Georges Casimir

Ataluren (PTC124) induces cystic fibrosis transmembrane conductance regulator protein expression and activity in children with nonsense mutation cystic fibrosis.

RATIONALE Nonsense (premature stop codon) mutations in mRNA for the cystic fibrosis transmembrane conductance regulator (CFTR) cause cystic fibrosis (CF) in approximately 10% of patients. Ataluren (PTC124) is an oral drug that permits ribosomes to readthrough premature stop codons in mRNA to produce functional protein. OBJECTIVES To evaluate ataluren activity, safety, and pharmacokinetics in children with nonsense mutation CF. METHODS Patients were assessed in two 28-day cycles, comprising 14 days on and 14 days off ataluren. Patients took ataluren three times per day (morning, midday, and evening) with randomization to the order of receiving a lower dose (4, 4, and 8 mg/kg) and a higher dose (10, 10, and 20 mg/kg) in the two cycles. MEASUREMENTS AND MAIN RESULTS The study enrolled 30 patients (16 male and 14 female, ages 6 through 18 yr) with a nonsense mutation in at least one allele of the CFTR gene, a classical CF phenotype, and abnormal baseline nasal epithelial chloride transport. Ataluren induced a nasal chloride transport response (at least a -5-mV improvement) or hyperpolarization (value more electrically negative than -5 mV) in 50% and 47% of patients, respectively, with more hyperpolarizations at the higher dose. Improvements were seen in seven of nine nonsense mutation genotypes represented. Ataluren significantly increased the proportion of nasal epithelial cells expressing apical full-length CFTR protein. Adverse events and laboratory abnormalities were infrequent and usually mild. Ataluren pharmacokinetics were similar to those in adults. CONCLUSIONS In children with nonsense mutation CF, ataluren can induce functional CFTR production and is well tolerated.

Basophil activation tests for the diagnosis of food allergy in children

Background Positive skin prick tests (SPT) for food allergens and specific IgE (sIgE) in serum indicate sensitization but do not enable distinction between sensitized but tolerant and clinically allergic patients.

Sleep Duration among Black and White Americans: Results of the National Health Interview Survey

INTRODUCTION Epidemiologic studies have shown the importance of habitual sleep duration as an index of health and mortality risks. However, little has been done to ascertain ethnic differences in sleep duration in a national sample. This study compares sleep duration in a sample of black and white participants in the National Health Interview Survey (NHIS). METHOD Data were collected from 29,818 Americans (age range 18-85 years) who participated in the 2005 NHIS. The NHIS is a cross-sectional household interview survey that uses a multistage area probability design, thus permitting representative sampling of U.S. households. During face-to-face interviews conducted by trained interviewers from the U.S. Census Bureau, respondents provided demographic data and information about physician-diagnosed chronic conditions, estimated habitual sleep duration and functional capacity, and rated their mood. RESULTS Fishers exact test results indicated that blacks were less likely than whites to report sleeping 7 hours (23% vs. 30%; chi2 = 94, p < 0.0001). Blacks were more likely to experience both short sleep (< or = 5 hours) (12% vs. 8%, chi2 = 44, p < 0.0001) and long sleep (> or = 9 hours) (11% vs. 9%, chi2 = 23, p < 0.0001). Logistic regression analysis, adjusting for differences in sociodemographic factors, depression, functional capacity and medical illnesses, demonstrated that black ethnicity was a significant predictor of extreme sleep duration (Wald = 46, p < 0.0001; OR = 1.35, 95% CI: 1.24-1.47). DISCUSSION Independent of several sociodemographic and medical factors, blacks had more prevalent short and long sleep durations, suggesting greater variation in habitual sleep time. Therefore, blacks might be at increased risks of developing medical conditions associated with short and long sleep.

Molecular mechanisms of cell death in periventricular leukomalacia.

Objective: To investigate the cytokine-related molecular cascade leading to neural cell death in periventricular leukomalacia (PVL). Methods: The authors explored potential tumor necrosis factor α (TNFα) signaling pathways in human brains with PVL and conducted in situ immunohistochemical investigations to search for possible expression of cytokine receptors in these brains. They also investigated likely links to molecules potentially involved in neurocytotoxicity, particularly pathways involving nitrosative-induced apoptosis. Results: TNFα overexpression was associated with immune reactivity for p75TNFαR2 and p55TNFαR1 receptors in affected PVL areas. p75TNFαR2 labeling was intense on cerebrovascular endothelial cells in PVL areas, whereas no vascular p55TNFαR1 immunoreactivity was detected therein. Immune labeling for both receptors was detected on many white matter parenchymal cells. In contrast, there was no immune reactivity for either receptor in tissues taken from non-PVL areas. Additionally, in situ overexpression of inducible nitric oxide synthase was found in PVL brain regions where apoptotic cell death was detected. Conclusions: Both p75TNFαR2 and p55TNFαR1 receptors and nitric oxide may be implicated in the pathogenesis of periventricular leukomalacia.

