Sex Differences in the Risk of Barrett's Esophagus Associated With the Metabolic Effects of Obesity.

GOAL: The goal of this study was to determine if there is an association between the insulin-insulin-like growth factor axis, the metabolic syndrome (MetS), type 2 diabetes mellitus and risk of Barrett's esophagus (BE), and if these associations are modified by sex. BACKGROUND: BE is more common in males. Gastroesophageal reflux disease, the major risk factor for BE occurs at similar frequencies in both sexes, suggesting that sex-related factors such as the metabolic effects of abdominal obesity may be important in the causation of BE. MATERIALS AND METHODS: A structured interview, anthropometric measures, and fasting blood were collected within a population-based case-control study. We recruited 227 BE cases (70% male) and 241 population controls, frequency matched by age and sex. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for association with BE using multivariable logistic regression models. RESULTS: Hyperinsulinemia (highest vs. lowest tertile, OR=1.9; 95% CI: 1.2-3.1), Homeostatic Model Assessment of Insulin Resistance (OR=1.9; 95% CI: 1.2-3.1) and the MetS (OR=1.8; 95% CI: 1.2-2.6) were independently associated with an increased risk of BE. With each additional MetS criterion, there was a 20% increased risk of BE (OR=1.2; 95% CI: 1.0-1.4). When stratified by sex, these associations were found in males but not females. We found no association with serum measures of insulin-like growth factors or interleukin-6 and risk of BE. CONCLUSION: Hyperinsulinemia, insulin resistance, and the MetS are associated with the risk of BE in males but not females, suggesting these factors may contribute to the higher prevalence of BE in males.

The effect of glucocorticoids on Thrombospondin-1, Osteocalcin and the Thrombospondin-1:Osteocalcin ratio in humans.

OBJECTIVE: Thrombospondin-1 (TSP1), a matricellular protein, and Osteocalcin (OCN), a noncollagenous protein secreted by osteoblasts, are known to be up- and down-regulated, respectively, by glucocorticoids. The aim of this study was to determine whether a ratio between TSP1:OCN was altered by changes in glucocorticoid activity in humans. DESIGN: Prospective observational study. SETTING: Tertiary university hospital in Queensland, Australia. PATIENTS AND MEASUREMENTS: Patients with Cushing's syndrome (CS, n = 19), asthma or giant cell arteritis on chronic prednisolone treatment (PRED, n = 13), adrenal insufficiency (AI, n = 16) and healthy volunteers (HV, n = 20). Plasma TSP1 and serum total OCN were measured by immunoassay at 0800h, 1200h and 1600h in patients with CS, patients with AI taking replacement glucocorticoids, HV before and after 4 mg dexamethasone and PRED patients predose at 800 and 4 hours post-dose at 1200 hours. RESULTS: Plasma TSP1 in CS was higher (P < .0001), and serum OCN was lower (P < .0001) than HV. The TSP1:OCN ratio in HV increased significantly after 4 mg dexamethasone (P < .0001) and in AI after taking their hydrocortisone replacement therapy (P < .001). PRED patients had a higher TSP1:OCN ratio compared with HV at both 800 and 1200 hours (both P < .001), but no significant change occurred from pre- to post-dose. A TSP1:OCN ratio of >73 at 800 hours differentiated CS from HV with a sensitivity of 95% and a specificity of 100%. CONCLUSIONS: The TSP1:OCN ratio is elevated in patients on prednisolone and in patients with CS compared with healthy volunteers. It may be a useful biomarker of total body glucocorticoid activity in humans.

Gene networks associated with non-syndromic intellectual disability.

