Exploring prospects of novel drugs for tuberculosis

Tuberculosis remains a disease with an enormous impact on public health worldwide. With the continuously increasing epidemic of drug-resistant tuberculosis, new drugs are desperately needed. However, even for the treatment of drug-sensitive tuberculosis, new drugs are required to shorten the treatment duration and thereby prevent development of drug resistance. Within the past ten years, major advances in tuberculosis drug research have been made, leading to a considerable number of antimycobacterial compounds which are now in the pipeline. Here we discuss a number of these novel promising tuberculosis drugs, as well as the discovery of two new potential drug targets for the development of novel effective drugs to curb the tuberculosis pandemic, ie, the coronin 1 and protein kinase G pathways. Protein kinase G is secreted by mycobacteria and is responsible for blocking lysosomal delivery within the macrophage. Coronin 1 is responsible for activating the phosphatase, calcineurin, and thereby preventing phagosome-lysosome fusion within the macrophage. Blocking these two pathways may lead to rapid killing of mycobacteri

Simple flow cytometric detection of haemozoin containing leukocytes and erythrocytes for research on diagnosis, immunology and drug sensitivity testing

<p>Abstract</p> <p>Background</p> <p>Malaria pigment (haemozoin, Hz) has been the focus of diverse research efforts. However, identification of Hz-containing leukocytes or parasitized erythrocytes is usually based on microscopy, with inherent limitations. Flow cytometric detection of depolarized Side-Scatter is more accurate and its adaptation to common bench top flow cytometers might allow several applications. These can range from the <it>ex-vivo </it>and <it>in-vitro </it>detection and functional analysis of Hz-containing leukocytes to the detection of parasitized Red-Blood-Cells (pRBCs) to assess antimalarial activity.</p> <p>Methods</p> <p>A standard benchtop flow cytometer was adapted to detect depolarized Side-Scatter. Synthetic and <it>Plasmodium falciparum </it>Hz were incubated with whole blood and PBMCs to detect Hz-containing leukocytes and CD16 expression on monocytes. C5BL/6 mice were infected with <it>Plasmodium berghei </it>ANKA or <it>P. berghei </it>NK65 and Hz-containing leukocytes were analysed using CD11b and Gr1 expression. Parasitized RBC from infected mice were identified using anti-Ter119 and SYBR green I and were analysed for depolarized Side Scatter. A highly depolarizing RBC population was monitored in an <it>in-vitro </it>culture incubated with chloroquine or quinine.</p> <p>Results</p> <p>A flow cytometer can be easily adapted to detect depolarized Side-Scatter and thus, intracellular Hz. The detection and counting of Hz containing leukocytes in fresh human or mouse blood, as well as in leukocytes from <it>in-vitro </it>experiments was rapid and easy. Analysis of CD14/CD16 and CD11b/Gr1 monocyte expression in human or mouse blood, in a mixed populations of Hz-containing and non-containing monocytes, appears to show distinct patterns in both types of cells. Hz-containing pRBC and different maturation stages could be detected in blood from infected mice. The analysis of a highly depolarizing population that contained mature pRBC allowed to assess the effect of chloroquine and quinine after only 2 and 4 hours, respectively.</p> <p>Conclusions</p> <p>A simple modification of a flow cytometer allows for rapid and reliable detection and quantification of Hz-containing leukocytes and the analysis of differential surface marker expression in the same sample of Hz-containing <it>versus </it>non-Hz-containing leukocytes. Importantly, it distinguishes different maturation stages of parasitized RBC and may be the basis of a rapid no-added-reagent drug sensitivity assay.</p

Paradox of HIV stigma in an integrated chronic disease care in rural South Africa : viewpoints of service users and providers

Funding: This research conducted by SA was funded by the following: 1) The Agincourt Health and Socio-Demographic Surveillance System, a node of the South African Population Research Infrastructure Network (SAPRIN) and is supported by the National Department of Science and Innovation, the Medical Research Council and the University of the Witwatersrand, South Africa, and the Wellcome Trust, UK (grants 058893/Z/99/A; 069683/Z/02/Z; 085477/Z/08/Z; 085477/B/08/Z); 2) Fogarty International Centre of the National Institutes of Health under the award number D43 TW008330; and 3) an African Doctoral Dissertation Research Fellowship Programme award to the corresponding author. The funding for the publication of this article was provided by the Lown Scholars Program, Department of Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewedPublisher PD

Differences among rice cultivars in their adaptation to low ionic strength solution with toxic level of aluminum that mimics tropical acid soil conditions

BACKGROUND: Spatio-temporal variations in malaria burden are currently complex and costly to measure, but are important for decision-making. We measured the spatio-temporal variation of clinical malaria incidence at a fine scale in a cohort of children under five in an endemic area in rural Chikhwawa, Malawi, determined associated factors, and monitored adult mosquito abundance. METHODS: We followed-up 285 children aged 6-48 months with recorded geolocations, who were sampled in a rolling malaria indicator survey, for one year (2015-2016). Guardians were requested to take the children to a nearby health facility whenever ill, where health facility personnel were trained to record malaria test results and temperature on the child's sick-visit card; artemisinin-based combination therapy was provided if indicated. The cards were collected and replaced 2-monthly. Adult mosquitoes were collected from 2-monthly household surveys using a Suna trap. The head/thorax of adult Anopheles females were tested for presence of Plasmodium DNA. Binomial logistic regression and geospatial modelling were performed to determine predictors of and to spatially predict clinical malaria incidence, respectively. RESULTS: Two hundred eighty two children, with complete results, and 267.8 child-years follow-up time were included in the analysis. The incidence rate of clinical malaria was 1.2 cases per child-year at risk; 57.1% of the children had at least one clinical malaria case during follow-up. Geographical groups of households where children experienced repeated malaria infections overlapped with high mosquito densities and high entomological inoculation rate locations. CONCLUSIONS: Repeated malaria infections within household groups account for the majority of cases and signify uneven distribution of malaria risk within a small geographical area

Nutritional status and HIV in rural South African children.

