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Melissa officinalis L. ameliorates oxidative anxiety as well as inflammation and also upregulates Nrf2/HO-1 signaling in the hippocampus involving pilocarpine-induced test subjects.
In mice, IL-31 induced skin and lung fibrosis. No synergy was seen with TGFβ, which supressed IL-31RA. CONCLUSION IL-31/IL-31RA is confirmed as a candidate pro-fibrotic pathway, which may contribute to skin and lung fibrosis in a subset of scleroderma patients. © The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email [email protected] Although consensus supports eradication of Helicobacter pylori infections, antimicrobial resistance has substantially reduced eradication rates with most current therapies. Objective To assess the effectiveness of a novel rifabutin-based therapy (RHB-105) for H pylori eradication. Design Phase 3, double-blind trial (ERADICATE Hp2). (ClinicalTrials.gov NCT03198507). Setting 55 clinical research sites in the United States. Participants 455 treatment-naive adults with epigastric discomfort and confirmed H pylori infection. Intervention RHB-105 (amoxicillin, 3 g; omeprazole, 120 mg; and rifabutin, 150 mg) versus active comparator (amoxicillin, 3 g, and omeprazole, 120 mg), given as 4 capsules every 8 hours for 14 days. Measurements Between-group difference for H pylori eradication rate, demonstrated by 13C urea breath test 4 weeks after treatment, analyzed by using the χ2 test. Results In the intention-to-treat population, the eradication rate was higher with RHB-105 than with the active comparator (228 vs. 227 patients, respectively; 83.8% [95% CI, 78.4% to 88.0%] vs. 57.7% [95% CI, 51.2% to 64.0%]; P less then 0.001). Eradication rates were unaffected by resistance to clarithromycin or metronidazole. 5-Ethynyl-2'-deoxyuridine purchase No rifabutin resistance was detected. The most commonly reported adverse events (incidence ≥5%) were diarrhea (10.1% with RHB-105 vs. 7.9% with active comparator), headache (7.5% vs. 7.0%), and nausea (4.8% vs. 5.3%). Limitation Persons of Asian descent were excluded because of their higher prevalence of poor cytochrome P450 2C19 metabolizers. Conclusion These findings suggest potential for RHB-105 as first-line empirical H pylori therapy, addressing an unmet need in the current environment of increasing antibiotic resistance. Primary Funding Source RedHill Biopharma Ltd.Hahnemann University Hospital provided care for Philadelphians starting in 1848, but its recent history has been riddled with financial turmoil that culminated in its rapid closure in summer 2019. As the hospital shuttered its doors to patients, it also orphaned 583 medical trainees. This crisis exposed vulnerabilities in graduate medical education (GME). In a firsthand account of the situation that developed in Philadelphia and reached academic institutions across the country, the authors reflect on lessons learned that may help leaders at other institutions mitigate the inevitable difficulties that arise when academic hospitals close. These lessons pertain to handling panic and administrative burdens in the aftermath of closure, the importance of well-defined processes, a clear understanding of GME funding, and strategies for placement of trainees that minimize disruption of their education.Background L-thyroxine does not improve hypothyroid symptoms among adults with subclinical hypothyroidism (SCH). However, those with greater symptom burden before treatment may still benefit. Objective To determine whether L-thyroxine improves hypothyroid symptoms and tiredness among older adults with SCH and greater symptom burden. Design Secondary analysis of the randomized, placebo-controlled trial TRUST (Thyroid Hormone Replacement for Untreated Older Adults with Subclinical Hypothyroidism Trial). (ClinicalTrials.gov NCT01660126). Setting Switzerland, Ireland, the Netherlands, and Scotland. Participants 638 persons aged 65 years or older with persistent SCH (thyroid-stimulating hormone level of 4.60 to 19.9 mIU/L for >3 months and normal free thyroxine level) and complete outcome data. Intervention L-thyroxine or matching placebo with mock dose titration. Measurements 1-year change in Hypothyroid Symptoms and Tiredness scores (range, 0 to 100; higher scores indicate more symptoms) on the Thyroid-Related Qore or Tiredness score modified the effects of L-thyroxine versus placebo (P for interaction = 0.20 and 0.82, respectively). Limitation Post hoc analysis, small sample size, and examination of only patients with 1-year outcome data. Conclusion In older adults with SCH and high symptom burden at baseline, L-thyroxine did not improve hypothyroid symptoms or tiredness compared with placebo. Primary Funding Source European Union FP7.On March 11, 2020, the World Health Organization declared COVID-19 a pandemic1. The outbreak containment strategies in China based on non-pharmaceutical interventions (NPIs) appear to be effective2, but quantitative research is still needed to assess the efficacy of NPIs and their timings3. Using epidemiological and anonymised human movement data4,5, here we develop a modelling framework that uses daily travel networks to simulate different outbreak and intervention scenarios across China. We estimated that there were a total of 114,325 COVID-19 cases (interquartile range 76,776 - 164,576) in mainland China as of February 29, 2020. Without NPIs, the COVID-19 cases would likely have shown a 67-fold increase (interquartile range 44 - 94) by February 29, 2020, with the effectiveness of different interventions varying. The early detection and isolation of cases was estimated to have prevented more infections than travel restrictions and contact reductions, but combined NPIs achieved the strongest and most rapid effect. The lifting of travel restrictions