CFTR Protein: Not Just a Chloride Channel?

Cystic fibrosis (CF) is a recessive genetic disease caused by mutations in a gene encoding a protein called Cystic Fibrosis Transmembrane Conductance Regulator (CFTR). The CFTR protein is known to acts as a chloride (Cl-) channel expressed in the exocrine glands of several body systems where it also regulates other ion channels, including the epithelial sodium (Na+) channel (ENaC) that plays a key role in salt absorption. This function is crucial to the osmotic balance of the mucus and its viscosity. However, the pathophysiology of CF is more challenging than a mere dysregulation of epithelial ion transport, mainly resulting in impaired mucociliary clearance (MCC) with consecutive bronchiectasis and in exocrine pancreatic insufficiency. This review shows that the CFTR protein is not just a chloride channel. For a long time, research in CF has focused on abnormal Cl- and Na+ transport. Yet, the CFTR protein also regulates numerous other pathways, such as the transport of HCO3-, glutathione and thiocyanate, immune cells, and the metabolism of lipids. It influences the pH homeostasis of airway surface liquid and thus the MCC as well as innate immunity leading to chronic infection and inflammation, all of which are considered as key pathophysiological characteristics of CF.

Immunoglobulin G: A useful outcome marker in the follow-up of cystic fibrosis patients?

BACKGROUND AND METHODS: Hypergammaglobulinemia (hyper-IgG) and hypogammaglobulinemia (hypo-IgG) have been reported in patients with cystic fibrosis (CF). Although the clinical respiratory course is paradoxically different, depending on the IgG status, this association remains elusive. Therefore, we performed a longitudinal study to assess the annual evolution of IgG profiles in a cohort of pediatric patients with CF, from their diagnosis until 2016. We then compared clinical findings with the patients' IgG status to determine whether IgG status could reflect the respiratory clinical course of patients with CF. RESULTS: Among the 66 patients with CF that were aged between 12 months and 18 years in 2016 (mean age: 9.3 years [SD: 5.2]), hypo-IgG was observed in 15.2% and no hyper-IgG was identified. Longitudinal assessment since diagnosis revealed no hyper-IgG but 33.3% of patients had at least one sample showing hypo-IgG, among which two patients displayed persistent hypo-IgG. The number of pulmonary exacerbations, duration of antibiotic therapy, and erythrocyte sedimentation rate were all lower in hypo-IgG patients. No difference was observed for the genotype, chronic Pseudomonas aeruginosa or Staphylococcus aureus infection, and in the parameters of lung function. CONCLUSION: The IgG profile of pediatric patients with CF has changed over recent decades, particularly with regard to hyper-IgG. In a significant portion of the pediatric CF population, hypo-IgG is transient and only identifiable in longitudinal assessments. This study reinforces that hypo-IgG patients paradoxically present a more favorable course of clinical status. Therefore, IgG levels could be a useful outcome marker in the follow-up of patients with CF.

Sex and inflammation in respiratory diseases: a clinical viewpoint.

