Association of cystic fibrosis transmembrane conductance regulator gene variants with acute lung injury in African American children with pneumonia*.

OBJECTIVES: The cystic fibrosis transmembrane conductance regulator regulates fluid balance in alveolar epithelial cells and appears to modulate the inflammatory response. To determine whether more severe lung injury in children who develop community-acquired pneumonia is associated with variations known to affect function in the gene coding for cystic fibrosis transmembrane conductance regulator. DESIGN: A prospective cohort genetic association study of lung injury in children with community-acquired pneumonia. SETTING: Three major tertiary care children's hospitals. SUBJECTS: Caucasian and African American children with community-acquired pneumonia either evaluated in the emergency department or admitted to the hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Caucasian and African American children with pneumonia were genotyped for the most common variants reported to affect cystic fibrosis transmembrane conductance regulator function, the p.508del mutation, the (TG)mTn variable repeat region, and the M470V polymorphism in the cystic fibrosis transmembrane conductance regulator gene. Genotypes and haplotypes were determined, and the association of high-risk alleles or high-risk haplotypes (defined as the presence of at least one variant known to decrease the level of functional cystic fibrosis transmembrane conductance regulator) with the need for mechanical ventilation or the development of acute lung injury was evaluated. Forty-two children in the Caucasian cohort (n = 304) required mechanical ventilation; 32 developed acute lung injury. Forty-three children in the African American cohort (n = 474) required mechanical ventilation; 29 developed acute lung injury. In African American children, high-risk (TG)mTn alleles known to result in decreased levels of functional cystic fibrosis transmembrane conductance regulator were associated with the need for mechanical ventilation (p = .0013) and the development of acute lung injury (p = .0061). Multivariable analysis demonstrated that high-risk (TG)mTn alleles were independently associated with mechanical ventilation (odds ratios = 3.19; 95% confidence interval, 1.63-6.26) and acute lung injury (odds ratios = 3.36; 95% confidence interval, 1.50-7.53) in African American children. CONCLUSION: Genetic variation in cystic fibrosis transmembrane conductance regulator is associated with acute lung injury in African American children with community-acquired pneumonia.

Effect of trifluoperazine on toxicity, HIF-1α induction and hepatocyte regeneration in acetaminophen toxicity in mice.

Oxidative stress and mitochondrial permeability transition (MPT) are important mechanisms in acetaminophen (APAP) toxicity. The MPT inhibitor trifluoperazine (TFP) reduced MPT, oxidative stress, and toxicity in freshly isolated hepatocytes treated with APAP. Since hypoxia inducible factor-one alpha (HIF-1α) is induced very early in APAP toxicity, a role for oxidative stress in the induction has been postulated. In the present study, the effect of TFP on toxicity and HIF-1α induction in B6C3F1 male mice treated with APAP was examined. Mice received TFP (10mg/kg, oral gavage) prior to APAP (200mg/kg IP) and at 7 and 36h after APAP. Measures of metabolism (hepatic glutathione and APAP protein adducts) were comparable in the two groups of mice. Toxicity was decreased in the APAP/TFP mice at 2, 4, and 8h, compared to the APAP mice. At 24 and 48h, there were no significant differences in toxicity between the two groups. TFP lowered HIF-1α induction but also reduced the expression of proliferating cell nuclear antigen, a marker of hepatocyte regeneration. TFP can also inhibit phospholipase A(2), and cytosolic and secretory PLA(2) activity levels were reduced in the APAP/TFP mice compared to the APAP mice. TFP also lowered prostaglandin E(2) expression, a known mechanism of cytoprotection. In summary, the MPT inhibitor TFP delayed the onset of toxicity and lowered HIF-1α induction in APAP treated mice. TFP also reduced PGE(2) expression and hepatocyte regeneration, likely through a mechanism involving PLA(2).

Normal interstage growth after the norwood operation associated with interstage home monitoring.

