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Background: In children with suspected aspiration, clinical swallow assessment (CSA) may be supplemented with video-fluoroscopic swallow studies (VFSS) to inform feeding management. Aim: To assess the diagnostic accuracy of CSA, compared to VFSS and evaluate the impact of VFSS on feeding management and clinical status. Method: Retrospective case review of children who underwent CSA, followed by VFSS in a tertiary centre. Results: 113 children underwent VFSS at age 2.2 (0.1-17.9) years, median (range). Diagnoses were syndromic entities (38, 34%), CNS dysfunction (28, 25%), anatomic abnormalities (18, 16%), CNS malformation (7, 6%), neuromuscular disease (6, 5%) and other (16, 14%). 62% had laryngeal penetration or aspiration per CSA, compared to 38% per VFSS, p VFSS based feeding route recommendations differed significantly from those based on prior CSA, p=0.04. Following VFSS, the rate of orally fed children rose from 66% to 78%, p=0.006. However, exclusive gastrostomy feeding also increased, from 7% to 12%, p=0.005. In the year after VFSS, compared to the year prior, total hospital admissions fell from 364 to 252, p Conclusion: CSA overestimated the presence of overall swallowing abnormalities, but underestimated silent aspirations. VFSS led to change in feeding route and advice, which was associated with clinical improvement.

Objective: The causes of subfertility in women with CF though multifactorial are not well described. Our aim in this study was to determine the prevalence and factors associated with female subfertility among women with CF. Methods: A retrospective multinational study from 11 CF centers in 5 countries (Israel, France, Spain, Italy, UK) including women with CF was undertaken. Sub/infertility was defined as not achieving a spontaneous pregnancy after one year of unprotected sexual intercourse. Data including genetics, pancreatic insufficiency (PI), prevalence of diabetes (CFRD), lung function, nutritional status measured by body mass index (BMI), sputum bacterial colonization, and rate of pulmonary exacerbations were collected from patients' files. Results: Out of 605 women, 241 attempted pregnancy. Of these, 84 (35%) had subfertility, and 67 of them eventually became pregnant. Females attempting conception were older but had better pulmonary function and nutrition compared to those who did not. In a multivariate analysis, PI (OR 1.9 [1.03–3.5], p =.04) and older age (OR 3.9 [2.1–7.3] p

Background Severe epistaxis is often difficult to control in patients with hereditary hemorrhagic telangiectasia (HHT). Propranolol has been shown to have antiangiogenic properties in vitro and in vivo and is commonly used to treat hemangiomas. We present our experience with topical nasal propranolol for the treatment of moderate to severe epistaxis in patients with HHT. Methods Retrospective case series. Six patients with HHT were treated with 0.5 cm3 of 1.5% propranolol gel, applied to each nostril twice daily for at least 12 weeks. Outcome measures were epistaxis severity score (ESS), hemoglobin level, and number of blood transfusions prior to and while on treatment. Local and systemic side effects were recorded. Results The mean duration of treatment was 30 ± 5.6 weeks. A significant improvement in the ESS was found in all patients, with a mean decrease from 6.4 ± 2.1 at treatment onset to 3.5 ± 1.7 at 12 weeks (p = 0.028). Hemoglobin level increased significantly from 8.4 ± 3.1 to 11.0 ± 1.8 g/dL at 12 weeks (p = 0.043). The mean number of blood transfusions decreased from 4.5 ± 4.9 before treatment to 2.5 ± 2.9 at 12 weeks and 0.3 ± 0.8 at 24 weeks, but the difference did not reach statistical significance (p = 0.109 for both). No significant side effects of treatment were recorded. Conclusions These preliminary results suggest that topical propranolol may be effective for the treatment of epistaxis in patients with HHT. A prospective controlled trial is required to confirm our findings.

Objectives To assess the characteristics that correlate with better outcomes after lung transplantation for patients with cystic fibrosis (CF). Methods We retrospectively reviewed the charts of all patients with CF who underwent lung transplantation between 1996-2014 at Rabin Medical Center, Israel. Results Fifty patients with CF underwent 55 lung transplantations. Eighteen patients (36%) died during the study period. Actuarial survival was 83%, 68%, 62% and 39% at 1, 3, 5 and 10 years, respectively. Better survival correlated with: BMI at 6-months and 1-year after transplantation (p=0.002 and p=0.003, respectively), ischemic time of less than 300 minutes (p=0.023), absence of liver disease (p=0.012) and Jewish compared to Arab ethnicity (p=0.007). Freedom from bronchiolitis obliterans syndrome (BOS) was 87%, 75% and 72% at 1, 3 and 5 years, respectively. BOS was more common and appeared earlier in the Arab than in the Jewish population (p=0.012, p=0.007). Additionally, prolonged time free of BOS correlated with male gender (p=0.039), older age (p

Background Ivacaftor is a drug that increases the probability of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel remaining open. Information about the efficacy of ivacaftor in patients carrying the rare p.Ser549Arg (S549R) CFTR mutation is sparse. Aim Efficacy of ivacaftor treatment in patients carrying the p.Ser549Arg (S549R) CFTR mutation. Methods Data obtained from CF patients receiving ivacaftor for one year. Results Eight CF patients, mean age 21 ± 10 years, received ivacaftor. After one year, significant improvement was found in FEV 1 , increasing from 74% to 88% (p 25-75 , 59%–76% (p = 0.019). Sweat chloride concentration decreased from 116 ± 8 mmol/L to 51 ± 17 mmol/L (p Conclusions Ivacaftor therapy resulted in significant clinical improvement in patients carrying the p.Ser549Arg (S549R) CFTR mutation.

Background Airway infections in Primary Ciliary Dyskinesia (PCD) are caused by different microorganisms, including pseudomonas aeruginosa (PA). The aim of this study was to investigate the association of PA colonization and the progression of lung disease in PCD. Methods Data from 11PCD centers were retrospectively collected from 2008 to 2013. Patients were considered colonized if PA grew on at least two separate sputum cultures; otherwise, they were classified as non-colonized . These two groups were compared on the lung function computed tomography (CT) Brody score and other clinical parameters. Results Data were available from 217 patients; 60 (27.6%) of whom were assigned to the colonized group. Patients colonized with PA were older and were diagnosed at a later age. Baseline forced expiratory volume at 1 s (FEV 1 ) was lower in the colonized group (72.4 ± 22.0 vs. 80.1 ± 18.9, % predicted, p = 0.015), but FEV 1 declined throughout the study period was similar in both groups. The colonized group had significantly worse CT-Brody scores (36.07 ± 24.38 vs. 25.56 ± 24.2, p = 0.034). A subgroup analysis with more stringent definitions of colonization revealed similar results. Conclusions Lung PA colonization in PCD is associated with more severe disease as shown by the FEV 1 and CT score. However, the magnitude of decline in pulmonary function was similar in colonized and non-colonized PCD patients.

Objective Propranolol is the treatment of choice for infantile hemangiomas requiring medical intervention. Although contraindicated in asthma, its bronchoconstrictive effect in infants and children has not been extensively studied. We aimed to assess the incidence of wheezing episodes in infants and children treated with propranolol for infantile hemangiomas. Study Design A retrospective case-control study. Setting: a tertiary pediatric hospital. Patients: All Children followed for infantile hemangioma between 2009 and 2014. Children followed conservatively served as control group and were matched 1:1 for gender and month of birth by random matching to children treated with propranolol. Interventions: All respiratory episodes (asthma, wheezing, stridor, and pneumonia) and respiratory associated hospitalizations were recorded from hospital records, from the primary care physician visits records and pharmacy prescriptions. The main outcome measure was the incidence of respiratory episodes in the treatment and the control groups. Results A total of 1828 clinic visits were reviewed for 683 children. In addition, primary care physician visits records were available in 80% of them. Two hundred and sixteen children were treated with propranolol. Incidence of respiratory episodes and recurrent respiratory episodes was similar in the propranolol and control groups (8.3% vs 12%, P = 0.265; 3.7% vs 6.5%, P = 0.274, respectively). Time to first episode was similar in the treatment and control groups (5.03 ± 3.32 vs 4.45 ± 3.21 months, respectively, P = 0.09). Respiratory hospital admission rate was similar in both groups. Conclusions Propranolol treatment does not exacerbate wheezing episodes in infants and children.

