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Background: Although cough is a commonly reported symptom, objective quantitation of cough during normal activity has not been performed in patients with CF., Methods: An ambulatory device was used to characterize cough over 24 hours. Pulmonary function and subject-reported coughing were also assessed., Results: Patients included 19 clinically stable adults with CF (males:females=10:9; median age [range]=26 [19-57] years; median %-predicted FEV(1) [range]=65 [44-106]%). Median [range] cough rate was 27 [13-66] coughs/hour, with values while awake of 41 [20-102] and while asleep of 2 [0.1-7] (p<0.0001, Wilcoxon signed-rank test). Subjective reporting was consistent with objective data for wake-sleep differences, but correlated poorly with objective waking cough rate., Conclusions: Outpatient cough quantitation in patients with CF is feasible, indicates frequent coughing even during clinical stability, and may be useful in therapeutic trials in CF., (Copyright © 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.)

Objective: To identify the characteristics of CF patients with hemoptysis in Israel and to compare clinical features and risk factors to a control group of CF patients without hemoptysis., Design: Retrospective chart review., Patients: All CF patients in Israel who experienced hemoptysis between 2001 and 2005 and a control group of sex- and age-matched patients with no history of hemoptysis., Results: 40/440 CF patients (9.1%) experienced hemoptysis during the study period, 50% were male. Ten patients (25%) were under 13 years old at the first hemoptysis episode. Pulmonary exacerbation was the precipitating factor in 90%. Twenty three patients showed moderate or major hemoptysis. 35/40 patients responded well to conservative therapy. Bronchial artery embolization (BAE) was performed in 5 patients with no recurrence of bleed within 24 h. However all of these patients experienced recurrent hemoptysis. One patient died during the follow-up period because of end stage lung disease. Pulmonary function tests, body-mass index, coagulation tests, pancreatic status, presence of bronchiectasis, sputum cultures and genetic mutations were similar in the two groups. A high incidence (57.5%) of associated diseases including cystic fibrosis related diabetes, cirrhosis and portal hypertension, and distal intestinal obstruction syndrome was found among hemoptysis patients, compared to only 5.2% in the control group (p<0.001)., Conclusions: Hemoptysis, even major, did not seem to be a risk factor for mortality in our patients. A higher incidence of hemoptysis was found in our pediatric patients compared to other series. BAE shows a high immediate rate of success in controlling hemoptysis, but does not prevent future disease.

Background: Nasal potential difference (NPD) measurement is an electrophysiological test that assesses cystic fibrosis transmembrane conductance regulator (CFTR) activity and is a recognized diagnostic tool in CF. The aim of this study is to assess in the long term the role of NPD in patients whose diagnosis is questionable., Methods: We performed follow up study on 70 patients with questionable CF (QCF) who were divided previously into two groups according to their NPD results: patients who likely have CF (QCF-CF) (n = 24), and those who likely do not have CF (QCF-non-CF) (n = 46)., Results: Sixty out of 70 patients were available for study. Sixteen patients in the QCF-CF group were being followed up at CF Centers as opposed to 1 in the QCF-non-CF group (P < 0.01). Seven patients from the QCF-CF group developed sinusitis during the follow up years compared to none from the QCF-non-CF group. During the years of the follow up, 17 QCF-non-CF patients were diagnosed with other medical conditions that could explain their previous symptoms. On repeated NPD measurement in the QCF-CF group, the results were similar to the original test., Conclusions: This study supports the diagnostic role of NPD measurement. Larger cohort studies are required for confirmation.

