Ramipril therapy in integrin α1-null, autosomal recessive Alport mice triples lifespan: mechanistic clues from RNA-seq analysis.

The standard of care for patients with Alport syndrome (AS) is angiotensin-converting enzyme (ACE) inhibitors. In autosomal recessive Alport (ARAS) mice, ACE inhibitors double lifespan. We previously showed that deletion of Itga1 in Alport mice [double-knockout (DKO) mice] increased lifespan by 50%. This effect seemed dependent on the prevention of laminin 211-mediated podocyte injury. Here, we treated DKO mice with vehicle or ramipril starting at 4 weeks of age. Proteinuria and glomerular filtration rates were measured at 5-week intervals. Glomeruli were analyzed for laminin 211 deposition in the glomerular basement membrane (GBM) and GBM ultrastructure was analyzed using transmission electron microscopy (TEM). RNA sequencing (RNA-seq) was performed on isolated glomeruli at all time points and the results were compared with cultured podocytes overlaid (or not) with recombinant laminin 211. Glomerular filtration rate declined in ramipril-treated DKO mice between 30 and 35 weeks. Proteinuria followed these same patterns with normalization of foot process architecture in ramipril-treated DKO mice. RNA-seq revealed a decline in the expression of Foxc2, nephrin (Nphs1), and podocin (Nphs2) mRNAs, which was delayed in the ramipril-treated DKO mice. GBM accumulation of laminin 211 was delayed in ramipril-treated DKO mice, likely due to a role for α1ß1 integrin in CDC42 activation in Alport mesangial cells, which is required for mesangial filopodial invasion of the subendothelial spaces of the glomerular capillary loops. Ramipril synergized with Itga1 knockout, tripling lifespan compared with untreated ARAS mice. © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Seasonal exacerbation of esophageal eosinophilia in children with eosinophilic esophagitis and allergic rhinitis.

BACKGROUND: Evidence supports a possible link between eosinophilic esophagitis (EoE) and environmental aeroallergens, which can manifest as seasonal exacerbation of esophageal eosinophilia. Few studies have examined this link in pediatric patients with EoE. OBJECTIVE: To identify the proportion of patients with seasonal induced esophageal eosinophilia. METHODS: A retrospective chart review was conducted of all patients diagnosed with EoE at the authors' institution. Demographic data were collected by chart review. Seasonal variation or flare was defined as a change from fewer than to at least 15 eosinophils per high-power field and a minimum of a 2-fold increase in eosinophil count between 2 consecutive biopsy specimens in different seasons without dietary or medication modifications. RESULTS: Of the 1,180 patients with EoE, 160 (14%) were suspected of having aeroallergen-associated triggers by history. Of these 160 patients, 32 (20%) had biopsy examination-confirmed variation of EoE triggered by aeroallergens. Most of these patients were boys (84%), all had a history or examination consistent with allergic rhinitis, and most had a history of asthma (75%). Thirty-two subjects had obvious seasonal variation, 22 of whom also had known food-induced symptoms. CONCLUSION: Children with EoE and allergic rhinitis might have exacerbations in their esophageal eosinophilia during certain seasons depending on the specific aeroallergens to which they are sensitized. Identification of environmental allergens to sensitized patients is important and can guide therapy.

Increased risks of Maternal Mental Health Conditions Following the COVID-19 Pandemic.

Background: Women are at an increased risk of developing psychiatric conditions such as anxiety and depression during pregnancy. Psychiatric conditions during pregnancy can put mothers and fetuses at risk of worse physical and mental health before, during, and after the completion of a pregnancy. Previous research indicates that women pregnant during COVID-19 were at a greater risk of developing mental health conditions and being exposed to stressors. While most of the research in the field focuses solely on maternal mental health or interactions between stressors and maternal mental health, little research has been done comparing maternal mental health, demographic variables, and socioeconomic variables across pre-, during-, and post-COVID-19 time periods. Methods: We conducted an observational cohort study of 703 mothers divided into pre-, during-, and post-COVID-19 groups based on time of enrollment. Results: Rates of maternal anxiety (p < 0.001), medication use for anxiety (p < 0.001), depression (p < 0.001), medication use for depression (p < 0.001), history of postpartum depression (p < 0.001), and medication use for other psychiatric conditions (p < 0.001) significantly increased during COVID-19 and remained at elevated levels post-COVID-19 compared with pre-COVID-19. Income >150% of the poverty level (p = 0.003), food security level (p = 0.010), marital status (p = 0.001), and private insurance type (p < 0.001) were significantly increased during COVID-19 compared with pre-COVID-19 levels. Conclusions: Future work should focus on stratifying the effects of the COVID-19 pandemic on maternal mental health by race and ethnicity and establishing guidelines to support maternal mental health during epidemics and pandemics.