OBJECTIVES: Seasonal variations in asthma are widely recognized, with the highest incidence during September. This retrospective population study aimed to investigate whether this holds true in a large group of asthmatic children in primary care and to assess the impact of age, gender, urban/rural living, and population sector. METHODS: The key study outcomes were the diagnosis of asthma exacerbations and asthma medication prescriptions, recorded by family physicians during 2005 to 2009. These were analyzed by “week of diagnosis” in Clalit Health Services’ electronic medical record database. Regression models were built to assess relative strength of secular trends, seasonality, and age-group in explaining the incidence of asthma exacerbations. RESULTS: A total of 919 873 children aged 2 to 15 years were identified. Of these, 82 234 (8.9%) were asthmatic, 61.6% boys and 38.4% girls; 49.1% aged 2 to 5 years, 24.1% 6 to 9 years, and 26.8% 10 to 15 years. We observed a 2.01-fold increase in pediatric asthma exacerbations and 2.28-fold increase in prescriptions of asthma bronchodilator medications during September (weeks 37–39 vs weeks 34–36) compared with August. The association between the opening of school and the incidence of asthma-related visits to the primary care physician was greatest in children aged 2 to 5 years (odds ratio, 2.15) and 6 to 11 years (1.90-fold). Adolescents (age 12–15 years) had a lesser peak (1.81-fold). In late fall there was a second rise, lasting with fluctuations throughout winter, with a trough in summer. CONCLUSIONS: Returning to school after summer is strongly associated with an increased risk for asthma exacerbations and unscheduled visits to the primary care physician.

We created an Eclipse plug-in called FrenchPress that offers students feedback on their Java programming style. It is designed not for novices but for students taking their second or third Java course. Advanced beginner students know enough to produce a program with the desired input/output behavior, but fail to understand it could still be poorly written. Large class sizes in introductory courses make it difficult for instructors to give their students individualized attention. FrenchPress automates a small subset of the feedback students might have received from educators. The system diagnoses issues characteristic of programmers who have not yet assimilated the object-oriented paradigm, such as misuse of the public modifier, fields that should have been local variables, and instance variables that should have been class constants. We conducted a classroom trial of the plug-in covering four assignments in data structures and algorithms. Among students whose code triggered one or more diagnostic rules, the percentage who modified their program in response to FrenchPress feedback varied from a high of 59% on the first project to a low of 23% on the second and fourth projects. On the user surveys following each assignment, 56–66% of respondents said they were satisfied with FrenchPress performance.

Summary Introduction Pulmonary complications following hematopoietic stem cell transplantation (HSCT) are common and often subclinical. Thus, periodic pulmonary function testing (PFT) is mandatory. This study sought to evaluate the effectiveness of long-term PFT surveillance for children undergoing HSCT and identify potential risk factors. Methods We reviewed long-term PFT for HSCT patients at a tertiary pediatric center. Inclusion criteria were PFT prior to and at least once following HSCT. Results Fifty-seven patients performed 202 spirometry and 193 plethysmographic maneuvers; 41 were tested during the first year after HSCT, but only 29 were evaluated consistently long term (2–12 years). FVC and FEV1 decreased gradually suggesting a restrictive ventilatory defect: FVC % predicted [mean ± SD] dropped from 91 ± 14% to 85 ± 17% after 0–24 months and 80 ± 19% beyond 2 years (P = 0.01) whereas FEV1 dropped from 95 ± 16% to 88 ± 19% and 82 ± 20%, respectively (P = 0.002). A slight reduction in TLC was observed. Those undergoing allogeneic HSCT had a greater decline in FVC (P = 0.025) and FEV1 (P = 0.025) as did those conditioned with radiation, regarding both FVC (P = 0.003) and FEV1 (P = 0.002). Decline occurred earlier (≤2 years) after chemotherapy compared with radiation. Seven children had severe irreversible obstruction at >2 years despite therapeutic intervention. Conclusions Most survivors of childhood HSCT maintain almost normal pulmonary function although mild restrictive lung disease may develop, particularly following allogeneic HSCT and conditioning with radiation. Severe airways obstruction developed in a small minority. The surveillance protocol for PFT needs to be followed more stringently to enable intervention possibly before early subclinical changes progress and become irreversible. Pediatr Pulmonol. 2014; 49:1124–1132. © 2013 Wiley Periodicals, Inc.

Lung clearance index (LCI) reflects ventilation inhomogeneity and is raised in obstructive airway disease. Feasibility of multiple breath washout (MBW) measurement during acute lung disease in infants is unknown. As a further measure of disease, exhaled nitric oxide (eNO) may paradoxically decrease in acute bronchiolitis. We hypothesized that MBW measurements were attainable in infants with bronchiolitis and that LCI was raised and eNO reduced, compared to normal controls.Infants with acute bronchiolitis were tested with sulfur hexafluoride (SFTwenty-nine infants with bronchiolitis aged 3.7 ± 2.3 months (mean ± SD) and 23 controls aged 4.2 ± 2.5 months (P = 0.07) were evaluated. Fifteen of 29 (52%) infants with bronchiolitis and 19/23 (83%) controls achieved ≥2 valid MBW measurements. Reasons for test failure included waking up during facemask application and an irregular respiratory pattern. LCI was 8.4 ± 0.8 in the study group and 7.3 ± 0.7 in controls (P 0.001). ENO was 2.3 ± 2.7 ppb in the study group and 7.9 ± 6.9 ppb in controls (P = 0.004).MBW measurements during natural sleep are feasible but technically challenging in infants with acute bronchiolitis. LCI is raised compared to healthy controls. Larger trials, possibly using sedation protocols and shortened washout periods, are required to corroborate these findings. LCI can potentially serve as an objective indicator of severity and could be considered as a biomarker for future interventional trials.

The killing of natural killer (NK) cells is regulated by activating and inhibitory NK receptors that recognize mainly class I major histocompatibility complex (MHC) proteins. In transporter associated with antigen processing (TAP2)-deficient patients, killing of autologous cells by NK cells is therefore expected. However, none of the TAP2-deficient patients studied so far have suffered from immediate NK-mediated autoimmune manifestations. We have previously demonstrated the existence of a novel class I MHC-independent inhibitory mechanism of NK cell cytotoxicity mediated by the homophilic carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) interactions. Here, we identified 3 new siblings suffering from TAP2 deficiency. NK cells derived from these patients express unusually high levels of the various killer cell inhibitory receptors (KIRs) and the CEACAM1 protein. Importantly, the patients' NK cells use the CEACAM1 protein to inhibit the killing of tumor and autologous cells. Finally, we show that the function of the main NK lysis receptor, NKp46, is impaired in these patients. These results indicate that NK cells in TAP2-deficient patients have developed unique mechanisms to reduce NK killing activity and to compensate for the lack of class I MHC-mediated inhibition. These mechanisms prevent the attack of self-cells by the autologous NK cells and explain why TAP2-deficient patients do not suffer from autoimmune manifestations in early stages of life.

