Profiling the Tox21 Chemical Collection for Acetylcholinesterase Inhibition

Background: Inhibition of acetylcholinesterase (AChE), a biomarker of organophosphorous and carbamate exposure in environmental and occupational human health, has been commonly used to identify potential safety liabilities. So far, many environmental chemicals, including drug candidates, food additives, and industrial chemicals, have not been thoroughly evaluated for their inhibitory effects on AChE activity. AChE inhibitors can have therapeutic applications (e.g., tacrine and donepezil) or neurotoxic consequences (e.g., insecticides and nerve agents).Objectives: The objective of the current study was to identify environmental chemicals that inhibit AChE activity using in vitro and in silico models.Methods: To identify AChE inhibitors rapidly and efficiently, we have screened the Toxicology in the 21st Century (Tox21) 10K compound library in a quantitative high-throughput screening (qHTS) platform by using the homogenous cell-based AChE inhibition assay and enzyme-based AChE inhibition assays (with or without microsomes). AChE inhibitors identified from the primary screening were further tested in monolayer or spheroid formed by SH-SY5Y and neural stem cell models. The inhibition and binding modes of these identified compounds were studied with time-dependent enzyme-based AChE inhibition assay and molecular docking, respectively.Results: A group of known AChE inhibitors, such as donepezil, ambenonium dichloride, and tacrine hydrochloride, as well as many previously unreported AChE inhibitors, such as chelerythrine chloride and cilostazol, were identified in this study. Many of these compounds, such as pyrazophos, phosalone, and triazophos, needed metabolic activation. This study identified both reversible (e.g., donepezil and tacrine) and irreversible inhibitors (e.g., chlorpyrifos and bromophos-ethyl). Molecular docking analyses were performed to explain the relative inhibitory potency of selected compounds.Conclusions: Our tiered qHTS approach allowed us to generate a robust and reliable data set to evaluate large sets of environmental compounds for their AChE inhibitory activity. https://doi.org/10.1289/EHP6993     

Determinants of health care costs in the senior elderly: age,comorbidity, impairment,or proximity to death?

Ageing is assumed to be accompanied by greater health care expenditures but the association is also viewed as a ‘red herring’. This study aimed to evaluate whether age is associated with health care costs in the senior elderly, using electronic health records for 98,220 participants aged 80 years and over registered with the UK Clinical Practice Research Datalink and linked Hospital Episode Statistics (2010–2014). Annual costs of health care utilization were estimated from a two-part model; multiple fractional polynomial models were employed to evaluate the non-linear association of age with predicted health care costs while also controlling for comorbidities, impairments, and death proximity. Annual health care costs increased from 80 years (£2972 in men, £2603 in women) to 97 (men; £4721) or 98 years (women; £3963), before declining. Costs were significantly elevated in the last year of life but this effect declined with age, from £10,027 in younger octogenarians to £7021 in centenarians. This decline was steeper in participants with comorbidities or impairments; £14,500 for 80–84-year-olds and £6752 for centenarians with 7+ impairments. At other times, comorbidity and impairments, not age, were main drivers of costs. We conclude that comorbidities, impairments, and proximity to death are key mediators of age-related increases in health care costs. While the costs of comorbidity among survivors are not generally associated with age, additional costs in the last year of life decline with age.     

Absence of CD4 or CD8 lymphocytes changes infiltration of inflammatory cells and profiles of cytokine expression in skin wounds,but does not impair healing

The involvement of lymphocytes in skin wound healing has not been studied extensively. This study shows that CD4 and CD8 cells are present in significant numbers in skin wounds with peak levels at days 5–10 and 7–10, respectively. Both subsets expressed inflammatory and/or regulatory cytokines. To examine the function of CD4 and CD8 lymphocytes in tissue repair, wound healing was examined in mice deficient for either CD4 or CD8 cells. Wounds in CD4 deficient mice exhibited an initial delayed infiltration of CD8 cells followed by a relative increase in CD8 cells at day 10 and thereafter. Wounds in CD4 deficient mice also displayed up‐regulated expression of IL1β, IL‐6, IL‐17, IFN‐γ, CXCL‐1 and down‐regulated expression of IL‐4 as compared to wild‐type mice. In contrast, wounds in CD8 deficient mice showed significantly decreased infiltration of CD4+ cells, neutrophils, and macrophages along with down‐regulated expression of IL1β, IL‐6, TNF‐α, CXCL‐1, CCL‐2 and up‐regulated expression of IL‐4 as compared to wild‐type mice. Despite these significant changes in cytokine expression and inflammatory cell infiltrate, the rate of wound closure, wound breaking strength, collagen content and angiogenesis in either CD4 or CD8 deficiency showed no significant difference from that of wild‐type mice. The results suggest that, despite being present and involved in wound inflammation, neither CD4+ nor CD8+ cells play critical roles in the healing process of skin wounds. Further studies are needed to investigate whether these cells might play critical roles in wounds that experience stress such as ischemia or infection.     