Non-syndromic intellectual disability (NS-ID) is a genetically heterogeneous disorder, with more than 200 candidate genes to date. Despite the increasing number of novel mutations detected, a relatively low number of recurrently mutated genes have been identified, highlighting the complex genetic architecture of the disorder. A systematic search of PubMed and Medline identified 245 genes harbouring non-synonymous variants, insertions or deletions, which were identified as candidate NS-ID genes from case reports or from linkage or pedigree analyses. From this list, 33 genes are common to syndromic intellectual disability (S-ID) and 58 genes are common to certain neurological and neuropsychiatric disorders that often include intellectual disability as a clinical feature. We examined the evolutionary constraint and brain expression of these gene sets, and we performed gene network and protein-protein interaction analyses using GeneGO MetaCoreTM and DAPPLE, respectively. The 245 NS-ID candidate genes were over-represented in axon guidance, synaptogenesis, cell adhesion and neurotransmission pathways, all of which are key neurodevelopmental processes for the establishment of mature neuronal circuitry in the brain. These 245 genes exhibit significantly elevated expression in human brain and are evolutionarily constrained, consistent with expectations for a brain disorder such as NS-ID that is associated with reduced fecundity. In addition, we report enrichment of dopaminergic and glutamatergic pathways for those candidate NS-ID genes that are common to S-ID and/or neurological and neuropsychiatric disorders that exhibit intellectual disability. Collectively, this study provides an overview and analysis of gene networks associated with NS-ID and suggests modulation of neurotransmission, particularly dopaminergic and glutamatergic systems as key contributors to synaptic dysfunction in NS-ID.

Identification of carboxypeptidase X (CPX)-1 as a positive regulator of adipogenesis.

Adipose tissue expansion occurs through a combination of hypertrophy of existing adipocytes and generation of new adipocytes via the process of hyperplasia, which involves the proliferation and subsequent differentiation of preadipocytes. Deficiencies in hyperplasia contribute to adipose tissue dysfunction and the association of obesity with chronic cardiometabolic diseases. Thus, increased understanding of hyperplastic pathways may be expected to afford novel therapeutic strategies. We have reported that fibroblast growth factor (FGF)-1 promotes proliferation and differentiation of human preadipocytes and recently demonstrated that bone morphogenetic protein and activin membrane-bound inhibitor (BAMBI) is a central, proximal effector. Herein, we describe the identification and characterization of carboxypeptidase X (CPX)-1, a secreted collagen-binding glycoprotein, as a novel downstream effector in human primary and Simpson-Golabi-Behmel syndrome preadipocytes. CPX-1 expression increased after treatment of preadipocytes with FGF-1, BAMBI knockdown, or induction of differentiation. CPX-1 knockdown compromised preadipocyte differentiation coincident with reduced collagen expression. Furthermore, preadipocytes differentiated on matrix derived from CPX-1 knockdown cells exhibited reduced Glut4 expression and insulin-stimulated glucose uptake. Finally, CPX-1 expression was increased in adipose tissue from obese mice and humans. Collectively, these findings establish CPX-1 as a positive regulator of adipogenesis situated downstream of FGF-1/BAMBI that may contribute to hyperplastic adipose tissue expansion via affecting extracellular matrix remodeling.-Kim, Y.-H., Barclay, J. L., He, J., Luo, X., O'Neill, H. M., Keshvari, S., Webster, J. A., Ng, C., Hutley, L. J., Prins, J. B., Whitehead, J. P. Identification of carboxypeptidase X (CPX)-1 as a positive regulator of adipogenesis.

Longitudinal evaluation of the natural history of conservatively managed nonfunctioning pituitary adenomas.