OBJECTIVE: Computed tomography is commonly used in the diagnosis of pediatric lung disease. Although the radiation is not negligible, the yield has never been studied. METHODS: Clinical and imaging data were collected for all children who underwent chest computed tomography, as part of the diagnostic process. Cases were grouped according to type of lung disease, based on clinical data and the question addressed to the radiologist. A positive yield was defined as computed tomography providing ≥1 of the following: (1) a diagnosis, (2) a clinically important new finding that had not been recognized previously, (3) alteration of the plan for further evaluation or treatment, or (4) exclusion of lung disease. No yield was defined when computed tomography did not add new information and did not affect evaluation or treatment. RESULTS: Ages ranged from 2 weeks to 16 years, and 59% were male. The overall positive yield was 61% (64 of 105 cases). Yields were relatively low, that is, 23% (8 of 35 cases) for the evaluation of diffuse lung disease, 46% (6 of 13 cases) for localized disease, 50% (6 of 12 cases) for pleural disease, and 98% (41 of 42 cases) for congenital malformations. CONCLUSIONS: The yield of chest computed tomography depends on the type of disease. Computed tomography has a significant yield for congenital anomalies. The yield is particularly low in the evaluation of acquired diffuse pulmonary disease and is relatively low in acquired focal lung disease. We suggest that chest computed tomography be used more judiciously.

Objectives: Most patients with cystic fibrosis (CF) have pancreatic insufficiency; however, 15% of the patients are pancreatic sufficient (PS). Several laboratory tests have been developed to distinguish between pancreatic insufficiency and PS. The gold standard to determine pancreatic function apart from direct pancreatic stimulation test is the 72-hour fecal fat excretion, expressed as coefficient of fat absorption (CFA). The aim was to test the correlation between 2 other tests, fecal elastase-1 and serum immunoreactive trypsinogen (IRT), as compared with fecal fat excretion. Patients and Methods: 21 patients with CF-PS performed the 3 tests of fecal fat excretion, fecal elastase-1, and IRT. Correlation between the tests was evaluated by the k statistics test, sensitivity and specificity, and positive and negative predictive values. Results: CFA was abnormal in 5 patients, elastase was

GOALS: To understand the relationship between acute recurrent pancreatitis and cystic fibrosis transmembrane conductance regulator (CFTR) dysfunction. BACKGROUND: An emerging number of patients present with a nonclassic phenotype of cystic fibrosis (CF) with partial features or single-organ disease only. The association between the phenotype of recurrent pancreatitis CFTR dysfunction is unclear. METHODS: Patients with idiopathic recurrent pancreatitis were referred for electrophysiologic investigation. RESULTS: Thirty-three patients (18 males) aged 20+/-12 years with recurrent pancreatitis were studied. Three patients had mild asthma and 1 patient had mild ulcerative colitis. There was no family history of CF. All patients had normal imaging of the pancreatic duct by endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography. No patient was pancreatic insufficient. Mean sweat chloride values were 41+/-14 meq/L (range: 18 to 64). Nasal potential difference (NPD) measurement was pathologic in 7 patients. Mean basal potential difference in these 7 patients was -33+/-13 mV and there was an abnormal response to chloride-free and isoproterenol solutions. There was no difference in sweat chloride concentration between the 2 groups. Mutation analysis revealed W1282X/5T, D1152H/5T, and W1282X/- in 3 patients with abnormal NPD and 1 W1282X allele was found in 1 patient with normal NPD. CONCLUSIONS: In this series, 21% of patients with recurrent pancreatitis have abnormalities of CFTR function. Patients presenting with recurrent, "idiopathic" pancreatitis require CFTR function testing.

Background Chronic inflammation and infection in patients with cystic fibrosis (CF) and other lung diseases begin early, making noninvasive diagnostic techniques vital. As induced sputum (IS) testing is useful in older patients, we investigated its adaptation to young nonexpectorating children. Methods Following the inhalation of a 4.5% saline solution, sputum was collected by nasopharyngeal or oropharyngeal suction for culture and testing for inflammatory markers, with paired preceding oropharyngeal cough swabs (OCSs) in a subgroup. Specimens from 48 IS procedures (46 successful) in 20 CF children (median age, 3 years) were compared with 8 specimens from 8 non-CF pulmonary patients (median age, 4.5 years). Results The procedure was safe, with arterial oxygen saturation remaining at ≥ 96%. Cultures from 14 of 46 CF patients (30%) grew Pseudomonas aeruginosa , whereas cultures from 19 of 46 CF patients (41%) had no growth. Cultures from seven of eight non-CF subjects grew bacteria, but none were P aeruginosa . Comparing 29 paired IS and OCS samples, 11 and 5 samples, respectively, cultured P aeruginosa (not significant), whereas 12 and 21 samples, respectively, had no growth (p = 0.02). A correlation was found between the independent inflammatory markers NE and both interleukin (IL)-8 ( r = 0.85; p r = 0.35; p r = 0.41; p Conclusions IS testing in the young is feasible, safe, and clinically useful, and could serve as an outcome measure for new therapies.

Spirometry data in cystic fibrosis (CF) patients in early childhood is scarce, and the ability of spirometry to detect airways obstruction is debatable.To evaluate the ability of spirometry to detect airflow obstruction in CF patients in early childhood.CF children (age range, 2.5 to 6.9 years) in stable clinical condition were recruited from five CF centers. The children performed guided spirometry (SpiroGame; patented by Dr. Vilzone, 2003). Spirometry indices were compared to values of a healthy early childhood population, and were analyzed with relation to age, gender, and clinical parameters (genotype, pancreatic status, and presence of Pseudomonas in sputum or oropharyngeal cultures).Seventy-six of 93 children tested performed acceptable spirometry. FVC, FEV1, forced expiratory flow in 0.5 s (FEV0.5), and forced expiratory flow at 50% of vital capacity (FEF50) were significantly lower than healthy (z scores, mean +/- SD: - 0.36 +/- 0.58, - 0.36 +/- 0.72, - 1.20 +/- 0.87; and - 1.80 +/- 1.47, respectively; p0.01); z scores for FEV1 and FVC were similar over the age ranges studied. However, z scores for FEV0.5 and forced expiratory flow at 25 to 75% of vital capacity were significantly lower in older children compared to younger children (p0.001), and a higher proportion of 6-year-old than 3-year-old children had z scores that were2 SDs below the mean (65% vs 5%, p0.03). Girls demonstrated lower FEF50 than boys (z scores: - 2.42 +/- 1.91 vs - 1.56 +/- 1.23; p0.001). Clinical parameters evaluated were not found to influence spirometric indices.Spirometry elicited by CF patients in early childhood can serve as an important noninvasive tool for monitoring pulmonary status. FEV0.5 and flow-related volumes might be more sensitive than the traditional FEV1 in detecting and portraying changes in lung function during early childhood.

As asthma-like symptoms are common in CF, we evaluated reversible airway obstruction and associated characteristics.Retrospective analysis of charts including spirometry and bronchodilator response.Of 190 CF patients (103 at Schneider's, 87 at Hadassah), aged 14.4 (4-76) years, median (range), 39% had reversible obstruction (ΔFEV1% predicted ≥12%), associated with younger age (p=0.01) and severe genotype (p=0.02). There was no association with family history of asthma, serum IgE, blood eosinophils, pancreatic status, FEV140% predicted, Aspergillus or pseudomonas infection. Of patients with reversible obstruction, 74% were on bronchodilator and 68% on inhaled corticosteroid therapy but 54% and 57% respectively receiving these therapies did not have reversible obstruction.Reversible airway obstruction is common in CF, more frequent in younger patients and with severe genotype, with no correlation to markers of atopy or CF clinical severity. Bronchodilator and inhaled corticosteroid therapies are commonly prescribed even without reversible obstruction.