Insomnia symptoms and repressive coping in a sample of older Black and White women.

BackgroundThis study examined whether ethnic differences in insomnia symptoms are mediated by differences in repressive coping styles.MethodsA total of 1274 women (average age = 59.36 ± 6.53 years) participated in the study; 28% were White and 72% were Black. Older women in Brooklyn, NY were recruited using a stratified, cluster-sampling technique. Trained staff conducted face-to-face interviews lasting 1.5 hours acquiring sociodemographic data, health characteristics, and risk factors. A sleep questionnaire was administered and individual repressive coping styles were assessed. Fishers exact test and Spearman and Pearson analyses were used to analyze the data.ResultsThe rate of insomnia symptoms was greater among White women [74% vs. 46%; χ2 = 87.67, p < 0.0001]. Black women scored higher on the repressive coping scale than did White women [Black = 37.52 ± 6.99, White = 29.78 ± 7.38, F1,1272 = 304.75, p < 0.0001]. We observed stronger correlations between repressive coping and insomnia symptoms for Black [rs = -0.43, p < 0.0001] than for White women [rs = -0.18, p < 0.0001]. Controlling for variation in repressive coping, the magnitude of the correlation between ethnicity and insomnia symptoms was substantially reduced. Multivariate adjustment for differences in sociodemographics, health risk factors, physical health, and health beliefs and attitudes had little effect on the relationships.ConclusionRelationships between ethnicity and insomnia symptoms are jointly dependent on the degree of repressive coping, suggesting that Black women may be reporting fewer insomnia symptoms because of a greater ability to route negative emotions from consciousness. It may be that Blacks cope with sleep problems within a positive self-regulatory framework, which allows them to deal more effectively with sleep-interfering psychological processes to stressful life events and to curtail dysfunctional sleep-interpreting processes.

FGFR1 mutations cause Hartsfield syndrome, the unique association of holoprosencephaly and ectrodactyly

Background Harstfield syndrome is the rare and unique association of holoprosencephaly (HPE) and ectrodactyly, with or without cleft lip and palate, and variable additional features. All the reported cases occurred sporadically. Although several causal genes of HPE and ectrodactyly have been identified, the genetic cause of Hartsfield syndrome remains unknown. We hypothesised that a single key developmental gene may underlie the co-occurrence of HPE and ectrodactyly. Methods We used whole exome sequencing in four isolated cases including one case-parents trio, and direct Sanger sequencing of three additional cases, to investigate the causative variants in Hartsfield syndrome. Results We identified a novel FGFR1 mutation in six out of seven patients. Affected residues are highly conserved and are located in the extracellular binding domain of the receptor (two homozygous mutations) or the intracellular tyrosine kinase domain (four heterozygous de novo variants). Strikingly, among the six novel mutations, three are located in close proximity to the ATPs phosphates or the coordinating magnesium, with one position required for kinase activity, and three are adjacent to known mutations involved in Kallmann syndrome plus other developmental anomalies. Conclusions Dominant or recessive FGFR1 mutations are responsible for Hartsfield syndrome, consistent with the known roles of FGFR1 in vertebrate ontogeny and conditional Fgfr1-deficient mice. Our study shows that, in humans, lack of accurate FGFR1 activation can disrupt both brain and hand/foot midline development, and that FGFR1 loss-of-function mutations are responsible for a wider spectrum of clinical anomalies than previously thought, ranging in severity from seemingly isolated hypogonadotropic hypogonadism, through Kallmann syndrome with or without additional features, to Hartsfield syndrome at its most severe end.

Early referral to cystic fibrosis specialist centre impacts on respiratory outcome.

BACKGROUND Published studies concerning the impact of specialist care on lung disease in cystic fibrosis remain limited and most are either biased due to comparison with historical controls and/or underpowered. METHODS In this retrospective multicentric study, data from all CF children fulfilling the following criteria were collected: 1) Age 6-<18 at the end of 2003; 2) diagnosis before 8 y; 3) follow-up in an accredited CF Belgian centre; 4) at least 1 spirometry and respiratory culture available for 2003. Group A included children referred > or =2 years after the diagnosis. Patients from Group A were then matched with a single early referred patient on the basis of 2 criteria: same centre, as closest age as possible (Group B). RESULTS Data from 217 children were collected (Group A: 67/217). Late referred patients had a lower FEV(1) (77.2%+/-22.4 vs 86.7% pred.+/-19.4, p=0.01) and a higher prevalence of Pseudomonas aeruginosa (38.6 vs 17.5%, p<0.05). CONCLUSION In this population of CF children, a delay of 6.1 y (vs 0.1 y) between diagnosis and referral to a specialist clinic resulted in poorer respiratory outcome at age 13.

Gender differences in inflammatory markers in children.

