High-fat feeding promotes obesity via insulin receptor/PI3K-dependent inhibition of SF-1 VMH neurons

Steroidogenic factor 1 (SF-1)-expressing neurons of the ventromedial hypothalamus (VMH) control energy homeostasis, but the role of insulin action in these cells remains undefined. We show that insulin activates phosphatidylinositol-3-OH kinase (PI3K) signaling in SF-1 neurons and reduces firing frequency in these cells through activation of K(ATP) channels. These effects were abrogated in mice with insulin receptor deficiency restricted to SF-1 neurons (SF-1(ΔIR) mice). Whereas body weight and glucose homeostasis remained the same in SF-1(ΔIR) mice as in controls under a normal chow diet, they were protected from diet-induced leptin resistance, weight gain, adiposity and impaired glucose tolerance. High-fat feeding activated PI3K signaling in SF-1 neurons of control mice, and this response was attenuated in the VMH of SF-1(ΔIR) mice. Mimicking diet-induced overactivation of PI3K signaling by disruption of the phosphatidylinositol-3,4,5-trisphosphate phosphatase PTEN led to increased body weight and hyperphagia under a normal chow diet. Collectively, our experiments reveal that high-fat diet-induced, insulin-dependent PI3K activation in VMH neurons contributes to obesity development.     

Spotlight on Tesamorelin in HIV-Associated Lipodystrophy

Tesamorelin (Egrifta?) is a synthetic analog of human growth hormone-releasing hormone (also known as growth hormone-releasing factor) that stimulates the synthesis and release of endogenous growth hormone. It is the first and, so far, only treatment indicated for the reduction of excess abdominal fat in patients with HIV-associated lipodystrophy. This article reviews the pharmacological properties, clinical efficacy and tolerability of tesamorelin in patients with HIV-associated central fat accumulation. Subcutaneous tesamorelin was effective in reducing visceral adipose tissue (VAT), but did not affect subcutaneous adipose tissue to a clinically significant extent in two 26-week, well designed, clinical trials in patients with HIV-associated central fat accumulation. This reduction in VAT was maintained in the longer term in patients who continued to receive tesamorelin until week 52 in the extension phases of the two trials. However, discontinuation of therapy during this period resulted in the reaccumulation of VAT. Tesamorelin therapy was also associated with significant improvements in other body composition measures (e.g. trunk fat and waist circumference) and improvements were generally seen in some body image parameters (e.g. belly image distress). Tesamorelin was generally well tolerated, with treatment-emergent serious adverse events occurring in <4% of patients during 26 weeks of therapy. Most of these events were injection-site reactions or events known to be associated with growth hormone therapy (e.g. arthralgia, headache and peripheral edema). Although long-term clinical experience is needed to further assess the benefits and risks of therapy, current evidence suggests that tesamorelin may be useful for reducing visceral adiposity in patients with HIV-associated lipodystrophy, thereby potentially improving self image.     

Alkoxyphenyl methanesulfonamides: synthesis, anti-inflammatory effect, and docking studies

A series of 2-alkoxyphenyl methanesulfonamide-based compounds were synthesised and evaluated for their anti-inflammatory activity in carrageenan-induced rat paw edema model. The compounds 4–7 showed comparable anti-inflammatory activity to rofecoxib and indomethacin, the standard drugs taken in both the studies. The synthesised compounds were also investigated for their gastric ulcerogenic potential and found to be non-ulcerogenic at the test doses. In silico (docking studies) were done to investigate the hypothetical binding mode of the target compounds to the cyclooxygenase isoenzyme (COX-2). A binding model has been proposed based on the docking studies to explain the observed pharmacological activity of the test compounds. Selected physicochemical parameters for the target compounds suggest good drug transport properties and potential bioavailability.     

Mucoadhesive buccal patches based on interpolymer complexes of chitosan–pectin for delivery of carvedilol

The study was designed to develop bioadhesive patches of carvedilol hydrochloride using chitosan (CH) and pectin (PE) interpolymer complexes and to systematically evaluate their in vitro and in vivo performances. Mucoadhesive buccal patches of carvedilol were prepared using solvent casting method. The physicochemical interaction between CH and PE was investigated by FTIR and DSC studies. The patches were evaluated for their physical characteristics like mass variation, content uniformity, folding endurance, ex vivo mucoadhesion strength, ex vivo mucoadhesion time, surface pH, in vitro drug release, in situ release study, and in vivo bioavailability study. The swelling index of the patches was found to be proportional to the PE concentration. The surface pH of all the formulated bioadhesive patches was found to lie between 6.2 and 7.2. The optimized bioadhesive patch (C1, CH:PE 20:80) showed bioadhesive strength of 22.10 ± 0.20 g, in vitro release of 98.73% and ex vivo mucoadhesion time of 451 min with in a period of 8 h. The optimized patch demonstrated good in vitro and in vivo results. The buccal delivery of carvedilol in rabbits showed a significant improvement in bioavailability of carvedilol from patches when compared to oral route.     

