Clinical implications of vitamin B₁₂ as redox-active cofactor

Vitamin B12 is a redox-active compound containing a cobalt atom that cycles between oxidation states. Superoxide scavenging induces its oxidation, disabling activation of the enzymes methionine synthase and methylmalonyl-CoA mutase, disrupting gene expression and energy production. High-dosed vitamin B12 may be clinically used to reduce oxidative stress and preserve cofactor functions

Burden and factors associated with schistosomiasis and soil-transmitted helminth infections among school-age children in Huambo, Uige and Zaire provinces, Angola

Background: Schistosomiasis and soil-transmitted helminths (STHs) contribute high disease burdens amongst the neglected tropical diseases (NTDs) and are public health problems in Angola. This study reports the prevalence, intensity and risk factors for schistosomiasis and STH infection in Huambo, Uige and Zaire provinces, Angola, to inform a school-based preventive chemotherapy program. Methods: A two-stage cluster design was used to select schools and schoolchildren to participate in parasitological and water, sanitation and hygiene (WASH) surveys across Huambo, Uige, and Zaire provinces. Point-of-care circulating cathodic antigen and urinalysis rapid diagnostic tests (RDTs) were used to determine the prevalence of Schistosoma mansoni and S. haematobium, respectively. Kato-Katz was used to identify and quantify STH species and quantify and compare with RDTs for S. mansoni. Urine filtration was used to quantify and compare with RDTs for S. haematobium. Descriptive statistics were used for prevalence and infection intensity of schistosomiasis and STH infection. Performance of RDTs was assessed through specificity and Cohen’s Kappa agreement with microscopy. A multivariate regression analysis was used to determine demographic and WASH factors associated with schistosomiasis and STH infection. Results: A total 575 schools and 17,093 schoolchildren participated in the schistosomiasis survey, of which 121 schools and 3649 schoolchildren participated in the STH survey. Overall prevalence of S. mansoni was 21.2% (municipality range 0.9–74.8%) and S. haematobium 13.6% (range 0–31.2%), with an overall prevalence of schistosomiasis of 31.4% (range 5.9–77.3%). Overall prevalence of Ascaris lumbricoides was 25.1% (range 0–89.7%), hookworm 5.2% (range 0–42.6%), and Trichuris trichiura 3.6% (range 0–24.2%), with an overall prevalence of STH infection of 29.5% (range 0.8–89.7%). Ecological zone and ethnicity were factors associated with schistosomiasis and STH infection, with older age and female sex additional risk factors for S. haematobium. Conclusions: Most municipalities met World Health Organization defined prevalence thresholds for a schistosomiasis preventive chemotherapy program. A STH preventive chemotherapy program is indicated for nearly all municipalities in Uige and select municipalities in Huambo and Zaire. The association between ecological zone and ethnicity with schistosomiasis and STH infection necessitates further evaluation of home and school environmental, sociodemographic and behavioural factors to inform targeted control strategies to complement preventive chemotherapy programs

Natural Selection Footprints Among African Chicken Breeds and Village Ecotypes

Natural selection is likely a major factor in shaping genomic variation of the African indigenous rural chicken, driving the development of genetic footprints. Selection footprints are expected to be associated with adaptation to locally prevailing environmental stressors, which may include diverse factors as high altitude, disease resistance, poor nutrition, oxidative and heat stresses. To determine the existence of a selection footprint, 268 birds were randomly sampled from three indigenous ecotypes from East Africa (Rwanda and Uganda) and North Africa (Baladi), and two registered Egyptian breeds (Dandarawi and Fayoumi). Samples were genotyped using the chicken Affymetrix 600K Axiom® Array. A total of 494,332 SNPs were utilized in the downstream analysis after implementing quality control measures. The intra-population runs of homozygosity (ROH) that occurred in >50% of individuals of an ecotype or in >75% of a breed were studied. To identify inter-population differentiation due to genetic structure, FST was calculated for North- vs. East-African populations and Baladi and Fayoumi vs. Dandarawi for overlapping windows (500 kb with a step-size of 250 kb). The ROH and FST mapping detected several selective sweeps on different autosomes. Results reflected selection footprints of the environmental stresses, breed behavior, and management. Intra-population ROH of the Egyptian chickens showed selection footprints bearing genes for adaptation to heat, solar radiation, ion transport and immunity. The high-altitude-adapted East-African populations’ ROH showed a selection signature with genes for angiogenesis, oxygen-heme binding and transport. The neuroglobin gene (GO:0019825 and GO:0015671) was detected on a Chromosome 5 ROH of Rwanda–Uganda ecotypes. The sodium-dependent noradrenaline transporter, SLC6A2 on a Chromosome 11 ROH in Fayoumi breed may reflect its active behavior. Inter-population FST among Egyptian populations reflected genetic mechanisms for the Fayoumi resistance to Newcastle Disease Virus (NDV), while FST between Egyptian and Rwanda–Uganda populations indicated the Secreted frizzled related protein 2, SFRP2, (GO:0009314) on Chromosome 4, that contributes to melanogenic activity and most likely enhances the Dandarawi chicken adaptation to high-intensity of solar radiation in Southern Egypt. These results enhance our understanding of the natural selection forces role in shaping genomic structure for adaptation to the stressful African conditions

