Is stopping secondary prophylaxis safe in HIV-positive talaromycosis patients? Experience from Myanmar.

OBJECTIVES: The aim of the study was to determine whether it is safe to stop secondary prophylaxis in patients with talaromycosis after immune reconstitution with a sustained increase in CD4 count to ≥ 100 cells/µL after antiretroviral therapy (ART). METHODS: A retrospective cohort analysis was performed in HIV-infected patients treated for talaromycosis between June 2009 and June 2017 in Medical Action Myanmar (MAM) clinics. RESULTS: Among a cohort of 5466 HIV-infected patients, 41 patients were diagnosed with and treated for clinical talaromycosis. All the patients were on ART and had a CD4 count < 100 cells/µL. Of these 41 patients, 24 patients (71%) were skin smear positive for talaromycosis, while results were negative in 17 patients. Median CD4 count and haemoglobin concentration were 24 cells/µL and 7.7 g/dL, respectively. Seventy-three per cent (30) were male. Among the 41 patients, 11 (27%) died and six (15%) were transferred to other centres. Twenty-four patients (58% of the total diagnosed) stopped itraconazole secondary prophylaxis after starting active ART with CD4 counts > 100 cells/µL for at least 1 year. Throughout the duration of follow-up post itraconazole cessation, the observed incidence of relapse was zero with a total follow-up of 93.8 person-years (95% confidence interval 0-4 per 100 person-years). The median (25th, 75th percentile) duration of follow-up post-prophylaxis discontinuation was 2.8 (2.1, 6.3) years. CONCLUSIONS: Secondary prophylaxis can be safely stopped in patients with talaromycosis after immune reconstitution with a sustained increase in CD4 count to ≥ 100 cells/µL after highly active antiretroviral therapy.

Integration of HIV services with primary care in Yangon, Myanmar: a retrospective cohort analysis.

OBJECTIVES: Integration of HIV care with general healthcare may improve patient engagement. We assessed patient outcomes in four clinics offering HIV care integrated into primary care clinics in Yangon, Myanmar. METHODS: We carried out a retrospective cohort analysis of 4551 patients who started antiretroviral therapy between 2009 and 2017. Mortality and disengagement from care were assessed using Cox regression. RESULTS: People living with HIV presented late with low CD4 counts [median (25th , 75th percentile) = 178 (65, 308) from 4216 patients] and advanced HIV (69% with stage 3 or 4). Survival was 0.95 at 1 year and 0.90 at 5 years. Males were at a higher risk of mortality than females [unadjusted hazard ratio (uHR) = 1.6 (95% CI: 1.3-2.0). Patients linked to HIV care via antenatal care or partner/parent notification were at reduced risk of mortality [uHR = 0.4 (95% CI: 0.1-1.0) and uHR = 0.5 (95% CI: 0.3-0.7)] relative to patients who presented for HIV testing. The cumulative incidence of disengagement was 0.06 at 1 year and 0.15 at 5 years. Young adults had a higher risk of disengagement than did children and older patients. Women linked to HIV care via antenatal care services were at increased risk of disengagement relative to patients who came for HIV testing (uHR = 2.4; 95% CI: 1.7-3.4). Mortality and disengagement remained steady over calendar time as the programme scaled up. CONCLUSIONS: HIV care within a primary care model is effective to attain early linkage to care, with high survival. However, close attention should be given to disengagement from care, in particular for pregnant women.

Comparative genetic stock structure in three species of commercially exploited Indo-Malay Carangidae (Teleosteii, Perciformes).

We examine genetic structuring in three commercially important species of the teleost family Carangidae from Malaysian waters: yellowtail scad Atule mate, bigeye scad Selar crumenophthalmus and yellowstripe scad Selaroides leptolepis, from the Indo-Malay Archipelago. In view of their distribution across contrasting habitats, we tested the hypothesis that pelagic species display less genetic divergence compared with demersal species, due to their potential to undertake long-distance migrations in oceanic waters. To evaluate population genetic structure, we sequenced two mitochondrial (mt)DNA [650 bp of cytochrome oxidase I (coI), 450 bp of control region (CR)] and one nuclear gene (910 bp of rag1) in each species. One hundred and eighty samples from four geographical regions within the Indo-Malay Archipelago including a population of yellowtail from Kuwait were examined. Findings revealed that the extent of genetic structuring among populations in the semi-pelagic and pelagic, yellowtail and bigeye were lower than demersal yellowstripe, consistent with the hypothesis that pelagic species display less genetic divergence compared with demersal species. The yellowtail phylogeny identified three distinct clades with bootstrap values of 86%-99% in mtDNA and 63%-67% in rag1. However, in bigeye, three clades were also observed from mtDNA data while only one clade was identified in rag1 dataset. In yellowstripe, the mtDNA tree was split into three closely related clades and two clades in rag1 tree with bootstraps value of 73%-99% and 56% respectively. However, no geographic structure appears in both mtDNA and rag1 datasets. Hierarchical molecular variance analysis (AMOVA), pair wise FST comparisons and the nearest-neighbour statistic (Snn ) showed significant genetic differences among Kuwait and Indo-Malay yellowtail. Within the Indo-Malay Archipelago itself, two distinct mitochondrial lineages were detected in yellowtail suggesting potential cryptic species. Findings suggests varying degrees of genetic structuring, key information relevant to management of exploited stocks, though more rapidly evolving genetic markers should be used in future to better delimit the nature and dynamics of putative stock boundaries.

