BDNF–TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms

Depression is a core symptom of methamphetamine (METH) withdrawal during the first several weeks of abstinence. However, the precise mechanisms underlying METH withdrawal symptoms remain unknown. Brain-derived neurotrophic factor (BDNF) and its specific receptor, tropomyosin-related kinase (TrkB), have a role the in pathophysiology of depression. In this study, we examined the role of BDNF–TrkB signaling in different brain regions of male mice with METH withdrawal symptoms. Repeated METH (3 mg kg⁻¹ per day for 5 days) administration to mice caused a long-lasting depression-like behavior including anhedonia. Western blot analysis showed that BDNF levels in the nucleus accumbens (NAc) of METH-treated mice were significantly higher than those of control mice whereas BDNF levels in other regions, including the prefrontal cortex and hippocampus, were not altered. METH-induced depression-like behavior, behavioral sensitization and dendritic changes in the NAc shell were improved by subsequent subchronic administration of TrkB antagonist ANA-12 (0.5 mg kg⁻¹ per day for 14 days), but not TrkB agonist 7,8-dihydroxyflavone (10 mg kg⁻¹ per day for 14 days). In vivo microdialysis showed that METH (1 mg kg⁻¹)-induced dopamine release in NAc shell of METH-treated mice was attenuated after subsequent subchronic ANA-12 administration. Interestingly, a single bilateral infusion of ANA-12 into the NAc shell, but not NAc core, showed a rapid and long-lasting therapeutic effect. However, ketamine and paroxetine had no effect. These findings suggest that increased BDNF–TrkB signaling in the NAc shell has an important role in the behavioral abnormalities after withdrawal from repeated METH administration, and that TrkB antagonists are potential therapeutic drugs for withdrawal symptoms in METH abusers.     

Childhood physical abuse predicts stressor-evoked activity within central visceral control regions

Early life experience differentially shapes later stress reactivity, as evidenced by both animal and human studies. However, early experience-related changes in the function of central visceral neural circuits that control stress responses have not been well characterized, particularly in humans. The paraventricular nucleus of the hypothalamus (PVN), bed nucleus of the stria terminalis (BNST), amygdala (Amyg) and subgenual anterior cingulate cortex (sgACC) form a core visceral stress-responsive circuit. The goal of this study is to examine how childhood emotional and physical abuse relates to adulthood stressor-evoked activity within these visceral brain regions. To evoke acute states of mental stress, participants (n = 155) performed functional magnetic resonance imaging (fMRI)-adapted versions of the multi-source interference task (MSIT) and the Stroop task with simultaneous monitoring of mean arterial pressure (MAP) and heart rate. Regression analyses revealed that childhood physical abuse correlated positively with stressor-evoked changes in MAP, and negatively with unbiased, a priori extractions of fMRI blood-oxygen level-dependent signal change values within the sgACC, BNST, PVN and Amyg (n = 138). Abuse-related changes in the function of visceral neural circuits may reflect neurobiological vulnerability to adverse health outcomes conferred by early adversity.     

Familial inflammatory inclusion body myositis

OBJECTIVE: To compare familial inflammatory inclusion body myositis (IBM) with hereditary inclusion body myopathies and sporadic IBM. PATIENTS AND METHODS: Clinical, biological, MRI, and histological data were analysed in two siblings with inflammatory IBM and compared with those of patients with sporadic and hereditary IBM. RESULTS: Both patients had a clinical phenotype of sporadic IBM, which differs from hereditary myopathies because of late age of onset--respectively 65 and 66 years, and different pattern of muscular involvement--asymmetric, mainly distal but also involving quadriceps. MRI showed selective fatty infiltration and oedema in the extensor compartment of thigh muscles. The diagnosis of IBM was confirmed by muscle biopsy, showing muscle fibres containing numerous rimmed vacuoles, a characteristic shared by all types of IBM. In contrast with hereditary IBM, histological analysis also showed inflammatory mononuclear infiltrate invading non-necrotic fibres, ragged red and oxidase c negative fibres, and positive Congo red staining. Moreover, HLA class II typing disclosed DR beta 1 0301 haplotype, which is significantly related to sporadic but not to hereditary IBM. With steroid treatment and monthly intravenous immunoglobulins, the disease was stabilised in both patients at protracted follow up. CONCLUSION: Sporadic and familial inflammatory IBM share the same clinical, biological, MRI, and histological features.     

