Inhaled nitric oxide for high-altitude pulmonary edema

BACKGROUND. Pulmonary hypertension is a hallmark of high-altitude pulmonary edema and may contribute to its pathogenesis. When administered by inhalation, nitric oxide, an endothelium-derived relaxing factor, attenuates the pulmonary vasoconstriction produced by short-term hypoxia. METHODS. We studied the effects of inhaled nitric oxide on pulmonary-artery pressure and arterial oxygenation in 18 mountaineers prone to high-altitude pulmonary edema and 18 mountaineers resistant to this condition in a high altitude laboratory (altitude, 4559 m). We also obtained lung-perfusion scans before and during nitric oxide inhalation to gain further insight into the mechanism of action of nitric oxide. RESULTS. In the high-altitude laboratory, subjects prone to high-altitude pulmonary edema had more pronounced pulmonary hypertension and hypoxemia than subjects resistant to high-altitude pulmonary edema. Arterial oxygen saturation was inversely related to the severity of pulmonary hypertension (r=-0.50, P=0.002). In subjects prone to high-altitude pulmonary edema, the inhalation of nitric oxide (40 ppm for 15 minutes) produced a decrease in mean (+/-SD) systolic pulmonary-artery pressure that was three times larger than the decrease in subjects resistant to such edema (25.9+/-8.9 vs. 8.7+/-4.8 mm Hg, P<0.001). Inhaled nitric oxide improved arterial oxygenation in the 10 subjects who had radiographic evidence of pulmonary edema (arterial oxygen saturation increased from 67+/-10 to 73+/-12 percent, P=0.047), whereas it worsened oxygenation in subjects resistant to high-altitude pulmonary edema. The nitric oxide-induced improvement in arterial oxygenation in subjects with high-altitude pulmonary edema was accompanied by a shift in blood flow in the lung away from edematous segments and toward nonedematous segments. CONCLUSIONS. The inhalation of nitric oxide improves arterial oxygenation in high-altitude pulmonary edema, and this beneficial effect may be related to its favorable action on the distribution of blood flow in the lungs. A defect in nitric nitric oxide synthesis may contribute to high-altitude pulmonary edema

Alpha-1 antitrypsin inhibits TMPRSS2 protease activity and SARS-CoV-2 infection

SARS-CoV-2 is a respiratory pathogen and primarily infects the airway epithelium. As our knowledge about innate immune factors of the respiratory tract against SARS-CoV-2 is limited, we generated and screened a peptide/protein library derived from bronchoalveolar lavage for inhibitors of SARS-CoV-2 spike-driven entry. Analysis of antiviral fractions revealed the presence of α1-antitrypsin (α1AT), a highly abundant circulating serine protease inhibitor. Here, we report that α1AT inhibits SARS-CoV-2 entry at physiological concentrations and suppresses viral replication in cell lines and primary cells including human airway epithelial cultures. We further demonstrate that α1AT binds and inactivates the serine protease TMPRSS2, which enzymatically primes the SARS-CoV-2 spike protein for membrane fusion. Thus, the acute phase protein α1AT is an inhibitor of TMPRSS2 and SARS-CoV-2 entry, and may play an important role in the innate immune defense against the novel coronavirus. Our findings suggest that repurposing of α1AT-containing drugs has prospects for the therapy of COVID-19

An SK3 Channel/nWASP/Abi-1 Complex Is Involved in Early Neurogenesis

BACKGROUND: The stabilization or regulated reorganization of the actin cytoskeleton is essential for cellular structure and function. Recently, we could show that the activation of the SK3-channel that represents the predominant SK-channel in neural stem cells, leads to a rapid local outgrowth of long filopodial processes. This observation indicates that the rearrangement of the actin based cytoskeleton via membrane bound SK3-channels might selectively be controlled in defined micro compartments of the cell. PRINCIPAL FINDINGS: We found two important proteins for cytoskeletal rearrangement, the Abelson interacting protein 1, Abi-1 and the neural Wiskott Aldrich Syndrome Protein, nWASP, to be in complex with SK3- channels in neural stem cells (NSCs). Moreover, this interaction is also found in spines and postsynaptic compartments of developing primary hippocampal neurons and regulates neurite outgrowth during early phases of differentiation. Overexpression of the proteins or pharmacological activation of SK3 channels induces obvious structural changes in NSCs and hippocampal neurons. In both neuronal cell systems SK3 channels and nWASP act synergistic by strongly inducing filopodial outgrowth while Abi-1 behaves antagonistic to its interaction partners. CONCLUSIONS: Our results give good evidence for a functional interplay of a trimeric complex that transforms incoming signals via SK3-channel activation into the local rearrangement of the cytoskeleton in early steps of neuronal differentiation involving nWASP and Abi-1 actin binding proteins