This 2-year cross-sectional evaluation of nontuberculous mycobacterial (NTM) infections involved all Israeli medical centers that treat cystic fibrosis patients. The study comprised 186 patients whose sputum was analyzed for NTM. The prevalence of NTM isolates was 22.6%, and 6.5% and 10.8% of the patients fulfilled the 1997 and 2007 American Thoracic Society criteria for NTM lung disease, respectively. Mycobacterium simiae (40.5%), M. abscessus (31.0%), and M. avium complex (14.3%) were the most prevalent. Presence of Aspergillus spp. in sputum and the number of sputum specimens processed for mycobacteria were the most significant predictors for isolation of NTM (odds ratio [OR] = 5.14, 95% confidence interval [CI] 1.87-14.11 and OR = 1.47, 95% CI 1.17-1.85, respectively). The incidence of NTM pulmonary infections is increasing among cystic fibrosis patients, reflecting the increase in longevity of such patients as well as environmental exposure to various species of mycobacteria.

Background: Nasal potential difference (NPD) measurement has been advocated as a diagnostic tool for cystic fibrosis (CF) patients and as a method for assessing the response to new therapies. The purpose of this study was to examine the reproducibility of NPD measurements performed in a single center., Methods: A total of 68 CF patients with a mean (+/- SD) age of 16 +/- 8 years (age range, 6 to 52 years) underwent NPD measurements on at least two occasions., Results: A total of 25 patients with classic CF (mean age, 21 +/- 8 years) and 43 patients with nonclassic CF (mean age, 14 +/- 8 years) underwent sweat tests and NPD measurements. The mean sweat chloride values were 102 +/- 18 and 54 +/- 14 mEq/L, respectively, for classic CF and nonclassic CF groups. All patients underwent repeat NPD measurements. The basal NPD and the response to amiloride (DeltaAmil) and response to Cl(-) free and isoproterenol (DeltaCl(-) free + iso) were very similar in both measurements. In the classic CF group, the basal potential difference values were -40 +/- 12 vs -39 +/- 11 mV (p = 0.57), respectively, for the first and second measurements; 27 +/- 9 vs 26 +/- 10 mV (p = 0.55), respectively, for DeltaAmil; and 2.1 +/- 3.8 vs 0.4 +/- 2.9 mV (p = 0.07), respectively, for DeltaCl(-) free + iso. In the nonclassic CF group, the values were -32 +/- 13 vs -28 +/- 10 mV (p = 0.008), respectively; 19 +/- 10 vs 17 +/- 8 mV (p = 0.388), respectively; and -3.2 +/- 4.6 vs -3.3 +/- 4.4 mV (p = 0.876), respectively., Conclusion: When performed in a single center, NPD is a reproducible test for CF patients and thus may be a useful outcome measurement for assessment of the efficacy of new treatments.

Background: Increased levels of oxidative stress result in pulmonary damage contributing to the development of chronic lung disease in cystic fibrosis (CF). The aim of this study was to investigate the longitudinal effect of serum vitamin A and E levels on the incidence of pulmonary exacerbations in pancreatic insufficient (PI) and pancreatic sufficient (PS) patients with CF., Materials and Methods: Patient records were retrospectively examined over a 3-year period and serum vitamin A and E levels were retrieved. Subsequently, levels of vitamin A and E were prospectively measured over a 2-year period at the onset of intravenous antibiotic therapy for acute exacerbation and at the first recovery visit., Results: Retrospectively, 597 pulmonary exacerbations were identified in 102 patients, 74 PI and 28 PS, with a mean age of 11.1 +/- 6.4 years (range, 1.5-27 y). An increased number of exacerbations was directly correlated with lower vitamin A and E levels, even within the normal range. Prospectively, 62 exacerbations were analyzed (43 PI patients and 19 PS patients). At onset of exacerbation, vitamin A and E levels were reduced in the PI patients (P < 0.001; P < 0.001) and the PS patients (P < 0.005; P < 0.07)., Conclusions: Reduced serum levels of vitamin A and E even in the normal range are associated with an increased rate of pulmonary exacerbations in CF. Further studies are required to confirm the necessity of supplementation of vitamins A and E to PS patients.