Trajectories of fasting plasma glucose variability and mortality in type 2 diabetes

Aim

To investigate the effect of changes in fasting plasma glucose (FPG) variability, as assessed by 2-year trajectories of FPG variability, on mortality risk in patients with type 2 diabetes (T2D).

Clearance of hepatitis B surface antigen (HBsAg) after surgical resection of hepatocellular carcinoma

The serum HBsAg in 4 chronic HBsAg carrier patients with hepatocellular carcinoma (HCC) cleared within 4-38 months after surgical resection of their hepatic tumors. Two patients developed anti-HBs. During the follow-up period from 21 to 28 months after HBsAg clearance, none of the patients regained positive serum HBsAg. Two patients who had had tissue HBsAg present, exclusively in the tumor, showed quick HBsAg clearance after resection. The other 2 patients had a delayed HBsAg clearance. One had tissue HBsAg in both the tumor and nontumoral liver. Only 1 patient had tissue HBsAg in the liver, but not in the tumor. During the same period of observation of 323 chronic HBsAg carriers, who had a variety of histologically-verified chronic liver diseases and were followed for more than 6 months, only 1 cleared the antigen. The spontaneous HBsAg clearance in our HBsAg carriers (1/323) was significantly lower than that (4/64) of HBsAg-positive HCC patients with tumor resection, P less than 0.004. The mechanisms of HBsAg clearance in HCC patients after surgical resection of tumors are discussed.     

Pregnancy and systemic lupus erythematosus

Pregnancy is widely authorized in systemic lupus erythematosus (SLE). Fertility is similar in SLE and in the general population although the age of menarche seems higher. Some cases of sterility might be attributed to SLE because of autoimmune ovaritis or antiphospholipid antibodies (aPL). These antibodies might lead to endothelial activation and thrombosis by influencing homeostasis, complement activation, inhibition of protein C and annexin V. They might have a deleterious effect on embryonic implantation by adhesion to the trophoblast, inhibition of invasion and placentation and decreased hCG production. The most important part of sterility seems secondary to the use of cyclophosphamide and might be prevented by acetate leuprolide administration. Maternal morbidity seems correlated to SLE activity (controlled by pregnancy planning), hypertension, preeclampsia, Hemolysis, Elevated Liver Enzymes, Low Platelets (HELLP) syndrome, therapy and aPL. Hydroxychloroquine (HCQ) should be maintained throughout pregnancy. Aspirin is prescribed alone in patients with asymptomatic aPL and in addition to heparin if there is a history of thrombosis or fetal loss with aspirin. Fetal and neonatal morbidity correlate with prematurity, adverse effects or maternal steroid therapy and maternal anti-SSA antibodies with 1 to 2% risk of congenital atrioventricular block. Abnormal obstetrical echography-doppler examination is the best predictor of pregnancy outcome. Abnormal ombilical artery flow on the second trimester echodoppler examination and history of thrombophlebitis predict fetal or neonatal death. Abnormal uterine notch on the second trimester echodoppler examination predicts adverse pregnancy outcome. Except for the preventive therapy of congenital atrioventricular block, modalities of SLE pregnancy monitoring and therapy are now well established.     

