A role for phospholipase D in angiotensin II-induced protein kinase D activation in adrenal glomerulosa cell models

The mineralocorticoid aldosterone plays an important role in regulating blood pressure, with excess causing hypertension and exacerbating cardiovascular disease. Previous studies have indicated a role for both phospholipase D (PLD) and protein kinase D (PKD) in angiotensin II (AngII)-regulated aldosterone production in adrenal glomerulosa cells. Therefore, the relationship between AngII-activated PLD and PKD was determined in two glomerulosa cell models, primary bovine zona glomerulosa (ZG) and HAC15 human adrenocortical carcinoma cells, using two inhibitors, 1-butanol and the reported PLD inhibitor, fluoro-2-indolyl des-chlorohalopemide (FIPI). FIPI was first confirmed to decrease PLD activation in response to AngII in the two glomerulosa cell models. Subsequently, it was shown that both 1-butanol and FIPI inhibited AngII-elicited PKD activation and aldosterone production. These results indicate that PKD is downstream of PLD and suggest that PKD is one of the mechanisms through which PLD promotes aldosterone production in response to AngII in adrenal glomerulosa cells.     

Lenalidomide‐based maintenance therapy reduces TNF receptor 2 on CD4 T cells and enhances immune effector function in acute myeloid leukemia patients

A major limitation to improved outcomes in acute myelogenous leukemia (AML) is relapse resulting from leukemic cells that persist at clinical remission. Regulatory T cells (Tregs), which are increased in AML patients, can contribute to immune evasion by residual leukemic cells. Tumor necrosis factor (TNF), a pro‐inflammatory cytokine present at high levels within patients, can induce TNF receptor‐2 (TNFR2) expression on Tregs. We hypothesized that since TNFR2 is required for Treg stabilization and TNFR2+ Tregs are potent suppressors, targeting TNFR2+ Tregs may restore the effectiveness of immune‐surveillance mechanisms. In this pilot study, we report AML patients in clinical remission have substantially increased levels of TNFR2+ T cells, including TNFR2+ Tregs and impaired effector CD4 T cell function with reduced IL‐2 and IFNγ production. The immunomodulatory drug, lenalidomide, and the demethylating agent, azacitidine have been moderately successful in treating AML patients, but their combined effects on TNFR2+ T cells, including Tregs are currently unknown. Our data indicates that although treatment with lenalidomide and azacitidine increased cytokine production by effector T cells in all patients, durable clinical remissions may be observed in patients with a concomitant reduction in TNFR2+ T cells and TNFR2+ Tregs. In vitro studies further demonstrated that lenalidomide can reduce TNFR2 expression and can augment effector cytokine production by T cells, which can be further enhanced by azacitidine. These results indicate that reduction of TNFR2+ T cells in AML postremission phase may result from combined azacitidine/lenalidomide therapy and may contribute to an improved clinical outcome. Am. J. Hematol. 89:795–802, 2014. © 2014 Wiley Periodicals, Inc.     

Mental health in South African adolescents living with HIV

We examined the prevalence of mental health conditions, social support, and associated factors among adolescents living with HIV. We conducted a cross-sectional analysis with adolescents (ages 9–19) attending a primary care clinic in Johannesburg, South Africa. We analyzed the results of four self-report tools: Children’s Depression Inventory–Short, Revised Manifest Anxiety Scale, Child Post-Traumatic Stress Disorder (PTSD) Checklist, and a modified version of the Medical Outcomes Study Social Support Scale. We used robust Poisson regression to quantify the association between social support and mental health. Among 278 adolescents, the majority were perinatally infected with HIV (92%), and had at least one deceased parent (59%). Depression symptom threshold scores were found among 8% of adolescents, and 7% screened positive for symptoms of anxiety. Few (1%) met the criteria for PTSD. Overall, 12% of adolescents screened positive for symptoms of depression, anxiety or PTSD. Older adolescents reported less social support than younger adolescents. Adolescents were less likely to have mental health symptoms if they had higher measures of social support (adjusted Prevalence Ratio 0.38, 95% CI 0.20–0.73). Attention should be paid to social support for adolescents living with HIV as this may play an important role in their mental health.     