Mutations in FOXP2 cause developmental verbal dyspraxia (DVD), but only a few cases have been described. We characterize 13 patients with DVD--5 with hemizygous paternal deletions spanning the FOXP2 gene, 1 with a translocation interrupting FOXP2, and the remaining 7 with maternal uniparental disomy of chromosome 7 (UPD7), who were also given a diagnosis of Silver-Russell Syndrome (SRS). Of these individuals with DVD, all 12 for whom parental DNA was available showed absence of a paternal copy of FOXP2. Five other individuals with deletions of paternally inherited FOXP2 but with incomplete clinical information or phenotypes too complex to properly assess are also described. Four of the patients with DVD also meet criteria for autism spectrum disorder. Individuals with paternal UPD7 or with partial maternal UPD7 or deletion starting downstream of FOXP2 do not have DVD. Using quantitative real-time polymerase chain reaction, we show the maternally inherited FOXP2 to be comparatively underexpressed. Our results indicate that absence of paternal FOXP2 is the cause of DVD in patients with SRS with maternal UPD7. The data also point to a role for differential parent-of-origin expression of FOXP2 in human speech development.

We have diagnosed a boy with cystic fibrosis (CF) due to paternal UPD presenting with overweight and developmental delay, not typical features to CF patients. Two previously reported patients with paternal UPD(7) did not present overgrowth. The discrepancy between the phenotype of this boy and the other two patients raises the question of imprinted genes or homozygotization of a disease-causing gene in paternal UPD7.

Oxygen supplementation may improve exercise tolerance and the physiological response to exercise in cystic fibrosis (CF) patients. Elevated barometric pressure at low altitude is a simple means of increasing the quantity of inspired oxygen. Our objectives were to examine the effect of natural oxygen enrichment (at the Dead Sea, 396 m below sea level) on exercise capacity, and the physiological responses to maximal and submaximal exercise in CF patients. Patients were tested twice: at sea level (barometric pressure, 754 +/- 6 mmHg, mean +/- SD), and at the Dead Sea (barometric pressure, 791 +/- 3 mmHg), in a randomized crossover design. We studied 14 CF patients (6 females, 8 males), aged 15-45 years, with moderate to severe lung disease (mean forced expired volume in 1 sec = 50.0 +/- 11.2% predicted). Tests at each site included resting spirometry, anthropometry, a graded submaximal exercise test, a maximal exercise test on a treadmill, and a 6-min walk test. Tests were performed in identical order at both sites. Tests at the Dead Sea were performed 72 hr after arrival. No differences between sites were observed in lung function at rest. Peak oxygen consumption was significantly improved at the Dead Sea compared with sea level (1.68 +/- 0.73 vs. 1.57 +/- 0.74 l/min, respectively, P = 0.05), along with an improvement in the ventilatory equivalent for oxygen (41.2 +/- 6.3 vs. 46.1 +/- 7.1, respectively, P < 0.05). During submaximal exercise, blood oxygen saturation improved at the Dead Sea compared with sea level at all exercise intensities (P < 0.05). In conclusion, these results suggest that even a brief stay at the Dead Sea area may have physiological benefits for CF patients with moderate to severe lung disease., ((c) 2006 Wiley-Liss, Inc.)