This review discusses sex differences in the prognosis of acute or chronic inflammatory diseases. The consequences of severe inflammation vary in relation to sex, depending on illness duration. In the majority of acute diseases, males present higher mortality rates, whereas continuous chronic inflammation associated with tissue damage is more deleterious in females. The recruitment of cells, along with its clinical expression, is more significant in females, as reflected by higher inflammatory markers. Given that estrogens or androgens are known to modulate inflammation, their different levels in males and females cannot account for the sexual dimorphism observed in humans and animals from birth to death with regard to inflammation. Numerous studies evaluated receptors, cytokine production, and clinical outcomes in both animals and humans, revealing that estrogens clearly modulate the immune response, but the results are contradictory and difficult to link to hormone concentrations. Even in prepubescent children, the presentation of acute pneumonia or chronic diseases mimics the adult pattern. Several genes located on the X chromosome have been shown to encode molecules involved in inflammation. Moreover, 10% to 15% of the genes from silenced X chromosome may escape inhibition. Females are also a mosaic of cells with genes from either paternal or maternal X chromosome. Therefore, polymorphism of X-linked genes would result in the presence of two cell populations with distinct regulatory arsenals, providing females with greater diversity to fight against infectious challenges, in comparison with the uniform cell populations in hemizygous males. The similarities observed between males and Turner syndrome patients using an endotoxin stimulation model support the difference in gene expression between monosomy and disomy for the X chromosome. Considering the enhanced inflammation in females, cytokine production may be assumed to be higher in females than males. Even if all results are not clear-cut, nonetheless, many studies have reported higher cytokine levels in both male humans and animals than in females. High IL-6 levels in males correlated with poorer prognosis and shorter longevity. A sound understanding of the basic regulatory mechanisms responsible for these gender differences may lead to new therapeutic targets.

Sleep in America: role of racial/ethnic differences.

Sleep duration in America has gradually declined over the last four decades and appears to have reached a plateau for the last six years, with recent studies reporting that the population's current average sleep duration is approximately 6 h. In this paper, we examine epidemiologic and community-based data on sleep complaints reported by American adults, specifically addressing the role of race/ethnicity in the subjective report of sleep problems. Subjective and objective findings indicate that black (throughout the text, we use the term black in lieu of African American for there are instances where we refer to individuals with self-ascribed race/ethnicity as black, African American, African, or Caribbean American; the term white is used to denote individuals of European descent). Americans have higher rates of long (≥9 h) and short (≤5 h) sleep than their white counterparts, and this may mediate a higher risk of cardiovascular disease, obesity and diabetes among blacks. In addition, studies show mixed results on sleep complaints among blacks compared to those among other ethnicities. This paper explores factors that may contribute to racial/ethnic differences in sleep including intra-ethnic variation, cultural biases, genetics and psychosocial factors.

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.

Chronic inflammatory diseases in children are more severe in girls.

In humans and animal models, females express higher immune reactivity and more robust inflammatory responses. We analyzed the expression of current inflammatory markers in 149 children (74 girls and 75 boys) with three chronic inflammatory diseases: 50 with asthma, 47 with cystic fibrosis, and 52 with sickle cell anemia to evaluate the potential differences in clinical response according to sex. Data including temperature, neutrophil count (NC), and C-reactive protein were recorded for each patient at several time points according to his/her disease. In asthma, NC was higher in girls than in males (P < 0.02), as were doses of cortisone (P < 0.04) or inhaled bronchodilators (P < 0.01) received at recovery. In cystic fibrosis, NC became significantly higher in girls at age 5 years (P < 0.003), whereas episodes of infection and antibiotic administration were already significantly more frequent in girls at age 2 years (P < 0.02 and P < 0.05, respectively). In sickle cell anemia, the number of crises since diagnosis and number of acute chest syndrome episodes were significantly higher in girls (P < 0.01 and P < 0.05, respectively). Our study extends the documentation of a relationship between sex, inflammatory markers, and clinical outcome in prepubescent children, suggesting a genetic predetermination is more likely than hormonal influence.

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/microL (range, 328-27,645 cells/microL) for girls and 6,774 cells/microL (range, 600-38,668 cells/microL) 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).

Cancer worry and insomnia complaints among American women.

One-third of women worrying about breast cancer report impaired ability to function daily. It is unclear whether women who worry about breast cancer would experience more sleep problems than those who do not. Data were obtained from a cross-sectional study of black and white women to investigate the association between breast cancer worry and insomnia complaints. Several questionnaires were administered during face-to-face interviews to elicit health and sociodemographic data. The present analyses focused on black and white women (n = 1,038; age range = 50-70 years) with no cancer antecedents or history. Overall, 62% of the women worried about breast cancer, and 49% reported insomnia complaints. Logistic regression analyses, adjusting for effects of age, ethnicity, family history, and perceived risk of developing breast cancer, yielded an odds ratio for insomnia complaints of 1.52 (95% CI: 1.15-2.02, p < .001) among women reporting breast cancer worry. More than one half of the women worrying about breast cancer were likely to report insomnia complaints, notwithstanding the fact that those women did not have a history of cancer. Although fewer black women reported breast cancer worry and insomnia complaints, they were as affected as white women by the impact of worry on mood and daily activities.

