Hepatitis B virus-related post-infectious glomerulonephritis: A case report

Hepatitis B virus infection is an uncommon cause of acute glomerulonephritis. We present a case of acute glomerulonephritis revealing a chronic viral  hepatitis B. A 45 year-old man was admitted in the nephrology department of Hassan II university hospital (Fez, Morocco) for nephritic syndrome with  advanced acute kidney injury. The investigations have revealed viral hepatitis B with a positive HBV-DNA and Others viral serology tests were negative. Renal biopsy showed a diffuse and global endocapillary proliferation without extra-capillary proliferation; and global deposits of C3 and Ig G On  immunofluorescence. There wasn't any other infectious cause. We thus retained the diagnosis of hepatitis B virus-associated acute  glomerulonephritis. He was given entecavir and corticosteroids. Three months later, the evolution was marked by the normalization of renal function, negativity of proteinuria and HBV DNA became undetectable. There was no relapse of glomerulonephritis and HBV viral load was still negative after one year follow-up

Temporal Effects in a Security Inspection Task: Breakdown of Performance Components

Data from certified screeners performing an x-ray inspection task for 4 hours, or 1000 images, were analyzed to identify the nature of the vigilance decrement. The expected vigilance decrement was found, with performance measured by probability of detection (PoD) and probability of false alarm [P(FA)] decreasing from hour 1 to hour 4. Correlations between PoD and P(FA) indicate that sensitivity between hours remained the same, however a shift in criterion (Beta) occurred. Significant decreases in both detection and stopping time were found from the first hour to the second, third, and fourth hour. Evidence of changes in the search component of the time per item was found to account for part of the vigilance decrement. As the task continued, participants spent less time actively searching the image, as opposed to other activities. Evidence is provided for truncation of active search as security inspection continues

Seven days treatment with the angiotensin II type 2 receptor agonist C21 in hospitalized COVID-19 patients; a placebo-controlled randomised multi-centre double-blind phase 2 trial

Background: COVID-19 morbidity and mortality remains high and the need for safe and effective drugs continues despite vaccines. Methods: Double-blind, placebo-controlled, multi-centre, randomised, parallel group phase 2 trial to evaluate safety and efficacy of oral angiotensin II type 2 receptor agonist C21 in hospitalized patients with COVID-19 and CRP ≥ 50-150 mg/L conducted at eight sites in India (NCT04452435). Patients were randomly assigned 100 mg C21 bid or placebo for 7 days in addition to standard of care. Primary endpoint: reduction in CRP. The study period was 21 July to 13 October 2020. Findings: 106 patients were randomised and included in the analysis (51 C21, 55 placebo). There was no significant group difference in reduction of CRP, 81% and 78% in the C21 and placebo groups, respectively, with a treatment effect ratio of 0.85 [90% CI 0.57, 1.26]. In a secondary analysis in patients requiring supplemental oxygen at randomisation, CRP was reduced in the C21 group compared to placebo. At the end of the 7-day treatment, 37 (72.5%) and 30 (54.5%) of the patients did not require supplemental oxygen in the C21 and placebo group, respectively (OR 2.20 [90% CI 1.12, 4.41]). A post hoc analysis showed that at day 14, the proportion of patients not requiring supplemental oxygen was 98% and 80% in the C21 group compared to placebo (OR 12.5 [90% CI 2.9, 126]). Fewer patients required mechanical ventilation (one C21 patient; four placebo patients), and C21 was associated with a numerical reduction in the mortality rate (one vs three in the C21 and placebo group, respectively). Treatment with C21 was safe and well tolerated. Interpretation: Among hospitalised patients with COVID-19 receiving C21 for 7 days there was no reduction in CRP compared to placebo. However, a post-hoc analysis indicated a marked reduction of requirement for oxygen at day 14. The day 14 results from this study justify further evaluation in a Phase 3 study and such a trial is currently underway. Funding: Vicore Pharma AB and LifeArc, UK

The missense mutation in Abcg5 gene in spontaneously hypertensive rats (SHR) segregates with phytosterolemia but not hypertension

BACKGROUND: Sitosterolemia is a recessively inherited disorder in humans that is associated with premature atherosclerotic disease. Mutations in ABCG5 or ABCG8, comprising the sitosterolemia locus, STSL, are now known to cause this disease. Three in-bred strains of rats, WKY, SHR and SHRSP, are known to be sitosterolemic, hypertensive and they carry a missense 'mutation' in a conserved residue of Abcg5, Gly583Cys. Since these rat strains are also know to carry mutations at other genetic loci and the extent of phytosterolemia is only moderate, it is important to verify that the mutations in Abcg5 are causative for phytosterolemia and whether they contribute to hypertension. METHODS: To investigate whether the missense change in Abcg5 is responsible for the sitosterolemia we performed a segregation analysis in 103 F2 rats from a SHR × SD cross. Additionally, we measured tail-cuff blood pressure and measured intestinal lipid transport to identify possible mechanisms whereby this mutation causes sitosterolemia. RESULTS: Segregation analysis showed that the inheritance of the Gly583Cys mutation Abcg5 segregated with elevated plant sterols and this pattern was recessive, proving that this genetic change is responsible for the sitosterolemia in these rat strains. Tail-cuff monitoring of blood pressure in conscious animals showed no significant differences between wild-type, heterozygous and homozygous mutant F2 rats, suggesting that this alteration may not be a significant determinant of hypertension in these rats on a chow diet. CONCLUSION: This study shows that the previously identified Gly583Cys change in Abcg5 in three hypertension-susceptible rats is responsible for the sitosterolemia, but may not be a major determinant of blood pressure in these rats