Background: Chronic lung disease of prematurity (CLDp) is attributed to a low gestational age of extreme prematurity (EP) and an immaturely developed respiratory system. We recently showed that school aged children born EP have similar lung function regardless of whether or not they developed Bronchopulmonary Dysplasia (BPD). We hypothesize that Forced Oscillation Technique (FOT) is superior to routine lung function tests in demonstrating sustained tissue damage and respiratory dysfunction in children with CLDp. Methods: A non-selective prospective cohort study. 58 children born EP, 29 with/ 29 without BPD (BPD/non-BPD), versus 24 matched healthy controls at a mean age of 10.2±1.5 yrs. FOT and spirometry were performed before and after administration of β2 agonist (BD). Results: No differences between BPD and non-BPD sub-groups were found in any spirometry or FOT indices measured at baseline or after BD. Compared to controls, CLDp children exhibited significantly lower FEV1, FEF50, mean respiratory reactance (Xavg), and higher resonance frequency (Fres) (p

Background: Lung transplantation is the last resort therapeutic option for end-stage lung disease in cystic fibrosis (CF). Aims: To evaluate the national Israeli experience with lung transplantation for patients with CF at Rabin Medical Center (RMC). To assess the characteristics that correlates with better outcomes. Methods: We retrospectively reviewed the medical charts of all CF patients who underwent lung transplantation between 1996-2014 at RMC. Results: Fifty CF patients underwent 54 lung transplantations between 1996-2014. Twenty-four were male (48%). Age at transplantation was 28.3±9.1 years (11-50 years). Eighteen patients (36%) died during the study period. For the whole group actuarial survival was 83%, 68%, 62% and 39% at 1, 3, 5 and 10 years respectively. Better survival correlated with: FEV1%>60% at 6 months post transplantation (p Freedom from BO was 87%, 75% and 72% at 1, 3 and 5 years respectively. BO was more common in Arab than the Jewish population (p=0.012). Longer time without BO correlated with: Male gender (p=0.039), Jewish compared to Arab ethnicity (p=0.007), older age (p Conclusions: Our survival and freedom from BO rates are similar the registry of the ISHLT 2014. BMI 1 year post transplantation is an important determinant of survival and longer time without BO. Arab ethnicity was correlated with higher incidence and earlier appearance of BO.

Introduction: Nocardiosis in Cystic Fibrosis (CF) associated with chronic antibiotic therapy, a changing pulmonary microbiome, improving diagnosis and increasing length of survival.Its role as a pathogen is debated and a recent report suggested that it doesn9t require antibiotic treatment. In our experience, however, Nocardia infection in CF can sometimes lead to inexorable pulmonary deterioration and even result in lung transplantation. Aim: To describe the spectrum of CF pulmonary nocardiosis and to assess whether steroid treatment or Allergic Broncho Pulmonary Aspergillosis (ABPA) are associated with pulmonary nocardiosis in CF. Methods: A retrospective chart review from 2002 - 2013, at two CF centers in Israel. Sputum was acquired every clinic visit for Ziehl Neelsen staining and culture on blood agar for 3 weeks. we considered Nocardia to be eradicated if 3 consecutive sputum cultures were negative. Results: We reviewed charts of 200 CF patients (2 months-63 years). Eight (4%) had at least one positive sputum culture for Nocardia . Two patterns of Nocardia infection were observed: a) four patients experienced a stormy clinical course, with respiratory deterioration, one requiring lung transplantation. Multiple courses of antibiotics were required and eradiacation was successful only in two. 3 of them had associated ABPA; b) 4 patients had a milder course with no or gradual deterioration. Treatment with Trimetoprim-sulfamethoxazol was initiated if clinical symptoms were present. Conclusions: Nocardia is often associated with significant lung disease in CF, possibly associated with ABPA or steroids. Aggressive multi-drug therapy should be instituted early when there is such deterioration.

Background Population carrier screening (PCS) has been available in Israel since 1999 and universally subsidized since 2008. We sought to evaluate its impact. Methods A retrospective review of governmental databanks, the national CF registry and CF centers. Results CF rate per 100,000 live births has decreased from 14.5 in 1990 to 6 in 2011. From 2004–2011 there were 95 CF births: 22 utilized PCS; 68 (72%) had 2 known CFTR mutations; 37% were pancreatic sufficient. At diagnosis, age was 6 (0–98) months; 53/95 had respiratory symptoms, 41/95 failure to thrive and 19/95 pseudomonas. Thirty-four (36%) were Arabs and 19 (20%) orthodox Jews, compared to 20% and 8% respectively, in the general population. Conclusions PCS markedly reduced CF birth rates with a shift towards milder mutations, but was often avoided for cultural reasons. As children regularly have significant disease at diagnosis, we suggest a balanced approach, utilizing both PCS and newborn screening.

We reviewed all cases of Nocardia infection in cystic fibrosis patients at 2 centers. Eight of 200 patients had Nocardia in sputum. Four developed severe lung disease, including 3 with associated allergic bronchopulmonary aspergillosis; 4 remained clinically stable. Nocardia is often associated with significant lung disease in cystic fibrosis, possibly associated with allergic bronchopulmonary aspergillosis or steroids.

Palivizumab reduces the severity of respiratory syncytial virus infection in premature infants, but whether there is a protective effect beyond the preschool age is unknown. This study sought to assess the short- and long-term effects of palivizumab immunization on respiratory morbidity and pulmonary function at school age in children born extremely prematurely.Infants born before 29 weeks' gestation in 2000 to 2003 were assessed at school age by parental questionnaire, hospital chart review, and lung function tests. Children born immediately before the introduction of routine palivizumab prophylaxis were compared with age-matched children who received palivizumab prophylaxis during the first respiratory syncytial virus season.Sixty-three children with a mean age 8.9 years were included: 30 had received palivizumab and 33 had not (control subjects). The groups were similar in terms of gestational age, birth weight, need for mechanical ventilation, and oxygen supplementation. Fifty-three percent of the palivizumab group, compared with 39% of the control group, had bronchopulmonary dysplasia (P = .14). Wheezing occurred in the first 2 years of life in 27% of the palivizumab group and in 70% of control subjects (P = .008); respective hospitalization rates were 33% and 70% (P = .001). At school age, rates of hyperresponsiveness (provocative concentration leading to a 20% fall in FEV11 mg/mL) were 33% and 48%, respectively (P = .38). Spirometry, lung volumes, diffusion, and exhaled nitric oxide were within normal limits, with no significant differences between groups.Palivizumab prophylaxis was associated with reduced wheezing episodes and hospitalizations during the first 2 years of life in children born extremely prematurely. However, it did not affect pulmonary outcome at school age.

Chemokines play a pivotal role in homeostatic and inflammatory migration of naive and activated natural killer (NK) subsets. Recent studies have shown that aberrant chemokine receptor expression on certain immune cells underlies the pathogenesis of clinical conditions in which recruitment of such cells is altered. Progressive accumulation of activated NK cells, subsequently resulting in the formation of chronic granulomatous lesions in the respiratory tract and the skin, has been described in a number of patients with transporter associated with antigen processing 2 (TAP-2) deficiency in the later stages of disease. Therefore, the goal of the present study was to elucidate whether the dysregulation of chemoattracting receptor expression on NK cells could explain abnormal navigation of these cells in TAP-2 deficiency. High-throughput proteomic comparison, followed by verification with flow cytometry, revealed that chronically activated NK cells derived from 3 newly identified patients with TAP-2 deficiency consistently expressed aberrant levels of CC chemokine receptor 2 (CCR2) chemokine receptor in vitro and in vivo. This expression pattern translated into specific responsiveness of chronically activated NK cells derived from patients with TAP-2 deficiency to multiple ligands of CCR2. Moreover, the in vivo elevated levels of interleukin-2 (IL-2) and monocyte chemoattractant protein-1 (MCP-1) detected in serum and bronchoalveolar lavage samples derived from these patients highlight the potential involvement of the CCR2 pathway in aberrant NK-cell retention at chronic inflammatory sites.