CONTEXT: The optimal management of nonfunctioning pituitary adenomas presenting without symptomatic mass effect remains uncertain. The objective of this study was to elucidate the natural history of nonfunctioning pituitary adenomas managed conservatively. DESIGN: Volumetric evaluation of tumour growth in serial pituitary MRI scans by a single observer and retrospective review of changes in pituitary function. PATIENTS: Patients with nonfunctioning pituitary adenomas who underwent at least 2 serial pituitary MRI scans over ≥6 months between 2003 and 2013 prior to any intervention. MEASUREMENTS: Primary end-point was a ≥20% increase in volume or surgery. Secondary end-points were rate of pituitary dysfunction and pituitary apoplexy. RESULTS: Fifty nonfunctioning pituitary adenomas (23 macroadenomas and 27 microadenomas, mean age 49, range 17-85 years) were identified. Mean follow-up was 36 months (range 6-79). An increase in volume occurred in macroadenomas (P < 0·01) but not in microadenomas (P = 0·44). A ≥20% increase in volume occurred in nine of 23 macroadenomas compared with two of 27 microadenomas (P < 0·05). Five macroadenomas (one with new visual field defect) and one microadenoma proceeded to surgery (P = 0·08). Hormone deficiency was present in four of 24 macroadenomas vs 0 of 27 microadenomas (P < 0·05) at baseline, while new hormone deficiency developed in only two macroadenomas during follow-up. Pituitary apoplexy occurred in one microadenoma. A growth rate of >10 mm3 /month assessed at approximately 2 years of follow-up among the macroadenoma group was highly predictive (sensitivity and specificity of 90%) of a ≥20% increase in volume or surgery. CONCLUSIONS: Nonfunctioning pituitary macroadenomas have a greater tendency to grow and require surgical intervention while microadenomas rarely progress.

Living well after breast cancer randomized controlled trial protocol: evaluating a telephone-delivered weight loss intervention versus usual care in women following treatment for breast cancer.

BACKGROUND: Obesity, physical inactivity and poor diet quality have been associated with increased risk of breast cancer-specific and all-cause mortality as well as treatment-related side-effects in breast cancer survivors. Weight loss intervention trials in breast cancer survivors have shown that weight loss is safe and achievable; however, few studies have examined the benefits of such interventions on a broad range of outcomes and few have examined factors important to translation (e.g. feasible delivery method for scaling up, assessment of sustained changes, cost-effectiveness). The Living Well after Breast Cancer randomized controlled trial aims to evaluate a 12-month telephone-delivered weight loss intervention (versus usual care) on weight change and a range of secondary outcomes including cost-effectiveness. METHODS/DESIGN: Women (18-75 years; body mass index 25-45 kg/m2) diagnosed with stage I-III breast cancer in the previous 2 years are recruited from public and private hospitals and through the state-based cancer registry (target n = 156). Following baseline assessment, participants are randomized 1:1 to either a 12-month telephone-delivered weight loss intervention (targeting diet and physical activity) or usual care. Data are collected at baseline, 6-months (mid-intervention), 12-months (end-of-intervention) and 18-months (maintenance). The primary outcome is change in weight at 12-months. Secondary outcomes are changes in body composition, bone mineral density, cardio-metabolic and cancer-related biomarkers, metabolic health and chronic disease risk, physical function, patient-reported outcomes (quality of life, fatigue, menopausal symptoms, body image, fear of cancer recurrence) and behaviors (dietary intake, physical activity, sitting time). Data collected at 18-months will be used to assess whether outcomes achieved at end-of-intervention are sustained six months after intervention completion. Cost-effectiveness will be assessed, as will mediators and moderators of intervention effects. DISCUSSION: This trial will provide evidence needed to inform the wide-scale provision of weight loss, physical activity and dietary interventions as part of routine survivorship care for breast cancer survivors. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry (ANZCTR) - ACTRN12612000997853 (Registered 18 September 2012).

Nutrient and immune sensing are obligate pathways in metabolism, immunity, and disease.

The growth and survival of multicellular organisms depend upon their abilities to acquire and metabolize nutrients, efficiently store and harness energy, and sense and fight infection. Systems for sensing and using nutrients have consequently coevolved alongside systems for sensing and responding to danger signals, including pathogens, and share many of the same cell signaling proteins and networks. Diets rich in carbohydrates and fats can overload these systems, leading to obesity, metabolic dysfunction, impaired immunity, and cardiovascular disease. Excessive nutrient intake promotes adiposity, typically altering adipocyte function and immune cell distribution, both of which trigger metabolic dysfunction. Here, we discuss novel mechanistic links between metabolism and immunity that underlie metabolic dysfunction in obesity. We aim to stimulate debate about how the endocrine and immune systems are connected through autocrine, paracrine, and neuroendocrine signaling in sophisticated networks that are only now beginning to be resolved. Understanding the expression and action of signaling proteins, together with modulating their receptors or pattern recognition using agonists or antagonists, will enable rational intervention in immunometabolism that may lead to novel treatments for obesity and metabolic dysfunction.