BACKGROUND: Achieving the Millennium Development Goals that aim to reduce malnutrition and child mortality depends in part on the ability of governments/policymakers to address nutritional status of children in general and those infected or affected by HIV/AIDS in particular. This study describes HIV prevalence in children, patterns of malnutrition by HIV status and determinants of nutritional status. METHODS: The study involved 671 children aged 12-59 months living in the Agincourt sub-district, rural South Africa in 2007. Anthropometric measurements were taken and HIV testing with disclosure was done using two rapid tests. Z-scores were generated using WHO 2006 standards as indicators of nutritional status. Linear and logistic regression analyses were conducted to establish the determinants of child nutritional status. RESULTS: Prevalence of malnutrition, particularly stunting (18%), was high in the overall sample of children. HIV prevalence in this age group was 4.4% (95% CI: 2.79 to 5.97). HIV positive children had significantly poorer nutritional outcomes than their HIV negative counterparts. Besides HIV status, other significant determinants of nutritional outcomes included age of the child, birth weight, maternal age, age of household head, and area of residence. CONCLUSIONS: This study documents poor nutritional status among children aged 12-59 months in rural South Africa. HIV is an independent modifiable risk factor for poor nutritional outcomes and makes a significant contribution to nutritional outcomes at the individual level. Early paediatric HIV testing of exposed or at risk children, followed by appropriate health care for infected children, may improve their nutritional status and survival.RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are

Epidemiological and clinical characteristics of international travelers with enteric fever and antibiotic resistance profiles of their isolates: A GeoSentinel analysis

Copyright © 2020 American Society for Microbiology. All Rights Reserved. Enteric fever, caused by Salmonella enterica serovar Typhi (S. Typhi) and S. enterica serovar Paratyphi (S. Paratyphi), is a common travel-related illness. Limited data are available on the antimicrobial resistance (AMR) patterns of these serovars among travelers. Records of travelers with a culture-confirmed diagnosis seen during or after travel from January 2007 to December 2018 were obtained from GeoSentinel. Traveler demographics and antimicrobial susceptibility data were analyzed. Isolates were classified as nonsusceptible if intermediate or resistant or as susceptible in accordance with the participating site’s national guidelines. A total of 889 travelers (S. Typhi infections, n = 474; S. Paratyphi infections, n = 414; coinfection, n = 1) were included; 114 (13%) were children of (41%) traveled to visit friends and relatives (VFRs) and acquired the infection in South Asia (71%). Child travelers with S. Typhi infection were most frequently VFRs (77%). The median trip duration was 31 days (interquartile range, 18 to 61 days), and 448 of 691 travelers (65%) had no pretravel consultation. Of 143 S. Typhi and 75 S. Paratyphi isolates for which there were susceptibility data, nonsusceptibility to antibiotics varied (fluoroquinolones, 65% and 56%, respectively; co-trimoxazole, 13% and 0%; macrolides, 8% and 16%). Two S. Typhi isolates (1.5%) from India were nonsusceptible to third-generation cephalosporins. S. Typhi fluoroquinolone nonsusceptibility was highest when infection was acquired in South Asia (70 of 90 isolates; 78%) and sub-Saharan Africa (6 of 10 isolates; 60%). Enteric fever is an important travel-associated illness complicated by AMR. Our data contribute to a better understanding of region-specific AMR, helping to inform empirical treatment options. Prevention measures need to focus on high-risk travelers including VFRs and children

Long-lasting insecticidal net source, ownership and use in the context of universal coverage: a household survey in eastern Rwanda

Contains fulltext : 162707.pdf (publisher's version ) (Open Access)BACKGROUND: Universal long-lasting insecticidal net (LLIN) coverage (ULC) has reduced malaria morbidity and mortality across Africa. Although information is available on bed net use in specific groups, such as pregnant women and children under 5 years, there is paucity of data on their use among the general population. Bed net source, ownership and determinants of use among individuals from households in an eastern Rwanda community 8 months after a ULC were characterized. METHODS: Using household-based, interviewer-administered questionnaires and interviewer-direct observations, data on bed net source, ownership and key determinants of net use, including demographics, socio-economic status indicators, house structure characteristics, as well as of bed net quantity, type and integrity, were collected from 1400 randomly selected households. Univariate and mixed effects logistic regression modelling was done to assess for determinants of bed net use. RESULTS: A total of 1410 households and 6598 individuals were included in the study. Overall, the proportion of households with at least one net was 92 % while bed net usage was reported among 72 % of household members. Of the households surveyed, a total ownership of 2768 nets was reported, of which about 96 % were reportedly LLINs received from the ULC. By interviewer-physical observation, 88 % of the nets owned were of the LLIN type with the remaining 12 % did not carry any mark to enable type recognition. The odds of bed net use were significantly lower among males and individuals: from households of low socio-economic status, from households with /=two sleeping spaces, and those reporting to have not slept on a bed. CONCLUSION: In this study, despite high a bed net coverage, over 25 % of members reported not to have slept under a bed net the night before the survey. Males were particularly less likely to use bed nets even where nets were available. Household socio-economic status, number of bed nets and type and number of sleeping spaces were key determinants of bed net use. To maximize impact of ULC, strategies that target males as well as those that ensure ITN coverage for all, address barriers to feasible and convenient bed net use including covering over all sleeping space types, and provide net hanging supports, are needed.10 p