Bezoar in gastro-jejunostomy presenting with symptoms of gastric outlet obstruction: a case report and review of the literature

<p>Abstract</p> <p>Introduction</p> <p>Gastric outlet obstruction usually presents with non-bilious vomiting, colicky epigastric pain, loss of appetite and occasionally, upper gastrointestinal bleeding. Causes can be classified as benign or malignant, or as extra- or intraluminal. Gastrojejunostomy is a well-recognised surgical procedure performed to bypass gastric outlet obstruction. A bezoar occurs most commonly in patients with impaired gastrointestinal motility or with a history of gastric surgery. It is an intestinal concretion, which fails to pass along the alimentary canal.</p> <p>Case presentation</p> <p>A 62-year-old Asian woman with a history of gastrojejunostomy for peptic ulcer disease was admitted to hospital with epigastric pain, vomiting and dehydration. All investigations concluded gastric outlet obstruction secondary to a "stricture" at the site of gastrojejunostomy. Subsequent laparotomy revealed that the cause of the obstruction was a bezoar.</p> <p>Conclusion</p> <p>Many bezoars can be removed endoscopically, but some will require operative intervention. Once removed, emphasis must be placed upon prevention of recurrence. Surgeons must learn to recognise and classify bezoars in order to provide the most effective therapy.</p

European consensus on essential steps of Minimally Invasive Ivor Lewis and McKeown Esophagectomy through Delphi methodology

BACKGROUND: Minimally invasive esophagectomy (MIE) is a complex and technically demanding procedure with a long learning curve, which is associated with increased morbidity and mortality. To master MIE, training in essential steps is crucial. Yet, no consensus on essential steps of MIE is available. The aim of this study was to achieve expert consensus on essential steps in Ivor Lewis and McKeown MIE through Delphi methodology. METHODS: Based on expert opinion and peer-reviewed literature, essential steps were defined for Ivor Lewis (IL) and McKeown (McK) MIE. In a round table discussion, experts finalized the lists of steps and an online Delphi questionnaire was sent to an international expert panel (7 European countries) of minimally invasive upper GI surgeons. Based on replies and comments, steps were adjusted and rephrased and sent in iterative fashion until consensus was achieved. RESULTS: Two Delphi rounds were conducted and response rates were 74% (23 out of 31 experts) for the first and 81% (27 out of 33 experts) for the second round. Consensus was achieved on 106 essential steps for both the IL and McK approach. Cronbach’s alpha in the first round was 0.78 (IL) and 0.78 (McK) and in the second round 0.92 (IL) and 0.88 (McK). CONCLUSIONS: Consensus among European experts was achieved on essential surgical steps for both Ivor Lewis and McKeown minimally invasive esophagectomy. SUPPLEMENTARY INFORMATION: The online version of this article (doi:10.1007/s00464-021-08304-5) contains supplementary material, which is available to authorized users

Cystathionine gamma-lyase is expressed in human atherosclerotic plaque microvessels and is involved in micro-angiogenesis

