IntroductionThis study explores factors associated with virological detectability, and viral re-suppression after enhanced adherence counselling, in adults and children on antiretroviral therapy (ART) in Swaziland.MethodsThis descriptive study used laboratory data from 7/5/2012 to 30/9/2013, which were linked with the national ART database to provide information on time on ART and CD4 count; information on enhanced adherence counselling was obtained from file review in health facilities. Multivariable logistic regression was used to explore the relationship between viral load, gender, age, time on ART, CD4 count and receiving (or not receiving) enhanced adherence counselling.ResultsFrom 12,063 patients undergoing routine viral load monitoring, 1941 (16%) had detectable viral loads. Children were more likely to have detectable viral loads (AOR 2.6, 95%CI 1.5–4.5), as were adolescents (AOR 3.2, 95%CI 2.2–4.8), patients with last CD4<350 cells/µl (AOR 2.2, 95%CI 1.7–2.9) or WHO Stage 3/4 disease (AOR 1.3, 95%CI 1.1–1.6), and patients on ART for longer (AOR 1.1, 95%CI 1.1–1.2). At retesting, 450 (54% of those tested) showed viral re-suppression. Children were less likely to re-suppress (AOR 0.2, 95%CI 0.1–0.7), as were adolescents (AOR 0.3, 95%CI 0.2–0.8), those with initial viral load> 1000 copies/ml (AOR 0.3, 95%CI 0.1–0.7), and those with last CD4<350 cells/µl (AOR 0.4, 95%CI 0.2–0.7). Receiving (or not receiving) enhanced adherence counselling was not associated with likelihood of re-suppression.ConclusionsChildren, adolescents and those with advanced disease were most likely to have high viral loads and least likely to achieve viral suppression at retesting; receiving adherence counselling was not associated with higher likelihood of viral suppression. Although the level of viral resistance was not quantified, this study suggests the need for ART treatment support that addresses the adherence problems of younger people; and to define the elements of optimal enhanced adherence support for patients of all ages with detectable viral loads.

This study investigated the unresolved issue of antigen-dependency and antigen-specificity of autoimmune disease suppression by CD4+CD25+ T cells (T regs). Based on autoimmune ovarian disease (AOD) in day 3 thymectomized (d3tx) mice and polyclonal T regs expressing the Thy1.1 marker, we determined: (a) the location of recipient T cell suppression, (b) the distribution of AOD-suppressing T regs, and (c) the relative efficacy of male versus female T regs. Expansion of recipient CD4+ T cells, activation/memory marker expression, and IFN-γ production were inhibited persistently in the ovary-draining LNs but not elsewhere. The cellular changes were reversed upon Thy1.1+ T reg depletion, with emergence of potent pathogenic T cells and severe AOD. Similar changes were detected in the regional LNs during autoimmune dacryoadenitis and autoimmune prostatitis suppression. Although the infused Thy1.1+ T regs proliferated and were disseminated in peripheral lymphoid organs, only those retrieved from ovary-draining LNs adoptively suppressed AOD at a suboptimal cell dose. By depriving d3tx recipients of ovarian antigens, we unmasked the supremacy of ovarian antigen-exposed female over male T regs in AOD suppression. Thus, disease suppression by polyclonal T regs depends on endogenous antigen stimulation; this occurs in a location where potent antigen-specific T regs accumulate and continuously negate pathogenic T cell response.

BACKGROUND AND PURPOSETo evaluate the hypothesis that activation of somatodendritic 5-HT1A autoreceptors in the dorsal raphe nucleus (DRN) produces the anti-emetic/anti-nausea effects of cannabidiol (CBD), a primary non-psychoactive cannabinoid found in cannabis. EXPERIMENTAL APPROACHThe potential of systemic and intra-DRN administration of 5-HT1A receptor antagonists, WAY100135 or WAY100635, to prevent the anti-emetic effect of CBD in shrews (Suncus murinus) and the anti-nausea-like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra-DRN administration of CBD to produce anti-nausea-like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5-HT1A receptors and to modify the ability of the 5-HT1A agonist, 8-OH-DPAT, to stimulate [ KEY RESULTSCBD suppressed nicotine-, lithium chloride (LiCl)-and cisplatin (20 mg·kg )-induced vomiting in the S. murinus and LiCl-induced conditioned gaping in rats. Anti-emetic and anti-nausea-like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti-nausea-like effects of systemic CBD, and (ii) CBD suppressed nausea-like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell-shaped dose-response curve) at enhancing the ability of 8-OH-DPAT to stimulate [ CONCLUSIONS AND IMPLICATIONSThese results suggest that CBD produced its anti-emetic/anti-nausea effects by indirect activation of the somatodendritic 5-HT1A autoreceptors in the DRN.

