Traumatic brain injury and the effects of diazepam, diltiazem, and MK-801 on GABA-A receptor subunit expression in rat hippocampus

<p>Abstract</p> <p>Background</p> <p>Excitatory amino acid release and subsequent biochemical cascades following traumatic brain injury (TBI) have been well documented, especially glutamate-related excitotoxicity. The effects of TBI on the essential functions of inhibitory GABA-A receptors, however, are poorly understood.</p> <p>Methods</p> <p>We used Western blot procedures to test whether <it>in vivo </it>TBI in rat altered the protein expression of hippocampal GABA-A receptor subunits α1, α2, α3, α5, β3, and γ2 at 3 h, 6 h, 24 h, and 7 days post-injuy. We then used pre-injury injections of MK-801 to block calcium influx through the NMDA receptor, diltiazem to block L-type voltage-gated calcium influx, or diazepam to enhance chloride conductance, and re-examined the protein expressions of α1, α2, α3, and γ2, all of which were altered by TBI in the first study and all of which are important constituents in benzodiazepine-sensitive GABA-A receptors.</p> <p>Results</p> <p>Western blot analysis revealed no injury-induced alterations in protein expression for GABA-A receptor α2 or α5 subunits at any time point post-injury. Significant time-dependent changes in α1, α3, β3, and γ2 protein expression. The pattern of alterations to GABA-A subunits was nearly identical after diltiazem and diazepam treatment, and MK-801 normalized expression of all subunits 24 hours post-TBI.</p> <p>Conclusions</p> <p>These studies are the first to demonstrate that GABA-A receptor subunit expression is altered by TBI <it>in vivo</it>, and these alterations may be driven by calcium-mediated cascades in hippocampal neurons. Changes in GABA-A receptors in the hippocampus after TBI may have far-reaching consequences considering their essential importance in maintaining inhibitory balance and their extensive impact on neuronal function.</p

Genes Involved in Feed Efficiency Identified in a Meta-Analysis of Rumen Tissue from Two Populations of Beef Steers

In cattle, the rumen is an important site for the absorption of feed by-products released by bacterial fermentation, and variation in ruminal function plays a role in cattle feed efficiency. Studies evaluating gene expression in the rumen tissue have been performed prior to this. However, validating the expression of genes identified in additional cattle populations has been challenging. The purpose of this study was to perform a meta-analysis of the ruminal transcriptome of two unrelated populations of animals to identify genes that are involved in feed efficiency across populations. RNAseq data from animals with high and low residual feed intake (RFI) from a United States population of cattle (eight high and eight low RFI) and a Canadian population of cattle (nine high and nine low RFI) were analyzed for differences in gene expression. A total of 83 differentially expressed genes were identified. Some of these genes have been previously identified in other feed efficiency studies. These genes included ATP6AP1, BAG6, RHOG, and YPEL3. Differentially expressed genes involved in the Notch signaling pathway and in protein turnover were also identified. This study, combining two unrelated populations of cattle in a meta-analysis, produced several candidate genes for feed efficiency that may be more robust indicators of feed efficiency than those identified from single populations of animals

Extracellular Calcium Modulates Actions of Orthosteric and Allosteric Ligands on Metabotropic Glutamate Receptor 1alpha

SUMMARY: Metabotropic glutamate receptor 1α (mGluR1α), a member of the family C G protein-coupled receptors (GPCRs), is emerging as a potential drug target for various disorders including chronic neuronal degenerative diseases. In addition to being activated by glutamate, mGluR1α is also modulated by extracellular Ca2+. However, the underlying mechanism is unknown. Moreover, it has long been challenging to develop receptor-specific agonists due to homologies within the mGluR family, and the Ca2+-binding site(s) on mGluR1α may provide an opportunity for receptor-selective targeting by therapeutics. In the present study, we show that our previously predicted Ca2+-binding site in the hinge region of mGluR1α is adjacent to the site where orthosteric agonists and antagonists bind on the extracellular domain of the receptor. Moreover, we have found that extracellular Ca2+ enhances mGluR1α-mediated intracellular Ca2+ responses evoked by the orthosteric agonist, L-quisqualate. Conversely, extracellular Ca2+ diminishes the inhibitory effect of the mGluR1α orthosteric antagonist, (s)-MCPG. In addition, selective positive (Ro 67-4853) and negative (CPCCOEt) allosteric modulators of mGluR1α potentiate and inhibit responses to extracellular Ca2+, respectively, in a manner similar to their effects on the response of mGluR1α to glutamate. Mutations at residues predicted to be involved in Ca2+-binding, including E325I, have significant effects on the modulation of responses to the orthosteric agonist, L-quisqualate, and the allosteric modulator Ro 67-4853 by extracellular Ca2+. These studies reveal that binding of extracellular Ca2+ to the predicted Ca2+-binding site in the ECD of mGluR1α modulates not only glutamate-evoked signaling but also the actions of both orthosteric ligands and allosteric modulators on mGluR1α

Gpr37l1 Modulates Seizure Susceptibility: Evidence from Mouse Studies and Analyses of a Human Gpr37l1 Variant