Attachment styles and sleep measures in a community-based sample of older adults.

BACKGROUND: Measures of attachment style are often used to appraise social and emotional health. In developmental literature, the concept of attachment is used to explain relationships between children and their adult caregivers. While both attachment styles and sleep patterns are conceived as developmentally organized systems, very few studies have explored the link between the two. The present study examined whether attachment styles and sleep measures are associated among older adults. METHODS: Relationships between attachment styles (i.e., secure, fearful, preoccupied, and dismissive) and subjective sleep measures were assessed utilizing data from 70 older participants (mean age: 68+/-6 years; Blacks: 59% and Whites: 41%) in a community-based study assessing subjective health characteristics. After obtaining informed consent, each participant provided demographic and socioeconomic data, as well as relevant medical and subjective data. RESULTS: Independent of participants' demographic and subjective factors, significant correlations were found between the preoccupied attachment dimension and sleep measures. Specifically, individuals scoring high on the preoccupied attachment dimension were more likely to report daytime napping (r(p)=0.31, p<0.01) and to use sleep-inducing medications (r(p)=0.37, p<0.05). No significant correlations were found among sleep measures and the secure, dismissive, and fearful dimensions. CONCLUSIONS: Important relations have been observed between specific attachment styles and subjective sleep factors in our data. Although only one-dimension (preoccupied) demonstrated statistical significance, a trend was observed, suggesting possible associations between the secure attachment style dimension and subjective sleep measures. Future studies are needed to broaden our understanding of the relationship between attachment styles and sleep patterns.

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: Fisher's 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.

Racial differences in suicidality in an older urban population.

PURPOSE: This study used epidemiological data of older African Americans and Caucasians living in an urban community to compare those factors associated with active or passive suicidal ideation in each racial group. DESIGN AND METHODS: Using 1990 census data for Brooklyn, New York, we attempted to interview all cognitively intact adults aged 55 or older in randomly selected block groups. The sample consisted of 214 Whites and 860 Blacks. We adapted George's social antecedent model to examine 19 independent variables; the dependent variable was based on lifetime history of passive or active suicidal ideation (hereafter, suicidality). We weighted the sample by race and gender. To control for sampling design effects, we used SUDAAN for data analysis. RESULTS: Whites reported higher prevalence than Blacks for current suicidality (5.8% vs 2.3%) and lifetime suicidality (14.8% vs 10.2%). None of the differences were significant. In logistic regression analysis conducted for each race, four variables were associated with suicidality within both races: higher depressive symptom scores, higher anxiety symptom scores, copes by using medications, and lower religiosity. Two variables were associated with suicidality only among Whites: higher use of spiritualists and copes by keeping calm. One variable, greater use of doctors for mental health problems, was significant only among Blacks. IMPLICATIONS: There were no racial differences in the prevalence of suicidality. Virtually all of the factors associated with suicidality are potentially ameliorable. Among both racial groups, suicidality is likely to be impacted by addressing depressive and anxiety symptoms and, when appropriate, by encouraging various coping strategies, especially religiosity.

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.

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

BACKGROUND: This study examined whether ethnic differences in insomnia symptoms are mediated by differences in repressive coping styles. METHODS: A 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. Fisher's exact test and Spearman and Pearson analyses were used to analyze the data. RESULTS: The rate of insomnia symptoms was greater among White women [74% vs. 46%; chi2 = 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. CONCLUSION: Relationships 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.