Resveratrol does not benefit patients with nonalcoholic fatty liver disease.

BACKGROUND & AIMS: Nonalcoholic fatty liver disease (NAFLD), characterized by accumulation of hepatic triglycerides (steatosis), is associated with abdominal obesity, insulin resistance, and inflammation. Although weight loss via calorie restriction reduces features of NAFLD, there is no pharmacologic therapy. Resveratrol is a polyphenol that prevents high-energy diet-induced steatosis and insulin resistance in animals by up-regulating pathways that regulate energy metabolism. We performed a placebo-controlled trial to assess the effects of resveratrol in patients with NAFLD. METHODS: Overweight or obese men diagnosed with NAFLD were recruited from hepatology outpatient clinics in Brisbane, Australia from 2011 through 2012. They were randomly assigned to groups given 3000 mg resveratrol (n = 10) or placebo (n = 10) daily for 8 weeks. Outcomes included insulin resistance (assessed by the euglycemic-hyperinsulinemic clamp), hepatic steatosis, and abdominal fat distribution (assessed by magnetic resonance spectroscopy and imaging). Plasma markers of inflammation, as well as metabolic, hepatic, and antioxidant function, were measured; transcription of target genes was measured in peripheral blood mononuclear cells. Resveratrol pharmacokinetics and safety were assessed. RESULTS: Eight-week administration of resveratrol did not reduce insulin resistance, steatosis, or abdominal fat distribution when compared with baseline. No change was observed in plasma lipids or antioxidant activity. Levels of alanine and aspartate aminotransferases increased significantly among patients in the resveratrol group until week 6 when compared with the placebo group. Resveratrol did not significantly alter transcription of NQO1, PTP1B, IL6, or HO1 in peripheral blood mononuclear cells. Resveratrol was well-tolerated. CONCLUSIONS: Eight weeks administration of resveratrol did not significantly improve any features of NAFLD, compared with placebo, but it increased hepatic stress, based on observed increases in levels of liver enzymes. Further studies are needed to determine whether agents that are purported to mimic calorie restriction, such as resveratrol, are safe and effective for complications of obesity. Clinical trials registration no: ACTRN12612001135808.

Whole-body substrate metabolism is associated with disease severity in patients with non-alcoholic fatty liver disease.

OBJECTIVES: In non-alcoholic fatty liver disease (NAFLD), hepatic steatosis is intricately linked with a number of metabolic alterations. We studied substrate utilisation in NAFLD during basal, insulin-stimulated and exercise conditions, and correlated these outcomes with disease severity. METHODS: 20 patients with NAFLD (mean ± SD body mass index (BMI) 34.1 ± 6.7 kg/m(2)) and 15 healthy controls (BMI 23.4 ± 2.7 kg/m(2)) were assessed. Respiratory quotient (RQ), whole-body fat (Fat ox) and carbohydrate (CHO ox) oxidation rates were determined by indirect calorimetry in three conditions: basal (resting and fasted), insulin-stimulated (hyperinsulinaemic-euglycaemic clamp) and exercise (cycling at an intensity to elicit maximal Fat ox). Severity of disease and steatosis were determined by liver histology, hepatic Fat ox from plasma ß-hydroxybutyrate concentrations, aerobic fitness expressed as VO2 peak, and visceral adipose tissue (VAT) measured by computed tomography. RESULTS: Within the overweight/obese NAFLD cohort, basal RQ correlated positively with steatosis (r=0.57, p=0.01) and was higher (indicating smaller contribution of Fat ox to energy expenditure) in patients with NAFLD activity score (NAS) ≥ 5 vs <5 (p=0.008). Both results were independent of VAT, % body fat and BMI. Compared with the lean control group, patients with NAFLD had lower basal whole-body Fat ox (1.2 ± 0.3 vs 1.5 ± 0.4 mg/kg FFM/min, p=0.024) and lower basal hepatic Fat ox (ie, ß-hydroxybutyrate, p=0.004). During exercise, they achieved lower maximal Fat ox (2.5 ± 1.4 vs. 5.8 ± 3.7 mg/kg FFM/min, p=0.002) and lower VO2 peak (p<0.001) than controls. Fat ox during exercise was not associated with disease severity (p=0.79). CONCLUSIONS: Overweight/obese patients with NAFLD had reduced hepatic Fat ox and reduced whole-body Fat ox under basal and exercise conditions. There was an inverse relationship between ability to oxidise fat in basal conditions and histological features of NAFLD including severity of steatosis and NAS.

