An Evaluation of GABAB Receptors on Modulating Neuroinflammation in a Non-Transgenic Animal Model of Alzheimer\u27s Disease

Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and distinct neuropathological hallmarks, including amyloid beta plaques and neurofibrillary tau tangles (NFT). Although the etiology remains to be discovered, several risk factors exist that significantly contribute to developing AD. Diabetes is one of the major risk factors associated with AD and is characterized by disrupted insulin signaling that may contribute to or exacerbate AD pathologies. Furthermore, both disorders result in increased neuroinflammation. Considerable evidence has demonstrated that a chronic inflammatory response, in particular chronic microglia activation, promotes A production as well as the hyperphosphorylation of tau through the sustained release and increased levels of several pro-inflammatory cytokines. These data make understanding the mechanisms driving the inflammatory response and treatment of the inflammation an important target in AD research. In addition to aberrant microglia functioning, the loss of a number of aspects of GABAergic signaling, including GABAB receptors, have been reported in clinical AD populations and animal models of AD. As microglia express functional GABAB receptors and activation on microglia appear to reduce their activity, GABA signaling may result in a decrease in pro-inflammatory cytokine production. Therefore, the purpose of this study is to investigate the role of GABAB in neuroinflammation encompassing to AD pathogenesis using a non-transgenic animal model related to diabetes. Using a low-dose schedule of streptozotocin (STZ) administration to induce a sustained hyperglycemic state, we treated with animals with a GABAB receptor agonist (baclofen) to reduce activated microglia and pro-inflammatory effects. We found that STZ administration led to significantly increased blood glucose levels, memory impairments in the novel object recognition task, hyperphosphorylated tau, increased activated microglia, and pro-inflammatory cytokines. Treatment with baclofen ameliorated the above changes induced by STZ. Therefore, GABAB receptors play a role in modulating microglia function and neuroinflammation

Alternations of NMDA and GABAB Receptor Function in Development: A Potential Animal Model of Schizophrenia

Schizophrenia is a debilitating mental disorder that affects up to 3% of the world population. The behavioral symptoms are categorized into positive and negative symptoms, which appear during late adolescence/early adulthood. Unfortunately, the underlying cellular and molecular mechanisms of the disease are poorly understood. Several hypotheses exist to explain mechanisms contributing to these behavioral alterations. One model proposes that a reduced function of the NMDA glutamate receptor on specific GABAergic interneurons may be responsible for deficits in schizophrenia. Post-mortem investigations provide evidence of reductions in both glutamate and GABA-related proteins in patients with schizophrenia. Further, GABAergic interneurons that are activated by glutamate via NMDA receptors are important for oscillatory activity involved with sensory processing and cognitive function. Alterations in the function of NMDA receptors on GABAeric interneurons are implicated in regulating neural network activity and, if disrupted, could potentially lead to altered brain function and deficits seen in schizophrenia. Several investigations have demonstrated reduction in NMDA receptor function or GABA receptor function induces deficits consistent with schizophrenia. Recent approaches have also focused on changes in NMDA or GABA function related to schizophrenia as a neurodevelopmental disorder. This approach suggests that alterations in either system during brain development may result in behavioral deficits later in life. The purpose of the below studies was to determine if changes in NMDA receptor function or alterations in downstream GABA receptor function during development in rodent pups results in behavioral or biochemical alterations in adulthood that are relevant to schizophrenia. The data reveal that altering these receptor systems in development produce deficits in adulthood. Changes in sensorimotor gating, spatial learning and memory, and differential expression of multiple GABA related proteins in the brain tissue were observed in these animals

Low-dose naltrexone as a treatment for chronic fatigue syndrome

Naltrexone is used as an off-label treatment in low doses for several chronic immune-modulated disorders in many countries. Although only small-scale clinical trials have been performed, these suggest efficacy in several diseases including Crohn’s disease, fibromyalgia and Gulf War Illness. Despite numerous internet reports of response to low-dose naltrexone (LDN), no clinical trials exist in people with chronic fatigue syndrome. This condition is characterised by chronic profound fatigue, postexertional malaise, pain and autonomic and neurocognitive disturbances. This series of three case reports compiled by people with long-term ill-health due to chronic fatigue syndrome shows the range of responses they observed when taking LDN, from life changing to a reduction in some symptoms only. Treatment doses ranged from 4 to 12 mg. Clinical trials may be warranted to explore the potential use of naltrexone in people with these debilitating illnesses which currently have no licensed treatments available

