Genotype analysis and phenotypic manifestations of children with intermediate sweat chloride test results

STUDY OBJECTIVES: Cystic fibrosis (CF) is one of the most common inherited diseases among whites. Since the cloning of the CF transmembrane conductance regulator (CFTR) gene, a number of studies have focused on associations between the genotype and phenotype in CF. This had led to the progressive identification of new groups of patients, including those who have mild lung disease and those who have normal sweat chloride values (< 60 mEq/L). The aim of the present work was to provide information on the genotype and the phenotypic characteristics of children with intermediate-range sweat chloride test results. PATIENTS AND RESULTS: We focused on children referred to the pulmonary department for various types of pulmonary disease and who had several sweat chloride test results with median values in the range of 40 to 60 mEq/L. Twenty-four patients over a 10-year period were enrolled (mean age, 4.8 years). Respiratory manifestations at initial evaluation included recurrent bronchitis, wheezing, chronic cough, and pneumonia. The duration of the follow-up ranged from 0.5 to 10.5 years. Sputum cultures revealed the presence of Haemophilus influenzae (10 children), Staphylococcus aureus (4 children), and Pseudomonas aeruginosa (3 children). Pancreatic insufficiency was found in two patients. Analysis of the entire coding sequence allowed identification of 16 known mutations in CFTR gene. Fifteen chromosomes (31.2%) carried a mutation in CFTR gene and one allele carried two mutations. Three patients were homozygous or double heterozygous (DeltaF508/DeltaF508, DeltaF508/3849 + 10 kb C-->T, S1235R/G551D). The 5-thymidine allele was identified in four children. CONCLUSION: These results indicate an higher frequency of CFTR gene mutations in patients with borderline sweat chloride test results, compared to data reported in the general population. They lead to the recommendations for complete pulmonary and GI investigations in this group of patients, as well as assiduous care and medical follow-up.     

Diagnosis,follow-up and management of sleep-disordered breathing in children with osteogenesis imperfecta

Objectives

Osteogenesis imperfecta (OI) is the most common genetic skeletal disorder. Extraskeletal findings are common but an association with sleep-disordered breathing (SDB) has never been described. The aim of this study was to investigate clinical features of children with OI and suspected SDB.

Effects of Developmental Activation of the AhR on CD4+ T-Cell Responses to Influenza Virus Infection in Adult Mice

Background: Epidemiological and animal studies indicate that maternal exposure to pollutants that bind the aryl hydrocarbon receptor (AhR) correlates with poorer ability to combat respiratory infection and lower antibody levels in the offspring. These observations point to an impact on CD4⁺ T cells. Yet, the consequence of developmental exposure to AhR ligands on the activation and differentiation of CD4⁺ T cells has not been directly examined.Objectives: Our goal was to determine whether maternal exposure to an AhR ligand directly alters CD4⁺ T cell differentiation and function later in life.Methods: C57BL/6 mice were exposed to a prototypical AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), in utero and via suckling. We then measured CD4⁺ T-cell activation and differentiation into distinct effector populations in adult offspring that were infected with influenza A virus (IAV). Reciprocal adoptive transfers were used to define whether modifications in CD4⁺ T-cell responses resulted from direct effects of developmental TCDD exposure on CD4⁺ T cells.Results: Developmental exposure skewed CD4⁺ T-cell responses to IAV infection. We observed fewer virus-specific, activated CD4⁺ T cells and a reduced frequency of conventional CD4⁺ effector-cell subsets. However, there was an increase in regulatory CD4⁺ T cells. Direct effects of AhR activation on CD4⁺ T cells resulted in impaired differentiation into conventional effector subsets; this defect was transferred to mice that had not been developmentally exposed to TCDD.Conclusions: Maternal exposure to TCDD resulted in durable changes in the responsive capacity and differentiation of CD4⁺ T cells in adult C57BL/6 mice.Citation: Boule LA, Winans B, Lawrence BP. 2014. Effects of developmental activation of the AhR on CD4⁺ T-cell responses to influenza virus infection in adult mice. Environ Health Perspect 122:1201–1208; http://dx.doi.org/10.1289/ehp.1408110     

Asthma in infants. Clinical and functional aspects]

BACKGROUND. The incidence of asthma in infancy is rising but its clinical and physiological components remain unclear. METHODS. A total of 24 infants, aged less than 48 months, in whom the first wheezing episode (WE) appeared before the age of 30 months (mean age: 9 months) underwent clinical examination and pulmonary function tests at least 2 weeks after the last WE. RESULTS. The mean WE frequency was 1.1 per month and the mean number of admissions for WE was 1.8. 63% of patients showed symptoms between WE and 50% had an allergic profile. There was no evidence of thoracic distension. Bronchial obstruction (BO) occurred in 71% of patients; among these, BO was distal or generalized in 59% and medium or severe in 47%. 12.5% of patients were hypoxemic at testing. BO was less severe in patients treated with theophylline; it was more frequent (87%) in those with symptoms between WE and/or several admissions, and/or admission to the intensive care unit. CONCLUSION. This study provides additional evidence that infants presenting with asthma at an early age have severe clinical and physiological profiles.     