Rosiglitazone improves insulin sensitivity and glucose tolerance in subjects with impaired glucose tolerance

OBJECTIVE: This study was designed to evaluate the effects of rosiglitazone (ROS) on insulin sensitivity, beta-cell function, and glycaemic response to glucose challenge and meal in subjects with impaired glucose tolerance (IGT). METHODS: Thirty patients with IGT (ages between 30 and 75 years and BMI (body mass index) < or = 27 kg/m2) were randomly assigned to receive either placebo (n = 15) or ROS (4 mg/day) (n = 15). All participants underwent a 75-g oral glucose tolerance test (OGTT), meal test, and frequently sampled intravenous glucose tolerance test (FSIGT) before and after the 12-week treatment. RESULTS: After 12 weeks of ROS treatment, there were significant increases in total cholesterol (TC) (4.25 +/- 0.22 vs 4.80 +/- 0.17 mmol/l, P < 0.001), high-density lipoprotein cholesterol (HDL-C) (1.25 +/- 0.07 vs 1.43 +/- 0.06 mmol/l, P < 0.05), and low-density lipoprotein cholesterol (LDL-C) (2.70 +/- 0.15 vs 3.37 +/- 0.17 mmol/l, P < 0.05) without changes in triglyceride concentration, TC/HDL-C and LDL-C/HDL-C ratio. Although the acute insulin response (AIR) to intravenous glucose and disposition index (measured as the ability of pancreatic beta-cell compensation in the presence of insulin resistance) remained unchanged, the insulin sensitivity (SI) and glucose effectiveness (SG) were remarkably elevated (0.38 +/- 0.06 vs 0.54 +/- 0.09 x 10(-5) min(-1)/pmol, P < 0.05; 0.017 +/- 0.002 vs 0.021 +/- 0.001 min(-1), P < 0.05, respectively) in the ROS group. The glucose, insulin, and c-peptide areas under curve (AUC) in response to OGTT and the glucose and insulin AUC during meal were significantly ameliorated in the ROS group. Five out of 15 (33%) and two out of 15 (13%) subjects treated with ROS and placebo, respectively, reversed to normal response during OGTT (P < 0.05). CONCLUSION: Rosiglitazone treatment significantly improved insulin resistance and reduced postchallenge glucose and insulin concentrations in patients with impaired glucose tolerance without remarkable effects on beta-cell secretory function.     

Enhanced Allergic Inflammation of Der p 2 Affected by Polymorphisms of MD-2 Promoter

Purpose

Myeloid differentiation-2 (MD-2) has been associated with endotoxin and inflammatory disorders because it can recognize lipopolysaccharide (LPS) binding and attenuate Toll-like receptor 4 (TLR4)-mediated signaling. However, its role in allergic inflammation has yet to be clarified. We examined whether single nucleotide polymorphisms (SNPs) in MD-2 promoter can affect MD-2 expression and aimed to clarify the relationship between Der p 2 allergy and SNPs of MD-2 promoter.

Methods

The function of SNPs of MD-2 promoter and the effects of cytokines and immunoglobulin on the secretion and mRNA expression were investigated in 73 allergic subjects with different MD-2 gene promoter variants. Peripheral blood mononuclear cells were cultured with or without LPS in the presence of Dermatophagoides pteronyssinus group 2 allergen (Der p 2), followed by mRNA extraction and cytokine expression analysis. The culture supernatants were collected for cytokine measurement.

Results

Patients with the MD-2 promoter SNPs (rs1809441/rs1809442) had increased mRNA expressions of MD-2, ε heavy chain of IgE (Cε), and interleukin (IL)-8; however, only MD-2 and IL-8 were further up-regulated after Der p 2 stimulation. Patients with SNPs of MD-2 promoter tended to have high levels of IL-1β, IL-6, IL-8, IL-10, and tumor necrosis factor (TNF)-α after Der p 2 and LPS stimulation. Increased secretions of IL-6, IL-8, and IL-10 were found to be up-regulated by Der p 2 stimulation, and an increased secretion of IFN-γ and decreased secretion of IL-4 were noted after LPS stimulation.

Conclusions

The high levels of proinflammatory cytokines secreted by Der p 2 were predetermined by MD-2 promoter SNPs (rs1809441/rs1809442). Through cytokine secretion by Der p 2 and LPS, these SNPs may serve as an indicator of the pathological phenotype of Der p 2-induced allergic inflammation.