Effects of metal ions and hydrogen peroxide on the phenotype of yeast hom6Δ mutant.

UNLABELLED: HOM6 is a major gene in the aspartate pathway which leads to biosynthesis of threonine and methionine. The phenotypes of the gene deletion mutant (hom6∆) in a variety of cultural conditions have previously provided meaningful insights into the biological roles of HOM6 and its upstream intermediate metabolites. Here, we conducted a survey on a spectrum of metal ions for their effect on the aspartate pathway and broader sulphur metabolism. We show that manganese (Mn(2+) ) promoted the growth of hom6∆ under both anaerobic and aerobic conditions. Unexpectedly, 4 mmol l(-1) hydrogen peroxide (H2 O2 ), a dose normally causing temporary cell growth arrest, enhanced the growth of hom6∆ under the anaerobic condition only, while it had no effect on the wild type strain BY4743. We propose that Mn(2+) and H2 O2 promote the growth of hom6∆ by reducing the accumulation of the toxic intermediate metabolite-aspartate ß-semialdehyde, via directing the aspartate pathway to the central sugar metabolism-tricarboxylic acid cycle. SIGNIFICANCE AND IMPACT OF THE STUDY: This study focuses on the yeast strain which lacks homoserine dehydrogenase encoded by HOM6 gene in aspartate metabolism. The HOM6-deletion mutant (hom6Δ) was analysed in the context of varying environmental parameters such as metal ions and oxidants, under anaerobic and aerobic conditions. We demonstrated that both manganese and hydrogen peroxide can promote the growth of hom6Δ, with the latter exerting such effect only under anaerobic condition. The findings are relevant to the research areas of ageing and anti-fungal drug development. It highlights the importance of interactions between gene expression and environmental factors as well as culture conditions.

Transcriptomic and biochemical evidence for the role of lysine biosynthesis against linoleic acid hydroperoxide-induced stress in Saccharomyces cerevisiae.

Amino acid biosynthesis forms part of an integrated stress response against oxidants in Saccharomyces cerevisiae and higher eukaryotes. Here we show an essential protective role of the l-lysine biosynthesis pathway in response to the oxidative stress condition induced by the lipid oxidant-linoleic acid hydroperoxide (LoaOOH), by means of transcriptomic profiling and phenotypic analysis, and using the deletion mutant dal80∆ and lysine auxotroph lys1∆. A comprehensive up-regulation of lysine biosynthetic genes (LYS1, LYS2, LYS4, LYS9, LYS12, LYS20 and LYS21) was revealed in dal80Δ following the oxidant challenge. The lysine auxotroph (lys1∆) exhibited a significant decrease in growth compared with that of BY4743 upon exposure to LoaOOH, albeit with the sufficient provision of lysine in the medium. Furthermore, the growth of wild type BY4743 exposed to LoaOOH was also greatly reduced in lysine-deficient conditions, despite a full complement of lysine biosynthetic genes. Amino acid analysis of LoaOOH-treated yeast showed that the level of cellular lysine remained unchanged throughout oxidant challenge, suggesting that the induced lysine biosynthesis leads to a steady-state metabolism as compared to the untreated yeast cells. Together, these findings demonstrate that lysine availability and its biosynthesis pathway play an important role in protecting the cell from lipid peroxide-induced oxidative stress, which is directly related to understanding environmental stress and industrial yeast management in brewing, wine making and baking.

Risk of having BRCA1 mutation in high-risk women with triple-negative breast cancer: a meta-analysis.