We previously demonstrated that the quinolone moxifloxacin prevents Candida albicans pneumonitis and epithelial nuclear factor kappaB (NF-kappaB) nuclear translocation in immunosuppressed mice.To explore the anti-inflammatory effects of moxifloxacin directly on a lung epithelial cell line.We studied the effect of clinically relevant concentrations of moxifloxacin (2.5-10 mg/L) on cytokine-induced activation of nitric oxide (NO) secretion, inducible NO synthase (iNOS) expression and the activation of signal transduction pathways of inflammation, NF-kappaB and the mitogen-activated protein kinases [extracellular signal-regulated kinases (ERK1/2) and C-Jun N-terminal kinase (JNK)], in the A549 lung epithelial cell line.Stimulation with the cytokines interleukin-1beta(IL-1beta)/interferon-gamma (IFN-gamma) increased NO up to 3.3-fold and moxifloxacin inhibited this up to 68% (P0.05). Similarly, the increase in iNOS levels was inhibited in cells pre-treated with moxifloxacin by up to 62%. IL-1beta stimulated a rapid increase in the activities of early intracellular signalling molecules, ERK1/2 and JNK. Moxifloxacin inhibited ERK1/2 by up to 100% and p-JNK activation by 100%. NF-kappaB, as measured by electrophoretic mobility shift assay, was inhibited up to 72% by moxifloxacin. Western-blot analysis revealed that IL-1beta enhanced NF-kappaB p65 and p50 proteins by 1.7- and 3.6-fold, respectively, whereas moxifloxacin inhibited the proteins by up to 60%.Moxifloxacin inhibits intracellular signalling, iNOS expression and NO secretion in a lung epithelial cell line. Future studies may uncover a primary site of quinolone immunomodulation, either upstream or at the cell membrane. Eventually, this quinolone might become an important therapy for inflammatory lung diseases.

Nontuberculous mycobacterial (NTM) infection, particularly due to Mycobacterium abscessus, is an emerging disease that can be relentlessly progressive, particularly in cystic fibrosis (CF) patients. The risk factors that were associated with this increasingly symptomatic infection in a group of CF patients were investigated. A total of 139 CF patients aged 2-52 yrs were reviewed. Sputum was cultured for NTM annually or whenever clinical deterioration was unexplained. In total, 12 patients (8.6%) had positive cultures and six (4.3%) met the criteria for NTM pulmonary disease (five with M. abscessus). Five had allergic bronchopulmonary aspergillosis (ABPA) compared with one out of 133 patients without NTM disease. Five had received systemic steroids (four as a treatment for ABPA) compared with only one out of 133 without NTM lung disease. All six NTM patients deteriorated markedly following mycobacterial infection, and forced expiratory volume in one second dropped 18-46%. Despite prolonged triple antibiotic therapy, M. abscessus was not eradicated, and four out of six did not return to baseline clinically. In conclusion, severe nontuberculous mycobacterial lung disease, particularly with Mycobacterium abscessus, is becoming a perplexing challenge in cystic fibrosis patients. Allergic bronchopulmonary aspergillosis and systemic steroids appear to be risk factors, although small patient numbers limit this to a descriptive observation. When pulmonary condition deteriorates, increased surveillance for mycobacteria would enable prompt diagnosis and treatment.

Morbidity and mortality in cystic fibrosis patients is mainly attributed to pulmonary infection and inflammation. Chemokines play a pivotal role in the inflammatory process. Although genotype-phenotype correlation in cystic fibrosis patients has been defined, a clear relationship between the defect in the cystic fibrosis transmembrane regulator (CFTR) gene and pulmonary inflammation has not been established. The aim of this study was to assess whether serum chemokines levels in cystic fibrosis patients correlate with genotype and pulmonary function tests, as well as with other clinical characteristics. Serum levels of interleukin-8, RANTES, and monocyte chemoattractant protein-1 were measured in 36 cystic fibrosis patients grouped according to their genotype. Group A included 25 patients who carried two mutations associated with a pathological sweat test and pancreatic insufficiency (deltaF508, W1282X, G542X, N1303K, S549R). Group B included 11 compound heterozygote patients who carried one mutation known to cause mild disease with borderline or normal sweat test and pancreatic sufficiency (3849+10kb C to T, 5T). Associations between chemokine levels, genotype, pulmonary function, Pseudomonas aeruginosa colonization, age, sweat chloride level, and pancreatic and nutritional status were examined. Mean interleukin-8 and monocyte chemoattractant protein-1 levels were significantly higher in group A than group B (11.4 +/- 2.1 pg/ml vs. 5 +/- 0.9 pg/ml and 157 +/- 16 pg/ml vs. 88.8 +/- 16.4 pg/ml, respectively) (P0.01). No difference in RANTES levels were found between groups. interleukin-8 levels were inversely related to forced expiratory volume in 1 s (r = -0.37, P0.02), while there was no association between the latter and RANTES and monocyte chemoattractant protein-1 levels. The Pseudomonas colonization rate was higher among group A patients than group B (88% vs. 40%, P0.01). No relationship was found between measured chemokines and age, sweat chloride levels, and pancreatic and nutritional status. Our study demonstrates an association between interleukin-8, forced expiratory volume, and cystic fibrosis genotype. Hence, elevated interleukin-8 serum levels could serve as an indicator of an early inflammatory process and encourage the initiation of anti-inflammatory treatment.

Patients with normal or borderline sweat tests present a diagnostic challenge. In spite of the availability of genetic analysis and measurement of nasal potential difference, there is still uncertainty in diagnosing cystic fibrosis in some patients. CA 19-9 is a tumor-associated antigen whose levels were previously found to be elevated in some cystic fibrosis patients. We investigated whether serum CA 19-9 levels can contribute to establishing the diagnosis of cystic fibrosis in patients with a borderline sweat test, and evaluated the influence of different clinical variables on CA 19-9 levels. Serum CA 19-9 levels were measured in 82 cystic fibrosis patients grouped according to their genotype and in 38 healthy individuals. Group A included 50 patients who carried two mutations previously found to be associated with a pathological sweat test and pancreatic insufficiency (DeltaF508, W1282X, G542X, N1303K, and S549R). Group B included 13 compound heterozygote cystic fibrosis patients who carried one mutation known to cause mild disease with a borderline or normal sweat test and pancreatic sufficiency (3849+10kb C-->T, 5T). Group C included 38 normal controls. Nineteen cystic fibrosis patients carried at least one unidentified mutation. An association between CA 19-9 levels and age, pulmonary function, pancreatic status, sweat chloride, previous pancreatitis, serum lipase, meconium ileus, distal intestinal obstruction, liver disease, and diabetes was investigated. The distribution of CA 19-9 levels was significantly different between the three groups ( p

