Visceral leishmaniasis patients display altered composition and maturity of neutrophils as well as impaired neutrophil effector functions

Immunologically, active visceral leishmaniasis (VL) is characterised by profound immunosuppression, severe systemic inflammatory responses and an impaired capacity to control parasite replication. Neutrophils are highly versatile cells, which play a crucial role in the induction as well as the resolution of inflammation, the control of pathogen replication and the regulation of immune responses. Neutrophil functions have been investigated in human cutaneous leishmaniasis, however, their role in human visceral leishmaniasis is poorly understood. In the present study we evaluated the activation status and effector functions of neutrophils in patients with active VL and after successful anti-leishmanial treatment. Our results show that neutrophils are highly activated and have degranulated; high levels of arginase, myeloperoxidase and elastase, all contained in neutrophils’ granules, were found in the plasma of VL patients. In addition, we show that a large proportion of these cells are immature. We also analysed effector functions of neutrophils that are essential for pathogen clearance and show that neutrophils have an impaired capacity to release neutrophil extracellular traps, produce reactive oxygen species and phagocytose bacterial particles, but not Leishmania parasites. Our results suggest that impaired effector functions, increased activation and immaturity of neutrophils play a key role in the pathogenesis of VL

Mortality rate among HIV-positive children on ART in Northwest Ethiopia: a historical cohort study.

BackgroundThough highly active antiretroviral therapy (HAART) has been available for more than a decade in Ethiopia, information regarding mortality rates of human immunodeficiency virus (HIV)-positive children after antiretroviral therapy antiretroviral therapy (ART) initiation is very scarce. Thus, this study intends to determine the predictors of mortality among HIV-positive children receiving ART in Amhara Region.MethodsA multicenter facility-based historical cohort study was conducted in 538 HIV-positive children on ART from January 2012 to February 2017. We employed a standardized data extraction tool, adapted from ART entry and follow-up forms. Descriptive analyses were summarized using the Kaplan-Meier survival curve and log rank test. Then, the Cox-proportional hazard regression model was employed to estimate the hazard of death up to five-years after ART initiation. Variables with p-values ≤0.25 in bivariable analysis were candidates to the multivariable analysis. Finally, variables with p-values ResultsThe cohort contributed a total follow-up time of 14,600 child-months, with an overall mortality rate of 3.2 (95% CI: 2.3, 4.3) per 100 child-years. This study also indicated that HIV-infected children presenting with opportunistic infections (OIs) (AHR: 2.5, 95% CI: 1.04, 5.9), anemia (AHR: 3.1, 95% CI: 1.4, 6.7), severe immunodeficiency (AHR: 4.4, 95% CI: 1.7, 11.7), severe stunting (AHR: 3.3, 95% CI: 1.4, 8.0), severe wasting (AHR: 3.1, 95% CI: 1.3, 7.3), and advanced disease staging (III and IV) (AHR: 3.0, 95% CI: 1.2, 7.1) were at higher risk of mortality.ConclusionA higher rate of mortality was observed in our study as compared to previous Ethiopian studies. HIV-positive children presenting with anemia, OIs, severe immunodeficiency, advanced disease staging (III and IV), severe stunting, and severe wasting were at higher risk of mortality

Undernutrition among Ethiopian adults living with HIV: a meta-analysis.

BackgroundMalnutrition and human immunodeficiency virus (HIV) are interlaced in a vicious cycle and worsened in low and middle-income countries. In Ethiopia, even though individuals are dually affected by both malnutrition and HIV, there is no a nationwide study showing the proportion of malnutrition among HIV-positive adults. Consequently, this review addressed the pooled burden of undernutrition among HIV-positive adults in Ethiopia.MethodsWe searched for potentially relevant studies through manual and electronic searches. An electronic search was carried out using the database of PubMed, Google Scholar, and Google for gray literature and reference lists of previous studies. A standardized data extraction checklist was used to extract the data from each original study. STATA Version 13 statistical software was used for our analysis. Descriptive summaries were presented in tables, and the quantitative result was presented in a forest plot. Heterogeneity within the included studies was examined using the Cochrane Q test statistics and I 2 test. Finally, a random-effects meta-analysis model was computed to estimate the pooled proportion of undernutrition among HIV-positive adults.ResultsAfter reviewing 418 studies, 15 studies met the inclusion criteria and were included in the meta-analysis. Findings from 15 studies revealed that the pooled percentage of undernutrition among HIV-positive adults in Ethiopia was 26% (95% CI: 22, 30%). The highest percentage of undernutrition (46.8%) was reported from Jimma University specialized hospital, whereas the lowest proportion of undernutrition (12.3%) was reported from Dilla Hospital. The subgroup analyses of this study also indicated that the percentage of undernourishment among HIV-positive adults is slightly higher in the Northern and Central parts of Ethiopia (27.5%) as compared to the Southern parts of Ethiopia (25%).ConclusionThis study noted that undernutrition among HIV-positive adults in Ethiopia was quite common. This study also revealed that undernutrition is more common among HIV-positive adults with advanced disease stage, anemia, diarrhea, CD4 count less than 200 cells/mm3, and living in rural areas. Based on our findings, we suggested that all HIV-positive adults should be assessed for nutritional status at the time of ART commencement