BACKGROUND AND PURPOSE Cannabinoid CB1 receptor antagonists reduce food intake and body weight, but clinical use in humans is limited by effects on the CNS. We have evaluated a novel cannabinoid antagonist (AM6545) designed to have limited CNS penetration, to see if it would inhibit food intake in rodents, without aversive effects. EXPERIMENTAL APPROACH Cannabinoid receptor binding studies, cAMP assays, brain penetration studies and gastrointestinal motility studies were carried out to assess the activity profile of AM6545. The potential for AM6545 to induce malaise in rats and the actions of AM6545 on food intake and body weight were also investigated. KEY RESULTS AM6545 binds to CB1 receptors with a Ki of 1.7 nM and CB2 receptors with a Ki of 523 nM. AM6545 is a neutral antagonist, having no effect on cAMP levels in transfected cells and was less centrally penetrant than AM4113, a comparable CB1 receptor antagonist. AM6545 reversed the effects of WIN55212‐2 in an assay of colonic motility. In contrast to AM251, AM6545 did not produce conditioned gaping or conditioned taste avoidance in rats. In rats and mice, AM6545 dose‐dependently reduced food intake and induced a sustained reduction in body weight. The effect on food intake was maintained in rats with a complete subdiaphragmatic vagotomy. AM6545 inhibited food intake in CB1 receptor gene‐deficient mice, but not in CB1/CB2 receptor double knockout mice. CONCLUSIONS AND IMPLICATIONS Peripherally active, cannabinoid receptor antagonists with limited brain penetration may be useful agents for the treatment of obesity and its complications.

ObjectivesTo evaluate the feasibility (population reached, costs) and effectiveness (positivity rates, linkage to care) of two strategies of community-based HIV testing and counselling (HTC) in rural Swaziland.MethodsStrategies used were mobile HTC (MHTC) and home-based HTC (HBHTC). Information on age, sex, previous testing and HIV results was obtained from routine HTC records. A consecutive series of individuals testing HIV-positive were followed up for 6 months from the test date to assess linkage to care.ResultsA total of 9 060 people were tested: 2 034 through MHTC and 7 026 through HBHTC. A higher proportion of children and adolescents (<20 years) were tested through HBHTC than MHTC (57% vs. 17%; P < 0.001). MHTC reached a higher proportion of adult men than HBHTC (42% vs. 39%; P = 0.015). Of 398 HIV-positive individuals, only 135 (34%) were enrolled in HIV care within 6 months. Of 42 individuals eligible for antiretroviral therapy, 22 (52%) started treatment within 6 months. Linkage to care was lowest among people who had tested previously and those aged 20–40 years. HBHTC was 50% cheaper (US$11 per person tested; $797 per individual enrolled in HIV care) than MHTC ($24 and $1698, respectively).ConclusionIn this high HIV prevalence setting, a community-based testing programme achieved high uptake of testing and appears to be an effective and affordable way to encourage large numbers of people to learn their HIV status (particularly underserved populations such as men and young people). However, for community HTC to impact mortality and incidence, strategies need to be implemented to ensure people testing HIV-positive in the community are linked to HIV care.ObjectifsEvaluer la faisabilité (population atteinte, coûts) et l'efficacité (taux de positivité, liaison aux soins) de deux stratégies de dépistage et conseil (DC) communautaire du VIH en zone rurale au Swaziland.MéthodesLes stratégies utilisées étaient des DC mobiles (DC-M) et le DC à domicile (DC-D). Les informations sur l’âge, le sexe, les tests précédents et les résultats VIH ont été obtenues à partir des dossiers de routine du DC. Une série d'individus séropositifs consécutifs a été suivie pendant six mois à partir de la date du test afin d’évaluer les liaisons aux soins.Résultats9.060 personnes ont été testées: 2.034 par le biais du DC-M et 7026 par le biais du DC-D. Une plus grande proportion d'enfants et d'adolescents (<20 ans) ont été testés par le biais du DC-D que par celui du DC-M (57% vs 17%; p <0,001). Le DC-M a atteint une proportion plus élevée d'hommes adultes que le DC-D (42% vs 39%; p = 0,015). Des 398 personnes séropositives, seules 135 (34%) ont été inscrites à des soins VIH dans les 6 mois. De 42 personnes admissibles à la thérapie antirétrovirale, 22 (52%) ont commencé le traitement dans les 6 mois. Les liaisons avec les soins étaient plus faibles chez les personnes qui ont effectué un dépistage auparavant et celles âgées de 20 à 40 ans. Le DC-D était 50% moins cher (11 $ US par personne testée, 797 $ par personne inscrite dans les...