Background: Congenital bilateral absence of the vas deferens (CBAVD) is presumed to occur prenatally and is present in over 99% of adult males with cystic fibrosis (CF). Aims: To describe ultrasonic features in male children with CF. We aimed to describe urogenital anomalies, comparing pancreatic sufficient and insufficient CF patients. Methods: Pelvic and scrotal ultrasonography were performed in 12 boys with CF aged 2–12 years and 16 age matched healthy controls. Results: Nine patients had pancreatic insufficiency (PI): seven had two severe mutations and two had unknown mutations. Three boys were pancreatic sufficient (PS), two with splicing mutations (5T and 3849+10kb C–T respectively) and borderline sweat tests. Seminal vesicles were visualised in 5/12 patients and 8/16 controls, compared to non-visualisation reported in all adults with CBAVD. Testicular microlithiasis was found in 4/18 PI, 0/6 PS, and 0/32 control testes, compared to 0.6–1.4% in healthy males and 15% in CF adults; 7/18 PI, 4/6 PS, and 0/32 control testes were smaller than predicted for age. The epididymal head was non-homogeneous with cysts, hypo-, or hyper-echogenicity in 5/18 PI, 1/6 PS, and 0/32 control testes. Conclusions: Genital abnormalities may occur early in CF, but are less common than described in adults. They are found more often in pancreatic insufficient than in pancreatic sufficient CF patients. However, a positive finding, if present, may aid in the diagnosis of the latter. A larger longitudinal study is recommended to better define the onset and progression of urogenital abnormalities.

Study objectives: Cystic fibrosis (CF) patients prefer exercise to most other forms of therapy, although objective improvement remains controversial. Israeli CF patients have attended a summer program in Switzerland for many years with subjective improvement. However, CF camps worldwide have been cancelled recently, due to fears of cross-infection with resistant organisms. Therefore, we evaluated the effect of attending the camp on pulmonary function, exercise tolerance, and nutritional state in CF patients. Design: Weight, resting pulmonary function, incremental exercise test results, and sputum culture findings were assessed before and after a 4-week intensive summer camp. Setting: Davos, Switzerland (altitude, 1,500 m). Patients: Thirteen Israeli CF patients (seven women and six men) with an age range of 9 to 25 years who had mild-to-moderate lung disease. No patients had Burkholderia cepacia detected in their sputum. Interventions: The program included a high-calorie diet, chest physiotherapy, daily mountain climbing, and indoor activities. Arterial oxygen saturation (SaO2) was maintained at > 88% during exertion. Results: Exercise tolerance improved significantly. The peak work capacity increased by 12.7%, the maximal oxygen uptake increased by 10%, and minute ventilation increased by 18.5% (p < 0.0005). Of the calculated parameters, the anaerobic threshold improved by 17%. Ventilation was always the limiting factor during exercise, although it improved. There was no significant change in resting lung function and pulse or in SaO2 decline at maximal exercise. The mean weight gain was 1 kg. No patient acquired B cepacia. Conclusions: An intensive summer camp improved exercise tolerance and nutrition in CF patients. This may explain improved patient well-being despite unchanged values for resting lung function. The reinstitution of summer camps, with special care to avoid cross-infection, should be considered. (CHEST 2002; 121:1117–1122)

Objectives. Lung lesions are increasingly diagnosed since the advent of routine prenatal ultrasound. These lesions seem to involute in 15% to 30% of cases. Postnatal evaluation is frequently limited, particularly when repeated ultrasound or initial chest radiographs are normal. As careful follow-up or resection may be required, accurate diagnosis is essential. The objective of this study was to determine whether prenatal lung lesions that seem to resolve are still present when evaluated more closely. Methods. We followed 24 cases of prenatally diagnosed lung lesions at our center, using repeated chest radiographs and chest computerized tomography (CT). Results. Some lesions caused mild mediastinal shift, but none showed hydrops fetalis. In 7 cases, the last prenatal ultrasound was negative. In 15 cases, initial postnatal chest radiograph was normal and in only 4 of these, the lesion was seen on later chest radiographs. This apparently high rate of resolution was, however, misleading. In 22 of the 23 cases in which CT was performed, lung cysts or lobar overinflation was clearly demonstrated. Conclusions. Apparent involution of lung lesions on serial prenatal ultrasounds or neonatal chest radiograph can be misleading. We strongly recommend repeated radiographs and chest CT for definitive diagnosis in all cases.

Objective Cystic fibrosis (CF) can be difficult to diagnose, even when newborn screening (NBS) tests yield positive results. This challenge is exacerbated by the multitude of NBS protocols, misunderstandings about screening vs diagnostic tests, and the lack of guidelines for presumptive diagnoses. There is also confusion regarding the designation of age at diagnosis. Study design To improve diagnosis and achieve standardization in definitions worldwide, the CF Foundation convened a committee of 32 experts with a mission to develop clear and actionable consensus guidelines on diagnosis of CF with an emphasis on screened populations, especially the newborn population. A comprehensive literature review was performed with emphasis on relevant articles published during the past decade. Results After reviewing the common screening protocols and outcome scenarios, 14 of 27 consensus statements were drafted that apply to screened populations. These were approved by 80% or more of the participants. Conclusions It is recommended that all diagnoses be established by demonstrating dysfunction of the CF transmembrane conductance regulator (CFTR) channel, initially with a sweat chloride test and, when needed, potentially with newer methods assessing membrane transport directly, such as intestinal current measurements. Even in babies with 2 CF-causing mutations detected via NBS, diagnosis must be confirmed by demonstrating CFTR dysfunction. The committee also recommends that the latest classifications identified in the Clinical and Functional Translation of CFTR project [http://www.cftr2.org/index.php] should be used to aid with CF diagnosis. Finally, to avoid delays in treatment, we provide guidelines for presumptive diagnoses and recommend how to determine the age of diagnosis.

International audience; The Curiosity rover discovered fine-grained sedimentary rocks, which are inferred to represent an ancient lake and preserve evidence of an environment that would have been suited to support a martian biosphere founded on chemolithoautotrophy. This aqueous environment was characterized by neutral pH, low salinity, and variable redox states of both iron and sulfur species. Carbon, hydrogen, oxygen, sulfur, nitrogen, and phosphorus were measured directly as key biogenic elements; by inference, phosphorus is assumed to have been available. The environment probably had a minimum duration of hundreds to tens of thousands of years. These results highlight the biological viability of fluvial-lacustrine environments in the post-Noachian history of Mars.

International audience; The Radiation Assessment Detector (RAD) on the Mars Science Laboratory's Curiosity rover began making detailed measurements of the cosmic ray and energetic particle radiation environment on the surface of Mars on 7 August 2012. We report and discuss measurements of the absorbed dose and dose equivalent from galactic cosmic rays and solar energetic particles on the martian surface for similar to 300 days of observations during the current solar maximum. These measurements provide insight into the radiation hazards associated with a human mission to the surface of Mars and provide an anchor point with which to model the subsurface radiation environment, with implications for microbial survival times of any possible extant or past life, as well as for the preservation of potential organic biosignatures of the ancient martian environment.