Progressive myoclonus epilepsies (PMEs) are disorders characterized by myoclonic and generalized seizures with progressive neurological deterioration. While several genetic causes for PMEs have been identified, the underlying causes remain unknown for a substantial portion of cases. Here we describe several affected individuals from a large, consanguineous family presenting with a novel PME in which symptoms begin in adolescence and result in death by early adulthood. Whole exome analyses revealed that affected individuals have a homozygous variant in GPR37L1 (c.1047G \u3e T [Lys349Asn]), an orphan G protein-coupled receptor (GPCR) expressed predominantly in the brain. In vitro studies demonstrated that the K349N substitution in Gpr37L1 did not grossly alter receptor expression, surface trafficking or constitutive signaling in transfected cells. However, in vivo studies revealed that a complete loss of Gpr37L1 function in mice results in increased seizure susceptibility. Mice lacking the related receptor Gpr37 also exhibited an increase in seizure susceptibility, while genetic deletion of both receptors resulted in an even more dramatic increase in vulnerability to seizures. These findings provide evidence linking GPR37L1 and GPR37 to seizure etiology and demonstrate an association between a GPR37L1 variant and a novel progressive myoclonus epilepsy

Acceptability, feasibility and cost of point of care testing for sexually transmitted infections among South African adolescents where syndromic management is standard of care

BACKGROUND: Young people (YP) in southern Africa are at substantial risk of HIV and sexually transmitted infections (STIs). Despite the epidemiological and biological link between STIs and HIV transmission and acquisition, infections such as Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) remain widely undiagnosed. Syndromic STI management is the standard of care in low- and middle-income countries (LMICs) despite a high prevalence of asymptomatic infections. We conducted an observational study to explore the acceptability, feasibility, and cost of a STI test-and-treat service for YP in Cape Town. METHODS: YP attending a mobile clinic (MC) and a youth centre clinic (YC) were offered STI screening. Urine testing for CT and NG using a 90-min molecular point-of-care (POC) test on the GeneXpert platform was conducted and treatment provided. Data were collated on demographics, sexual behaviour, presence of symptoms, uptake of same-day treatment, prevalence of CT/NG, and service acceptability. RESULTS: Three hundred sixty six participants were enrolled (median age 20, 83% female).57% (209/366) of participants tested positive for either CT (126/366, 34%) or NG (57/366, 16%) or co-infection (26/366, 7%). Clinical symptoms were a poor predictor of GeneXpert diagnosed CT or NG, with a sensitivity of 46.8% and 54.0% for CT and NG respectively. Although half of participants initially chose to receive same day results and treatment, only a third waited for results on the day. The majority of participants (91%) rated the service highly via a post-visit acceptability questionnaire. CONCLUSION: Curable STIs are highly prevalent in this population. STI screening using POC testing was feasible and acceptability was high. The study provides further impetus for moving policy beyond syndromic management of STIs in South Africa

No. 8 - The Cuban Embargo: Policy Outlook after 50 Years

Organized and sponsored by the Dean Rusk Center for International Law and Policy, The Cuban Embargo: Policy Outlook after 50 Years was a daylong conference exploring issues related to the impact of trade sanctions imposed by the United States on Cuba, pathways to lifting the embargo and potential U.S.-Cuba trade opportunities. Ambassador José R, Cabañas, the chief of mission at the Cuban Interests Section in Washinton, D.C., served as the keynote speaker for the event. The transcript of the conference proceedings has been edited for publication with the consent of the speakers

3D-визуализация в ультразвуковой дефектоскопии

На сегодняшний день существует множество средств визуализации ультразвуковых данных, но все они, как правило, интегрированы в дефектоскопы. Когда у нас возникает потребность извлечь данные сканирования, произвести собственную обработку, и представить в трехмерном изображении, то мы оказываемся лишенными возможности визуализации. Предложенное программное обеспечение на основе алгоритма SAFT позволяет произвести постобработку данных сканирования (А-сканов) и двумерную и трехмерную визуализацию

An assessment of opportunities and challenges for public sector involvement in the maternal health voucher program in Uganda

This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Continued inequities in coverage, low quality of care, and high out-of-pocket expenses for health services threaten attainment of Millennium Development Goals 4 and 5 in many sub-Saharan African countries. Existing health systems largely rely on input-based supply mechanisms that have a poor track record meeting the reproductive health needs of low-income and underserved segments of national populations. As a result, there is increased interest in and experimentation with results-based mechanisms like supply-side performance incentives to providers and demand-side vouchers that place purchasing power in the hands of low-income consumers to improve uptake of facility services and reduce the burden of out-of-pocket expenditures. This paper describes a reproductive health voucher program that contracts private facilities in Uganda and explores the policy and implementation issues associated with expansion of the program to include public sector facilities. Methods: Data presented here describes the results of interviews of six district health officers and four health facility managers purposefully selected from seven districts with the voucher program in southwestern Uganda. Interviews were transcribed and organized thematically, barriers to seeking RH care were identified, and how to address the barriers in a context where voucher coverage is incomplete as well as opportunities and challenges for expanding the program by involving public sector facilities were investigated. Results: The findings show that access to sexual and reproductive health services in southwestern Uganda is constrained by both facility and individual level factors which can be addressed by inclusion of the public facilities in the program. This will widen the geographical reach of facilities for potential clients, effectively addressing distance related barriers to access of health care services. Further, intensifying ongoing health education, continuous monitoring and evaluation, and integrating the voucher program with other services is likely to address some of the barriers. The public sector facilities were also seen as being well positioned to provide voucher services because of their countrywide reach, enhanced infrastructure, and referral networks. The voucher program also has the potential to address public sector constraints such as understaffing and supply shortages.Conclusions: Accrediting public facilities has the potential to increase voucher program coverage by reaching a wider pool of poor mothers, shortening distance to service, strengthening linkages between public and private sectors through public-private partnerships and referral systems as well as ensuring the awareness and buy-in of policy makers, which is crucial for mobilization of resources to support the sustainability of the programs. Specifically, identifying policy champions and consulting with key policy sectors is key to the successful inclusion of the public sector into the voucher program