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Cerebral cavernous malformations (CCMs) are anomalies of the cerebral vasculature. Loss of the CCM proteins CCM1/KRIT1, CCM2, or CCM3/PDCD10 trigger a MAPK-Krüppel-like factor 2 (KLF2) signaling cascade, which induces a pathophysiological pattern of gene expression. The downstream target genes that are activated by KLF2 are mostly unknown. Here we show that Chromobox Protein Homolog 7 (CBX7), component of the Polycomb Repressive Complex 1, contributes to pathophysiological KLF2 signaling during zebrafish cardiovascular development. CBX7/cbx7a mRNA is strongly upregulated in lesions of CCM patients, and in human, mouse, and zebrafish CCM-deficient endothelial cells. The silencing or pharmacological inhibition of CBX7/Cbx7a suppresses pathological CCM phenotypes in ccm2 zebrafish, CCM2-deficient HUVECs, and in a pre-clinical murine CCM3 disease model. Whole-transcriptome datasets from zebrafish cardiovascular tissues and human endothelial cells reveal a role of CBX7/Cbx7a in the activation of KLF2 target genes including TEK, ANGPT1, WNT9, and endoMT-associated genes. Our findings uncover an intricate interplay in the regulation of Klf2-dependent biomechanical signaling by CBX7 in CCM. This work also provides insights for therapeutic strategies in the pathogenesis of CCM., (© 2024. The Author(s).)

Apolipoprotein L1 (APOL1) high-risk genotypes are associated with increased risk of chronic kidney disease (CKD) in people of West African ancestry. Given the importance of endothelial cells (ECs) in CKD, we hypothesized that APOL1 high-risk genotypes may contribute to disease via EC-intrinsic activation and dysfunction. Single cell RNA sequencing (scRNA-seq) analysis of the Kidney Precision Medicine Project dataset revealed APOL1 expression in ECs from various renal vascular compartments. Utilizing two public transcriptomic datasets of kidney tissue from African Americans with CKD and a dataset of APOL1-expressing transgenic mice, we identified an EC activation signature; specifically, increased intercellular adhesion molecule 1 (ICAM-1) expression and enrichment in leukocyte migration pathways. In vitro , APOL1 expression in ECs derived from genetically modified human induced pluripotent stem cells and glomerular ECs triggered changes in ICAM-1 and platelet endothelial cell adhesion molecule 1 (PECAM-1) leading to an increase in monocyte attachment. Overall, our data suggest the involvement of APOL1 as an inducer of EC activation in multiple renal vascular beds with potential effects beyond the glomerular vasculature., Competing Interests: M.C., E.E., R.A., A.F., K.B-M., A.S., J.C., H.K.G, B.L., R.H., L.B., P.J.G., and M.L. are all AstraZeneca employees., (© 2023 The Authors.)

Introduction: Over the past few years, there has been an increase in lung and diaphragm ultrasound applications as a tool to evaluate the outcomes and settings of noninvasive respiratory supports. However, actual clinical practices in this field are yet to be known. The aim of this study was to investigate the current clinical utilization of ultrasound for noninvasive respiratory supports on an international level., Materials and Methods: The study employed an online survey consisting of 32 items, which was sent via email to intensivists, pulmonologists, emergency medicine physicians, and other specialists with expertise in using ultrasound and/or noninvasive respiratory supports., Result: We collected 52 questionnaires. The ultrasound study of diaphragm dysfunction was well-known by the majority of respondents (57.7%). Diaphragm performance was used as a weaning failure predictor (48.5%), as a predictor of noninvasive ventilation failure (38.5%) and as a tool for the ventilator settings adjustment (30.8%). In patients with acute respiratory failure, 48.1% used ultrasound to assess the damaged lung area to set up ventilatory parameters, 34.6% to monitor it after noninvasive ventilation application, and 32.7% to match it with the ventilatory settings for adjustment purposes. When administering high flow nasal cannula - oxygen therapy, 42.3% of participants used ultrasound to evaluate lung involvement and assess flow parameters., Conclusions: Lung and diaphragm ultrasound is an established clinical practice to evaluate noninvasive respiratory supports outcomes and settings. Further studies are needed to evaluate the educational aspects to increase confidence and indications for its use.

The first application of modern non-invasive mechanical ventilation (NIV) can be traced back to over 30 years ago when a patient suffering from Duchenne Muscular Dystrophy was successfully ventilated. Since then, the use of NIV has been on the rise throughout the world. Although a very modern and safe therapy, complications during its application are inevitable. In addition to some well-known complications, others have described more rare entities. In this article, we described such rare complications as pneumoperitoneum, pneumocephalus, parotitis, gastric perforation, and barotrauma. The purpose of this review was to describe unusual complications of NIV, their prevalence, and the mechanisms by which such complications arise. We performed a clinical review by searching PubMed, Embase, and Cochrane libraries with Mesh terms: 'non-invasive mechanical ventilation', 'high-flow nasal cannula', 'rare complication', 'unusual complication', and 'unexpected complication'. These terms were cross-referenced with other keywords: 'pneumoperitoneum', 'parotitis', 'pneumocephalus', 'gastric insufflation', and 'barotrauma'. We included 26 research papers. When applying mechanical ventilation, it is necessary to have a strong knowledge of the mechanics of the device as well as familiarity with the complications that may occur during its use, including less common ones. Prompt and effective treatment of such complications is required, as well as careful consideration of the potential causes of such events, during the application of NIV or HFNC.