since February 17, 2020 does not appear to lead to an increase in cases across China if the social distancing interventions can be maintained, even at a limited level of 25% reduction on average through late April. Our findings contribute to an improved understanding of NPIs on COVID-19 and to inform response efforts across the World.Reverse genetics has been an indispensable tool revolutionising insights into viral pathogenesis and vaccine development. Large RNA virus genomes, such as from Coronaviruses, are cumbersome to clone and manipulate in E. coli due to size and occasional instability1-3. Therefore, an alternative rapid and robust reverse genetics platform for RNA viruses would benefit the research community. Here we show the full functionality of a yeast-based synthetic genomics platform to genetically reconstruct diverse RNA viruses, including members of the Coronaviridae, Flaviviridae and Paramyxoviridae families. Viral subgenomic fragments were generated using viral isolates, cloned viral DNA, clinical samples, or synthetic DNA, and reassembled in one step in Saccharomyces cerevisiae using transformation associated recombination (TAR) cloning to maintain the genome as a yeast artificial chromosome (YAC). T7-RNA polymerase has been used to generate infectious RNA to rescue viable virus. Based on this platform we have been able to engineer and resurrect chemically-synthetized clones of the recent epidemic SARS-CoV-24 in only a week after receipt of the synthetic DNA fragments. The technical advance we describe here allows a rapidly response to emerging viruses as it enables the generation and functional characterization of evolving RNA virus variants-in real-time-during an outbreak.BACKGROUND Bronchopulmonary dysplasia remains one of the most common complications of prematurity, despite significant improvements in perinatal care. Functional modeling of human lung development and disease, like BPD, is limited by our ability to access the lung and to maintain relevant progenitor cell populations in culture. METHODS We supplemented Rho/SMAD signaling inhibition with mTOR inhibition to generate epithelial basal cell-like cell lines from tracheal aspirates of neonates. RESULTS Single-cell RNA-sequencing confirmed the presence of epithelial cells in tracheal aspirates obtained from intubated neonates. Using Rho/SMAD/mTOR triple signaling inhibition, neonatal tracheal aspirate-derived (nTAD) basal cell-like cells can be expanded long term and retain the ability to differentiate into pseudostratified airway epithelium. CONCLUSIONS Our data demonstrate that neonatal tracheal aspirate-derived epithelial cells can provide a novel ex vivo human cellular model to study neonatal lung development and disease. IMPACT Airway epithelial basal cell-like cell lines were derived from human neonatal tracheal aspirates.mTOR inhibition significantly extends in vitro proliferation of neonatal tracheal aspirate-derived basal cell-like cells (nTAD BCCs).nTAD BCCs can be differentiated into functional airway epithelium.nTAD BCCs provide a novel model to investigate perinatal lung development and diseases.INTRODUCTION Gonadotropin-releasing hormone (GnRH) deficiency causes hypogonadotropic hypogonadism (HH), a rare genetic disorder that impairs sexual reproduction. HH can be due to defective GnRH-secreting neuron development or function and may be associated with other clinical signs in overlapping genetic syndromes. With most of the cases being idiopathic, genetics underlying HH is still largely unknown. OBJECTIVE To assess the contribution of mutated Semaphorin 3G (SEMA3G) gene in the onset of a syndromic form of HH, characterized by intellectual disabilities and facial dysmorphic features. METHOD By combining homozygosity mapping with exome sequencing, we identified a novel variant in SEMA3G gene. We then applied mouse as a model organism to examine SEMA3G expression and its functional requirement in vivo. Further, we applied homology modelling in silico and cell culture assays in vitro to validate the pathogenicity of the identified gene variant. RESULTS We found that SEMA3G is expressed along the migratory route of GnRH neurons and in the developing pituitary; SEMA3G affects GnRH neuron development, but is redundant in the adult hypothalamic-pituitary-gonadal axis; mutated SEMA3G alters binding properties in silico and in vitro to its PlexinAs receptors and attenuates its effect on the migration of immortalized GnRH neurons. CONCLUSION In silico, in vitro and in vivo models revealed that SEMA3G regulates GnRH neuron migration and that its mutation affecting receptor selectivity may be responsible for the HH-related defects. © 2020 S. Karger AG, Basel.BACKGROUND Little information is available concerning prognostic factors of bronchopulmonary large cell neuroendocrine carcinomas (BP-LCNECs) and even less is known about combined LCNECs (Co-LCNECs). We investigated whether an integrated morphological, immunohistochemical and molecular approach could be used for their prognostic evaluation. METHODS Morphological (including combined features), proliferative (mitotic count/Ki-67 index), immunohistochemical (napsin A, p-40, TTF-1, CD44, OTP, SSTR2A, SSTR5, mASH1, p53, RB1, MDM2) and genomic (TP53, RB1, ATM, JAK2, KRAS, STK11) findings were analyzed from BP-LCNECs from 5 Italian centers, and correlated with overall survival (OS). Ki-67 was expressed as a percentage of positive cells in hot spot as indicated in the WHO 2019 Digestive System Tumors and, for Co-LCNEC, Ki-67 was evaluated only in the LCNEC component. RESULTS 111 LCNECs were distinguished in 70 pure LCNECs, 35 co-LCNECs [27 with adenocarcinoma (ADC); 8 with squamous cell carcinoma (SqCC) and 6 LCNECs with only napsin A immunoreactivity].
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