Objectives: Several studies have shown a linear correlation between nutritional status and pulmonary function in patients with cystic fibrosis. Our study aims were: 1) To evaluate the effect of nutritional supplementation via gastrostomy on nutritional, clinical, and pulmonary parameters, and 2) To identify predicting factors for success of long-term nutritional rehabilitation., Methods: Twenty-one Israeli patients, aged 8 months to 20 years, underwent gastrostomy insertion from 1992 to 2001. All patients were pancreatic insufficient, and all carried severe mutations (W1282X in 62% of the patients). Anthropometric and clinical data were obtained for each patient: 0-12 months before and 6-12 months and 18-24 months after gastrostomy placement. Standard deviation scores (SDS) for height, weight, and body mass index as well as percent of height-appropriate body weight were calculated., Results: The mean percent-of-predicted forced expiratory volume in 1 second (FEV1) decreased significantly during the first year of gastrostomy feeding (n = 16), from 44.2% +/- 13.9 to 41% +/- 13.3 (P = 0.05). However, during the second year of therapy (n = 10), a trend toward improvement was observed (from 39.4 +/- 12.1 to 41.4 +/- 16.1). Weight, and BMI z-scores as well as weight percent-of ideal body weight increased significantly. Height z-score for age decreased during the first year (from -1.9 +/- 1.3 to -2.1 +/- 1.4), However, a trend toward improvement was observed during the second year. A significant correlation was found between the change in weight z-score and height z-score during the first (r = 0.488, P = 0.016) and the second (r = 0.825, P < 0.001) years. There was no difference between compliers and noncompliers regarding height, weight, and BMI either before or after gastrostomy placement. A significant correlation between age at insertion of gastrostomy and improvement in height z-score (r = 0.52, P = 0.016) was observed. Cystic fibrosis related diabetes (n = 8) did not affect the response to supplemental feeding., Conclusions: We observed a trend toward improvement of pulmonary disease during the second year, and a significant improvement in weight, height, and BMI z-scores. Compliance, diabetes, and young age prior to tube insertion did not predict success of nutritional rehabilitation.

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.

The clinical spectrum of cystic fibrosis (CF) is influenced by the cystic fibrosis transmembrane conductance regulator (CFTR) genotype. However, variable courses of the disease were demonstrated among patients with identical genotypes. Since siblings share identical CFTR mutations and environmental factors, they can serve as a model to assess the effect of modifier genes on disease expression, and also to evaluate cross-infection. The aim of this study was to compare disease expression among siblings with CF. All sibling pairs treated at 7 CF centers in Israel were included in the study. Data were collected from patients' medical charts. Fifty families with at least 2 siblings were identified. As expected, the second-born sibling was diagnosed at an earlier age compared to the first-born. The mode of CF presentation at diagnosis showed significant familial concordance. In the families where the first sibling presented with gastrointestinal manifestations, 79% of the second siblings also presented with gastrointestinal manifestations. When gastrointestinal manifestations were absent in the first sibling, only 12% of the second siblings presented with gastrointestinal manifestations (P < 0.0001). Likewise, when the first sibling presented with respiratory symptoms, 60% of the second siblings presented with the similar symptoms. However, when the first sibling presented without respiratory symptoms, only 12% of the second siblings presented with respiratory symptoms (P < 0.001). Meconium ileus (MI) was present in 20 patients (21%). In 10 families where the first-born sibling had MI, 8 (80%) of the subsequent siblings had MI. On the other hand, in the 39 families where the first-born sibling did not have MI, only 2 (5%) subsequent siblings had MI (P < 0.001). Pancreatic insufficiency (PI) also had high familial concordance (P < 0.0001). Percentile growth for weights and heights and lung function (FVC, FEV(1), and FEF(25-75)) at ages 7 and 10 years were similar between siblings. P. aeruginosa grew from sputum in 89% of our study patients. When P. aeruginosa was isolated from the first-born patient, 91% of the second siblings were also positive for P. aeruginosa, whereas when the initial sibling was not a carrier of P. aeruginosa, only 50% of subsequent siblings were positive (P < 0.0001). This familial concordance was not observed for S. aureus. By contrast, the age of first isolation of P. aeruginosa and S. aureus was significantly earlier in the second sibling than in the first for the two bacteria: 10.3 +/- 5.1 vs. 7.3 +/- 5.2 years (P < 0.05) for P. aeruginosa, and 11.5 +/- 5.4 years vs. 6.8 +/- 5.1 years (P < 0.05) for S. aureus. CF siblings tend to share similar phenotypes that are not mutation-dependent. The lack of variability between siblings in mode of initial CF presentation, rates of MI, pulmonary function, and nutritional status supports the role of modifier genes in the determination of these factors.