After stage 1 palliation (S1P) with a Norwood operation, infants commonly experience growth failure during the initial interstage period. Growth failure during this high-risk period is associated with worse outcomes. This study evaluated the growth patterns of patients enrolled in the authors' interstage home-monitoring program (HMP), which uses a multidisciplinary team approach to nutrition management. From 2000 to 2009, 148 infants were enrolled in the HMP after S1P. Families recorded daily weights during the interstage period and alerted the interstage monitoring team about protocol violations of nutritional goals. Interstage monitoring and inpatient data from the S1P hospitalization were reviewed to identify risk factors for poor growth. Growth outcomes were compared with published norms from the Centers for Disease Control. Interstage survival for patients in the HMP was 98 % (145/148). Growth velocity during the interstage period was 26 ± 8 g/day. The weight-for-age z-scores decreased from birth to discharge after S1P (-0.4 ± 0.9 to -1.3 ± 0.9; p < 0.001) but then increased during the interstage period to the time of S2P (-0.9 ± 1; p < 0.001). The factors associated with improved growth during the interstage period included male gender, greater birth weight, full oral feeding at S1P discharge, and a later birth era. After S1P, infants enrolled in an HMP experienced normal growth velocity during the interstage period. Daily observation of oxygen saturation, weight change, and enteral intake together with implementation of a multidisciplinary feeding protocol is associated with excellent interstage growth and survival.

Timing and technique of pulmonary valve replacement in the patient with tetralogy of Fallot.

Residual right ventricular (RV) outflow tract pathology is universal among patients with repaired tetralogy of Fallot, and pulmonary regurgitation (PR) is also commonly present. Although tolerated in early life, by the second decade of life PR is associated with an increased risk of death because of ventricular arrhythmias. Pulmonary valve replacement (PVR) is a safe procedure that will eliminate PR, but timing and indications are evolving. Patients with arrhythmias or prolonged QRS duration are candidates for PVR. Patients with symptomatic exercise intolerance are likely to have improvement in symptoms and quality of life and should be offered PVR. Cardiac magnetic resonance has become an essential component of the management of the patient with tetralogy of Fallot with PR, and has identified the potential for and limitations of RV remodeling following PVR. Among patients with severe RV enlargement, particularly those with diminished RV or left ventricular function, there is an increased risk of adverse events and even asymptomatic patients with severe PR should be considered for PVR. Valve replacement is accomplished with homografts or heterografts, either stented bioprosthetic valves or valved conduits. In a retrospective analysis of the Children's Hospital of Wisconsin experience with PVR, there was no difference in survival or freedom from reintervention between heterografts and homografts.

HIDA, percutaneous transhepatic cholecysto-cholangiography and liver biopsy in infants with persistent jaundice: can a combination of PTCC and liver biopsy reduce unnecessary laparotomy?

BACKGROUND: Historically, HIDA is the initial diagnostic test in the evaluation of biliary atresia (BA). Non-excreting HIDA scans can yield false-positive results leading to negative laparotomy. OBJECTIVE: Cholestatic infants must be evaluated promptly to exclude biliary atresia (BA) and other treatable hepatic conditions. Intraoperative cholangiogram (IOC) is the gold standard for diagnosing BA, but requires surgical intervention. Percutaneous transhepatic cholecysto-cholangiography (PTCC) and liver biopsy are less invasive and have been described in small case series. We hypothesized that PTCC and liver biopsy effectively exclude BA, thus avoiding unnecessary IOC. MATERIALS AND METHODS: Retrospective review of cholestatic infants who underwent PTCC, biopsy or cholescintigraphy at a tertiary children's hospital from August 1998 to January 2009. Group differences were evaluated and the receiver operator curve and safety of PTCC determined. RESULTS: One-hundred twenty-eight cholestatic infants were reviewed. Forty-six (36%) underwent PTCC. Forty-one out of 46 (89%) had simultaneous PTCC and liver biopsy. PTCC was completed successfully in 19/23 (83%) children despite a small or absent GB on initial US. Negative laparotomy rate was 1/6 (17%) for simultaneous PTCC/liver biopsy. Complications occurred in 4/46 including bleeding (n=2), fever with elevated transaminases (n=1) and oxygen desaturations (n=1). CONCLUSION: PTCC, particularly when performed in combination with simultaneous liver biopsy, effectively excludes BA in cholestatic infants with acceptable morbidity. PTCC can frequently be performed when a contracted gallbladder is seen on initial US exam. Negative laparotomy rate is lowest when PTCC is coupled with simultaneous liver biopsy.