Testing for BRCA1 mutation has important clinical implications such as identifying risk of second primary cancers and risk of cancer in the family. This study seeks to quantify the risk of having BRCA1 mutation in female breast cancer patients with triple-negative phenotype compared with those with other phenotypes. We undertook a search of MEDLINE and EMBASE databases for relevant studies through 10 May 2013. Outcomes were calculated and reported as risk ratio and risk difference. 12 studies comprising 2533 breast cancer patients were included in the analysis. It was found that almost all eligible studies were performed on high-risk population with breast cancer. By analyzing the incidence rates of BRCA1 mutation in patients with triple-negative breast cancer (TNBC) and non-TNBC, our meta-analysis provides a relative risk of 5.65 [95% confidence interval (CI), 4.15-7.69] and risk difference of 0.22 (95% CI, 0.15-0.29). This implies that, in selected population with high-risk features, women with TNBC are approximately five and a half times more likely to have BRCA1 mutation compared with non-TNBC phenotype, and approximately two in nine women with TNBC harbor BRCA1 mutation. Triple-negative phenotype significantly increases the risk of having BRCA1 mutation in high-risk breast cancer patients compared with non-TNBC.

Rapid increase of NO release in plant cell cultures induced by cytokinin.

4,5-Diaminofluorescein, a fluorescence indicator for NO, was applied to detect the release of NO from plant cells. NO production was increased within 3 min when plant cell cultures (Arabidopsis, parsley, and tobacco) were treated by cytokinin and was dose-dependent and signal-specific in that other plant hormones and inactive cytokinin analog were not effective in stimulating of NO release. The response was quenched by addition of 2-(aminoethyl)-2-thiopseudourea, an inhibitor of the animal NO synthase, and by addition of an NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-1-oxy-3-oxide. These results imply that NO may act in cytokinin signal transduction.

Cardiovascular risk factors by ethnic group and menstrual status among 13- and 14-year-old Israeli schoolchildren.

BACKGROUND: Ethnic differences in cardiovascular risk factors have been demonstrated previously among Israeli children and adolescents. This study examines the prevalence of selected risk factors and risk factor clusters among 13- and 14-year old Israeli schoolchildren according to ethnic origin and other demographic variables, and takes into account the unique contribution of menstrual status of the girls to risk factor differences. METHODS: Demographic and menstrual status (for the girls) data were obtained for 299 West Jerusalem eighth grade students. Height, weight, and blood pressure were measured, and blood was obtained for total cholesterol, high density cholesterol (HDL), and triglyceride measurements. Differences in mean Body Mass Index (BMI), blood pressure, and lipids, as well as in the percentage of children with specific risk factors or total number of risk factors were tested for among the various demographic and menstrual status groups. RESULTS: BMI was statistically significantly greater among females (20.2 kg/m2) than among males (19.46 kg/m2), (p = .04) and among menstruating females (21.1 kg/m2) compared with non-menstruating females (17.9 kg/m2), (p = .000). Mean systolic blood pressure was higher among menstruating (109.8 mmHg) than non-menstruating (105.9 mmHg) females (p = .09). Statistically nonsignificant differences in mean systolic blood pressure and total cholesterol were found according to paternal country of origin. According to defined cutoff points, 8.7% of the students had elevated BMI, 2.8% had elevated systolic or diastolic blood pressure, and 13.0% had elevated total cholesterol. 17.5% of the students had one cardiovascular risk factor and 3.1% had two risk factors. CONCLUSIONS: The data demonstrate a high prevalence of cardiovascular risk factors without statistically significant ethnic differences in this population. Menstrual status exerted a unique effect upon BMI and systolic blood pressure. Pubertal status should be considered in the assessment of risk factors in early adolescents. Total-community-oriented intervention is recommended for this population.

Environmentally-related changes in red cell levels of ionic modulators of hemoglobin-O2 affinity in rainbow trout, Salmo gairdneri.

Hemoglobin content, plasma and red cell levels of chloride and magnesium and molar ion:hemoglobin ratios were examined in trout acclimatized to eight combinations of two treatment levels of temperature (5, 20 degrees C), O2 availability (less than or equal to 30%, greater than or equal to 75% saturation) and photoperiod (16L:8D, 8L:16D). Increases in hemoglobin content were associated with exposure to higher temperature, abbreviated daylength and hypoxia, with hypoxia greater than photoperiod greater than temperature. Under nominal "summer" conditions (20 degrees C, hypoxia, 16L:8D) photoperiodic influence was apparently masked by hypoxic and thermal effects. Temperature was the principal determinant of plasma and cellular chloride levels as well as [Cl:Hb]. O2 availability and photoperiod had little effect. Temperature was also the primary factor influencing magnesium, with hypoxia exerting a lesser influence. Photoperiod effects were negligible. With increased temperature and reduced O2 availability, plasma magnesium increased white cell magnesium levels and [Mg:Hb] declined. These observations suggest that with normal seasonal changes in environmental conditions, temperature-induced increases in the O2 requirements of summer trout are probably accompanied by increases in blood O2-carrying capacity and reductions in hemoglobin-O2 affinity with consequent increases in O2 delivery to tissues.