The sperm acrosome reaction and penetration of the egg follow zona pellucida binding only if the sperm has previously undergone the poorly understood maturation process known as capacitation. We demonstrate here that in vitro capacitation of bull, ram, mouse, and human sperm was accompanied by a time-dependent increase in actin polymerization. Induction of the acrosome reaction in capacitated cells initiated fast F-actin breakdown. Incubation of sperm in media lacking BSA or methyl-beta-cyclodextrin, Ca(2+), or NaHCO(3), components that are all required for capacitation, prevented actin polymerization as well as capacitation, as assessed by the ability of the cells to undergo the acrosome reaction. Inhibition of F-actin formation by cytochalasin D blocked sperm capacitation and reduced the in vitro fertilization rate of metaphase II-arrested mouse eggs. It has been suggested that protein tyrosine phosphorylation may represent an important regulatory pathway that is associated with sperm capacitation. We show here that factors known to stimulate sperm protein tyrosine phosphorylation (i.e., NaHCO(3), cAMP, epidermal growth factor, H(2)O(2), and sodium vanadate) were able to enhance actin polymerization, whereas inhibition of tyrosine kinases prevented F-actin formation. These data suggest that actin polymerization may represent an important regulatory pathway in with sperm capacitation, whereas F-actin breakdown occurs before the acrosome reaction.

Lung transplantation (Tx) is an optional treatment for cystic fibrosis (CF) patients with end-stage lung disease. The decision to place a patient on the Tx waiting list is frequently complex, difficult, and controversial. This study evaluated the current criteria for lung Tx and assessed additional parameters that may identify CF patients at high risk of death. Data were extracted from the medical records of 392 CF patients. Forty of these patients had a forced expiratory volume in 1 s (FEV(1)) less than 30% predicted, and nine of these 40 patients were transplanted. A comparison was performed between the survival of those transplanted (n = 9) and those not transplanted (n = 31), by means of Kaplan-Meier survival curves. The influence on survival of age, gender, nutritional status, sputum aspergillus, diabetes mellitus, recurrent hemoptysis, oxygen use, and the decline rate of FEV(1), were investigated by means of univariate and multivariate analyses. The rate of decline of FEV(1) was evaluated employing the linear regression model. CF patients with a FEV(1)< 30% and who did not receive a lung transplant had survived longer than CF patients who did receive a lung transplant (median survival 7.33 vs. 3.49 yr, 5-yr survival 73% vs. 29%). Two factors--rate of decline in FEV(1) values and age < 15 yr--were found to influence the mortality rate, while the other parameters examined did not. Our results indicate that the current criterion of FEV(1)< 30% predicted, alone is not sufficiently sensitive to predict the mortality rate in CF patients and time of referral for Tx, as many of these patients survive for long periods of time. Additional criteria to FEV(1)< 30%, should include rapidly declining FEV(1) values and age < 15 yr.

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., (Copyright 2000 Wiley-Liss, Inc.)

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.

Mutation analysis was performed on 42 unrelated Israeli Arab CF patients. The previously known mutations in this population, DF508, N1303K, G542X, 4010delTATT, and S549R(T>G), were identified in 57 CF alleles, leaving 28 CF alleles with unknown mutations. Screening of the coding sequence of the CFTR gene by a single strand conformation analysis (SSCA) and direct sequencing revealed three point mutations and two intragenic deletions, including 2183AA>G, R75X, S549R (A>C), 3120+1Kbdel8.6Kb and del(exon2). In the present sample of Israeli Arab patients, 12 mutations account for 92% of the CF alleles. The mutations DF508, N1303K, W1282X and 3120+1Kbdel8.6Kb were found in all Arab ethnic subgroups. The mutations G85E, R75X, 2183AA>G, and del(exon2) were confined to Muslim Arabs, and the mutations 4010delTATT, S549R(A>C) and G542X were confined to Christian Arabs. Hum Mutat 14:543, 1999., (Copyright 1999 Wiley-Liss, Inc.)