Prokaryotic restriction enzymes, recombinases and Cas proteins are powerful DNA engineering and genome editing tools. However, in many primary cell types, the efficiency of genome editing remains low, impeding the development of gene- and cell-based therapeutic applications. A safe strategy for robust and efficient enrichment of precisely genetically engineered cells is urgently required. Here, we screen for mutations in the receptor for Diphtheria Toxin (DT) which protect human cells from DT. Selection for cells with an edited DT receptor variant enriches for simultaneously introduced, precisely targeted gene modifications at a second independent locus, such as nucleotide substitutions and DNA insertions. Our method enables the rapid generation of a homogenous cell population with bi-allelic integration of a DNA cassette at the selection locus, without clonal isolation. Toxin-based selection works in both cancer-transformed and non-transformed cells, including human induced pluripotent stem cells and human primary T-lymphocytes, as well as it is applicable also in vivo, in mice with humanized liver. This work represents a flexible, precise, and efficient selection strategy to engineer cells using CRISPR-Cas and base editing systems.

Background: The influence of exercise on the pulmonary function is controverse, some studies have reported no sports influence, while the others have found positive correlation., Aim: To evaluate and compare the sports influence on pulmonary function: spirometry (VC, FVC, FEV1, FEV1/FVC), lung diffusing capacity (DLCO) and coefficient of the CO gas transfer (KCO) in two elite athletes groups and healthy sedentary controls., Method: Equally divided into aerobic and anaerobic group, 60 elite athletes were recruited, as well as 43 age-matched, healthy sedentary controls. All of the participants performed basic anthropometric measurements, spirometry, DLCO and KCO at rest. Kruskal-Wallis one way ANOVA test was used to determine differences between groups; Mann-Whitney U test was used for inter-groups differences and Pearson coefficient for pulmonary variables and anthropometric parameters correlation. Statistical analyses were performed using the SPSS computer statistic program, version 20., Results: No differences were found in pulmonary characteristics (spirometric function values, DLCO and KCO) in athletes and non-athletes at rest, as well as between aerobics and anaerobics. There were no correlations between the anthropometric parameters and the investigated respiratory function tests. DLCO (%) correlated positively with height in athletes playing anaerobic type of sport (karate and taekwondo) (p=0.036; r=0.544), and negatively in sedentary control group (p=0.030; r=-0.560). Regarding KCO, no differences were found., Conclusion: Spirometry indices and DLCO are not influenced either by aerobic or anaerobic training type, so benefits of sports on pulmonary indices or DLCO was not confirmed., (Copyright © 2017 Sociedade Portuguesa de Pneumologia. Published by Elsevier España, S.L.U. All rights reserved.)

Objective: To examine differences in lung function among sports that are of a similar nature and to determine which anthropometric/demographic characteristics correlate with lung volumes and flows., Methods: This was a cross-sectional study involving elite male athletes (N = 150; mean age, 21  4 years) engaging in one of four different sports, classified according to the type and intensity of exercise involved. All athletes underwent full anthropometric assessment and pulmonary function testing (spirometry)., Results: Across all age groups and sport types, the elite athletes showed spirometric values that were significantly higher than the reference values. We found that the values for FVC, FEV1, vital capacity, and maximal voluntary ventilation were higher in water polo players than in players of the other sports evaluated (p < 0.001). In addition, PEF was significantly higher in basketball players than in handball players (p < 0.001). Most anthropometric/demographic parameters correlated significantly with the spirometric parameters evaluated. We found that BMI correlated positively with all of the spirometric parameters evaluated (p < 0.001), the strongest of those correlations being between BMI and maximal voluntary ventilation (r = 0.46; p < 0.001). Conversely, the percentage of body fat correlated negatively with all of the spirometric parameters evaluated, correlating most significantly with FEV1 (r = -0.386; p < 0.001)., Conclusions: Our results suggest that the type of sport played has a significant impact on the physiological adaptation of the respiratory system. That knowledge is particularly important when athletes present with respiratory symptoms such as dyspnea, cough, and wheezing. Because sports medicine physicians use predicted (reference) values for spirometric parameters, the risk that the severity of restrictive disease or airway obstruction will be underestimated might be greater for athletes.

Background: Torsion of the pregnant uterus at term is a very infrequent obstetric event. It is usually associated with the presence of myoma or congenital deformities. Maternal prognosis is good after surgical treatment; however, prenatal mortality is high., Case Report: We report a case of posterior low transverse hysterectomy in a case of uterine torsion at 38 weeks' gestation, due to a large myoma. At presentation, her cervix was unfavorable and cardiotocography showed spontaneous deceleration demanding delivery by cesarean section. Following delivery, it was realized that the incision had been made on the posterior wall of the uterus and that the uterus was axially rotated by 180 degrees. The mother recovered uneventfully and both mother and the baby were discharged on the fifth postoperative day., Conclusion: Obstetricians must have uterine torsion in mind when performing a cesarean section in patients with myomas.

Conflict of Interest: NONE DECLARED., Introduction: P-wave abnormalities on the resting electrocardiogram have been associated with cardiovascular or pulmonary disease. So far, "Gothic" P wave and verticalization of the frontal plane axis is related to lung disease, particularly obstructive lung disease., Aim: We tested if inverted P wave in AVl as a lone criteria of P wave axis >70° could be screening tool for emphysema., Material and Method: 1095 routine electrocardiograms (ECGs) were reviewed which yielded 478 (82,1%) ECGs with vertical P-axis in sinus rhythm. Charts were reviewed for the diagnosis of COPD and emphysema based on medical history and pulmonary function tests., Conclusion: Electrocardiogram is very effective screening tool not only in cardiovascular field but in chronic obstructive pulmonary disease. The verticality of the P axis is usually immediately apparent, making electrocardiogram rapid screening test for emphysema.