Associations of weight and body composition at birth with body composition and cardiometabolic markers in children aged 10 y: the Ethiopian infant anthropometry and body composition birth cohort study

Background: Although birth weight (BW) has been associated with later cardiovascular disease and type 2 diabetes, the role of birth fat mass (BFM) and birth fat-free mass (BFFM) on cardiometabolic health is unclear. // Objectives: To examine associations of BW, BFM, and BFFM with later anthropometry, body composition, abdominal fat, and cardiometabolic markers. // Methods: Birth cohort data on standardized exposure variables (BW, BFM, and BFFM) and follow-up information at age 10 y on anthropometry, body composition, abdominal fat, and cardiometabolic markers were included. A linear regression analysis was used to assess associations of exposures with outcome variables, adjusting for maternal and child characteristics at birth and current body size in separate models. // Results: Among 353 children, mean (SD) age was 9.8 (1.0) y, and 51.5% were boys. In the fully adjusted model, 1-SD higher BW and BFFM were associated with 0.81 cm (95% CI: 0.21, 1.41 cm) and 1.25 cm (95% CI: 0.64, 1.85 cm) greater height at 10 y, respectively. The 1-SD higher BW and BFM were associated with 0.32 kg/m2 (95% CI: 0.14, 0.51 kg/m2) and 0.42 kg/m2 (95% CI: 0.25, 0.59 kg/m2) greater fat mass index at 10 y, respectively. In addition, 1-SD higher BW and BFFM were associated with 0.22 kg/m2 (95% CI: 0.09, 0.34 kg/m2) greater FFM index, whereas a 1-SD greater BFM was associated with a 0.05 cm greater subcutaneous adipose tissue (95% CI: 0.01, 0.11 cm). Furthermore, 1-SD higher BW and BFFM were associated with 10.3% (95% CI: 1.4%, 20.0%) and 8.3% (95% CI: −0.5%, 17.9%) greater insulin, respectively. Similarly, 1-SD higher BW and BFFM were associated with 10.0% (95% CI: 0.9%, 20.0%) and 8.5% (95% CI: −0.6%, 18.5%) greater homeostasis model assessment of insulin resistance, respectively. // Conclusions: BW and BFFM rather than BFM are predictors of height and FFM index at 10 y. Children with higher BW and BFFM showed higher insulin concentrations and homeostasis model assessment of insulin resistance at 10 y of age. // This trial was registered at ISRCTN as ISRCTN46718296

Associations of weight and body composition at birth with body composition and cardiometabolic markers in children aged 10 y: the Ethiopian infant anthropometry and body composition birth cohort study.

BACKGROUND: Although birth weight (BW) has been associated with later cardiovascular disease and type 2 diabetes, the role of birth fat mass (BFM) and birth fat-free mass (BFFM) on cardiometabolic health is unclear. OBJECTIVES: To examine associations of BW, BFM, and BFFM with later anthropometry, body composition, abdominal fat, and cardiometabolic markers. METHODS: Birth cohort data on standardized exposure variables (BW, BFM, and BFFM) and follow-up information at age 10 y on anthropometry, body composition, abdominal fat, and cardiometabolic markers were included. A linear regression analysis was used to assess associations of exposures with outcome variables, adjusting for maternal and child characteristics at birth and current body size in separate models. RESULTS: Among 353 children, mean (SD) age was 9.8 (1.0) y, and 51.5% were boys. In the fully adjusted model, 1-SD higher BW and BFFM were associated with 0.81 cm (95% CI: 0.21, 1.41 cm) and 1.25 cm (95% CI: 0.64, 1.85 cm) greater height at 10 y, respectively. The 1-SD higher BW and BFM were associated with 0.32 kg/m2 (95% CI: 0.14, 0.51 kg/m2) and 0.42 kg/m2 (95% CI: 0.25, 0.59 kg/m2) greater fat mass index at 10 y, respectively. In addition, 1-SD higher BW and BFFM were associated with 0.22 kg/m2 (95% CI: 0.09, 0.34 kg/m2) greater FFM index, whereas a 1-SD greater BFM was associated with a 0.05 cm greater subcutaneous adipose tissue (95% CI: 0.01, 0.11 cm). Furthermore, 1-SD higher BW and BFFM were associated with 10.3% (95% CI: 1.4%, 20.0%) and 8.3% (95% CI: -0.5%, 17.9%) greater insulin, respectively. Similarly, 1-SD higher BW and BFFM were associated with 10.0% (95% CI: 0.9%, 20.0%) and 8.5% (95% CI: -0.6%, 18.5%) greater homeostasis model assessment of insulin resistance, respectively. CONCLUSIONS: BW and BFFM rather than BFM are predictors of height and FFM index at 10 y. Children with higher BW and BFFM showed higher insulin concentrations and homeostasis model assessment of insulin resistance at 10 y of age. This trial was registered at ISRCTN as ISRCTN46718296