Pancreatic beta-cell IL-22 receptor deficiency induces age-dependent dysregulation of insulin biosynthesis and systemic glucose homeostasis.

The IL-22RA1 receptor is highly expressed in the pancreas, and exogenous IL-22 has been shown to reduce endoplasmic reticulum and oxidative stress in human pancreatic islets and promote secretion of high-quality insulin from beta-cells. However, the endogenous role of IL-22RA1 signaling on these cells remains unclear. Here, we show that antibody neutralisation of IL-22RA1 in cultured human islets leads to impaired insulin quality and increased cellular stress. Through the generation of mice lacking IL-22ra1 specifically on pancreatic alpha- or beta-cells, we demonstrate that ablation of murine beta-cell IL-22ra1 leads to similar decreases in insulin secretion, quality and islet regeneration, whilst increasing islet cellular stress, inflammation and MHC II expression. These changes in insulin secretion led to impaired glucose tolerance, a finding more pronounced in female animals compared to males. Our findings attribute a regulatory role for endogenous pancreatic beta-cell IL-22ra1 in insulin secretion, islet regeneration, inflammation/cellular stress and appropriate systemic metabolic regulation.

Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress ß-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

The risk of Barrett's esophagus associated with abdominal obesity in males and females.

Esophageal adenocarcinoma arises from Barrett's esophagus (BE). Both occur predominantly in males. The role of abdominal obesity in this sex distribution is uncertain. Our study aimed to determine whether there is an association between abdominal obesity and risk of BE and if present was it modified by sex. A structured interview and anthropometric measures were conducted within a population-based case-control study. We recruited 237 BE cases (70% male) and 247 population controls, frequency matched by age and sex. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression analysis. In the overall group and males, all measures of abdominal obesity [waist circumference (WC), waist-hip ratio (WHR), sagittal abdominal diameter (SAD) and waist-height ratio (WHtR)] were strongly associated with risk of BE (Overall: WC OR 2.2 95% CI 1.4-3.5, WHR 1.8 95% CI 1.2-2.9, SAD 2.3 95% CI 1.4-3.7, WHtR 1.9 95% CI 1.2-3.0, males WC 2.5 95% CI 1.4-4.3, WHR 2.4 95% CI 1.3-4.2, SAD 2.5 95% CI 1.4-4.3, WHtR 1.9 95% CI 1.1-3.4). These associations were minimally attenuated by adjusting for ever-symptoms of gastroesophageal reflux (GER). These findings suggest in males, non-GER factors related to abdominal obesity may be important in the development of BE. In females, there was modest association between measures of abdominal obesity and risk of BE but these were all abolished after adjusting for ever-symptoms of GER. The power to detect differences between sexes in the risk of BE associated with abdominal obesity was limited by the number of females in the study.

The effect of 25-hydroxyvitamin D on insulin sensitivity in obesity: is it mediated via adiponectin?

