Therefore, the developed system should be helpful for evaluating the potential of compounds to cause DILI under conditions where inducers of CYP1A2 are present. Effect of long-term treatment with cigarette smoke extract (CSE) on the function and expression of P-glycoprotein (P-gp) in lung alveolar epithelial cells was examined using A549/P-gp cell line expressing P-gp. CSE treatment suppressed P-gp activity in a concentration- and treatment time-dependent manner. The suppression of P-gp activity by CSE was irreversible for at least 96 h after removal of CSE. In addition, CSE treatment suppressed the expression of P-gp mRNA and protein. https://www.selleckchem.com/products/resigratinib.html In order to understand the mechanisms underlying P-gp suppression by CSE, the role of reactive oxygen species (ROS) was examined. CSE treatment increased intracellular ROS level, and suppressed catalase activity. α-Tocopherol suppressed ROS production by CSE, and ameliorated the suppression of P-gp activity by CSE, suggesting that ROS is involved in CSE-induced suppression of P-gp. The role of intracellular signaling pathways such as the nuclear factor κB and mitogen-activated protein kinase pathways was also examined. Among these pathways, the involvement of extracellular signal-regulated kinase (ERK) pathway was suggested. Taken together, long-term CSE treatment may suppress P-gp via modulation of ROS level and ERK pathway in alveolar epithelial cells. OBJECTIVE To examine the association between polymorphisms of the ciliary neurotrophic factor gene (CNTF) and total and central adiposity markers in adolescents. STUDY DESIGN This cross-sectional study involved 1057 European adolescents aged 12-18 years enrolled in the Healthy Lifestyle in Europe by Nutrition in Adolescence Cross-Sectional Study. Five polymorphisms of CNTF were genotyped, and the weight, height, waist and hip circumference, and triceps and subscapular skinfold thickness of the subjects were measured and recorded. RESULTS The T allele of rs2509914, the C allele of rs2515363, and the G allele of rs2515362 were significantly associated (after Bonferroni correction) with higher values for several adiposity markers under different inheritance models. The CNTF CCGGA haplotype (rs2509914, rs17489568, rs2515363 rs1800169, and rs2515362) was also significantly associated with lower body mass index, waist circumference, waist/height ratio, and waist/hip ratio values compared with the TCCGG haplotype under several inheritance models. CONCLUSIONS Three polymorphisms-rs2509914, rs2515363, and rs2515362-and the CCGGA haplotype of CNTF were significantly associated with adiposity in European adolescents. These results suggest the potential role of CTNF in the development of obesity-related phenotypes. Nationally representative data of 140 000 children in 2-parent households showed that fathers were more likely than mothers to report that a child was in good health and less likely to report the presence of a specific health condition, special health care needs, or unmet health service needs. OBJECTIVE To describe the epidemiology of and risk factors associated with acute kidney injury (AKI) during acyclovir treatment in neonates and infants. STUDY DESIGN We conducted a multicenter (n = 4), retrospective cohort study of all hospitalized infants age less then 60 days treated with intravenous acyclovir (≥1 dose) for suspected or confirmed neonatal herpes simplex virus disease from January 2011 to December 2015. Infants with serum creatinine measured both before acyclovir (baseline) and during treatment were included. We classified AKI based on changes in creatinine according to published neonatal AKI criteria and performed Cox regression analysis to evaluate risk factors for AKI during acyclovir treatment. RESULTS We included 1017 infants. The majority received short courses of acyclovir (median, 5 doses). Fifty-seven infants (5.6%) developed AKI during acyclovir treatment, with an incidence rate of AKI at 11.6 per 1000 acyclovir days. Cox regression analysis identified having confirmed herpes simplex virus disease (OR, 4.35; P = .002), receipt of ≥2 concomitant nephrotoxic medications (OR, 3.07; P = .004), receipt of mechanical ventilation (OR, 5.97; P = .001), and admission to an intensive care unit (OR, 6.02; P = .006) as risk factors for AKI during acyclovir treatment. CONCLUSIONS Among our cohort of infants exposed to acyclovir, the rate of AKI was low. Sicker infants and those exposed to additional nephrotoxic medications seem to be at greater risk for acyclovir-induced toxicity and warrant closer monitoring. OBJECTIVES To evaluate accuracy of systemic inflammatory response syndrome (SIRS) criteria in identifying culture-proven late-onset neonatal sepsis and to assess prevalence of organ dysfunction and its relationship with SIRS criteria. STUDY DESIGN This was a retrospective case-control study of patients in the Children's Hospital of Philadelphia level IV neonatal intensive care unit undergoing sepsis evaluations (concurrent blood culture and antibiotics). During calendar years 2016-2017, 77 case and 77 control sepsis evaluations were identified. Cases included infants who had sepsis evaluations with positive blood cultures and antibiotic duration ≥7 days. Controls were matched by gestational and postmenstrual age, and had sepsis evaluations with negative blood cultures and antibiotic duration ≤48 hours. SIRS criteria were determined at time of sepsis evaluation, and organ dysfunction evaluated in the 72 hours following sepsis evaluation. Statistical analysis included descriptive statistics, Mann-Whitney tests, and χ2 (Fisher exact) tests. RESULTS At time of sepsis evaluation, 42% of cases and 26% of controls met SIRS criteria. Among infants of ≤37 weeks postmenstrual age, SIRS criteria were met in only 17% of sepsis evaluations (4 of 23 in both cases and controls). Test characteristics for SIRS at diagnosis of culture-proven sepsis included sensitivity 42% and specificity 74%. Cases had higher rates of new organ dysfunction within 72 hours (40% vs 21%); however, 58% of cases developing organ dysfunction did not meet SIRS criteria at time of sepsis evaluation. Of 6 deaths (all cases with organ dysfunction), 2 did not meet SIRS criteria at sepsis evaluation. CONCLUSIONS SIRS criteria did not accurately identify culture-proven late-onset sepsis, with poorest accuracy in preterm infants. SIRS criteria did not predict later organ dysfunction or mortality.