Objective: The aim of this study was to define the role of possible risk factors for the development of cystic fibrosis (CF)-related liver disease and to analyze the association between liver disease and the different genotypes present in the Israeli CF patient population., Patients and Methods: All patients followed at the seven CF centers in Israel were included in this study. Liver disease was determined by persistently elevated serum liver enzymes and/or bilirubin, and/or significant ultrasonographic changes suggestive of chronic liver disease. The following clinical parameters were evaluated: ethnic origin, age at assessment of liver function, sex, history of meconium ileus, pancreatic function, history of distal intestinal obstruction syndrome, pulmonary function, and cystic fibrosis transmembrane conductance regulator mutation analysis., Results: Of the 288 patients screened, 80 (28%) had liver disease. Of the 256 patients with pancreatic insufficiency, 80 (31%) had liver disease compared with none of the 32 patients with pancreatic sufficiency. Genotype-phenotype correlation was performed on 207 patients carrying identified mutations that were previously classified according to phenotype severity. Liver disease was found in 56 (32%) of 173 patients carrying mutations associated with a severe phenotype and in 6 (38%) of 16 patients carrying at least one mutation associated with a variable genotype (G85E and/or 5T allele). None of the 18 patients carrying the 3849+10kb C->T mutation had liver disease. Prevalence of liver disease increased with age. No correlation was found between liver disease and severity of lung disease, nutritional status, history of meconium ileus, or distal intestinal obstruction syndrome., Conclusion: CF patients who have pancreatic insufficiency and carry mutations associated with a severe or a variable genotype are at increased risk to develop liver disease.

A deletion mutation of 8.6Kb in the CFTR gene, spanning the exons 17a, 17b and 18 was identified in 4 homozygous unrelated Palestinian CF patients. The patients were of various ethnic subgroups including Muslims, Christians and Druze. The deletion breakpoint occurred within an identical 4bp sequence in introns 16 and 18, and the mutation was defined as 3120+1Kbdel8.6Kb. A simple PCR based assay was designed and using this assay two compound heterozygote patients with the 3120+1Kbdel8.6Kb were identified. The 3120+1Kbdel8.6Kh hearing chromosomes had a common intragenic haplotype and variable flanking polymorphic markers, indicating that it is an ancient founder mutation.

We report four patients with cystic fibrosis and fulminant Clostridium difficile-associated colitis: two died, and one required hemicolectomy. Three of four patients carried the N1303K mutation. Severe and fatal C. difficile colitis can occur in cystic fibrosis patients, possibly with a genotype-specific predilection (i.e., N1303K/other). Because cystic fibrosis patients may have a wide spectrum of gastrointestinal symptoms, disease caused by C. difficile must be considered when these patients have acute abdominal pain, diarrhea, or severe leukocytosis.

The incidence of cystic fibrosis (CF) and the frequency of disease-causing mutations varies among different ethnic and geographic populations. The Jewish population around the world is comprised of two major ethnic groups; Ashkenazi and non-Ashkenazi. The latter is further classified according to country of origin. In this study, we analyzed the incidence of CF and the distribution of CF mutations in the general Jewish population in Israel and in most of the Jewish ethnic subgroups. The disease frequency varies considerably among the latter. Among Ashkenazi Jews, the frequency of CF is 1:3300, which is similar to the frequency in most Caucasian populations. Among non-Ashkenazi Jews, the disease occurs at a similar frequency among Jews from Libya (1:2700), Georgia (1:2700), Greece and Bulgaria (1:2400), but is rare in Jews from Yemen (1:8800), Morocco (1:15000), Iraq (1:32000), and Iran (1:39000). So far, only 12 mutations have been identified in Israeli Jews, and this enables the identification of 91% of the CF chromosomes in the entire Jewish CF population. However, in each Jewish ethnic group, the disease is caused by a different repertoire of mutations. The frequency of identified mutations is high in Ashkenazi Jews (95%), and in Jews originating from Tunisia (100%), Libya (91%), Turkey (90%), and Georgia (88%). However, a lower frequency of mutations can be identified in Moroccan (85%), Egyptian (50%), and Yemenite (0%) Jews. For genetic counseling of a Jewish individual, it is necessary to calculate the residual risk according to ethnic origin. Carrier screening of healthy Jewish individuals is currently feasible for Ashkenazi Tunisian, Libyan, Turkish, and Georgian Jews. These results provide the required information for genetic counseling of Jewish CF families and screening programs of Jewish populations worldwide.

