Genotoxicity of aqueous extracts of Tulbaghia violacea as determined through an Allium cepa assay

Tulbaghia violacea (wild garlic) is commonly used in traditional medicine for the treatment of various ailments including fungal infections, gastrointestinal ailments, asthma, fever, colds and pulmonary tuberculosis. We assessed the potential genotoxic effects of water extracts from the leaves, stems and roots of T. violacea using the Allium cepa assay. Extracts at concentrations of 100, 250, 500 and 1000 μg/mL were tested on root meristems of A. cepa. Ethidium bromide was used as a positive control whereas distilled water acted as a negative control. The results reveal that as the concentrations of the water extracts of T. violacea increased, the mitotic indices decreased. Similarly, the percentage of chromosomal aberrations was dependent on the concentration as well as on which part of the plant was used. The six most common chromosome aberrations included laggard chromosomes, chromosome bridges, c-mitosis, sticky chromosomes, formation of binuclei and formation of trinuclei. The presence of micronucleated cells at interphase also increased as the concentration of the water extracts increased. The results confirm that water extracts of T. violacea exert significant genotoxic effects at higher concentrations, with the stem extracts being more toxic than the leaf and root extracts at similar concentrations. Significance: • Water extracts of T. violacea – a plant commonly used in traditional medicine – were found to have significant genotoxic effects at higher concentrations

Impact of HIV drug resistance on HIV/AIDS associated mortality, new infections and antiretroviral therapy program costs in sub-Saharan Africa

To inform the level of attention to be given by antiretroviral therapy (ART) programs to HIV drug resistance (HIVDR), we used an individual-level model to estimate its impact on future AIDS deaths, HIV-incidence and ART program costs in sub-Saharan Africa (SSA) for a range of program situations. We applied this to SSA through the Spectrum-Goals model. In a situation in which current levels of pre-treatment HIVDR are over 10% (mean 15%), 16% of AIDS deaths (890,000 deaths) , 9% of new infections (450,000) and 8% ($6.5 billion) of ART program costs in SSA in 2016-2030 will be attributable to HIVDR

Fabrication and processing of bacterial cellulose/silvernanowire composites as transparent, conductive, andflexible films for optoelectronic applications

DATA AVAILABILITY : The data that support the findings of this study are avail-able in the supplementary material of this article.SUPPORTING INFORMATION : DATA S1 : Supplementary Information.This work reports on the engineering and fabrication of transparent, conductive, and flexible films made as a composite of bacterial cellulose microfibers (BMF), a polymer (either PVA or PEO), and silver nanowires (AgNWs) as viable and cost-effective replacements to commercial indium-tin oxide (ITO) and fluorine-doped tin oxide (FTO) transparent conductors. The studies conducted indicate that the optical and mechanical properties of BMF-polymer substrates are tuneable by varying the ratio of BMF to polymer. An optimized ratio of 70:30 of BMF to polymer was established for BMF-PVA and BMF-PEO composites. The optimized composite films were coated with varying amounts of AgNWs. As the AgNW loading increased, the deposition density of AgNW networks increased, while the sheet resistance and optical transmittance decreased. The optimum AgNW loading was determined at 0.20 mg for both composite films. The BMF-PVA-AgNW film displayed transmittance between 81% and 71% and an average resistivity of 9.462 ± 0.588 Ω/sq while the BMF-PEO-AgNW films showed transmittance between 73% and 65% and an average resistivity of 9.388 ± 0.1.375 Ω/sq. These properties compared well to that of commercial ITO and FTO glass substrates. The findings promote cellulose-based composites as low-cost, lightweight, and durable substrates for optoelectronic applications.The National Research Foundation South Africa and the University of KwaZulu-Natal (UKZN).http://wileyonlinelibrary.com/journal/appChemistr

On the Origin of the Treponematoses: A Phylogenetic Approach

For 500 years, controversy has raged around the origin of T. pallidum subsp. pallidum, the bacterium responsible for syphilis. Did Christopher Columbus and his men introduce this pathogen into Renaissance Europe, after contracting it during their voyage to the New World? Or does syphilis have a much older history in the Old World? This paper represents the first attempt to use a phylogenetic approach to solve this question. In addition, it clarifies the evolutionary relationships between the pathogen that causes syphilis and the other T. pallidum subspecies, which cause the neglected tropical diseases yaws and endemic syphilis. Using a collection of pathogenic Treponema strains that is unprecedented in size, we show that yaws appears to be an ancient infection in humans while venereal syphilis arose relatively recently in human history. In addition, the closest relatives of syphilis-causing strains identified in this study were found in South America, providing support for the Columbian theory of syphilis's origin