Catabolic fate and pharmacokinetic characterization of trastuzumab emtansine (T-DM1): an emphasis on preclinical and clinical catabolism

Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate in clinical development for the treatment of human epidermal growth factor receptor 2 (HER2)-positive cancers. Herein, we describe a series of studies to assess T-DM1 absorption, distribution, metabolism, and excretion (ADME) in rats as well as to assess human exposure to T-DM1 catabolites. Following administration of unlabeled and radiolabeled T-DM1 in female Sprague Dawley rats as a single dose, plasma, urine, bile and feces were assessed for mass balance, profiling and identification of catabolites. In rats, the major circulating species in plasma was T-DM1, while DM1 concentrations were low (1.08 to 15.6 ng/mL). The major catabolites found circulating in rat plasma were DM1, [N-maleimidomethyl] cyclohexane-1- carboxylate-DM1 (MCC-DM1), and Lysine-MCC-DM1. These catabolites identified in rats were also detected in plasma samples from patients with HER2-positive metastatic breast cancer who received single-agent T-DM1 (3.6 mg/kg every 3 weeks) in a phase 2 clinical study. There was no evidence of tissue accumulation in rats or catabolite accumulation in human plasma following multiple dosing. In rats, T-DM1 was distributed nonspecifically to the organs without accumulation. The major pathway of DM1-containing catabolite elimination in rats was the fecal/biliary route, with up to 80% of radioactivity recovered in the feces and 50% in the bile. The rat T-DM1 ADME profile is likely similar to the human profile, although there may be differences since trastuzumab does not bind the rat HER2- like receptor. Further research is necessary to more fully understand the T-DM1 ADME profile in humans.     

Targeting B cell responses in universal influenza vaccine design

Since its first administration in the 1940s, the influenza vaccine has provided tremendous relief against influenza infections. However, time has revealed the ultimate limit of the vaccine and the call for its reinvention has now come, just as we are beginning to appreciate the antibody immune responses vital in preventing infections. New strategies to design the influenza vaccine rely on selectively inducing broadly neutralizing antibodies that are specific for highly conserved viral epitopes. Such approaches take us away from the limited range of protection provided by current seasonal influenza vaccines and towards a future with a pan-influenza vaccine capable of providing universal strain coverage.     

Cross-national epidemiology of DSM-IV major depressive episode

Background

Major depression is one of the leading causes of disability worldwide, yet epidemiologic data are not available for many countries, particularly low- to middle-income countries. In this paper, we present data on the prevalence, impairment and demographic correlates of depression from 18 high and low- to middle-income countries in the World Mental Health Survey Initiative.

Methods

Major depressive episodes (MDE) as defined by the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DMS-IV) were evaluated in face-to-face interviews using the World Health Organization Composite International Diagnostic Interview (CIDI). Data from 18 countries were analyzed in this report (n = 89,037). All countries surveyed representative, population-based samples of adults.

Results

The average lifetime and 12-month prevalence estimates of DSM-IV MDE were 14.6% and 5.5% in the ten high-income and 11.1% and 5.9% in the eight low- to middle-income countries. The average age of onset ascertained retrospectively was 25.7 in the high-income and 24.0 in low- to middle-income countries. Functional impairment was associated with recency of MDE. The female: male ratio was about 2:1. In high-income countries, younger age was associated with higher 12-month prevalence; by contrast, in several low- to middle-income countries, older age was associated with greater likelihood of MDE. The strongest demographic correlate in high-income countries was being separated from a partner, and in low- to middle-income countries, was being divorced or widowed.

Conclusions

MDE is a significant public-health concern across all regions of the world and is strongly linked to social conditions. Future research is needed to investigate the combination of demographic risk factors that are most strongly associated with MDE in the specific countries included in the WMH.     

Nodule or pseudonodule? Differentiation in Hashimoto's thyroiditis with sonoelastography

Fine needle aspiration biopsy (FNAB) is the gold standard for the diagnosis of lymphoma in Hashimoto's thyroiditis and is able to differentiate between benign, inflammatory or malignant nodules, classifying them as either true nodules or pseudonodules. This technique is, however, invasive. The present study aimed to differentiate pseudonodules from true nodules by sonoelastography, a non-invasive technique, in 54 patients with Hashimoto's thyroiditis. The accuracy of sonoelastography to differentiate between true or pseudonodules was compared with the gold standard FNAB and with grey scale ultrasonography. The nodules were categorized into three groups: non-demarcated hypoechogenic, demarcated hyperecho genic, and demarcated hypoechogenic. Sono elastography findings were concordant with the cytopathological results and demonstrated that sono elastography was able to detect true thyroid nodules often misdiagnosed by conventional grey scale ultrasonography. Sonoelastography was found to have increased sensitivity for true nodule diagnosis compared with conventional grey scale ultrasonography and may eliminate unnecessary FNABs being carried out.     

Nontypeable Streptococcus pneumoniae as an otopathogen

Among 34 Streptococcus pneumoniae (Spn) sequential isolates from middle ear fluid, we found a case of a nontypeable S. pneumoniae (NT-Spn) in a child with acute otitis media (AOM). The strain was pneumolysin PCR positive and capsule gene PCR negative. Virulence of the NT-Spn was confirmed in a chinchilla model of AOM.     

Intestinal dysbiosis in inflammatory bowel disease

The worldwide incidence of inflammatory bowel disease (IBD) is increasing. Abundant literature has suggested that an imbalance between harmful and protective bacteria, or dysbiosis, of the intestine is largely responsible for the rising incidence of IBD. In this review, data supporting dysbiosis as a cause of IBD are presented. A comparison of the number of scientific publications in the US versus Europe on intestinal dysbiosis and microbiota revealed the US scientific community has a lower level of interest in studying dysbiosis and microbiota compared the research community in Europe. The rising trend of antibiotic use in the US provides further evidence of the lack of concern for the effect of dysbiosis on human health. Further research to understand the causal relationship between dysbiosis and IBD are needed to better guide clinical practice in using probiotics.