No clear explanation exists to understand how sex hormones and/or chromosomes affect the immune system. In vitro studies of human lymphoid cells also show sex differences in immune function. To evaluate these differences in frequent pediatric emergencies, we analyze the expression of inflammatory markers (C-reactive protein, erythrocyte sedimentation rate, and neutrophil count) underlying inflammatory processes in children: 482 children (241 girls and 241 boys) hospitalized for pneumonia (n = 384), pyelonephritis (n = 39), or bronchiolitis (n = 59) matched for age and sex. All patients were younger than 10 years. A control population of 97 children (50 girls and 47 boys) admitted for day surgery (tonsillectomy, circumcision, or strabismus) was included. We observed highly significant differences between girls and boys: median C-reactive protein concentration of 5.45 mg/dL (range, 0.2-36.0 mg/dL) for girls and 2.6 mg/dL (range, 0.3-37.3 mg/dL) for boys (P < 0.0001), and median erythrocyte sedimentation rate of 39.5 mm/h (range, 2-104 mm/h) for girls and 24 mm/h (range, 4-140 mm/h) for boys (P < 0.005). Neutrophil counts were also significantly different: a median of 8,796 cells/&mgr;L (range, 328-27,645 cells/&mgr;L) for girls and 6,774 cells/&mgr;L (range, 600-38,668 cells/&mgr;L) for boys (P < 0.02). The duration of fever after initiating antibiotic therapy was longer in girls than in boys, but there was no difference (Fisher exact test, P < 0.06). The present study documents a relationship between sex and both the production of inflammatory markers and neutrophil recruitment. Sex difference also showed more direct clinical relevance with associations seen between sex and both duration of fever and duration of disease (bronchiolitis P < 0.0007).

Effect of systemic inflammation on inspiratory and limb muscle strength and bulk in cystic fibrosis

RATIONALE Diaphragm thickness is increased in cystic fibrosis (CF), but it shows a marked variability between patients. The variable response of the diaphragm to loading may reflect the combined and opposite effects of training by the respiratory disease and systemic inflammation. OBJECTIVES To assess the impact of systemic inflammation on diaphragm and limb muscle strength and bulk in adult patients with CF. METHODS In 38 stable patients with CF and 20 matched control subjects, we measured fat-free mass (FFM), inspiratory muscle strength, diaphragm thickness, quadriceps and biceps strength and cross-sectional area, and circulating levels of leukocytes, C-reactive protein, IL-6, IL-8, IL-17, tumor necrosis factor-alpha, tumor necrosis factor-alpha soluble receptors, and immunoglobulin G. MEASUREMENTS AND MAIN RESULTS Patients had increases in several inflammatory markers that correlated with the severity of lung disease and nutritional depletion. Compared with control subjects, patients with CF had increased diaphragm thickness and inspiratory muscle strength and showed a trend toward a reduction in limb muscle strength and bulk. Multiple regression analyses identified FFM and airway resistance as independent predictors of diaphragm thickness, but systemic inflammation had no (or only a minor) predictive effect on FFM, inspiratory muscle strength, diaphragm thickness, and limb muscle strength and bulk. CONCLUSIONS In patients with CF, the intensity of systemic inflammation does not account significantly for the variance of FFM and diaphragm or limb muscle strength and bulk. Training of the diaphragm in CF occurs despite the presence of systemic inflammation.

Insomnia Symptoms in a Multiethnic Sample of American Women

BACKGROUND Ethnic disparities in socioeconomic factors, risk markers, and coping styles affect health status. This study examined whether those factors influence insomnia symptoms in a multiethnic sample of urban American women. METHODS Women (n = 1440, average age = 59.5 +/- 6.45 years) participating in the study were recruited using a stratified, cluster sampling technique. The sample comprises African Americans (22%), English-speaking Caribbeans (22%), Haitians (22%), Dominicans (12%), Eastern Europeans (11%), and European Americans (11%). Trained staff conducted face-to-face interviews lasting 1.5 hours acquiring demographic, health, and sleep data. RESULTS Analysis indicated significant ethnic differences in socioeconomics, risk markers, and health characteristics. The prevalence of insomnia symptoms (defined as either difficulty initiating sleep, difficulty maintaining sleep, or early morning awakening) among African Americans was 71%, English-speaking Caribbeans 34%, Haitians 33%, Dominicans 73%, Eastern Europeans 77%, and European Americans 70%. Hierarchical regression results showed that ethnicity explained 20% of the variance in the insomnia variable. Sociodemographic factors explained 5% of the variance, risk markers explained 5%, medical factors 20%, and coping styles 1%. Goodness-of-fit test indicated the model was reliable [chi-square = 276, p < 0.001], explaining 51% of the variance. CONCLUSIONS Findings show interethnic heterogeneity in insomnia symptoms, even among groups previously assumed to be homogeneous. Different factors seemingly influence rates of insomnia symptoms within each ethnic group examined. These findings have direct relevance in the management of sleep problems among women of different ethnic backgrounds. Understanding of ethnic/cultural factors affecting the sleep experience is important in interpreting subjective sleep data.