Erratum: Author Correction: Identification of genes required for eye development by high-throughput screening of mouse knockouts.

[This corrects the article DOI: 10.1038/s42003-018-0226-0.]

Oxidative damages in tubular epithelial cells in IgA nephropathy: role of crosstalk between angiotensin II and aldosterone

<p>Abstract</p> <p>Background</p> <p>Inhibition of the renin-angiotensin-aldosterone system (RAAS) slows down the progression of chronic renal diseases (CKD) including IgA nephropathy (IgAN). Herein, we studied the pathogenetic roles of aldosterone (Aldo) in IgAN.</p> <p>Methods</p> <p>Human mesangial cells (HMC) was activated with polymeric IgA (pIgA) from IgAN patients and the effects on the expression of RAAS components and TGF-β synthesis examined. To study the roles of RAAS in the glomerulotubular communication, proximal tubular epithelial cells (PTEC) was cultured with conditioned medium from pIgA-activated HMC with eplerenone or PD123319, the associated apoptotic event was measured by the generation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and reactive oxygen species (ROS).</p> <p>Results</p> <p>Polymeric IgA up-regulated the Aldo synthesis and aldosterone synthase expression by HMC. The release of TGF-β by HMC was up-regulated synergistically by AngII and Aldo and this was inhibited by incubation of HMC with losartan plus eplerenone. Cultured PTEC express the mineralocorticoid receptor, but not synthesizing aldosterone. Apoptosis, demonstrated by cleaved PARP expression and caspase 3 activity, was induced in PTEC activated by conditioned medium prepared from HMC cultured with pIgA from IgAN patients. This apoptotic event was associated with increased generation of NADPH oxidase and ROS. Pre-incubation of PTEC with PD123319 and eplerenone achieved complete inhibition of PTEC apoptosis.</p> <p>Conclusions</p> <p>Our data suggest that AngII and Aldo, released by pIgA activated HMC, served as mediators for inducing apoptosis of PTEC in glomerulo-tubular communications. Crosstalk between AngII and Aldo could participate in determining the tubular pathology of IgAN.</p

Identification of genes required for eye development by high-throughput screening of mouse knockouts.

Despite advances in next generation sequencing technologies, determining the genetic basis of ocular disease remains a major challenge due to the limited access and prohibitive cost of human forward genetics. Thus, less than 4,000 genes currently have available phenotype information for any organ system. Here we report the ophthalmic findings from the International Mouse Phenotyping Consortium, a large-scale functional genetic screen with the goal of generating and phenotyping a null mutant for every mouse gene. Of 4364 genes evaluated, 347 were identified to influence ocular phenotypes, 75% of which are entirely novel in ocular pathology. This discovery greatly increases the current number of genes known to contribute to ophthalmic disease, and it is likely that many of the genes will subsequently prove to be important in human ocular development and disease

Identification of genes required for eye development by high-throughput screening of mouse knockouts

International audienc

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Promoting Positive Mother–Infant Relationships: A Randomized Trial of Community Doula Support For Young Mothers