A non-surgical approach for male germ cell mediated gene transmission through transgenesis

Microinjection of foreign DNA in male pronucleus by in-vitro embryo manipulation is difficult but remains the method of choice for generating transgenic animals. Other procedures, including retroviral and embryonic stem cell mediated transgenesis are equally complicated and have limitations. Although our previously reported technique of testicular transgenesis circumvented several limitations, it involved many steps, including surgery and hemicastration, which carried risk of infection and impotency. We improved this technique further, into a two step non-surgical electroporation procedure, for making transgenic mice. In this approach, transgene was delivered inside both testes by injection and modified parameters of electroporation were used for in-vivo gene integration in germ cells. Using variety of constructs, germ cell integration of the gene and its transmission in progeny was confirmed by PCR, slot blot and immunohistochemical analysis. This improved technique is efficient, requires substantially less time and can be easily adopted by various biomedical researchers

Stereocomplex Formation of Densely Grafted Brush Polymers

In this report, we explore the capability of macromolecules to interdigitate into densely grafted molecular brush copolymers. We demonstrate that by using the tendency for stereocomplexation between poly(l-lactide) and poly(d-lactide) as a driving force complementary linear polymers and brush copolymers can form a stereocomplex. However, stereocomplex formation between complementary brush copolymers is restricted and only partially observed when the side chains are of a critical molecular weight

Letter to the Editor: 1H and 15N sequential assignment and solution secondary structure of 15N labelled human pancreatic ribonuclease

Several members of the RNase A (bovine pancreatic ribonuclease) superfamily exhibit anticancer activity. Among the mammalian members of the superfamily, most of the antitumour activity studies have been carried out with a dimeric RNase from bovine seminal vesicles (BS-RNase) (Youle and D’Alessio, 1997). These studies show that dimer formation is crucial for cytotoxicity. Investigations are underway to transfer by protein engineering the structural determinants responsible for the antitumour activity of BS-RNase to a human immunocompatible backbone (Piccoli et al., 1999). Knowledge of the 3D structures of the involved proteins is central to rationally fulfil this objective. As a first step, human pancreatic ribonuclease (HPRNase), a 127-residue monomeric protein (Beintema et al., 1984) was constructed (Russo et al., 1993). The expressed recombinant protein was undistinguishable from the natural product isolated from human pancreas (Weickmann et al., 1981). Here, we present the assignment of practically all of its 1H and 15N spectral resonances, as well as its secondary structure in aqueous solution. The cytotoxic activity of ribonucleases has been related to their ability to evade the cytosolic ribonuclease inhibitor (RI) (Murthy and Sirdeshmukh, 1992). The structure of HP-RNase will be useful to introduce changes in it in order to increase its resistance to RI.This work was supported by the European Commission under the INCO-Copernicus Project No. IC15 CT 96-0903. The assistance of the Ministerio de Asuntos Exteriores (Spain) and OMFB (Hungary) (project E26/97) is gratefully acknowledged

Loss of TET2 in human hematopoietic stem cells alters the development and function of neutrophils

Somatic mutations commonly occur in hematopoietic stem cells (HSCs). Some mutant clones outgrow through clonal hematopoiesis (CH) and produce mutated immune progenies shaping host immunity. Individuals with CH are asymptomatic but have an increased risk of developing leukemia, cardiovascular and pulmonary inflammatory diseases, and severe infections. Using genetic engineering of human HSCs (hHSCs) and transplantation in immunodeficient mice, we describe how a commonly mutated gene in CH, TET2, affects human neutrophil development and function. TET2 loss in hHSCs produce a distinct neutrophil heterogeneity in bone marrow and peripheral tissues by increasing the repopulating capacity of neutrophil progenitors and giving rise to low-granule neutrophils. Human neutrophils that inherited TET2 mutations mount exacerbated inflammatory responses and have more condensed chromatin, which correlates with compact neutrophil extracellular trap (NET) production. We expose here physiological abnormalities that may inform future strategies to detect TET2-CH and prevent NET-mediated pathologies associated with CH

Dynamic Gene Regulatory Networks Drive Hematopoietic Specification and Differentiation.

Metazoan development involves the successive activation and silencing of specific gene expression programs and is driven by tissue-specific transcription factors programming the chromatin landscape. To understand how this process executes an entire developmental pathway, we generated global gene expression, chromatin accessibility, histone modification, and transcription factor binding data from purified embryonic stem cell-derived cells representing six sequential stages of hematopoietic specification and differentiation. Our data reveal the nature of regulatory elements driving differential gene expression and inform how transcription factor binding impacts on promoter activity. We present a dynamic core regulatory network model for hematopoietic specification and demonstrate its utility for the design of reprogramming experiments. Functional studies motivated by our genome-wide data uncovered a stage-specific role for TEAD/YAP factors in mammalian hematopoietic specification. Our study presents a powerful resource for studying hematopoiesis and demonstrates how such data advance our understanding of mammalian development.This work was funded by a Longer Larger (LoLa) consortium grant from the Biotechnology and Biological Sciences Research Council, UK, to the senior authors and the corresponding author, computing infrastructure grants from the Wellcome Trust and National Institute for Health Research to B.G., grants from Cancer Research UK to G.L. and V.K., and funding from the Bloodwise charity to C.B.This is the final version of the article. It first appeared from Cell Press via http://dx.doi.org/10.1016/j.devcel.2016.01.02