Effects of a yoga intervention on lipid profiles of diabetes patients with dyslipidemia

ObjectiveThe present study was conducted to assess the effectiveness of yoga in the management of dyslipidemia in patients of type 2 diabetes mellitus.MethodsThis randomized parallel study was carried out in Medical College Trivandrum, Kerala, India. Hundred type 2 diabetics with dyslipidemia were randomized into control and yoga groups. The control group was prescribed oral hypoglycemic drugs. The yoga group practiced yoga daily for 1 h duration along with oral hypoglycemic drugs for 3 months. The lipid profiles of both the groups were compared at the start and at the end of 3 months.ResultsAfter intervention with yoga for a period of 3 months the study group showed a decrease in total cholesterol, triglycerides and LDL, with an improvement in HDL.ConclusionYoga, being a lifestyle incorporating exercise and stress management training, targets the elevated lipid levels in patients with diabetes through integrated approaches.     

Prevalence and Characterization of Thrombocytopenia in Pregnancy in Indian Women

To find the prevalence and causes of thrombocytopenia during pregnancy. An analytical prospective observational study was conducted in Department of Obstetrics & Gynecology, CSMMU, Lucknow. 1079 antenatal women screened for thrombocytopenia and investigated for cause and management strategies and fetomaternal outcome were recorded. Prevalence of thrombocytopenia was 8.8%. Gestational thrombocytopenia was seen in 64.2%, obstetric in 22.1% and medical in 13.68% cases. Mean platelet count in controls was lower with a significant fall (P < 0.001) in the platelet count as pregnancy advanced. Hypertensive and hepatic disorders were the most common obstetric causes of thrombocytopenia. Mode of delivery was not affected by thrombocytopenia. Maternal morbidity and mortality was seen only in medical and obstetric thrombocytopenia. The low platelet counts and declining trend with increasing gestational age predispose Indian women to risk of thrombocytopenia and a routine platelet count is suggested.     

Zimbabwe's national AIDS levy: A case study

Background: We conducted a case study of the Zimbabwe National AIDS Trust Fund (‘AIDS Levy’) as an approach to domestic government financing of the response to HIV and AIDS.

Methods: Data came from three sources: a literature review, including a search for grey literature, review of government documents from the Zimbabwe National AIDS Council (NAC), and key informant interviews with representatives of the Zimbabwean government, civil society and international organizations.

Findings: The literature search yielded 139 sources, and 20 key informants were interviewed. Established by legislation in 1999, the AIDS Levy entails a 3% income tax for individuals and 3% tax on profits of employers and trusts (which excluded the mining industry until 2015). It is managed by the parastatal NAC through a decentralized structure of AIDS Action Committees. Revenues increased from inception to 2006 through 2008, a period of economic instability and hyperinflation. Following dollarization in 2009, annual revenues continued to increase, reaching US$38.6 million in 2014. By policy, at least 50% of funds are used for purchase of antiretroviral medications. Other spending includes administration and capital costs, HIV prevention, and monitoring and evaluation. Several financial controls and auditing systems are in place. Key informants perceived the AIDS Levy as a ‘homegrown’ solution that provided country ownership and reduced dependence on donor funding, but called for further increased transparency, accountability, and reduced administrative costs, as well as recommended changes to increase revenue.

Conclusions: The Zimbabwe AIDS Levy has generated substantial resources, recently over US$35 million per year, and signals an important commitment by Zimbabweans, which may have helped attract other donor resources. Many key informants considered the Zimbabwe AIDS Levy to be a best practice for other countries to follow.