The diagnosis of cystic fibrosis (CF) is based on characteristic clinical and laboratory findings. However, a subgroup of patients present with an atypical phenotype that comprises partial CF phenotype, borderline sweat tests and one or even no common cystic fibrosis transmembrane conductance regulator (CFTR) mutations. The aim of this study was to evaluate the role of nasal potential difference (PD) measurements in the diagnosis of CF patients with an atypical presentation and in a population of patients suspected to have CF.Nasal PD was measured in 162 patients from four different groups: patients with classical CF (n=31), atypical phenotype (n=11), controls (n=50), and patients with questionable CF (n=70). The parameter, or combination of nasal PD parameters was calculated in order to best discriminate all CF patients (including atypical CF) from the non-CF group.The patients with atypical CF disease had intermediate values of PD measurements between the CF and non-CF groups. The best discriminate model that assigned all atypical CF patients as CF used: e(response to chloride-free and isoproterenol/response to amiloride)with a cut-off >0.70 to predict a CF diagnosis. When this model was applied to the group of 70 patients with questionable CF, 24 patients had abnormal PD similar to the atypical CF group. These patients had higher levels of sweat chloride concentration and increased rate of CFTR mutations.Nasal potential difference is useful in diagnosis of patients with atypical cystic fibrosis. Taking into account both the sodium and chloride transport elements of the potential difference allows for better differentiation between atypical cystic fibrosis and noncystic fibrosis patients. This calculation may assist in the diagnostic work-up of patients whose diagnosis is questionable.

BackgroundNontuberculous mycobacteria (NTM) are emerging infections in the CF population.AimsTo assess NTM infection prevalence and associated features in our CF clinic population.MethodsPatient records, 2002–2011, were reviewed for NTM infection. FEV1, pancreatic function, sputum microbiology, and serum cytokines were compared in patients with and without NTM infection.ResultsIncidence rate of NTM infection increased from 0 in 2002 to 8.7% in 2011 (p

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene containing a premature termination signal are expected to produce little or no CFTR chloride channels. It has been shown in vitro, that aminoglycoside antibiotics can increase the frequency of erroneous insertion of nonsense codons hence permitting the translation of CFTR alleles carrying missense mutations to continue reading to the end of the gene. This led to the appearance of functional CFTR channels at the apical plasma membrane. The aim of this research was to determine if topical application of gentamicin to the nasal epithelium of patients with cystic fibrosis (CF) carrying stop mutations can express, in vivo, functional CFTR channels. Nine CF patients carrying stop mutations (mean age 23 +/- 11 yr, range 12 to 46 yr) received gentamicin drops (0.3%, 3 mg/ml) three times daily intranasally for a total of 14 d. Nasal potential difference (PD) was measured before and after the treatment. Before gentamicin application all the patients had abnormal nasal PD typical of CF. After gentamicin treatment, significant repolarization of the nasal epithelium representing chloride transport was increased from -1 +/- 1 mV to -10 +/- 11 mV (p < 0. 001). In conclusion, gentamicin may influence the underlying chloride transport abnormality in patients with CF carrying stop mutations.

An infant with cystic fibrosis and her asthmatic father were diagnosed as suffering from allergic bronchopulmonary aspergillosis (ABPA). Cystic fibrosis was diagnosed in the infant at 6 weeks of age, and gene mutations were W1282X/G542X. She was diagnosed definitively as suffering from ABPA at age 3.5 years, but had suggestive symptoms from age 11 months. This may be the youngest age described to date for ABPA. The child responded well to systemic steroid therapy, but remained steroid-dependent over the next 4 years. Treatment with itraconazole enabled a marked reduction in steroid dosage. The father was an asthmatic, and a heterozygote for the cystic fibrosis transmembrane regulator (CFTR) mutation W1282X. He had a normal sweat test, atopy, and moderate reversible airway obstruction. There was no proven exposure to Aspergillus in the home environment. The importance of considering the diagnosis of ABPA even in infancy, the therapeutic dilemmas, and the possible role of abnormal CFTR function in the development of ABPA are discussed.

Patients with normal or borderline sweat test present a diagnostic challenge. In spite of the availability of different methods such as genetic analysis and measurements of nasal potential difference, uncertainty in diagnosing cystic fibrosis (CF) in some patients still exists. Neonates with CF have high serum lipase levels, which decline over time in pancreatic-insufficient patients, whereas pancreatic-sufficient patients demonstrate high serum lipase levels beyond infancy. Because patients with borderline or normal sweat test are almost always pancreatic sufficient, this study was aimed to assess whether serum lipase levels may be of help in establishing the diagnosis of CF in these patients. Serum lipase levels were measured in 100 CF patients and in 17 healthy individuals. Patients were grouped according to their genotype. Group A patients (n = 70) carried two mutations previously found to be associated with a pathologic sweat test and pancreatic insufficiency (delta F508, W1282X, G542X, N1303K, S549R). Group B (n = 30) were compound heterozygote patients who carried one mutation known to cause mild disease with borderline or normal sweat tests and pancreatic sufficiency (3849+10kb C-->T, 5T). Group C included 17 healthy controls. Serum lipase levels ranged between 2 and 104.4 U/L (mean +/- SD 16.9 +/- 14.7), 6.1-200 U/L (mean +/- SD 53.9 +/- 47.9), and 8.5-27.8 U/L (mean +/- SD 16.9 +/- 5.1) in Groups A, B, and C, respectively, with some overlapping between groups. The distribution of lipase levels was significantly different in Group B vs Groups A and C (P < 0.01). High lipase levels were found in 63.3% (19/30) of Group B patients, but in only 4.3% (3/70) and 0% (0/17) of Group A and C, respectively. Lipase levels were found to be inversely related to sweat chloride concentrations (r = -0.19, P < 0.05). Patients with borderline or normal sweat tests had high lipase levels, whereas low lipase levels were associated with pathologic sweat tests. Our findings indicate that the serum lipase level is genetically determined and that it has a useful role in the diagnosis of CF. Thus, in patients with borderline sweat tests and high lipase levels, the diagnosis of CF should be considered.

Background: There are no data currently available on the correct schedule for the initiation of treatment with nebulized suspension of budesonide in children with recurrent wheezing episodes. We compared the efficacy and safety of starting with a high dose followed by a stepwise decrease to a continuous low dose. Methods: In a double-blind design, 42 children aged 6 months to 3 years were randomly allocated to receive either a high starting dose of 1 mg budesonide twice daily followed by a stepwise decrease of 25% every second day for 1 week (group A) or a low dose of 0.25 mg twice daily for 1 week (group B). Efficacy was assessed with daily symptom scores and the systemic effect of the corticosteroids with the adrenocorticotropic hormone test. Results: The two groups were comparable for all parameters evaluated. During the first week of treatment, there was a significant decrease in asthmatic symptomatology only in group A: a 59% decrease for wheezing ( p = 0.0001), 39% for diurnal cough ( p = 0.036), and 39% for nocturnal cough ( p = 0.04). Mean time to clinical response was 3.0 days in group A and 5.7 days in group B ( p = 0.02). This early improvement was sustained for the rest of the follow-up period. The high dose starting schedule was not associated with any change in serum cortisol level. Conclusions: The administration of nebulized suspension of budesonide at a high starting dose schedule followed by a rapid (1 week) stepwise decrease yields a significant early improvement in asthma symptoms and causes no change in serum cortisol levels.

Pulmonary complications following hematopoietic stem cell transplantation (HSCT) are common and often subclinical. Thus, periodic pulmonary function testing (PFT) is mandatory. This study sought to evaluate the effectiveness of long-term PFT surveillance for children undergoing HSCT and identify potential risk factors.We reviewed long-term PFT for HSCT patients at a tertiary pediatric center. Inclusion criteria were PFT prior to and at least once following HSCT.Fifty-seven patients performed 202 spirometry and 193 plethysmographic maneuvers; 41 were tested during the first year after HSCT, but only 29 were evaluated consistently long term (2-12 years). FVC and FEV(1) decreased gradually suggesting a restrictive ventilatory defect: FVC % predicted [mean ± SD] dropped from 91 ± 14% to 85 ± 17% after 0-24 months and 80 ± 19% beyond 2 years (P = 0.01) whereas FEV(1) dropped from 95 ± 16% to 88 ± 19% and 82 ± 20%, respectively (P = 0.002). A slight reduction in TLC was observed. Those undergoing allogeneic HSCT had a greater decline in FVC (P = 0.025) and FEV(1) (P = 0.025) as did those conditioned with radiation, regarding both FVC (P = 0.003) and FEV(1) (P = 0.002). Decline occurred earlier (≤2 years) after chemotherapy compared with radiation. Seven children had severe irreversible obstruction at2 years despite therapeutic intervention.Most survivors of childhood HSCT maintain almost normal pulmonary function although mild restrictive lung disease may develop, particularly following allogeneic HSCT and conditioning with radiation. Severe airways obstruction developed in a small minority. The surveillance protocol for PFT needs to be followed more stringently to enable intervention possibly before early subclinical changes progress and become irreversible.

