Brain glutamate and gamma-aminobutyrate (GABA) metabolism in thiamin-deficient rats

The brain metabolism of glutamate and gamma-aminobutyrate (GABA) was investigated in thiamin-deficient and pair-fed control rats, in order to determine whether the GABA shunt may provide an important alternative to 2-oxo-glutarate dehydrogenase (EC 1.2.4.2) in energy-yielding metabolism in thiamin deficiency. Brains from thiamin-deficient animals contained less glutamate, 2-oxo-glutarate and GABA than those from control animals. The brain content of ATP was unaffected by thiamin deficiency. After intracerebroventricular injection of [14C]glutamate, the specific radioactivity of GABA in the brains from deficient animals was 45-50% higher than that in controls, suggesting a considerable increase in the metabolic flux through the GABA shunt in thiamin deficiency. Brain GABA showed a marked circumannual variation, with a peak in mid-summer and a minimum value in mid-winter

Brugia malayi Excreted/Secreted Proteins at the Host/Parasite Interface: Stage- and Gender-Specific Proteomic Profiling

Relatively little is known about the filarial proteins that interact with the human host. Although the filarial genome has recently been completed, protein profiles have been limited to only a few recombinants or purified proteins of interest. Here, we describe a large-scale proteomic analysis using microcapillary reverse-phase liquid chromatography-tandem-mass spectrometry to identify the excretory-secretory (ES) products of the L3, L3 to L4 molting ES, adult male, adult female, and microfilarial stages of the filarial parasite Brugia malayi. The analysis of the ES products from adult male, adult female, microfilariae (Mf), L3, and molting L3 larvae identified 852 proteins. Annotation suggests that the functional and component distribution was very similar across each of the stages studied; however, the Mf contributed a higher proportion to the total number of identified proteins than the other stages. Of the 852 proteins identified in the ES, only 229 had previous confirmatory expressed sequence tags (ESTs) in the available databases. Moreover, this analysis was able to confirm the presence of 274 “hypothetical” proteins inferred from gene prediction algorithms applied to the B. malayi (Bm) genome. Not surprisingly, the majority (160/274) of these “hypothetical” proteins were predicted to be secreted by Signal IP and/or SecretomeP 2.0 analysis. Of major interest is the abundance of previously characterized immunomodulatory proteins such as ES-62 (leucyl aminopeptidase), MIF-1, SERPIN, glutathione peroxidase, and galectin in the ES of microfilariae (and Mf-containing adult females) compared to the adult males. In addition, searching the ES protein spectra against the Wolbachia database resulted in the identification of 90 Wolbachia-specific proteins, most of which were metabolic enzymes that have not been shown to be immunogenic. This proteomic analysis extends our knowledge of the ES and provides insight into the host–parasite interaction

Theory of disk accretion onto supermassive black holes

Accretion onto supermassive black holes produces both the dramatic phenomena associated with active galactic nuclei and the underwhelming displays seen in the Galactic Center and most other nearby galaxies. I review selected aspects of the current theoretical understanding of black hole accretion, emphasizing the role of magnetohydrodynamic turbulence and gravitational instabilities in driving the actual accretion and the importance of the efficacy of cooling in determining the structure and observational appearance of the accretion flow. Ongoing investigations into the dynamics of the plunging region, the origin of variability in the accretion process, and the evolution of warped, twisted, or eccentric disks are summarized.Comment: Mostly introductory review, to appear in "Supermassive black holes in the distant Universe", ed. A.J. Barger, Kluwer Academic Publishers, in pres

Deprescribing interventions and their impact on medication adherence in community-dwelling older adults with polypharmacy: a systematic review

Background: Polypharmacy, and the associated adverse drug events such as non-adherence to prescriptions, is a common problem for elderly people living with multiple comorbidities. Deprescribing, i.e. the gradual withdrawal from medications with supervision by a healthcare professional, is regarded as a means of reducing adverse effects of multiple medications including non-adherence. This systematic review examines the evidence of deprescribing as an effective strategy for improving medication adherence amongst older, community dwelling adults. Methods: A mixed methods review was undertaken. Eight bibliographic database and two clinical trials registers were searched between May and December 2017. Results were double screened in accordance with pre-defined inclusion/exclusion criteria related to polypharmacy, deprescribing and adherence in older, community dwelling populations. The Mixed Methods Appraisal Tool (MMAT) was used for quality appraisal and an a priori data collection instrument was used. For the quantitative studies, a narrative synthesis approach was taken. The qualitative data was analysed using framework analysis. Findings were integrated using a mixed methods technique. The review was performed in accordance with the PRISMA reporting statement. Results: A total of 22 original studies were included, of which 12 were RCTs. Deprescribing with adherence as an outcome measure was identified in randomised controlled trials (RCTs), observational and cohort studies from 13 countries between 1996 and 2017. There were 17 pharmacy-led interventions; others were led by General Practitioners (GP) and nurses. Four studies demonstrated an overall reduction in medications of which all studies corresponded with improved adherence. A total of thirteen studies reported improved adherence of which 5 were RCTs. Adherence was reported as a secondary outcome in all but one study. Conclusions: There is insufficient evidence to show that deprescribing improves medication adherence. Only 13 studies (of 22) reported adherence of which only 5 were randomised controlled trials. Older people are particularly susceptible to non-adherence due to multi-morbidity associated with polypharmacy. Bio-psycho-social factors including health literacy and multi-disciplinary team interventions influence adherence. The authors recommend further study into the efficacy and outcomes of medicines management interventions. A consensus on priority outcome measurements for prescribed medications is indicated

