SUMMARY Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification. Though GLS deficiency diminished initial T cell activation and proliferation and impaired differentiation of Th17 cells, loss of GLS also increased Tbet to promote differentiation and effector function of CD4 Th1 and CD8 CTL cells. This was associated with altered chromatin accessibility and gene expression, including decreased PIK3IP1 in Th1 cells that sensitized to IL-2-mediated mTORC1 signaling. In vivo, GLS null T cells failed to drive Th17-inflammatory diseases, and Th1 cells had initially elevated function but exhausted over time. Transient GLS inhibition, however, led to increased Th1 and CTL T cell numbers. Glutamine metabolism thus has distinct roles to promote Th17 but constrain Th1 and CTL effector cell differentiation.

Timing of birth in relationship to winter virus season confers a differential and definable risk of developing early childhood asthma, establishing winter virus seasonality as a causal factor in asthma development. Delay of exposure or prevention of winter viral infection during early infancy could prevent asthma.

Background-Infants hospitalized for bronchiolitis have a high rate of early childhood asthma. It is not known whether bronchiolitis severity correlates with the risk of early childhood asthma or with asthma-specific morbidity.

Respiratory syncytial virus (RSV) infects all children early in life, is the most common cause of infant lower respiratory tract infections, and causes disease exacerbations in children with asthma. Episodes of lower respiratory tract infection in early life are associated with asthma development. Whether RSV infection early in life directly causes asthma or simply identifies infants who are genetically predisposed to develop subsequent wheezing is debatable. Recent studies suggest that these two explanations are not mutually exclusive, and are likely both important in asthma development. An open-label study of RSV immunoprophylaxis administered to preterm infants reduced recurrent wheezing by 50%. Clinical trials of infant RSV prevention, delay or severity reduction on the outcome of childhood asthma would confirm the causal relationship between RSV infection and asthma, and offer a primary prevention strategy.

OBJECTIVE To estimate the year-round burden of healthcare visits attributable to bronchiolitis and identify risk factors for bronchiolitis in term, healthy infants. PATIENTS AND METHODS We conducted a population-based, retrospective cohort study of 103,670 term, non-low birth weight infants enrolled in Tennessee Medicaid, 1995 to 2003. We followed infants through the first year of life. Risk factors for bronchiolitis during infancy and rates of inpatient, emergency department, and outpatient visits during the study period were calculated using claims data. RESULTS Over the 9 study years, rates of bronchiolitis visits per 1000 infant years were: 238 (outpatient), 77 (emergency department), and 71 (hospitalization). Average annual rates of bronchiolitis visits increased 41% from 188 to 265/1000 infant years from 1996-1997 to 2002-2003 (test of trend, p<.001). Analysis of the linear trend in 500 gram increments demonstrated a negative association between increasing birth weight and bronchiolitis diagnosis (p<0.0001). There was a significant, negative trend between maternal age and infant bronchiolitis diagnosis. Compared to infants of mothers aged 20-29 years, infants of mothers aged 15-19 had a small increase in risk of having a bronchiolitis visit (Hazard ratio 1.05, 95% Confidence Interval 1.01-1.09), while infants of older mothers were less likely to have a visit including women aged 30-39 (Hazard ratio 0.76, 95% Confidence Interval 0.72-0.79) and 40-44 (Hazard ratio 0.54, 95% CI 0.43-0.68). CONCLUSIONS The disease burden of bronchiolitis is substantial with increasing rates of all types of visits among term, otherwise healthy infants enrolled in Tennessee Medicaid from 1995 to 2003. Protective factors in this cohort of term infants included higher birth weight and older maternal age.