Cardiac Safety of TGF-β Receptor I Kinase Inhibitor LY2157299 Monohydrate in Cancer Patients in a First-in-Human Dose Study

Transforming growth factor-beta (TGF-β) signaling plays an important role in the fetal development of cardiovascular organs and in the repair mechanisms of the heart. Hence, inhibitors of the TGF-β signaling pathway require a careful identification of a safe therapeutic window and a comprehensive monitoring of the cardiovascular system. Seventy-nine cancer patients (67 glioma and 12 solid tumor) enrolled in a first-in-human dose study and received the TGF-β inhibitor LY2157299 monohydrate (LY2157299) as monotherapy (n = 53) or in combination with lomustine (n = 26). All patients were monitored using 2D echocardiography/color and Spectral Doppler (2D Echo with Doppler) every 2 months, monthly electrocardiograms, thorax computer tomography scans every 6 months, and monthly serum brain natriuretic peptide (BNP), troponin I, cystatin C, high-sensitivity C-reactive protein (hs-CRP). Administration of LY2157299 was not associated with medically relevant cardiovascular toxicities, including patients treated ≥6 months (n = 13). There were no increases of troponin I, BNP, or hs-CRP or reduction in cystatin C levels, which may have been considered as signs of cardiovascular injury. Blood pressure was generally stable during treatment. Imaging with echocardiography/Doppler showed an increase in mitral and tricuspid valve regurgitation by two grades of severity in only one patient with no concurrent clinical symptoms of cardiovascular injury. Overall, this comprehensive cardiovascular monitoring for the TGF-β inhibitor LY2157299 did not detect medically relevant cardiac toxicity and hence supports the evaluation of LY2157299 in future clinical trials

Pharmacokinetic, pharmacodynamic and biomarker evaluation of transforming growth factor-β receptor I kinase inhibitor, galunisertib, in phase 1 study in patients with advanced cancer

Purpose Transforming growth factor-beta (TGF-β) signaling plays a key role in epithelial-mesenchymal transition (EMT) of tumors, including malignant glioma. Small molecule inhibitors (SMI) blocking TGF-β signaling reverse EMT and arrest tumor progression. Several SMIs were developed, but currently only LY2157299 monohydrate (galunisertib) was advanced to clinical investigation. Design The first-in-human dose study had three parts (Part A, dose escalation, n = 39; Part B, safety combination with lomustine, n = 26; Part C, relative bioavailability study, n = 14). Results A preclinical pharmacokinetic/pharmacodynamic (PK/PD) model predicted a therapeutic window up to 300 mg/day and was confirmed in Part A after continuous PK/PD. PK was not affected by co-medications such as enzyme-inducing anti-epileptic drugs or proton pump inhibitors. Changes in pSMAD2 levels in peripheral blood mononuclear cells were associated with exposure indicating target-related pharmacological activity of galunisertib. Twelve (12/79; 15 %) patients with refractory/relapsed malignant glioma had durable stable disease (SD) for 6 or more cycles, partial responses (PR), or complete responses (CR). These patients with clinical benefit had high plasma baseline levels of MDC/CCL22 and low protein expression of pSMAD2 in their tumors. Of the 5 patients with IDH1/2 mutation, 4 patients had a clinical benefit as defined by CR/PR and SD ≥6 cycles. Galunisertib had a favorable toxicity profile and no cardiac adverse events. Conclusion Based on the PK, PD, and biomarker evaluations, the intermittent administration of galunisertib at 300 mg/day is safe for future clinical investigation

Drug Resistance Mutations for Surveillance of Transmitted HIV-1 Drug-Resistance: 2009 Update

Programs that monitor local, national, and regional levels of transmitted HIV-1 drug resistance inform treatment guidelines and provide feedback on the success of HIV-1 treatment and prevention programs. To accurately compare transmitted drug resistance rates across geographic regions and times, the World Health Organization has recommended the adoption of a consensus genotypic definition of transmitted HIV-1 drug resistance. In January 2007, we outlined criteria for developing a list of mutations for drug-resistance surveillance and compiled a list of 80 RT and protease mutations meeting these criteria (surveillance drug resistance mutations; SDRMs). Since January 2007, several new drugs have been approved and several new drug-resistance mutations have been identified. In this paper, we follow the same procedures described previously to develop an updated list of SDRMs that are likely to be useful for ongoing and future studies of transmitted drug resistance. The updated SDRM list has 93 mutations including 34 NRTI-resistance mutations at 15 RT positions, 19 NNRTI-resistance mutations at 10 RT positions, and 40 PI-resistance mutations at 18 protease positions