A requisite role for induced regulatory T cells in tolerance based on expanding antigen receptor diversity.

Although both natural and induced regulatory T (nTreg and iTreg) cells can enforce tolerance, the mechanisms underlying their synergistic actions have not been established. We examined the functions of nTreg and iTreg cells by adoptive transfer immunotherapy of newborn Foxp3-deficient mice. As monotherapy, only nTreg cells prevented disease lethality, but did not suppress chronic inflammation and autoimmunity. Provision of Foxp3-sufficient conventional T cells with nTreg cells reconstituted the iTreg pool and established tolerance. In turn, acute depletion of iTreg cells in rescued mice resulted in weight loss and inflammation. Whereas the transcriptional signatures of nTreg and in vivo-derived iTreg cells were closely matched, there was minimal overlap in their T cell receptor (TCR) repertoires. Thus, iTreg cells are an essential nonredundant regulatory subset that supplements nTreg cells, in part by expanding TCR diversity within regulatory responses.

Trends in pulmonary function and prevalence of asthma in hexamethylene diisocyanate workers during a 19-year period.

OBJECTIVE: To identify if 1,6-hexamethylene diisocyanate (HDI) workers demonstrated an increased prevalence of occupational asthma or accelerated decline in pulmonary function. METHODS: Employees from two plants manufacturing or producing 1,6-HDI monomer and/or HDI polyisocyanates were matched to a control population by age, gender, race, and smoking status. A random coefficient regression analysis compared the decline in pulmonary function test values over time. Retrospective medical review was used to identify potential cases of occupationally induced asthma. RESULTS: No significantly accelerated annual decline in force expiratory volume after 1 second in the HDI exposure group compared to the matched control group was observed. No cases of adult onset asthma, beyond those present at time of hire, and no cases of occupational asthma were identified. CONCLUSIONS: This study provides support for the current American Conference of Governmental Industrial Hygienists threshold limit value time-weighted average of 5 ppb.

Genetic variation in MYLK and lung injury in children and adults with community-acquired pneumonia.

OBJECTIVE: To investigate whether selected single nucleotide polymorphisms in the myosin light chain kinase gene are associated with more severe lung injury in children and adults with community-acquired pneumonia. Previous studies have demonstrated an association between single nucleotide polymorphisms in the myosin light chain kinase gene and increased severity of acute lung injury in adults. DESIGN: Prospective, case-control genetic association study. SETTING: Three tertiary children's hospitals and one adult healthcare system. PATIENTS: A total of 800 pediatric patients and 393 adult patients. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Genetic variation in the myosin light chain kinase gene was examined. The pediatric cohort was predominantly composed of African American (n = 443) and Caucasian (n = 253) children. A total of 393 patients made up the adult cohort. Within the pediatric cohort, single nucleotide polymorphisms rs16834493, rs820463, and rs9840993 were genotyped in the African American patients, whereas single nucleotide polymorphisms rs960224, rs33264, rs11718105, and rs9289225 were genotyped in the Caucasian patients. One single nucleotide polymorphism (rs820336) was genotyped in both groups. Genotyping in the adult cohort included rs820336, rs860224, rs33264, and rs11718105. Genotyping was performed using the Taqman Assay. Data were analyzed separately for African Americans and Caucasians and for children and adults. No associations were observed between the myosin light chain kinase gene single nucleotide polymorphisms genotyped in children with community-acquired pneumonia and increased severity of lung injury. Similarly, no associations were observed between myosin light chain kinase gene single nucleotide polymorphisms genotyped in adults with community-acquired pneumonia and increased severity of lung injury. CONCLUSIONS: No association between the selected single nucleotide polymorphisms in the myosin light chain kinase gene and either the need for positive-pressure ventilation or the development of acute lung injury/acute respiratory distress syndrome was observed in children with community-acquired pneumonia. This suggests that variation in this gene may play less of a role in lung injury in children or adults with community-acquired pneumonia than in adults with sepsis or trauma.