic resonance imaging (MRI) studies have revealed thinner cortices and smaller subcortical volumes in patients with schizophrenia. However, group-level comparisons may mask considerable within-group heterogeneity, which has largely remained unnoticed in the literature.OBJECTIVES To compare brain structural variability between individuals with schizophrenia and healthy controls and to test whether respective variability reflects the polygenic risk score (PRS) for schizophrenia in an independent sample of healthy controls. DESIGN, SETTING, AND PARTICIPANTSThis case-control and polygenic risk analysis compared MRI-derived cortical thickness and subcortical volumes between healthy controls and patients with schizophrenia across 16 cohorts and tested for associations between PRS and MRI features in a control cohort from the UK Biobank.

Gluten proteins from wheat, rye, barley and, in rare cases, oats, are responsible for triggering hypersensitivity reactions such as celiac disease, non-celiac gluten sensitivity and wheat allergy. Well-defined reference materials (RM) are essential for clinical studies, diagnostics, elucidation of disease mechanisms and food analyses to ensure the safety of gluten-free foods. Various RM are currently used, but a thorough characterization of the gluten source, content and composition is often missing. However, this characterization is essential due to the complexity and heterogeneity of gluten to avoid ambiguous results caused by differences in the RM used. A comprehensive strategy to isolate gluten protein fractions and gluten protein types (GPT) from wheat, rye, barley and oat flours was developed to obtain well-defined RM for clinical assays and gluten-free compliance testing. All isolated GPT (ω5-gliadins, ω1,2-gliadins, α-gliadins, γ-gliadins and high- and low-molecular-weight glutenin subunits from wheat, ω-secalins, γ-75k-secalins, γ-40k-secalins and high-molecular-weight secalins from rye, C-hordeins, γ-hordeins, B-hordeins and D-hordeins from barley and avenins from oats) were fully characterized using analytical reversed-phase high-performance liquid chromatography (RP-HPLC), sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), N-terminal sequencing, electrospray-ionization quadrupole time-of-flight mass spectrometry (LC-ESI-QTOF-MS) and untargeted LC-MS/MS of chymotryptic hydrolyzates of the single GPT. Taken together, the analytical methods confirmed that all GPT were reproducibly isolated in high purity from the flours and were suitable to be used as RM, e.g., for calibration of LC-MS/MS methods or enzyme-linked immunosorbent assays (ELISAs).

Wheat-dependent exercise-induced anaphylaxis (WDEIA) is a rare, but potentially severe food allergy exclusively occurring when wheat ingestion is accompanied by augmenting cofactors. It is clinically characterized by anaphylactic reactions ranging from urticaria and angioedema to dyspnoea, hypotension, collapse, and shock. WDEIA usually develops after ingestion of wheat products followed by physical exercise. Other cofactors are acetylsalicylic acid and other non-steroidal anti-inflammatory drugs, alcohol, and infections. The precise mechanisms of WDEIA remain unclear; exercise and other cofactors might increase gastrointestinal allergen permeability and osmolality, redistribute blood flow, or lower the threshold for IgE-mediated mast cell degranulation. Among wheat proteins, ω5-gliadin and high-molecular-weight glutenin subunits have been reported to be the major allergens. In some patients, WDEIA has been discussed to be caused by epicutaneous sensitization with hydrolysed wheat gluten included in cosmetics. Diagnosis is made based on the patient's history in combination with allergy skin testing, determination of wheat-specific IgE serum antibodies, basophil activation test, histamine release test, and/or exercise challenge test. Acute treatment includes application of adrenaline or antihistamines. The most reliable prophylaxis of WDEIA is a gluten-free diet. In less severe cases, a strict limitation of wheat ingestion before exercise and avoidance of other cofactors may be sufficient.

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One of the major risk factors for global death and disability is alcohol, tobacco, and illicit drug use. While there is increasing knowledge with respect to individual factors promoting the initiation and maintenance of substance use disorders (SUDs), disease trajectories involved in losing and regaining control over drug intake (ReCoDe) are still not well described. Our newly formed German Collaborative Research Centre (CRC) on ReCoDe has an interdisciplinary approach funded by the German Research Foundation (DFG) with a 12‐year perspective. The main goals of our research consortium are (i) to identify triggers and modifying factors that longitudinally modulate the trajectories of losing and regaining control over drug consumption in real life, (ii) to study underlying behavioral, cognitive, and neurobiological mechanisms, and (iii) to implicate mechanism‐based interventions. These goals will be achieved by: (i) using mobile health (m‐health) tools to longitudinally monitor the effects of triggers (drug cues, stressors, and priming doses) and modify factors (eg, age, gender, physical activity, and cognitive control) on drug consumption patterns in real‐life conditions and in animal models of addiction; (ii) the identification and computational modeling of key mechanisms mediating the effects of such triggers and modifying factors on goal‐directed, habitual, and compulsive aspects of behavior from human studies and animal models; and (iii) developing and testing interventions that specifically target the underlying mechanisms for regaining control over drug intake.