Cost-effectiveness of public-health policy options in the presence of pretreatment NNRTI drug resistance in sub-Saharan Africa : a modelling study

BACKGROUND: There is concern over increasing prevalence of non-nucleoside reverse-transcriptase inhibitor (NNRTI) resistance in people initiating antiretroviral therapy (ART) in low-income and middle-income countries. We assessed the effectiveness and cost-effectiveness of alternative public health responses in countries in sub-Saharan Africa where the prevalence of pretreatment drug resistance to NNRTIs is high. METHODS: The HIV Synthesis Model is an individual-based simulation model of sexual HIV transmission, progression, and the effect of ART in adults, which is based on extensive published data sources and considers specific drugs and resistance mutations. We used this model to generate multiple setting scenarios mimicking those in sub-Saharan Africa and considered the prevalence of pretreatment NNRTI drug resistance in 2017. We then compared effectiveness and cost-effectiveness of alternative policy options. We took a 20 year time horizon, used a cost effectiveness threshold of US$500 per DALY averted, and discounted DALYs and costs at 3% per year. FINDINGS: A transition to use of a dolutegravir as a first-line regimen in all new ART initiators is the option predicted to produce the most health benefits, resulting in a reduction of about 1 death per year per 100 people on ART over the next 20 years in a situation in which more than 10% of ART initiators have NNRTI resistance. The negative effect on population health of postponing the transition to dolutegravir increases substantially with higher prevalence of HIV drug resistance to NNRTI in ART initiators. Because of the reduced risk of resistance acquisition with dolutegravir-based regimens and reduced use of expensive second-line boosted protease inhibitor regimens, this policy option is also predicted to lead to a reduction of overall programme cost. INTERPRETATION: A future transition from first-line regimens containing efavirenz to regimens containing dolutegravir formulations in adult ART initiators is predicted to be effective and cost-effective in low-income settings in sub-Saharan Africa at any prevalence of pre-ART NNRTI resistance. The urgency of the transition will depend largely on the country-specific prevalence of NNRTI resistance. FUNDING: Bill & Melinda Gates Foundation, World Health Organization

Growth, immune and viral responses in HIV infected African children receiving highly active antiretroviral therapy: a prospective cohort study

<p>Abstract</p> <p>Background</p> <p>Scale up of paediatric antiretroviral therapy in resource limited settings continues despite limited access to routine laboratory monitoring. We documented the weight and height responses in HIV infected Ugandan children on highly active antiretroviral therapy and determined clinical factors associated with successful treatment outcomes.</p> <p>Methods</p> <p>A prospective cohort of HIV infected children were initiated on HAART and followed for 48 weeks. Body mass index for age z scores(BAZ), weight and height-for-age z scores (WAZ & HAZ) were calculated: CD4 cell % and HIV-1 RNA were measured at baseline and every 12 weeks. Treatment outcomes were classified according to; both virological and immunological success (VS/IS), virological failure and immunological success (VF/IS). virological success and immunological failure (VS/IF) and both virological and immunological failure (VF/IF).</p> <p>Results</p> <p>From March 2004 until May 2006, 124 HIV infected children were initiated on HAART. The median age (IQR) was 5.0 years (2.1 - 7.0) and 49% (61/124) were female. The median [95% confidence interval (CI)] BAZ, WAZ and HAZ at baseline were 0.29 (-2.9, -1.2), -1.2 (-2.1, -0.5) and -2.06 (-2.9, -1.2) respectively. Baseline median CD4 cell % and log10 HIV-1 RNA were; 11.8% (7.5-18.0) and 5.6 (5.2-5.8) copies/ml. By 48 weeks, mean WAZ and HAZ in the VF/IS group, which was younger, increased from - 0.98 (SD 1.7) to + 1.22 (SD 1.2) and from -1.99 (1.7) to + 0.76 (2.4) respectively. Mean increase in WAZ and HAZ in the VS/IF group, an older group was modest, from -1.84 (1.3) to - 0.41 (1.2) and -2.25 (1.2) to -1.16 (1.3) respectively. Baseline CD4 cell % [OR 6.97 95% CI (2.6 -18.6)], age [OR 4.6 95% CI (1.14 -19.1)] and WHO clinical stage [OR 3.5 95%CI (1.05 -12.7)] were associated with successful treatment outcome.</p> <p>Conclusions</p> <p>HIV infected Ugandan children demonstrated a robust increase in height and weight z scores during the first 48 weeks of HAART, including those who failed to completely suppress virus. Older children initiating HAART with severe immune suppression were less likely to achieve a successful treatment outcome. These data emphasize the importance of initiating HAART early to ensure adequate immune and growth responses.</p