Accumulating evidence has demonstrated that up-regulation of the angiotensin (Ang)-converting enzyme (ACE)/AngII/AngII type 1 receptor (AT1R) axis aggravates pulmonary fibrosis. The recently discovered ACE2/Ang-(1-7)/Mas axis, which counteracts the activity of the ACE/AngII/AT1R axis, has been shown to protect against pulmonary fibrosis. However, the mechanisms by which ACE2 and Ang-(1-7) attenuate pulmonary fibrosis remain unclear. We hypothesized that up-regulation of the ACE2/Ang-(1-7)/Mas axis protects against bleomycin (BLM)-induced pulmonary fibrosis by inhibiting the mitogen-activated protein kinase (MAPK)/NF-κB pathway. In vivo, Ang-(1-7) was continuously infused into Wistar rats that had received BLM or AngII. In vitro, human fetal lung-1 cells were pretreated with compounds that block the activities of AT1R, Mas (A-779), and MAPKs before exposure to AngII or Ang-(1-7). The human fetal lung-1 cells were infected with lentivirus-mediated ACE2 before exposure to AngII. In vivo, Ang-(1-7) prevented BLM-induced lung fibrosis and AngII-induced lung inflammation by inhibiting the MAPK phosphorylation and NF-κB signaling cascades. However, exogenous Ang-(1-7) alone clearly promoted lung inflammation. In vitro, Ang-(1-7) and lentivirus-mediated ACE2 inhibited the AngII-induced MAPK/NF-κB pathway, thereby attenuating inflammation and α-collagen I production, which could be reversed by the Mas inhibitor, A-779. Ang-(1-7) inhibited AngII-induced lung fibroblast apoptotic resistance via inhibition of the MAPK/NF-κB pathway and activation of the BCL-2-associated X protein/caspase-dependent mitochondrial apoptotic pathway. Ang-(1-7) alone markedly stimulated extracellular signal-regulated protein kinase 1/2 phosphorylation and the NF-κB cascade. Up-regulation of the ACE2/Ang-(1-7)/Mas axis protected against pulmonary fibrosis by inhibiting the MAPK/NF-κB pathway. However, close attention should be paid to the proinflammatory effects of Ang-(1-7).

OBJECTIVE The purpose of this study was to describe antidepressant medication use patterns during pregnancy and pregnancy outcomes. STUDY DESIGN We evaluated a cohort of 228,876 singleton pregnancies that were covered by Tennessee Medicaid, 1995–2007. RESULTS Of 23,280 pregnant women with antidepressant prescriptions before pregnancy, 75% of them filled none in the second or third trimesters of pregnancy, and 10.7% of them used antidepressants throughout pregnancy. Filling 1, 2, and ≥3 antidepressant prescriptions during the second trimester was associated with shortened gestational age by 1.7 (95% confidence interval [CI], 1.2–2.3), 3.7 (95% CI, 2.8–4.6), and 4.9 (95% CI, 3.9–5.8) days, when controlled for measured confounders. Third-trimester selective serotonin reuptake inhibitor use was associated with infant convulsions; adjusted odds ratios were 1.4 (95% CI, 0.7–2.8); 2.8 (95% CI, 1.9 –5.5); and 4.9 (95% CI, 2.6–9.5) for filling 1, 2, and ≥3 prescriptions, respectively. CONCLUSION Most women discontinue antidepressant medications before or during the first trimester of pregnancy. Second-trimester antidepressant use is associated with preterm birth, and third-trimester selective serotonin reuptake inhibitor use is associated with infant convulsions.

Objective-We tested the hypothesis that long-term resistance exercise combined with intradialytic oral nutrition (IDON) supplementation will improve markers of muscle mass and strength further compared to IDON alone in chronic hemodialysis (CHD) patients. Design-Randomized controlled trial.Setting-Outpatient Dialysis Unit at an academic center.Main outcome measure-Lean body mass (LBM). Muscle strength and other nutritional parameters were measured as secondary outcomes.Patients-Thirty-two participants (age 43±13 yrs, 21 male) on CHD Design-Subjects were randomly assigned to IDON plus resistance exercise (NS+EX) or IDON (NS) alone for 6 months. IDON consisted of a lactose-free formula consisting of protein, carbohydrate and fat. Three sets of 12 repetitions of leg-press were completed prior to each dialysis session in the NS+EX arm.Results-22 out of 32 participants completed the 6-month intervention. There were no statistically significant differences between the study interventions with respect to changes in LBM and body weight when comparing NS+EX to NS. There were also no statistically significant differences in any of the secondary outcomes measured in the study. Body weight (80.3±16.6 kg, 81.1±17.5 kg and 80.9±18.2 kg at baseline, month 3 and month 6, respectively, P=0.02) and 1-Repetition Maximum (468±148 lb, 535±144 lb, 552±142 lb, respectively, P=0.001) increased statistically significantly during the study for all patients combined.Conclusion-This study did not show further benefits of additional resistance exercise on longterm somatic protein accretion above and beyond nutritional supplementation alone. When both treatments groups were combined, body weight and muscle strength improved during the study.