Atherosclerotic plaques are classically divided into stable and vulnerable plaques. Vulnerable plaques are prone to rupture with a risk for infarction. High intraplaque microvessel density predisposes to plaque vulnerability. Hydrogen sulfide (H2S) is a proangiogenic gasotransmitter which is endogenously produced by cystathionine gamma-lyase (CSE), and is believed to have vasculoprotective effects. However, due to its proangiogenic effects, H2S may result in pathological angiogenesis in atherosclerotic plaques, thereby increasing plaque vulnerability. The aim of this study was to determine CSE expression pattern in atherosclerotic plaques, and investigate whether CSE is involved in micro-angiogenesis in vitro. Endarterectomy plaques were studied for CSE expression, and the role of CSE in micro-angiogenesis was studied in vitro. CSE is expressed in plaques with similar levels in both stable and vulnerable plaques. CSE co-localized with von Willebrand Factor-positive microvessel endothelial cells and alphasmooth- muscle actin-positive SMCs. In vitro, inhibition of CSE in HMEC-1 reduced tube formation, cell viability/proliferation, and migration which was restored after culture in the presence of H2S donor GYY4137. CSE is expressed in intraplaque microvessels, and H2S is a stimulator of micro-angiogenesis in vitro. Due to this pro-angiogenic effect, high levels of CSE in atherosclerotic plaques may be a potential risk for plaque vulnerability

Assessment of p.Phe508del-CFTR functional restoration in pediatric primary cystic fibrosis airway epithelial cells

© 2018 Sutanto et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Mutations in the cystic fibrosis transmembrane regulator (CFTR) gene can reduce function of the CFTR ion channel activity and impair cellular chloride secretion. The gold standard method to assess CFTR function of ion transport using the Ussing chamber requires a high number of airway epithelial cells grown at air-liquid interface, limiting the application of this method for high throughput screening of potential therapeutic compounds in primary airway epithelial cells (pAECs) featuring less common CFTR mutations. This study assessed an alternative approach, using a small scale halide assay that can be adapted for a personalized high throughput setting to analyze CFTR function of pAEC. Methods Pediatric pAECs derived from children with CF (pAEC CF ) were established and expanded as monolayer cultures, before seeding into 96-well plates for the halide assay. Cells were then transduced with an adenoviral construct containing yellow fluorescent protein (eYFP) reporter gene, alone or in combination with either wild-type CFTR (WT-CFTR) or p.Phe508-del CFTR. Four days post transduction, cells were stimulated with forskolin and genistein, and assessed for quenching of the eYFP signal following injection of iodide solution into the assay media. Results Data showed that pAEC CF can express eYFP at high efficiency following transduction with the eYFP construct. The halide assay was able to discriminate functional restoration of CFTR in pAEC CF treated with either WT-CFTR construct or the positive controls syntaxin 8 and B-cell receptor-associated protein 31 shRNAs. Significance The current study demonstrates that the halide assay can be adapted for pediatric pAEC CF to evaluate restoration of CFTR function. With the ongoing development of small molecules to modulate the folding and/or activity of various mutated CFTR proteins, this halide assay presents a small-scale personalized screening platform that could assess therapeutic potential of molecules across a broad range of CFTR mutations

Identification and Characterization of a Small Molecule that Activates Thiosulfate Sulfurtransferase and Stimulates Mitochondrial Respiration

The enzyme Thiosulfate sulfurtransferase (TST, EC 2.8.1.1), is a positive genetic predictor of diabetes type 2 and obesity. As increased TST activity protects against the development of diabetic symptoms in mice, an activating compound for TST may provide therapeutic benefits in diabetes and obesity. We identified a small molecule activator of human TST through screening of an inhouse small molecule library. Kinetic studies in vitro suggest that two distinct isomers of the compound are required for full activation as well as an allosteric mode of activation. Additionally, we studied the effect of TST protein and the activator on TST activity through mitochondrial respiration. Molecular docking and molecular dynamics (MD) approaches supports an allosteric site for the binding of the activator, which is supported by the lack of activation in the E. coli. mercaptopyruvate sulfurtransferase. Finally, we show that increasing TST activity in isolated mitochondria increases mitochondrial oxygen consumption. This article is protected by copyright. All rights reserved.</p