FKBP5 polymorphisms influence pre‐learning stress‐induced alterations of learning and memory

FK506 binding protein 51 (FKBP5) is a co‐chaperone of heat shock protein 90 and significantly influences glucocorticoid receptor sensitivity. Single nucleotide polymorphisms (SNPs) in the FKBP5 gene are associated with altered hypothalamus–pituitary–adrenal (HPA) axis function, changes in the structure and function of several cognitive brain areas, and increased susceptibility to post‐traumatic stress disorder, major depression, bipolar disorder and suicidal events. The mechanisms underlying these associations are largely unknown, but it has been speculated that the influence of these SNPs on emotional memory systems may play a role. In the present study, 112 participants were exposed to the socially evaluated cold pressor test (stress) or control (no stress) conditions immediately prior to learning a list of 42 words. Participant memory was assessed immediately after learning (free recall) and 24 h later (free recall and recognition). Participants provided a saliva sample that enabled the genotyping of three FKBP5 polymorphisms: rs1360780, rs3800373 and rs9296158. Results showed that stress impaired immediate recall in risk allele carriers. More importantly, stress enhanced long‐term recall and recognition memory in non‐carriers of the risk alleles, effects that were completely absent in risk allele carriers. Follow‐up analyses revealed that memory performance was correlated with salivary cortisol levels in non‐carriers, but not in carriers. These findings suggest that FKBP5 risk allele carriers may possess a sensitized stress response system, perhaps specifically for stress‐induced changes in corticosteroid levels, which might aid our understanding of how SNPs in the FKBP5 gene confer increased risk for stress‐related psychological disorders and their related phenotypes.     

Anti-inflammatory effects of the anticonvulsant drug levetiracetam on electrophysiological properties of astroglia are mediated via TGFβ1 regulation

BACKGROUND AND PURPOSE

The involvement of astrocytes as immune-competent players in inflammation and the pathogenesis of epilepsy and seizure-induced brain damage has recently been recognized. In clinical trials and practice, levetiracetam (LEV) has proven to be an effective antiepileptic drug (AED) in various forms of epileptic seizures, when applied as mono- or added therapy. Little is known about the mechanism(s) of action of LEV. Evidence so far suggests a mode of action different from that of classical AEDs. We have shown that LEV restored functional gap junction coupling and basic membrane properties in an astrocytic inflammatory model in vitro.

EXPERIMENTAL APPROACH

Here, we used neonatal rat astrocytes co-cultured with high proportions (30%) of activated microglia or treated with the pro-inflammatory cytokine interleukin-1β to provoke inflammatory responses. Effects of LEV (50 µg·mL⁻¹) on electrophysiological properties of astrocytes (by whole cell patch clamp) and on secretion of TGFβ1 (by elisa) were studied in these co-cultures.

KEY RESULTS

LEV restored impaired astrocyte membrane resting potentials via modification of inward and outward rectifier currents, and promoted TGFβ1 expression in inflammatory and control co-cultures. Furthermore, LEV and TGFβ1 exhibited similar facilitating effects on the generation of astrocyte voltage-gated currents in inflammatory co-cultures and the effects of LEV were prevented by antibody to TGFβ1.

CONCLUSIONS AND IMPLICATIONS

Our data suggest that LEV is likely to reduce the harmful spread of excitation elicited by seizure events within the astro-glial functional syncytium, with stabilizing consequences for neuronal–glial interactions.     

Potential contribution of cytochrome P450 2B6 to hepatic 4-hydroxycyclophosphamide formation in vitro and in vivo

Results from retrospective studies on the relationship between cytochrome P450 (P450) 2B6 (CYP2B6) genotype and cyclophosphamide (CY) efficacy and toxicity in adult cancer patients have been conflicting. We evaluated this relationship in children, who have faster CY clearance and receive different CY-based regimens than adults. These factors may influence the P450s metabolizing CY to 4-hydroxycyclophosphamide (4HCY), the principal precursor to CY's cytotoxic metabolite. Therefore, we sought to characterize the in vitro and in vivo roles of hepatic CYP2B6 and its main allelic variants in 4HCY formation. CYP2B6 is the major isozyme responsible for 4HCY formation in recombinant P450 Supersomes. In human liver microsomes (HLM), 4HCY formation correlated with known phenotypic markers of CYP2B6 activity, specifically formation of (S)-2-ethyl-1,5-dimethyl-3,3-diphenyl pyrrolidine and hydroxybupropion. However, in HLM, CYP3A4/5 also contributes to 4HCY formation at the CY concentrations similar to plasma concentrations achieved in children (0.1 mM). 4HCY formation was not associated with CYP2B6 genotype at low (0.1 mM) or high (1 mM) CY concentrations potentially because CYP3A4/5 and other isozymes also form 4HCY. To remove this confounder, 4HCY formation was evaluated in recombinant CYP2B6 enzymes, which demonstrated that 4HCY formation was lower for CYP2B6.4 and CYP2B6.5 compared with CYP2B6.1. In vivo, CYP2B6 genotype was not directly related to CY clearance or ratio of 4HCY/CY areas under the curve in 51 children receiving CY-based regimens. Concomitant chemotherapy agents did not influence 4HCY formation in vitro. We conclude that CYP2B6 genotype is not consistently related to 4HCY formation in vitro or in vivo.     