Superior T memory stem cell persistence supports long-lived T cell memory

Long-lived memory T cells are able to persist in the host in the absence of antigen; however, the mechanism by which they are maintained is not well understood. Recently, a subset of human T cells, stem cell memory T cells (TSCM cells), was shown to be self-renewing and multipotent, thereby providing a potential reservoir for T cell memory throughout life. However, their in vivo dynamics and homeostasis still remain to be defined due to the lack of suitable animal models. We identified T cells with a TSCM phenotype and stem cell–like properties in nonhuman primates. These cells were the least-differentiated memory subset, were functionally distinct from conventional memory cells, and served as precursors of central memory. Antigen-specific TSCM cells preferentially localized to LNs and were virtually absent from mucosal surfaces. They were generated in the acute phase of viral infection, preferentially survived in comparison with all other memory cells following elimination of antigen, and stably persisted for the long term. Thus, one mechanism for maintenance of long-term T cell memory derives from the unique homeostatic properties of TSCM cells. Vaccination strategies designed to elicit durable cellular immunity should target the generation of TSCM cells

Participation in adherence clubs and on-time drug pickup among HIV-infected adults in Zambia: a matched-pair cluster randomized trial

Background: Current models of HIV service delivery, with frequent facility visits, have led to facility congestion, patient and healthcare provider dissatisfaction, and suboptimal quality of services and retention in care. The Zambian urban adherence club (AC) is a health service innovation designed to improve on-time drug pickup and retention in HIV care through off-hours facility access and pharmacist-led group drug distribution. Similar models of differentiated service delivery (DSD) have shown promise in South Africa, but observational analyses of these models are prone to bias and confounding. We sought to evaluate the effectiveness and implementation of ACs in Zambia using a more rigorous study design. Methods and findings: Using a matched-pair cluster randomized study design (ClinicalTrials.gov: NCT02776254), 10 clinics were randomized to intervention (5 clinics) or control (5 clinics). At each clinic, between May 19 and October 27, 2016, a systematic random sample was assessed for eligibility (HIV+, age ≥ 14 years, on ART >6 months, not acutely ill, CD4 count not 7 days late). Intervention effect was estimated using unadjusted Kaplan–Meier survival curves and a Cox proportional hazards model to derive an adjusted hazard ratio (aHR). Medication possession ratio (MPR) and implementation outcomes (adoption, acceptability, appropriateness, feasibility, and fidelity) were additionally evaluated as secondary outcomes. Baseline characteristics were similar between 571 intervention and 489 control participants with respect to median age (42 versus 41 years), sex (62% versus 66% female), median time since ART initiation (4.8 versus 5.0 years), median CD4 count at study enrollment (506 versus 533 cells/mm3), and baseline retention (53% versus 55% with at least 1 late drug pickup in previous 12 months). The rate of late drug pickup was lower in intervention participants compared to control participants (aHR 0.26, 95% CI 0.15–0.45, p < 0.001). Median MPR was 100% in intervention participants compared to 96% in control participants (p < 0.001). Although 18% (683/3,734) of AC group meeting visits were missed, on-time drug pickup (within 7 days) still occurred in 51% (350/683) of these missed visits through alternate means (use of buddy pickup or early return to the facility). Qualitative evaluation suggests that the intervention was acceptable to both patients and providers. While patients embraced the convenience and patient-centeredness of the model, preference for traditional adherence counseling and need for greater human resources influenced intervention appropriateness and feasibility from the provider perspective. The main limitations of this study were the small number of clusters, lack of viral load data, and relatively short follow-up period. Conclusions: ACs were found to be an effective model of service delivery for reducing late ART drug pickup among HIV-infected adults in Zambia. Drug pickup outside of group meetings was relatively common and underscores the need for DSD models to be flexible and patient-centered if they are to be effective

An 800-million-solar-mass black hole in a significantly neutral Universe at redshift 7.5

Quasars are the most luminous non-transient objects known and as a result they enable studies of the Universe at the earliest cosmic epochs. Despite extensive efforts, however, the quasar ULAS J1120+0641 at z=7.09 has remained the only one known at z>7 for more than half a decade. Here we report observations of the quasar ULAS J134208.10+092838.61 (hereafter J1342+0928) at redshift z=7.54. This quasar has a bolometric luminosity of 4e13 times the luminosity of the Sun and a black hole mass of 8e8 solar masses. The existence of this supermassive black hole when the Universe was only 690 million years old---just five percent of its current age---reinforces models of early black-hole growth that allow black holes with initial masses of more than about 1e4 solar masses or episodic hyper-Eddington accretion. We see strong evidence of absorption of the spectrum of the quasar redwards of the Lyman alpha emission line (the Gunn-Peterson damping wing), as would be expected if a significant amount (more than 10 per cent) of the hydrogen in the intergalactic medium surrounding J1342+0928 is neutral. We derive a significant fraction of neutral hydrogen, although the exact fraction depends on the modelling. However, even in our most conservative analysis we find a fraction of more than 0.33 (0.11) at 68 per cent (95 per cent) probability, indicating that we are probing well within the reionization epoch of the Universe.Comment: Updated to match the final journal versio

Differentiated care preferences of stable patients on ART in Zambia: a discrete choice experiment