Foreign body aspiration (FBA) should be suspected in every child with acute onset of cough or wheezing. Although a choking episode occurs in 80-90% of cases of FBA, it is not necessarily diagnostic. Furthermore, in many cases neither physical examination nor chest x-ray, including fluoroscopy, are diagnostic; their results may be completely normal in up to 17-25% of cases of FBA. Bronchoscopy is therefore mandatory when there is a convincing history of FBA, regardless of physical or radiologic findings. This can be done with either the flexible or rigid bronchoscope, or with both.

Twenty-eight subjects with chronic respiratory disease were investigated for clinical data, ciliary beat frequency of nasal mucosa (10 cases), and ciliary ultrastructure. The cases were divided into two groups: those considered compatible with primary ciliary dyskinesia (genetic), and those not fitting into this category (others). A case was defined as genetic if one or more of the following were present: dextrocardia, ciliary beat frequency less than 10 Hz, or an average dynein arm count (outer, inner, or both) of less than two per ciliary cross-section. In each of the genetic cases at least two of these parameters were present. The percentage of malformed microtubules was calculated from the total number of evaluated cross-sections for each case. Ciliary microtubular abnormalities of any kind were no more frequent in cases of primary ciliary dyskinesia than in other cases. The same was true for transposition and radial spoke defects.

The value of perfusion scintigraphy as a screening test for children who have suffered from several episodes of recurrent localized pneumonia was evaluated in 32 patients aged 1-15 years. Perfusion studies were carried out using macroaggregated albumin (MAA) labeled with technetium 99m. In 9 patients (28%), large lobar or multisegmental perfusion defects were demonstrated. Their final diagnoses proved to be bronchiectasis (5 patients), bronchomalacia (2 cases), agenesis of a lobe (1 subject), and lobar sequestration (1 patient). In 23 children (72%), the perfusion scintigraphic patterns were normal or diffusely nonhomogeneous. All of these patients improved clinically on a 1- to 2.9-year follow-up. We conclude that a normal perfusion scintigraphy is a useful screening test for excluding structural lung abnormalities in pediatric patients with recurrent localized pneumonia. Children showing a pattern of lobar or multisegmental perfusion defects should be further investigated to rule out structural abnormalities as an underlying cause of disease.

Fundamental to the pathogenesis of obstructive sleep apnea (OSA) is the interaction of physiologic and anatomic alterations of the upper airway. However, many patients with OSA have no identifiable abnormality of the upper airway, and they have been termed idiopathic. In an attempt to find a structural deviation in upper airway anatomy, we performed acoustic echography and cephalometric roentgenograms in 9 male patients with OSA and no clinical evidence of upper airway abnormality. Mean cross-sectional area of the pharynx by acoustic reflection was less in these patients (3.7 +/- 0.8 cm2) than in subjects in a control group (5.3 +/- 0.6 cm2) (p less than 0.001). Mean glottic cross-sectional area was less in the patient group (1.5 +/- 0.5 cm2) than in the control group (2.7 +/- 0.5) (p less than 0.001). There was a significant correlation between the number of apneas per sleep hour and pharyngeal cross-sectional area (r = 0.87, p less than 0.01). Cephalometric analysis indicated that the patients had smaller mandibles by a mean of 5.4 +/- 6.6 mm (p less than 0.05). The overall posterior displacement of the mandibular symphysis, which is representative of the skeletal support of the anterior pharyngeal wall and is dependent on both mandibular size and position, was highly significant (6.4 +/- 4.7 mm) (p less than 0.01). Furthermore, there was a significant correlation between the number of apnea episodes per sleep hour and the total posterior displacement (r = 0.67, p less than 0.05). This study indicates that patients with so-called idiopathic OSA may have an anatomic predisposition to the development of upper airway occlusion that may not be detectable on clinical examination.