Oseltamivir-resistant influenza A 2009 H1N1 virus in immunocompromised patients

Please cite this paper as: Couturier et al. (2010). Oseltamivir-resistant influenza A 2009 H1N1 virus in immunocompromised patients. Influenza and Other Respiratory Viruses 4(4), 199–204. Background First-line treatment of influenza A 2009 H1N1 relies on neuraminidase inhibitors such as oseltamivir. Resistance conferred by the H275Y neuraminidase gene mutation is concerning and likely to increase. Objectives To characterize oseltamivir resistance in a hospital-based patient population. Patients and Methods All available respiratory specimens positive for influenza A by direct fluorescent antibody, RT-PCR, or culture from patients at the University of Utah 5/09-12/09 were collected. Specimens were confirmed as 2009 H1N1 by the Utah Department of Health. RT-PCR and pyrosequencing were used to test for the H275Y mutation (CDC protocol). Pyro Mark Q24 AQ software (Qiagen, Valencia, CA, USA) was used to allow for quantitative H275Y mutation analysis. Medical records of patients with resistant virus were reviewed. Results We tested 191 influenza A virus-positive samples from 187 unique patients. Fifty (27%) patients were hospitalized. Four patient specimens (2·1%) were found to carry the H275Y mutation. Three patients were hospitalized, representing 6% of inpatient samples tested. Three patients had undergone hematopoietic stem cell transplant in the past year. Two patients died. Their influenza viruses were confirmed to be oseltamivir-resistant at an independent reference laboratory and through the Center for Disease Control and Prevention (CDC). One patient reported no history of prior oseltamivir exposure. Conclusions Widespread oseltamivir resistance among 2009 H1N1 remains a potential threat. Rapid techniques, such as pyrosequencing, which has the additional benefit of identifying mixed mutant populations of virus, may play a key role in identifying at-risk individuals and potentially unsuspected cases. Targeted surveillance of immunocompromised patients will be critical toward improving future influenza planning and therapy.     

Peer Reviewed: Lessons Learned From a Collaborative to Improve Care for Patients With Diabetes in 17 Community Health Centers,Massachusetts, 2006

Introduction

In 2006, the Massachusetts League of Community Health Centers convened a collaborative to systematically improve health care delivery for patients with diabetes in 17 community health centers. Our goal was to identify facilitators of and barriers to success reported by teams that participated in this collaborative.

Methods

The collaborative''s activities lasted 13 months. At their conclusion, we interviewed participating team members. We asked about their teams'' successes, challenges, and take-home messages for future collaborative efforts. We organized their responses into common themes by using the Chronic Care Model as a framework.

Results

Themes that emerged as facilitators of success included shifting clinic focus to more actively involve patients and to promote their self-management; improving the understanding and implementation of professional guidelines; and expanding staff roles to accommodate these goals. Patient registries were perceived as beneficial but lacking adequate technical support. Other barriers were staffing and time constraints.

Conclusions

Cooperative efforts to improve health care delivery for people with diabetes may benefit from educating the health care team about guidelines, establishing a stronger role for the patient as part of the health care team, and providing adequate technical instruction and support for the use of clinical databases.     

