Age-determined expression of priming protease TMPRSS2 and localization of SARS-CoV-2 in lung epithelium

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) novel coronavirus 2019 (COVID-19) global pandemic has led to millions of cases and hundreds of thousands of deaths. While older adults appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of developing mouse lung with temporally resolved immunofluorescence in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike protein primer TMPRSS2 was highest in ciliated cells and type I alveolar epithelial cells (AT1), and TMPRSS2 expression increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases detected SARS-CoV-2 RNA most frequently in ciliated and secretory cells in airway epithelium and AT1 cells in peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing TMPRSS2. Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in lung epithelium and suggest that developmental regulation of TMPRSS2 may underlie the relative protection of infants and children from severe respiratory illness.     

Cognition in older women: the importance of daytime movement

OBJECTIVES: To determine whether an objective measure of daytime movement is associated with better cognitive function in women in their 80s. DESIGN: Cross‐sectional. SETTING: A study of health and aging. PARTICIPANTS: Two thousand seven hundred thirty‐six older women without evidence of dementia. MEASUREMENTS: Daytime movement was assessed using actigraphy, which involved wearing a watch‐like device that objectively quantified accelerometer motion over a mean of 3.0±0.8 days. Cognitive function was measured using the Trail‐Making Test, Part B (Trails B) and the Mini‐Mental State Examination (MMSE). Cognitive impairment was defined as performing 1.5 standard deviations (SDs) worse than the mean on a given test. RESULTS: Participants had a mean age of 83±4; 10% were African American. After adjustment for age, race, and education, women in the highest movement quartiles had better mean cognitive test scores (20±0.3 seconds faster on Trails B and 0.3±0.2 points higher on MMSE, both P<.001) than those in the lowest quartile and were less likely to be cognitively impaired (odds ratio (OR)=0.61, 95% confidence interval (CI)=0.41–0.92 for Trails B; OR=0.68, 95% CI=0.44–1.07 for MMSE). Associations were similar in different subgroups and were independent of self‐reported walking, medical comorbidities, physical function, and other health‐related behaviors. CONCLUSION: Daytime movement as measured objectively using actigraphy was associated with better cognitive function and lower odds of cognitive impairment in women in their 80s. Additional studies are needed to clarify the direction of the association and to explore potential mechanisms.     

Mild Gestational Diabetes Mellitus and Long-Term Child Health

OBJECTIVETo evaluate whether treatment of mild gestational diabetes mellitus (GDM) confers sustained offspring health benefits, including a lower frequency of obesity.RESULTSFive hundred of 905 eligible offspring (55%) were enrolled. Maternal baseline characteristics were similar between the follow-up treated and untreated groups. The frequencies of BMI ≥95th (20.8% and 22.9%) and 85th (32.6% and 38.6%) percentiles were not significantly different in treated versus untreated offspring (P = 0.69 and P = 0.26). No associations were observed for BMI z score, log waist circumference, log triglycerides, HDL cholesterol, blood pressure, or log HOMA-estimated insulin resistance (HOMA-IR). The effect of treatment was different by sex for fasting glucose and log HOMA-IR (P for interaction = 0.002 and 0.02, respectively) but not by age-group (5–6 and 7–10 years) for any outcomes. Female offspring of treated women had significantly lower fasting glucose levels.CONCLUSIONSAlthough treatment for mild GDM has been associated with neonatal benefits, no reduction in childhood obesity or metabolic dysfunction in the offspring of treated women was found. However, only female offspring of women treated for mild GDM had lower fasting glucose.     

Increased dietary sodium induces COX2 expression by activating NFκB in renal medullary interstitial cells

High salt diet induces renal medullary cyclooxygenase 2 (COX2) expression. Selective blockade of renal medullary COX2 activity in rats causes salt-sensitive hypertension, suggesting a role for renal medullary COX2 in maintaining systemic sodium balance. The present study characterized the cellular location of COX2 induction in the kidney of mice following high salt diet and examined the role of NFκB in mediating this COX2 induction in response to increased dietary salt. High salt diet (8 % NaCl) for 3 days markedly increased renal medullary COX2 expression in C57Bl/6 J mice. Co-immunofluorescence using a COX2 antibody and antibodies against aquaporin-2, ClC-K, aquaporin-1, and CD31 showed that high salt diet-induced COX2 was selectively expressed in renal medullary interstitial cells. By using NFκB reporter transgenic mice, we observed a sevenfold increase of luciferase activity in the renal medulla of the NFκB-luciferase reporter mice following high salt diet, and a robust induction of enhanced green fluorescent protein (EGFP) expression mainly in renal medullary interstitial cells of the NFκB-EGFP reporter mice following high salt diet. Treating high salt diet-fed C57Bl/6 J mice with selective IκB kinase inhibitor IMD-0354 (8 mg/kg bw) substantially suppressed COX2 induction in renal medulla, and also significantly reduced urinary prostaglandin E₂ (PGE₂). These data therefore suggest that renal medullary interstitial cell NFκB plays an important role in mediating renal medullary COX2 expression and promoting renal PGE₂ synthesis in response to increased dietary sodium.     

Does blood pressure inevitably rise with age?: longitudinal evidence among forager-horticulturalists

The rise in blood pressure with age is a major risk factor for cardiovascular and renal disease, stroke, and type 2 diabetes mellitus. Age-related increases in blood pressure have been observed in almost every population, except among hunter-gatherers, farmers, and pastoralists. Here we tested for age-related increases in blood pressure among Tsimane forager-farmers. We also test whether lifestyle changes associated with modernization lead to higher blood pressure and a greater rate of age-related increase in blood pressure. We measured blood pressure longitudinally on 2248 adults age ≥ 20 years (n=6468 observations over 8 years). Prevalence of hypertension was 3.9% for women and 5.2% for men, although diagnosis of persistent hypertension based on multiple observations reduced prevalence to 2.9% for both sexes. Mixed-effects models revealed systolic, diastolic, and pulse blood pressure increases of 2.86 (P<0.001), 0.95 (P<0.001), and 1.95 mmHg (P<0.001) per decade for women and 0.91 (P<0.001), 0.93 (P<0.001), and -0.02 mmHg (P=0.93) for men, substantially lower than rates found elsewhere. Lifestyle factors, such as smoking and Spanish fluency, had minimal effect on mean blood pressure and no effect on age-related increases in blood pressure. Greater town proximity was associated with a lower age-related increase in pulse pressure. Effects of modernization were, therefore, deemed minimal among Tsimane, in light of their lean physique, active lifestyle, and protective diet.