A genome-wide survey of CD4+ lymphocyte regulatory genetic variants identifies novel asthma genes

Background: Genome-wide association studies have yet to identify the majority of genetic variants involved in asthma. We hypothesized that expression quantitative trait locus (eQTL) mapping can identify novel asthma genes by enabling prioritization of putative functional variants for association testing. Objective: We evaluated 6,706 cis-acting expression-associated variants (eSNP) identified through a genome-wide eQTL survey of CD4+ lymphocytes for association with asthma. Methods: eSNP were tested for association with asthma in 359 asthma cases and 846 controls from the Childhood Asthma Management Program, with verification using family-based testing. Significant associations were tested for replication in 579 parent-child trios with asthma from Costa Rica. Further functional validation was performed by Formaldehyde Assisted Isolation of Regulatory Elements (FAIRE)-qPCR and Chromatin-Immunoprecipitation (ChIP)-PCR in lung derived epithelial cell lines (Beas-2B and A549) and Jurkat cells, a leukemia cell line derived from T lymphocytes. Results: Cis-acting eSNP demonstrated associations with asthma in both cohorts. We confirmed the previously-reported association of ORMDL3/GSDMB variants with asthma (combined p=2.9 × 108). Reproducible associations were also observed for eSNP in three additional genes: FADS2 (p=0.002), NAGA (p=0.0002), and F13A1 (p=0.0001). We subsequently demonstrated that FADS2 mRNA is increased in CD4+ lymphocytes in asthmatics, and that the associated eSNPs reside within DNA segments with histone modifications that denote open chromatin status and confer enhancer activity. Conclusions: Our results demonstrate the utility of eQTL mapping in the identification of novel asthma genes, and provide evidence for the importance of FADS2, NAGA, and F13A1 in the pathogenesis of asthma

Posterior urethral valves: Persistent renin angiotensin system activation after valve ablation and role of pre-emptive therapy with angiotensin converting enzyme-inhibitors on renal recovery

Aim: To study renin angiotensin system (RAS) activity after posterior urethral valve ablation and the role of early induction of angiotensin converting enzyme-inhibitors (ACE-I) on the outcome of renal function. Materials and Methods: Thirty four children underwent valve ablation in which therapy with ACE-I was started 40.5 ± 4.1 (range 32-47 months) formed the study group. Post-ACE-I data were collected after mean duration of 18.2 ± 4.0 (12-28 months). Plasma renin activity (PRA), urinary micro albumin, glomerular filtration rate (GFR), and serum creatinine, before and after therapy were monitored. Results: Therapy with ACE-I resulted in a fall in micro albuminuria by 45.7% and 42.0% in patients without and with vesico ureteral reflux, respectively, and improvement in split renal function by 6.6% and 5.9% GFR respectively. A similar response was noted in patients without and with renal scars. Conclusion: The decline in renal function after valve ablation is accompanied by activation of RAS reflected in a gradual rise in PRA. Therapy with ACE-I stabilizes and then improves renal function, thereby, retarding the pace of renal damage

Sacral myxopapillary ependymoma with extensive osteolysis

Myxopapillary ependymoma rarely presents as a primary intra-sacral lesion and extensive bony destruction is unusual. Radiological features do not help in distinction from other commoner sacral tumors, like chordoma. Hence, histopathology serves as the best diagnostic modality for this differentiation. We report the case of a 42-year-old man with a primary intra-sacral myxopapillary ependymoma causing extensive osteolysis

Role of bone marrow derived pluripotent stem cells in peripheral nerve repair in adult rats: A morphometric evaluation

Objectives: Semi-quantitative and quantitative assessment of the effect of bone marrow-derived mononuclear cells (BM-MNC) on early and late phase of nerve regeneration in rat sciatic nerve model. Materials and Methods: Sciatic nerve transection and repair was performed in 50 inbred female Wistar albino rats divided equally in two groups. In the test group the gap was filled with BM-MNCs obtained from the two male rats and fibrin sealant, while in the control group only fibrin sealant was used. Sciatic nerve was harvested at 15 days and at 60 days interval. Parameters of regeneration were assessed at anastomosis (G), intermediate distal (C), and distal site (A). Semi-quantitative (histopathological) and quantitative (morphometric) parameters were analyzed. Results: At 15 days there was a statistically significant difference found in mean axon diameter, mean nerve thickness and myelin thickness at the repair site (P < 0.05). However, in the distal areas, the axons were sparse and myelin rings were very thin in both the groups. At 60 days, the difference in above-mentioned parameters was statistically significant at the distal most sites. FISH assay confirmed the presence of Y chromosome, confirming the presence of BM-MNCs from the male rats. Conclusions: Transplanting BM-MNC S at the site of peripheral nerve injury leads to significantly better recovery. These differences were evident at the repair site and at the intermediate distal site at 15 days and at the distal most sites at 60 days. With practically no ethical issue regarding their isolation and application, they can be easily used for clinical trials

Epigenetics may characterize asymptomatic COVID-19 infection.

RT-PCR is the foremost clinical test for diagnosis of COVID-19. Unfortunately, PCR-based testing has limitations and may not result in a positive test early in the course of infection before symptoms develop. Enveloped RNA viruses, such as coronaviruses, alter peripheral blood methylation and DNA methylation signatures may characterize asymptomatic versus symptomatic infection. We used Illumina's Infinium MethylationEPIC BeadChip array to profile peripheral blood samples from 164 patients who tested positive for SARS-CoV-2 by RT-PCR, of whom 8 had no symptoms. Epigenome-wide association analysis identified 10 methylation sites associated with infection and a quantile-quantile plot showed little inflation. These preliminary results suggest that differences in methylation patterns may distinguish asymptomatic from symptomatic infection

Treatment of invasive IMP-4 Enterobacter cloacae infection in transplant recipients using ceftazidime/avibactam with aztreonam: A case series and literature review

Infections caused by carbapenemase-producing Enterobacteriaceae (CPE) are an emerging threat in both solid organ and stem cell transplant recipients. Invasive CPE infections in transplant recipients are associated with a high mortality, often due to limited therapeutic options and antibacterial toxicities. One of the most therapeutically challenging group of CPE are the metallo-β-lactamase (MBL)-producing Gram-negative bacteria, which are now found worldwide, and often need treatment with older, highly toxic antimicrobial regimens. Newer β-lactamase inhibitors such as avibactam have well-established activity against certain carbapenemases such as Klebsiella pneumoniae carbapenemases (KPC), but have no activity against MBL-producing organisms. Conversely, aztreonam has activity against MBL-producing organisms but is often inactivated by other co-existing β-lactamases. Here, we report four cases of invasive MBL-CPE infections in transplant recipients caused by IMP-4-producing Enterobacter cloacae who were successfully treated with a new, mechanism-driven antimicrobial combination of ceftazidime/avibactam with aztreonam. This novel antimicrobial combination offers a useful treatment option for high-risk patients with CPE infection, with reduced drug interactions and toxicity.Kelly A. Cairns, Victoria Hall, Genevieve E. Martin, David W.J. Griffin, James D. Stewart, Sadid F. Khan ... et al