Diseases of the pulmonary lymphatic system in children

Diseases of the lymphatic system in children include a group of exceptional conditions difficult to manage. The anatomy of lymphatic system is complex in the lung. Variable from one subject to another, its complex physiology plays an important role in air-blood exchanges occurring in the lung. In the pulmonary interstitium and in the pleura, the lymphatic system acts like an overflow valve capable of regulating variations in interstitial fluid. The presence or development of dysplasic lymphatics causes leakage, dilatation, and reflux of the lymph through incontinent valves leading to chylothorax and/or fluid overload in the pulmonary interstitium. Symptomatic care is usually proposed, based on a fat-free diet supplemented with light-chain triglycerides and liposoluble vitamins. Other therapeutic options can be proposed. Medical options include cytotoxic agents, somatostatin, and interferon-alpha. Surgery may also be useful, but an assessment of therapeutic efficacy is very difficult due to partial effects and the small number of cases studied.     

Toll-like receptor 9: a new target of ischemic preconditioning in the brain.

Preconditioning with lipopolysaccharide (LPS), a toll-like receptor 4 (TLR4) ligand, provides neuroprotection against subsequent cerebral ischemic brain injury, through a tumor necrosis factor (TNF)alpha-dependent process. Here, we report the first evidence that another TLR, TLR9, can induce neuroprotection. We show that the TLR9 ligand CpG oligodeoxynucleotide (ODN) can serve as a potent preconditioning stimulus and provide protection against ischemic brain injury. Our studies show that systemic administration of CpG ODN 1826 in advance of brain ischemia (middle cerebral artery occlusion (MCAO)) reduces ischemic damage up to 60% in a dose- and time-dependent manner. We also offer evidence that CpG ODN preconditioning can provide direct protection to cells of the central nervous system, as we have found marked neuroprotection in modeled ischemia in vitro. Finally, we show that CpG preconditioning significantly increases serum TNFalpha levels before MCAO and that TNFalpha is required for subsequent reduction in damage, as mice lacking TNFalpha are not protected against ischemic injury by CpG preconditioning. Our studies show that preconditioning with a TLR9 ligand induces neuroprotection against ischemic injury through a mechanism that shares common elements with LPS preconditioning via TLR4.     

Effects of exercise on glycemic control and body mass in type 2 diabetes mellitus: a meta-analysis of controlled clinical trials

Acclimatization to moderate high altitude accompanied by training at low altitude (living high–training low) has been shown to improve sea level endurance performance in accomplished, but not élite, runners. Whether élite athletes, who may be closer to the maximal structural and functional adaptive capacity of the respiratory (i.e. oxygen transport from environment to mitochondria) system, may achieve similar performance gains is unclear. To answer this question, we studied 14 élite men and eight élite women before and after 27 days of living at 2500 m while performing high‐intensity training at 1250 m. The altitude sojourn began 1 week after the USA Track and Field National Championships, when the athletes were close to their season's fitness peak. Sea level 3000‐m time trial performance was significantly improved by 1.1% (95% confidence limits 0.3–1.9%). One‐third of the athletes achieved personal best times for the distance after the altitude training camp. The improvement in running performance was accompanied by a 3% improvement in maximal oxygen uptake (72.1 ± 1.5–74.4 ± 1.5 ml kg^{? 1} min^{? 1}). Circulating erythropoietin levels were near double initial sea level values 20 h after ascent (8.5 ± 0.5–16.2 ± 1.0 IU ml^?1). Soluble transferrin receptor levels were significantly elevated on the 19th day at altitude, confirming a stimulation of erythropoiesis (2.1 ± 0.7–2.5 ± 0.6 μ g ml^‐1). Hb concentration measured at sea level increased 1 g dl^?1 over the course of the camp (13.3 ± 0.2–14.3 ± 0.2 g dl^?1). We conclude that 4 weeks of acclimatization to moderate altitude, accompanied by high‐intensity training at low altitude, improves sea level endurance performance even in élite runners. Both the mechanism and magnitude of the effect appear similar to that observed in less accomplished runners, even for athletes who may have achieved near maximal oxygen transport capacity for humans.