Hypertension in Zimbabwe: A meta-analysis to quantify its burden and policy implications

AIM: To estimate the pooled prevalence of hypertension in Zimbabwe and describe its trend since independence in 1980 using secondary source data. METHODS: MEDLINE, EMBASE and Scopus databases from April 1980 to December 2013 were searched for population and community based studies on the prevalence of hypertension among adults (≥ 18 years) in Zimbabwe. The key words used were “prevalence”, “epidemiologic studies”, “hypertension” or “high blood pressure”, based on the cut-off (≥ 140 mmHg systolic blood pressure and/or ≥ 90 mmHg diastolic blood pressure). We conducted a meta-analysis on the published studies, using the random-effects model to estimate the pooled prevalence. RESULTS: The search retrieved 87 publications, of which four studies met the selection criteria. The four studies had a total of 4829 study participants between 1997 and 2010 across 5 provinces in Zimbabwe. Two studies were in urban areas, while the other two had mixed study settings (urban and rural). The overall pooled prevalence of hypertension was 30% (95%CI: 19%, 42%, I²= 98%, χ² = 164.15, P = 0.00). CONCLUSION: Our results show a high prevalence of hypertension in Zimbabwe, with urban areas having higher prevalence than rural areas.     

The cost-effectiveness of unilateral cochlear implants in UK adults

The European Journal of Health Economics - The National Institute for Health and Care Excellence (NICE) updated its eligibility criteria for unilateral cochlear implants (UCIs) in 2019. NICE...     

Low incidence of abacavir hypersensitivity reaction among African children initiating antiretroviral therapy

Hypersensitivity reactions are reported in approximately 5% of adults receiving abacavir, but there are few published data in children. Among 1150 African children receiving antiretroviral therapy in a randomized trial, suspected hypersensitivity reactions to abacavir were rare (0.3%; 95% CI, 0.01-0.9). Patients were managed successfully through the provision of clear guidelines and education of clinical staff, children, and their caregivers.     

Strain-level analysis of gut-resident pro-inflammatory viridans group Streptococci suppressed by long-term cotrimoxazole prophylaxis among HIV-positive children in Zimbabwe

ABSTRACT

Antimicrobials have become a mainstay of healthcare in the past century due to their activity against pathogens. More recently, it has become clear that they can also affect health via their impact on the microbiota and inflammation. This may explain some of their clinical benefits despite global increases in antimicrobial resistance (AMR) and reduced antimicrobial effectiveness. We showed in a randomized controlled trial of stopping versus continuing cotrimoxazole prophylaxis among HIV-positive Zimbabwean children taking antiretroviral therapy (ART), that continuation of cotrimoxazole persistently suppressed gut-resident viridans group streptococcal species (VGS) that were associated with intestinal inflammation. In this addendum, we provide a broader overview of how antibiotics can shape the microbiota and use high read-depth whole metagenome sequencing data from our published study to investigate whether (i) the impact of cotrimoxazole on gut VGS and (ii) VGS associated inflammation, is attributable to strain-level variability. We focus on S. salivarius, the VGS species that was most prevalent in the cohort and for which there was sufficient genome coverage to differentiate strains. We demonstrate that suppression of S. salivarius by cotrimoxazole is not strain specific, nor did stool concentration of the pro-inflammatory mediator myeloperoxidase vary by S. salivarius strain. We also show that gut-resident S. salivarius strains present in this study population are distinct from common oral strains. This is the first analysis of how cotrimoxazole prophylaxis used according to international treatment guidelines for children living with HIV influences the gut microbiome at the strain-level. We also provide a detailed review of the literature on the mechanisms by which suppression of VGS may act synergistically with cotrimoxazole’s anti-inflammatory effects to reduce gut inflammation. A greater understanding of the sub-clinical effects of antibiotics offers new insights into their responsible clinical use.