Use of selected complementary and alternative medicine (CAM) treatments in veterans with cancer or chronic pain: a cross-sectional survey

BACKGROUND: Complementary and alternative medicine (CAM) is emerging as an important form of care in the United States. We sought to measure the prevalence of selected CAM use among veterans attending oncology and chronic pain clinics and to describe the characteristics of CAM use in this population. METHODS: The self-administered, mail-in survey included questions on demographics, health beliefs, medical problems and 6 common CAM treatments (herbs, dietary supplements, chiropractic care, massage therapy, acupuncture and homeopathy) use. We used the chi-square test to examine bivariate associations between our predictor variables and CAM use. RESULTS: Seventy-two patients (27.3%) reported CAM use within the past 12 months. CAM use was associated with more education (p = 0.02), higher income (p = 0.006), non-VA insurance (p = 0.003), additional care outside the VA (p = 0.01) and the belief that lifestyle contributes to illness (p = 0.015). The diagnosis of chronic pain versus cancer was not associated with differential CAM use (p = 0.15). Seventy-six percent of CAM non-users reported that they would use it if offered at the VA. CONCLUSION: Use of 6 common CAM treatments among these veterans is lower than among the general population, but still substantial. A large majority of veterans reported interest in using CAM modalities if they were offered at the VA. A national assessment of veteran interest in CAM may assist VA leaders to respond to patients' needs

Regulation of CCL2 Expression by an Upstream TALE Homeodomain Protein-Binding Site That Synergizes with the Site Created by the A-2578G SNP

CC Chemokine Ligand 2 (CCL2) is a potent chemoattractant produced by macrophages and activated astrocytes during periods of inflammation within the central nervous system. Increased CCL2 expression is correlated with disease progression and severity, as observed in pulmonary tuberculosis, HCV-related liver disease, and HIV-associated dementia. The CCL2 distal promoter contains an A/G polymorphism at position -2578 and the homozygous -2578 G/G genotype is associated with increased CCL2 production and inflammation. However, the mechanisms that contribute to the phenotypic differences in CCL2 expression are poorly understood. We previously demonstrated that the -2578 G polymorphism creates a TALE homeodomain protein binding site (TALE binding site) for PREP1/PBX2 transcription factors. In this study, we identified the presence of an additional TALE binding site 22 bp upstream of the site created by the -2578 G polymorphism and demonstrated the synergistic effects of the two sites on the activation of the CCL2 promoter. Using chromatin immunoprecipitation (ChIP) assays, we demonstrated increased binding of the TALE proteins PREP1 and PBX2 to the -2578 G allele, and binding of IRF1 to both the A and G alleles. The presence of TALE binding sites that form inverted repeats within the -2578 G allele results in increased transcriptional activation of the CCL2 distal promoter while the presence of only the upstream TALE binding site within the -2578 A allele exerts repression of promoter activity

Physics of Neutron Star Crusts

The physics of neutron star crusts is vast, involving many different research fields, from nuclear and condensed matter physics to general relativity. This review summarizes the progress, which has been achieved over the last few years, in modeling neutron star crusts, both at the microscopic and macroscopic levels. The confrontation of these theoretical models with observations is also briefly discussed.Comment: 182 pages, published version available at <http://www.livingreviews.org/lrr-2008-10

Early mortality experience in a large military cohort and a comparison of mortality data sources

<p>Abstract</p> <p>Background</p> <p>Complete and accurate ascertainment of mortality is critically important in any longitudinal study. Tracking of mortality is particularly essential among US military members because of unique occupational exposures (e.g., worldwide deployments as well as combat experiences). Our study objectives were to describe the early mortality experience of Panel 1 of the Millennium Cohort, consisting of participants in a 21-year prospective study of US military service members, and to assess data sources used to ascertain mortality.</p> <p>Methods</p> <p>A population-based random sample (n = 256,400) of all US military service members on service rosters as of October 1, 2000, was selected for study recruitment. Among this original sample, 214,388 had valid mailing addresses, were not in the pilot study, and comprised the group referred to in this study as the invited sample. Panel 1 participants were enrolled from 2001 to 2003, represented all armed service branches, and included active-duty, Reserve, and National Guard members. Crude death rates, as well as age- and sex-adjusted overall and age-adjusted, category-specific death rates were calculated and compared for participants (n = 77,047) and non-participants (n = 137,341) based on data from the Social Security Administration Death Master File, Department of Veterans Affairs (VA) files, and the Department of Defense Medical Mortality Registry, 2001-2006. Numbers of deaths identified by these three data sources, as well as the National Death Index, were compared for 2001-2004.</p> <p>Results</p> <p>There were 341 deaths among the participants for a crude death rate of 80.7 per 100,000 person-years (95% confidence interval [CI]: 72.2,89.3) compared to 820 deaths and a crude death rate of 113.2 per 100,000 person-years (95% CI: 105.4, 120.9) for non-participants. Age-adjusted, category-specific death rates highlighted consistently higher rates among study non-participants. Although there were advantages and disadvantages for each data source, the VA mortality files identified the largest number of deaths (97%).</p> <p>Conclusions</p> <p>The difference in crude and adjusted death rates between Panel 1 participants and non-participants may reflect healthier segments of the military having the opportunity and choosing to participate. In our study population, mortality information was best captured using multiple data sources.</p