There has been substantial recent interest in using vitamin D to improve insulin sensitivity and preventing/delaying diabetes in those at risk. There is little consensus on the physiological mechanisms and whether the association is direct or indirect through enhanced production of insulin-sensitising chemicals, including adiponectin. We examined cross-sectional associations between serum 25-hydroxyvitamin D (25(OH)D) and insulin sensitivity (Matsuda index), parathyroid hormone (PTH), waist circumference, body mass index (BMI), triglycerides (TG), total and high molecular weight (HMW) adiponectin, HMW : total adiponectin ratio (HMW : total adiponectin), and total cholesterol : HDL cholesterol ratio (TC:HDL cholesterol) in 137 Caucasian adults of mean age 43.3 ± 8.3 years and BMI 38.8 ± 6.9 kg/m(2). Total adiponectin (standardised ß = 0.446; p < 0.001), waist circumference (standardised ß = -0.216; p < 0.05), BMI (standardised ß = -0.212; p < 0.05), and age (standardised ß = -0.298; p < 0.001) were independently associated with insulin sensitivity. Serum 25(OH)D (standardised ß = 0.114; p = 0.164) was not associated with insulin sensitivity, total or HMW adiponectin, HMW : total adiponectin, or lipids. Our results provide the novel finding that 25(OH)D is not associated with HMW adiponectin or HMW : total adiponectin in nondiabetic, obese adults and support the lack of association between 25(OH)D and lipids noted by others in similar groups of patients.

Vitamin D does not improve the metabolic health of patients with chronic kidney disease stage 3-4: a randomized controlled trial.

AIM: To assess the impact of vitamin D supplementation (cholecalciferol) on the insulin sensitivity and metabolic health of patients with chronic kidney disease (CKD). METHODS: Twenty-eight adult patients with CKD stages 3-4 were recruited from the outpatient department of the Princess Alexandra Hospital (Brisbane, Australia) to a double-blind randomized trial of cholecalciferol (vitamin D3) 2000 IU/day or placebo for 6 months. Metabolic parameters at baseline were compared with 20 non-CKD adults. The primary outcome was an improvement in insulin resistance (glucose disposal rate, GDR) at 6 months (quantified by hyperinsulinaemic euglycaemic clamp). Carbohydrate and lipid oxidation rates were assessed by indirect calorimetry. RESULTS: At baseline, patients were significantly insulin-resistant compared with lean younger non-CKD individuals (n = 9; GDR 3.42 vs. 5.76 mg/kg per minute, P = 0.001), but comparable with their age-, gender- and weight-matched non-CKD counterparts (n = 11; 3.42 vs. 3.98 mg/kg per minute, P = 0.4). 25-Hydroxyvitamin D did not change in the placebo group, but rose from 95 ± 37 to 146 ± 25 nmol/L with treatment (P = 0.0001). Post treatment, there was no difference in GDR between groups (GDR 3.38 vs. 3.52 mg/kg per minute, ancova P = 0.4). There was a relative increase in hyperinsulinaemic oxidative disposal of glucose with treatment (within-group P = 0.03). CONCLUSION: Supplementation with cholecalciferol in CKD 3-4 results in appreciable increases in 25-hydroxyvitamin D concentrations, but does not increase insulin sensitivity. The insulin resistance observed was similar among age-, sex- and body mass index-matched individuals with and without CKD. Whether renal dysfunction per se has any influence on the insulin sensitivity of an individual should be the subject of future work.

Blood glucose modulation and safety of efferent vagus nerve stimulation in a type 2 diabetic rat model.