The role of B cells and regulatory T cells in the reduced in vitro IgG synthesis of cystic fibrosis (CF) patients was studied. Intact proportion, proliferation, and differentiation of B cells and reduced suppressor and helper T-cell function were found. To explore the T-cell defects further, CF sera or supernatant derived from Pseudomonas aeruginosa cultures (PA supernatant) was added to the relevant T helper- and suppressor-cell assays. Both CF sera derived from PA-positive patients and PA supernatant interfered with the appearance of interleukin 2 (IL-2) receptors and with the functional enhancement caused by exogenously added IL-2. PA-negative CF patients, however, also had functional T-cell defects and inhibitory sera, but these sera did not affect IL-2 pathways. Thus different serum factors and intrinsic T-cell defects in CF patients are suggested.

To determine what relationship might exist between gastroesophageal reflux and nocturnal asthma, we studied nine patients with asthma and seven control subjects overnight in the sleep laboratory, monitoring sleep state, esophageal pH, tidal volume (including the relative contribution of rib cage and abdomen), and oxygen saturation. There were 15 episodes of gastroesophageal reflux, in three patients with asthma and four control subjects. There were no significant differences between the two groups in the number of reflux episodes, duration of the longest episode, and the percentage of reflux time. Thirteen of the 15 episodes occurred during the awake state or after movement arousal. None of the episodes caused coughing, wheezing, or changes in oxygen saturation in any of the subjects. These patients with chronic asthma did not have an increased incidence of gastroesophageal reflux at night, and reflux did not play any role in the production of their nighttime symptoms.

Nine children who survived the development of Wilson-Mikity (W-M) syndrome were studied at a mean age of 7.6 +/- 0.3 years. Persistent respiratory symptoms during the year preceding the study were present in one child. Pulmonary function studies demonstrated a significant degree of airway obstruction in 3 children. Positive methacholine challenge was observed in 6 children indicating bronchial hyperreactivity. Abnormal chest radiographs were present in 3 children. One showed the characteristic appearances of asthma with air trapping, bronchial wall thickening and redistribution of pulmonary vessels. The other child showed minimal residual peribronchial thickening and the third child had normal lungs, but a rather prominent pulmonary artery segment. Echocardiographic studies revealed enlarged right ventricular cavity in 2 children. However, the pre-ejection period and the systolic time intervals were all within normal limits. It appears that unlike patients with bronchopulmonary dysplasia survivors of W-M syndrome have a good prognosis.

Eight patients (aged 8 to 22 years) with the Pierre Robin syndrome underwent sleep studies. Seven demonstrated significant although minor degrees of increased sleep disturbances and apneas, and less time spent in the rapid-eye-movement (REM) stage of sleep. One patient who had previously undergone mandibular corrective surgery had major sleep abnormalities (central apnea index of 81.7 although an obstructive sleep apnea index of only 1.9). The patients had small mandibles, as demonstrated by lateral cephalometric roentgenography, and mildly increased right ventricular diastolic dimensions, as shown by M-mode echocardiography. Snoring was present in all of these patients and in 13 of 22 patients questioned from our Pierre Robin clinic. We conclude that minor abnormalities in sleep, mandibular size, and right ventricular size persist well into adolescence in the majority of patients with Pierre Robin syndrome. These appear to be clinically insignificant; however, a small percentage of such patients may continue to have major sleep disturbances.