Mars' Atmosphere from Curiosity The Sample Analysis at Mars (SAM) instrument on the Curiosity rover that landed on Mars in August last year is designed to study the chemical and isotopic composition of the martian atmosphere. Mahaffy et al. (p. 263 ) present volume-mixing ratios of Mars' five major atmospheric constituents (CO 2 , Ar, N 2 , O 2 , and CO) and isotope measurements of 40 Ar/ 36 Ar and C and O in CO 2 , based on data from one of SAM's instruments, obtained between 31 August and 21 November 2012. Webster et al. (p. 260 ) used data from another of SAM's instruments obtained around the same period to determine isotope ratios of H, C, and O in atmospheric CO 2 and H 2 O. Agreement between the isotopic ratios measured by SAM with those of martian meteorites, measured in laboratories on Earth, confirms the origin of these meteorites and implies that the current atmospheric reservoirs of CO 2 and H 2 O were largely established after the period of early atmospheric loss some 4 billion years ago.

Objective Growth delay in cystic fibrosis is frequent and is usually the result of several interacting causes. It most often derives from severe respiratory impairment and severe malabsorption. There are however patients whose clinical condition is not severe enough to be held accountable for this phenomenon. We aimed at describing patients who showed growth delay, who were not affected by severe pulmonary disease or malabsorption and who, when tested, showed a reduced GH secretion after stimulation with conventional agents. We noticed a disproportionately large prevalence of growth hormone (GH) release deficit (GHRD) in pediatric cystic fibrosis (CF) patients. Patients and methods We examined all patients under our care in the period 2006–11, who were older than 5 and younger than 16years old. We focussed on those who fell below the 3rd height percentile, or whose growth during the previous 18months faltered by >2SD, and who did not present clinical conditions that could reasonably explain their failure to thrive. These patients were subjected to standard GH provocative tests. Results Out of 285 who matched the age criterion, 33 patients also matched the height percentile criterion. While 15/33 suffered clinical conditions that could reasonably explain their failure to thrive, 18/33 underwent GH release provocative tests and 12/18 showed a release deficit. Conclusions We conclude that impaired GH secretion is more frequent among CF patients compared to the prevalence of GH deficiency in the general population and that GH release impairment may be an independent cause of growth delay in CF. Our findings are in agreement with recent studies that have described low GH levels in CF piglets and in neonates with CF [1].

The aim of this study was to determine the long-term pulmonary outcome of extreme prematurity at a single tertiary-care center from 1997 to 2001 in the postsurfactant era.We assessed symptoms, exhaled nitric oxide, spirometry, methacholine challenge (provocative concentration of methacholine required to decrease FEV₁ by 20% [PC(20)]), lung volumes, diffusion, and cardiopulmonary exercise tolerance.Of 279 infants born, 192 survived to discharge, and 79 of these developed bronchopulmonary dysplasia (BPD) (65 mild, 12 moderate, two severe). We studied a subgroup of 53 neurologically intact preterm subjects aged 10 ± 1.5 years (28 with BPD [born, 26.2 ± 1.4 weeks; birth weight, 821 ± 164 g] and 25 without BPD [born, 27.2 ± 1 weeks; birth weight, 1,050 ± 181 g]) and compared them with 23 term control subjects. Of the BPD cases, 21 were mild, seven were moderate, and none was severe; 77.4% of subjects received antenatal steroids, and 83% received postnatal surfactant. Sixty percent of the preterm subjects wheezed at age2 years compared with 13% of the control subjects (P.001), but only 13% wheezed in the past year compared with 0% of control subjects (not significant). For preterm and control subjects, respectively (mean ± SD), FEV₁ % predicted was 85% ± 10% and 94% ± 10% (P.001), with limited reversibility; residual volume/total lung capacity was 29.3% ± 5.5% and 25% ± 8% (P.05); diffusing capacity/alveolar volume was 89.6% ± 9.2% and 97% ± 10% (P.005); and PC(20) was 6.5 ± 5.8 mg/mL and 11.7 ± 5.5 mg/mL (P.001). PC(20) was4 mg/mL in 49% of preterm subjects despite normal exhaled nitric oxide. Most measurements were similar in premature subjects with and without BPD. Peak oxygen consumption and breathing reserve were normal, but % predicted maximal load (measured in Watts) was 69% ± 15% for subjects with BPD compared with 88% ± 23% for subjects without and 86% ± 20% for control subjects (P.01).Pulmonary outcome was encouraging at mid-childhood for neurologically intact survivors in the postsurfactant era. Despite mechanical ventilation and oxygen therapy, most had no or mild BPD. Changes found probably reflect the hypoplastic lungs of prematurity.

The recently acquired ability to identify 97% of CF carriers in an Israeli Ashkenazi population, prompts an evaluation of a nationwide screening programme. In 1993, the programme would first screen and counsel 9,261 parents, then 396 spouses of carrier parents and finally screen 16.5 fetuses where both parents are carriers. Assuming 92% of screened parents choose abortion of fetus screened positive, 2.33 cases of CF will be prevented in 1993 at a direct cost of $781,000. The $326,000 direct costs of preventing a CF case, exceed the lifetime excess direct costs per case of $297,000. However, benefits of screening also accrue to subsequent pregnancies, resulting in a direct benefit ($14.45 million) to cost ($10.39 million) ratio of 1.39/1 for the period 1993-2032. When benefits and costs resulting from mortality changes, work absences and transport costs are included, the benefit ($15.95 million) to cost ($13.88 million) ratio falls to 1.15/1. Benefit-cost ratios are lower for other ethnic groups in Israel, due to lower carrier rates and lower mutation detection abilities. A CF screening programme will increase the freedom of individuals choice, but should be carried out carefully in order to minimize stigmatization and even discrimination against CF carriers.

Primary ciliary dyskinesia most often arises from loss of the dynein motors that power ciliary beating. Here we show that DNAAF3 (also known as PF22), a previously uncharacterized protein, is essential for the preassembly of dyneins into complexes before their transport into cilia. We identified loss-of-function mutations in the human DNAAF3 gene in individuals from families with situs inversus and defects in the assembly of inner and outer dynein arms. Knockdown of dnaaf3 in zebrafish likewise disrupts dynein arm assembly and ciliary motility, causing primary ciliary dyskinesia phenotypes that include hydrocephalus and laterality malformations. Chlamydomonas reinhardtii PF22 is exclusively cytoplasmic, and a PF22-null mutant cannot assemble any outer and some inner dynein arms. Altered abundance of dynein subunits in mutant cytoplasm suggests that DNAAF3 (PF22) acts at a similar stage as other preassembly proteins, for example, DNAAF2 (also known as PF13 or KTU) and DNAAF1 (also known as ODA7 or LRRC50), in the dynein preassembly pathway. These results support the existence of a conserved, multistep pathway for the cytoplasmic formation of assembly competent ciliary dynein complexes.