Vagus nerve stimulation is emerging as a promising treatment for type 2 diabetes. Here, we evaluated the ability of stimulation of the vagus nerve to reduce glycemia in awake, freely moving metabolically compromised rats. A model of type 2 diabetes (n = 10) was induced using a high-fat diet and low doses of streptozotocin. Stimulation of the abdominal vagus nerve was achieved by pairing 15 Hz pulses on a distal pair of electrodes with high-frequency blocking stimulation (26 kHz, 4 mA) on a proximal pair of electrodes to preferentially produce efferent conducting activity (eVNS). Stimulation was well tolerated in awake, freely moving rats. During 1 h of eVNS, glycemia decreased in 90% of subjects (-1.25 ± 1.25 mM h, p = 0.017), and 2 dB above neural threshold was established as the most effective "dose" of eVNS (p = 0.009). Following 5 weeks of implantation, eVNS was still effective, resulting in significantly decreased glycemia (-1.7 ± 0.6 mM h, p = 0.003) during 1 h of eVNS. There were no overt changes in fascicle area or signs of histopathological damage observed in implanted vagal nerve tissue following chronic implantation and stimulation. Demonstration of the biocompatibility and safety of eVNS in awake, metabolically compromised animals is a critical first step to establishing this therapy for clinical use. With further development, eVNS could be a promising novel therapy for treating type 2 diabetes.

Changes in antibiotic distribution due to pancreatitis.

This work sought to define how pancreatitis affected antibiotic distribution in a perfused rat pancreas model. The distribution kinetics of four antibiotics were examined in control animals and animals with pancreatitis. Meropenem and piperacillin distributed into the extracellular space, and their distribution kinetics were unaffected by pancreatitis. In contrast, in pancreatic cells from animals with pancreatitis, ciprofloxacin showed a reduced uptake and clindamycin showed a reduced distribution.

Resveratrol--pills to replace a healthy diet?

Nutrapharmacology, or the use of bioactive food compounds at pharmacological doses is emerging as a therapeutic approach to target the complex metabolic dysregulations in ageing and obesity-related chronic disease. Resveratrol, a polyphenol found in the skin of grapes, and other edible plants and related food products, has received extensive attention through the link with the French paradox, and later with its chemopreventive activity demonstrated in vitro and in animal cancer models. A plethora of laboratory investigations has provided evidence for the multi-faceted properties of resveratrol and suggests that resveratrol may target ageing and obesity-related chronic disease by regulating inflammation and oxidative stress. A number of obstacles stand in the path to clinical usage however, not least the lack of clinical evidence to date, and the myriad of doses and formulations available. Further, data on the effects of resveratrol consumption in a capsule vs. food form is conflicting, and there are uncertain effects of long term dosing. The review will summarize the human pharmacokinetic and pharmacodynamic published data, and the topics for research if resveratrol is to become a multi-target therapeutic agent addressing chronic disease.

Whole genome investigation of an atypical autism case identifies a novel ANOS1 mutation with subsequent diagnosis of Kallmann syndrome.

We report an actionable secondary finding from whole-genome sequencing (WGS) of a 10-year-old boy with autism. WGS identified non-synonymous variants in several genes, including a nonsense mutation in the ANOS1 gene which is an X-linked cause of Kallmann syndrome. WGS can provide insights into complex genetic disorders such as autism, and actionable incidental findings can offer the potential for therapeutic interventions.

Inhibition of inosine monophosphate dehydrogenase reduces adipogenesis and diet-induced obesity.

We previously described a putative role for inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in de novo guanine nucleotide biosynthesis, in lipid accumulation. Here we present data which demonstrate that IMPDH activity is required for differentiation of preadipocytes into mature, lipid-laden adipocytes and maintenance of adipose tissue mass. In 3T3-L1 preadipocytes inhibition of IMPDH with mycophenolic acid (MPA) reduced intracellular GTP levels by 60% (p<0.05) and blocked adipogenesis (p<0.05). Co-treatment with guanosine, a substrate in the salvage pathway of nucleotide biosynthesis, restored GTP levels and adipogenesis demonstrating the specificity of these effects. Treatment of diet-induced obese mice with mycophenolate mofetil (MMF), the prodrug of MPA, for 28 days did not affect food intake or lean body mass but reduced body fat content (by 36%, p=0.002) and adipocyte size (p=0.03) and number. These data suggest that inhibition of IMPDH may represent a novel strategy to reduce adipose tissue mass.