Stilbene derivatives promote Ago2-dependent tumour-suppressive microRNA activity

It is well known that natural products are a rich source of compounds for applications in medicine, pharmacy, and biology. However, the exact molecular mechanisms of natural agents in human health have not been clearly defined. Here, we demonstrate for the first time that the polyphenolic phytoalexin resveratrol promotes expression and activity of Argonaute2 (Ago2), a central RNA interference (RNAi) component, which thereby inhibits breast cancer stem-like cell characteristics by increasing the expression of a number of tumour-suppressive miRNAs, including miR-16, -141, -143, and -200c. Most importantly, resveratrol-induced Ago2 resulted in a long-term gene silencing response. We also found that pterostilbene, which is a natural dimethylated resveratrol analogue, is capable of mediating Ago2-dependent anti-cancer activity in a manner mechanistically similar to that of resveratrol. These findings suggest that the dietary intake of natural products contributes to the prevention and treatment of diseases by regulating the RNAi pathway

Effects of the TLR2 Agonists MALP-2 and Pam3Cys in Isolated Mouse Lungs

Background: Gram-positive and Gram-negative bacteria are main causes of pneumonia or acute lung injury. They are recognized by the innate immune system via toll-like receptor-2 (TLR2) or TLR4, respectively. Among all organs, the lungs have the highest expression of TLR2 receptors, but little is known about the pulmonary consequences of their activation. Here we studied the effects of the TLR2/6 agonist MALP-2, the TLR2/1 agonist Pam 3Cys and the TLR4 agonist lipopolysaccharide (LPS) on pro-inflammatory responses in isolated lungs. Methodology/Principal Findings: Isolated perfused mouse lungs were perfused for 60 min or 180 min with MALP-2 (25 ng/ mL), Pam3Cys (160 ng/mL) or LPS (1 mg/mL). We studied mediator release by enzyme linked immunosorbent assay (ELISA), the activation of mitogen activated protein kinase (MAPK) and AKT/protein kinase B by immunoblotting, and gene induction by quantitative polymerase chain reaction. All agonists activated the MAPK ERK1/2 and p38, but neither JNK or AKT kinase. The TLR ligands upregulated the inflammation related genes Tnf, Il1b, Il6, Il10, Il12, Ifng, Cxcl2 (MIP-2a) and Ptgs2. MALP-2 was more potent than Pam 3Cys in inducing Slpi, Cxcl10 (IP10) and Parg. Remarkable was the strong induction of Tnc by MALP2, which was not seen with Pam 3Cys or LPS. The growth factor related genes Areg and Hbegf were not affected. In addition, all three TLR agonists stimulated the release of IL-6, TNF, CXCL2 and CXCL10 protein from the lungs

Genomic features and computational identification of human microRNAs under long-range developmental regulation

<p>Abstract</p> <p>Background</p> <p>Recent functional studies have demonstrated that many microRNAs (miRNAs) are expressed by RNA polymerase II in a specific spatiotemporal manner during the development of organisms and play a key role in cell-lineage decisions and morphogenesis. They are therefore functionally related to a number of key protein coding developmental genes, that form genomic regulatory blocks (GRBs) with arrays of highly conserved non-coding elements (HCNEs) functioning as long-range enhancers that collaboratively regulate the expression of their target genes. Given this functional similarity as well as recent zebrafish transgenesis assays showing that the miR-9 family is indeed regulated by HCNEs with enhancer activity, we hypothesized that this type of miRNA regulation is prevalent. In this paper, we therefore systematically investigate the regulatory landscape around conserved self-transcribed miRNAs (ST miRNAs), with their own known or computationally inferred promoters, by analyzing the hallmarks of GRB target genes. These include not only the density of HCNEs in their vicinity but also the presence of large CpG islands (CGIs) and distinct patterns of histone modification marks associated with developmental genes.</p> <p>Results</p> <p>Our results show that a subset of the conserved ST miRNAs we studied shares properties similar to those of protein-coding GRB target genes: they are located in regions of significantly higher HCNE/enhancer binding density and are more likely to be associated with CGIs. Furthermore, their putative promoters have both activating as well as silencing histone modification marks during development and differentiation. Based on these results we used both an elevated HCNE density in the genomic vicinity as well as the presence of a bivalent promoter to identify 29 putative GRB target miRNAs/miRNA clusters, over two-thirds of which are known to play a role during development and differentiation. Furthermore these predictions include miRNAs of the miR-9 family, which are the only experimentally verified GRB target miRNAs.</p> <p>Conclusions</p> <p>A subset of the conserved miRNA loci we investigated exhibits typical characteristics of GRB target genes, which may partially explain their complex expression profiles during development.</p

Track E Implementation Science, Health Systems and Economics

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/138412/1/jia218443.pd