Doulas, whose traditional role is to support women during labor and delivery, are being increasingly utilized within community‐based programs where a primary goal is supporting mother–infant relationships. The present study investigated the effect of doula services on parenting among young, low‐income mothers. A total of 248 pregnant women were randomly assigned to receive either doula services or routine medical and social services. The doulas provided prenatal home visitation, support during labor and delivery, and 3 months of postpartum home visitation. Parenting was assessed through video recordings of mother–infant interaction at 4, 12, and 24 months of child age and maternal report of parenting attitudes and stress. Intent‐to‐treat analyses showed that mothers who had received doula services endorsed more child‐centered parenting values, showed more positive engagement with their infants, and were more likely to respond to infant distress at 4 months. Their infants were less likely to show visible upset during observed interactions. Most effects of the program on parent and child behavior faded over time. Community doula intervention is a promising practice for supporting parenting and parent–infant interaction. Integration of doulas into longer term home‐visiting models might sustain the early impact of doula services and enhance parenting services offered by traditional home‐visiting programs. El servicio de “Doulas,” cuyo papel tradicional es apoyar a las mujeres durante el parto, está siendo utilizado con más frecuencia dentro de programas con base comunitaria donde una meta primordial es apoyar las relaciones madre‐infante. El presente estudio investigó el efecto que el servicio de “doula,” tiene en la crianza entre madres jóvenes de bajos recursos. 248 mujeres embarazadas fueron asignadas al azar para recibir bien el servicio de “doula,” bien los servicios médicos y sociales rutinarios. El servicio de “doula” proveyó visitas prenatales a casa, apoyo durante el parto, y tres meses de visitas a casa posteriormente al parto. La crianza fue evaluada por medio de grabaciones de vídeo de las interacciones madre‐infante a los 4, 12 y 24 meses de edad del niño, y por el reporte maternal de las actitudes y el estrés de la crianza. Los análisis basados en la “intención de tratamiento” mostraron que las madres que habían recibido el servicio de “doula” aprobaban valores de crianza más enfocados en el niño, mostraban un involucramiento más positivo con sus infantes, y estaban más propensas a responder a la angustia del infante a los 4 meses. Sus infantes estaban menos propensos a mostrar un disgusto visible durante las interacciones observadas. La mayoría de los efectos del programa sobre la crianza y la conducta del niño desaparecieron con el tiempo. La intervención del servicio comunitario de “doula” es una práctica para apoyar la crianza y la interacción madre‐infante. La integración del servicio de “doula” en modelos de visita a casa a más largos plazos pudiera mantener el impacto inicial de estos servicios y mejorar los servicios de crianza ofrecidos por programas tradicionales de visita a casa. Les doulas, dont le rôle traditionnel est de soutenir les femmes durant le travail et l’accouchement, sont de plus en plus utilisées au soin de programmes axés sur la communauté où le but principal est de soutenir les relations mères‐nourrisson. Cette étude s’est penchée sur l’effet des services de doulas sur le parentage chez de jeunes mères issues de milieux dévaforisés. 248 femmes enceintes ont été designées au hasard pour soit recevoir des services doula ou soit recevoir les services médicaux et sociaux de routine. La doula a offert des visites prénatales à domicile, un soutien durant le travail et l’accouchement, et trois mois de visites à domicile après l’accouchement. Le parentage a été évalué à travers des enregistrements vidéos de l’interaction mère‐nourrisson à 4, 12, et 24 moois pour l’enfant et des compte‐rendus maternels d’attitudes parentales et de stress. Les analyses Intention‐de‐traiter ont démontré que les mères ayant reçu les services doula faisaient preuves de plus de valeurs de parentage centrées sur l’enfant, d’un engagement plus positif avec leurs nourrissons, et étaient plus à même de réagir à la détresse du nourrisson à 4 mois. Les nourrissons étaient moins à même de faire preuve de contrariété visible durent les interactions observées. La plupart des effets du programme sur le comportement du parent et de l’enfant ont passés avec le temps. L’intervention d’une doula communautaire est une pratique pleine de promesse pour le soutien au parentage et à l’interaction parent‐nourrisson. L’intégration des doulas dans des modèles de visite à domicile à plus lolng terme pourrait soutenir l’impact précoce des services de doula et améliorer les services de parentage offerts par les programmes de visite à domicile traditionnels. Doulas, deren traditionelle Aufgabe es ist, Frauen während der Geburtswehen und der Geburt zu unterstützen, werden zunehmend in Community‐basierten Programmen eingesetzt, die als primäres Ziel das Unterstützen der Mutter‐Kind‐Beziehungen anstreben. Die vorliegende Studie untersuchte die Wirkung der Dienstleistungen von Doulas auf das Erziehungsverhalten junger Mütter mit niedrigem Einkommen. 248 schwangere Frauen wurden entweder den Doula‐Dienstleistungen oder medizinischen und sozialen Routinedienstleistungen randomisiert zugewiesen. Die Doulas führten pränatale Hausbesuche durch, unterstützen bei den Wehen und der Geburt und nahmen drei Monate nach der Geburt Hausbesuche vor. Das Erziehungsverhalten wurde anhand von Videoaufnahmen der Mutter‐Kind‐Interaktionen im Kindesalter von 4, 12 und 24 Monaten und über mütterliche Berichte bezüglich Erziehungseinstellungen und ‐belastungen untersucht. Intent‐to‐treat‐Analysen zeigten, dass Mütter, die Doula‐Dienstleistungen erhielten mehr kindzentrierte Erziehungswerte befürworteten, mehr positive Beschäftigungen mit ihren Kindern zeigten, und häufiger auf das viermonatige Kind, wenn es Kummer hatte, eingehen konnten. Ihre Kinder zeigten mit einer geringeren Wahrscheinlichkeit sichtbaren Ärger während der beobachteten Interaktionen. Die meisten Effekte des Programms auf das elterliche und kindliche Verhalten verschwanden im Laufe der Zeit. Die Doula‐Intervention ist ein vielversprechendes Verfahren zur Unterstützung des Erziehungsverhaltens und der Eltern‐Kind‐Interaktion. Die Integration von Doulas in längerfristige Hausbesuchsmodelle könnten die Effekte der frühen Doula‐Dienstleistungen aufrechterhalten und die Dienstleistungen für Erziehungsverhalten, die im Rahmen traditioneller Hausbesuchsprogramme angeboten werden, verbessern. 抄録：ドゥーラDoulaの伝統的な役割は陣痛と出産の時に女性を支援することだったが、母－乳幼児関係を支援することを主な目的とする地域社会を基盤とするプログラムcommunity‐based programsでますます利用されるようになっている。この研究では、若い低所得の母親達の間で、ドゥーラサービスが育児に与える影響を調査した。248人の妊婦が、ドゥーラサービスか、通常の医学的社会的サービスかに無作為に割り当てられた。ドゥーラは出産前の家庭訪問、陣痛と出産の間の支援、および出産３か月後の家庭訪問を提供した。育児は、乳児の月齢4、12、及び24か月時の母－乳児相互交流のビデオ記録および養育態度とストレスについての母親の報告から評価した。包括解析分析Intent‐to‐treat analysesから、ドゥーラサービスを受けた女性は、より子どもを中心とした育児に価値を置くことを認め、乳児とポジティブな関わりを見せ、そして、４か月時の乳児の不快により応答する傾向があることがわかった。乳児は、観察された相互交流の間に明らかなぐずりを示すことが少ない傾向があった。親と子どもに対するプログラムの効果の大部分は、時間が経つと消えていった。地域のドゥーラ介入は、育児と親－乳児相互交流を支援するための有望な実践である。ドゥーラを長期にわたる家庭訪問モデルと統合することにより、ドゥーラサービスの早期の影響を持続させ、伝統的な家庭訪問プログラムにより提供される育児サービスを増強するかもしれない。Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/100142/1/imhj21400.pd