Genetic association of the human corticotropin releasing hormone receptor 1 (CRHR1) with binge drinking and alcohol intake patterns in two independent samples

To investigate the role of the corticotropin releasing hormone receptor 1 (CRHR1) in patterns of human alcohol drinking and its potential contribution to alcohol dependence, we analysed two independent samples: a sample of adolescents, which consisted of individuals from the 'Mannheim Study of Risk Children' (MARC), who had little previous exposure to alcohol, and a sample of alcohol-dependent adults, who met DSM-IV criteria of alcohol dependence. Following determination of allelic frequencies of 14 polymorphisms of the CRHR1 gene, two haplotype tagging (ht)SNPs discriminating between haplotypes with a frequency of > or =0.7% were identified. Both samples were genotyped and systematically examined for association with the htSNPs of CRHR1. In the adolescent sample, significant group differences between genotypes were observed in binge drinking, lifetime prevalence of alcohol intake and lifetime prevalence of drunkenness. The sample of adult alcohol-dependent patients showed association of CRHR1 with high amount of drinking. This is the first time that an association of CRHR1 with specific patterns of alcohol consumption has been reported. Our findings support results from animal models, suggesting an importance of CRHR1 in integrating gene-environment effects in alcohol use disorders.     

Weight gain in gestational diabetes: the effect of treatment modality

Objective: To evaluate treatment effectiveness (diet alone, insulin or glyburide) on maternal weight gain in gestational diabetes (GDM).

Methods: GDM patients were treated with diet alone, insulin or glyburide. Weight gain was stratified into: prior to GDM diagnosis, from diagnosis to delivery and total pregnancy weight gain. Good glycemic control was defined as mean blood glucose ≤105?mg/dl and obesity as Body Mass Index (BMI)?≥?30?kg/m², overweight BMI 25–29?kg/m² and normal <?25?kg/m².

Results: Total weight gain was similar in all the treatment groups. Two-thirds of weight gain occurred prior to diagnosis (diet 85%, insulin 67% and glyburide 78%). Post-diagnosis, patients on diet alone gained less weight than those on insulin or glyburide (p?<?0.001); insulin-treated patients showed greater weight gain than glyburide-treated patients (p?<?0.001). Patients on diet with good glycemic control showed less weight gain after diagnosis than patients on insulin or glyburide (2.8?±?13, 6.6?±?10, 5.2?±?7.9 lbs, respectively, p?<?0.02). Poorly-controlled patients, regardless of treatment, had similar patterns of weight gain throughout pregnancy.

Conclusion: Patterns of maternal weight gain in GDM pregnancies are associated with treatment modality and level of glycemic control.     

Effect of a 10-week strength training program and recovery drink on body composition, muscular strength and endurance, and anaerobic power and capacity

OBJECTIVE: We investigated whether postexercise consumption of a supplement containing whey protein, amino acids, creatine, and carbohydrate combined with a strength training program promotes greater gains in fat-free mass (FFM), muscle strength and endurance, and anaerobic performance compared with an isocaloric, carbohydrate-only control drink combined with strength training. METHODS: The study was double blind and randomized, and the experimental supplement was compared with a carbohydrate-only control. Forty-one males (n = 20 in control group, n = 21 in the supplement group; mean age, 22.2 y) participated in a 4 d/wk, 10-wk periodized strength training program. Subjects had to complete at least 70% of the workouts. Before and after 10 wk of strength training, subjects were tested for body composition by using hydrostatic weighing and skinfold thicknesses, one repetition maximum strength and muscular endurance for the bench press and 45-degree leg press, and anaerobic performance using a 30-s Wingate test. Thirty-three subjects (80.5%) completed the training program (n = 15 in control group, n = 18 in the supplement); these 33 subjects also completed all post-training test procedures. Data were analyzed with two-way analysis of variance with repeated measures on time. P <== 0.05 was set as statistically significant. All statistical analyses, including calculation of effect size and power, were completed with SPSS 11.0. RESULTS: Across groups, FFM increased during 10 wk of strength training. Although there was no statistically significant time x group interaction for FFM, there was a trend toward a greater increase in FFM for the supplement group (+3.4 kg) compared with the control group (+1.5 kg; P = 0.077). The effect size (eta(2) = 0.100) was moderately large. Percentage of body fat declined and fat mass was unchanged; there were no differences between groups. One repetition maximum strength for the bench press and 45-degree leg press increased, but there were no differences between groups. Muscular endurance expressed as the number of repetitions completed with 85% of the one repetition maximum was unchanged; external work, which was estimated as repetitions completed x resistance used, increased for the 45-degree leg press but not for the bench press over the 10-wk training period; there were no time x group interactions for either measurement. Anaerobic power and capacity improved, but there were no differences between groups for these variables or for fatigue rate. CONCLUSIONS: Consumption of a recovery drink after strength training workouts did not promote greater gains in FFM compared with consumption of a carbohydrate-only drink; however, a trend toward a greater increase in FFM in the supplement group suggests the need for longer-term studies. Performance variables such as muscle strength and endurance and anaerobic performance were not improved when compared with the carbohydrate-only group.