Mutations and variants of ONECUT1 in diabetes

Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine

European guideline on IgG4-related digestive disease – UEG and SGF evidence-based recommendations

The overall objective of these guidelines is to provide evidence-based recommendations for the diagnosis and management of immunoglobulin G4 (IgG4)-related digestive disease in adults and children. IgG4-related digestive disease can be diagnosed only with a comprehensive work-up that includes histology, organ morphology at imaging, serology, search for other organ involvement, and response to glucocorticoid treatment. Indications for treatment are symptomatic patients with obstructive jaundice, abdominal pain, posterior pancreatic pain, and involvement of extra-pancreatic digestive organs, including IgG4-related cholangitis. Treatment with glucocorticoids should be weight-based and initiated at a dose of 0.6–0.8 mg/kg body weight/day orally (typical starting dose 30-40 mg/day prednisone equivalent) for 1 month to induce remission and then be tapered within two additional months. Response to initial treatment should be assessed at week 2–4 with clinical, biochemical and morphological markers. Maintenance treatment with glucocorticoids should be considered in multi-organ disease or history of relapse. If there is no change in disease activity and burden within 3 months, the diagnosis should be reconsidered. If the disease relapsed during the 3 months of treatment, immunosuppressive drugs should be added

Implications of early respiratory support strategies on disease progression in critical COVID-19 : a matched subanalysis of the prospective RISC-19-ICU cohort

Background: Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. Methods: Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. Results: Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). Conclusion: In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk

European guidelines for the diagnosis and treatment of pancreatic exocrine insufficiency: UEG, EPC, EDS, ESPEN, ESPGHAN, ESDO, and ESPCG evidence-based recommendations

\ua9 2024 The Author(s). United European Gastroenterology Journal published by Wiley Periodicals LLC on behalf of United European Gastroenterology.Pancreatic exocrine insufficiency (PEI) is defined as a reduction in pancreatic exocrine secretion below the level that allows the normal digestion of nutrients. Pancreatic disease and surgery are the main causes of PEI. However, other conditions and upper gastrointestinal surgery can also affect the digestive function of the pancreas. PEI can cause symptoms of nutritional malabsorption and deficiencies, which affect the quality of life and increase morbidity and mortality. These guidelines were developed following the United European Gastroenterology framework for the development of high-quality clinical guidelines. After a systematic literature review, the evidence was evaluated according to the Oxford Center for Evidence-Based Medicine and the Grading of Recommendations Assessment, Development, and Evaluation methodology, as appropriate. Statements and comments were developed by the working groups and voted on using the Delphi method. The diagnosis of PEI should be based on a global assessment of symptoms, nutritional status, and a pancreatic secretion test. Pancreatic enzyme replacement therapy (PERT), together with dietary advice and support, are the cornerstones of PEI therapy. PERT is indicated in patients with PEI that is secondary to pancreatic disease, pancreatic surgery, or other metabolic or gastroenterological conditions. Specific recommendations concerning the management of PEI under various clinical conditions are provided based on evidence and expert opinions. This evidence-based guideline summarizes the prevalence, clinical impact, and general diagnostic and therapeutic approaches for PEI, as well as the specifics of PEI in different clinical conditions. Finally, the unmet needs for future research are discussed

A first update on mapping the human genetic architecture of COVID-19

peer reviewe

Patterns of alcohol consumption and acute myocardial infarction: a case-crossover analysis

Background: Alcohol consumption has been causally related to the incidence of coronary heart disease, but the role of alcohol before the event has not been explored in depth. This study tested the hypothesis that heavy drinking (binge drinking) increases the risk of subsequent acute myocardial infarctions (AMI), whereas light to moderate drinking occasions decrease the risk. Methods: Case-crossover design of 250 incident AMI cases in Switzerland, with main hypotheses tested by conditional logistic regression. Results: Alcohol consumption 12 h before the event significantly increased the risk of AMI (OR 3.1; 95% CI 1.4-6.9). Separately, the effects of moderate and binge drinking before the event on AMI were of similar size but did not reach significance. In addition, AMI patients showed more binge drinking than comparable control subjects from the Swiss general population. Conclusions: We found no evidence that alcohol consumption before the event had protective effects on AMI. Instead, alcohol consumption increased the risk