Background: Although differentiated service delivery (DSD) models for stable patients on antiretroviral therapy (ART) offer a range of health systems innovations, their comparative desirability to patients remains unknown. We conducted a discrete choice experiment to quantify service attributes most desired by patients to inform model prioritization Methods: Between July and December 2016 a sample of HIV-positive adults on ART at 12 clinics in Zambia were asked to choose between two hypothetical facilities which differed across six DSD attributes. We used mixed logit models to explore preferences, heterogeneity and trade-offs Results: Of 486 respondents, 59% were female and 85% resided in urban locations. Patients strongly preferred infrequent clinic visits (3 vs. 1-month visits: β (i.e. relative utility) =2.84; p <0.001). Milder preferences were observed for: waiting time for ART pick-up (1 vs. 6 hrs.; β=-0.67; p<0.001) or provider (1 vs. 3 hrs.; β=-0.41; p=0.002); ‘buddy’ ART collection (β=0.84; p <0.001); and ART pick-up location (clinic vs. community: β=0.35; p=0.028). Urban patients demonstrated a preference for collecting ART at a clinic (β=1.32, p<0.001), and although the majority of rural patients preferred community ART pick-up (β=-0.74, p=0.049), 40% of rural patients still preferred facility ART collection. Conclusions: Stable patients on ART primarily want to attend clinic infrequently, supporting a focus in Zambia on optimizing multi-month prescribing over other DSD features - particularly in urban areas. Substantial preference heterogeneity highlights the need for DSD models to be flexible, and accommodate both setting features and patient choice in their design

Obesity and prevalence of chronic diseases in the 1999–2000 Italian National Health Survey

<p>Abstract</p> <p>Background</p> <p>There is consistent evidence that obesity is a correlate of mortality. Less information is available about the relation between body weight and the prevalence of diseases. We investigated the prevalence of overweight and obesity and their relationship with 14 groups of chronic diseases in a Mediterranean population using data from the Italian National Survey collected in 1999–2000.</p> <p>Methods</p> <p>A sample of 52,300 families was randomly selected using a complex stratified multistage design, within strata of geographical areas, municipalities, and household sizes, to produce estimates representative of the whole Italian population. Data were collected by civil servants both with an interview and a self-reported questionnaire.</p> <p>Results</p> <p>The present study documents an increase in the prevalence of overweight among Italian adults in the last decades and an increased prevalence of several chronic conditions in obese or overweight individuals. A general pattern of a positive association between excess weight and chronic disease was observed for both sexes. The ratio of the prevalences of cardiovascular diseases, diabetes and chronic respiratory diseases was higher in obese versus normal-weight individuals in the age group under 45 years.</p> <p>Conclusion</p> <p>To reduce the prevalence of chronic diseases a policy promoting a healthier individual lifestyle is becoming more and more desirable.</p

Does clinical equipoise apply to cluster randomized trials in health research?

This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, Weijer and colleagues set out six areas of inquiry that must be addressed if the cluster trial is to be set on a firm ethical foundation. This paper addresses the third of the questions posed, namely, does clinical equipoise apply to CRTs in health research? The ethical principle of beneficence is the moral obligation not to harm needlessly and, when possible, to promote the welfare of research subjects. Two related ethical problems have been discussed in the CRT literature. First, are control groups that receive only usual care unduly disadvantaged? Second, when accumulating data suggests the superiority of one intervention in a trial, is there an ethical obligation to act

Autism-Associated Gene Expression in Peripheral Leucocytes Commonly Observed between Subjects with Autism and Healthy Women Having Autistic Children

Autism spectrum disorder (ASD) is a severe neuropsychiatric disorder which has complex pathobiology with profound influences of genetic factors in its development. Although the numerous autism susceptible genes were identified, the etiology of autism is not fully explained. Using DNA microarray, we examined gene expression profiling in peripheral blood from 21 individuals in each of the four groups; young adults with ASD, age- and gender-matched healthy subjects (ASD control), healthy mothers having children with ASD (asdMO), and asdMO control. There was no blood relationship between ASD and asdMO. Comparing the ASD group with control, 19 genes were found to be significantly changed. These genes were mainly involved in cell morphology, cellular assembly and organization, and nerve system development and function. In addition, the asdMO group possessed a unique gene expression signature shown as significant alterations of protein synthesis despite of their nonautistic diagnostic status. Moreover, an ASD-associated gene expression signature was commonly observed in both individuals with ASD and asdMO. This unique gene expression profiling detected in peripheral leukocytes from affected subjects with ASD and unaffected mothers having ASD children suggest that a genetic predisposition to ASD may be detectable even in peripheral cells. Altered expression of several autism candidate genes such as FMR-1 and MECP2, could be detected in leukocytes. Taken together, these findings suggest that the ASD-associated genes identified in leukocytes are informative to explore the genetic, epigenetic, and environmental background of ASD and might become potential tools to assess the crucial factors related to the clinical onset of the disorder