Nationwide genetic analysis for molecularly unresolved cystic fibrosis patients in a multiethnic society: implications for preconception carrier screening.

BACKGROUND: Preconception carrier screening for cystic fibrosis (CF) is usually performed using ethnically targeted panels of selected mutations. This has been recently challenged by the use of expanded, ethnically indifferent, pan-population panels. Israel is characterized by genetically heterogeneous populations carrying a wide range of CFTR mutations. To assess the potential of expanding the current Israeli preconception screening program, we sought the subset of molecularly unresolved CF patients listed in the Israeli CF data registry comprising ~650 patients. METHODS: An Israeli nationwide genotyping of 152 CF cases, representing 176 patients lacking molecular diagnosis, was conducted. Molecular analysis included Sanger sequencing for all exons and splice sites, multiplex ligation probe amplification (MLPA), and next-generation sequencing of the poly-T/TG tracts. RESULTS: We identified 54 different mutations, of which only 16 overlapped the 22 mutations included in the Israeli preconception screening program. A total of 29/54 (53.7%) mutations were already listed as CF causing by the CFTR2 database, and only 4/54 (7.4%) were novel. Molecular diagnosis was reached in 78/152 (51.3%) cases. Prenatal diagnosis of 24/78 (30.8%) cases could have been achieved by including all CFTR2-causing mutations in the Israeli panel. CONCLUSIONS: Our data reveal an overwhelming hidden abundance of CFTR gene mutations suggesting that expanded preconception carrier screening might achieve higher preconception detection rates.

Mutation of serine/threonine protein kinase 36 (STK36) causes primary ciliary dyskinesia with a central pair defect.

Primary ciliary dyskinesia (PCD) is a genetic condition of impaired ciliary beating, characterized by chronic infections of the upper and lower airways and progressive lung failure. Defects of the outer dynein arms are the most common cause of PCD. In about half of the affected individuals, PCD occurs with situs inversus (Kartagener syndrome). A minor PCD subgroup including defects of the radial spokes (RS) and central pair (CP) is hallmarked by the absence of laterality defects, subtle beating abnormalities, and unequivocally apparent ultrastructural defects of the ciliary axoneme, making their diagnosis challenging. We identified homozygous loss-of-function mutations in STK36 in one PCD-affected individual with situs solitus. Transmission electron microscopy analysis demonstrates that STK36 is required for cilia orientation in human respiratory epithelial cells, with a probable localization of STK36 between the RS and CP. STK36 screening can now be included for this rare and difficult to diagnose PCD subgroup.

Eradication failure of newly acquired Pseudomonas aeruginosa isolates in cystic fibrosis.

Eradication of Pseudomonas aeruginosa (PA) is critical in cystic fibrosis (CF) patients. OBJECTIVES: To determine eradication success rate of newly acquired PA and to identify characteristics associated with eradication failure. METHODS: In an observational study, data from patients with newly acquired PA infection from 2007 to 2013 were collected. Clinical variables were compared in patients with and without successful eradication for ≥1year. RESULTS: Of 183 patients out of 740 (25%) from 7 CF Centers that had newly acquired PA, eradication succeeded in 72%. Patients with the highest risk of failure had multi-resistant PA, fewer sputum cultures taken, were older, and were diagnosed at a later age. The risk of eradication failure increased by 1.3% with each year of delayed CF diagnosis; successful eradication increased by 17% with each additional sputum culture taken. CONCLUSIONS: Delayed detection of PA infection leading to delayed treatment and growth of multi-resistant organisms is associated with eradication failure.

Lack of Association Between Haptoglobin Phenotype and Cystic Fibrosis Outcomes.

Haptoglobin (Hp), a heme-Iron chelator, has different isoforms which are associated with variable tendency toward infections: Hp 1-1, Hp 2-1, and Hp 2-2. Cystic fibrosis (CF) outcomes are variable and influenced by genetic and environmental factors. The aim of this study was to determine whether Hp phenotype influenced disease severity in CF. One hundred forty-two CF patients from two centers were analyzed for Haptoglobin phenotype using gel electrophoresis of hemoglobin enriched serum. Clinical and microbiological data including bacterial colonization status, lung function, presence of CF-related diabetes and liver disease, rate of exacerbation, and mortality were compared between Hp phenotype groups. We found a trend toward less mucoid PA among Hp 2-2 (20.4 %) compared with Hp 1-1 and Hp 2-1 individuals (33.3 %), p = 0.317. Hp 2-2 individuals also had less antibiotic courses, and lower inflammatory markers without statistical significance. Haptoglobin phenotype is unlikely to be an important modifier of CF phenotype.

[CYSTIC FIBROSIS SURVIVAL TRENDS IN CARMEL MEDICAL CENTER].

INTRODUCTION: Cystic fibrosis (CF) is an autosomal recessive disorder. The disorder is caused by a mutation in the gene that encodes a protein which functions as a chloride channel. The chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR) exists in the apical membrane of exocrine epithelial cells in the body. In the last 75 years the survival of CF patients has risen dramatically from a few months to the average age of 37 years. The rise in life expectancy is due to several reasons: improved medical treatment, treating patients in specialized CF centers, early diagnosis, respiratory physiotherapy and liver or lung transplantation. The purpose of this study was to review characteristics of our oldest living patients, transplantations and mortality of CF patients in our center. METHODS: Retrospective data have been collected regarding survival and other features in CF patients who were admitted to Carmel Medical Center in the years 2000 to 2013. RESULTS: One hundred and four CF patients were registered at the CF center between the years 2000 and 2013. Over this period 6 patients have passed away, all of whom were females. The average age of death was 21.4 years (not including one 10 months old baby who died from metabolic syndrome, not CF) with SD of 7 years, median of 20 and range of 17 years. The average age at the clinic is 22.5 years. The death incidence was less than 1% per year; the leading cause of death was respiratory failure. Of the living patients, ten patients are above the average survival age of 37 years. Four percent of the patients have undergone lung transplantation. CONCLUSIONS: CF is a multisystem disorder. In our center the mean age of death is in the third decade with an incidence of less than 1% per year, which is comparable to CF registries worldwide. Four percent of the patients have undergone lung transplantation. A gender gap with more female than male deaths was observed, a finding which was previously described in the literature. Life expectancy continues to rise as a result of early diagnosis, improved medical treatment and lung transplantation. As the age of survival rises, physicians with knowledge of adult internal medicine are needed to treat CF patients.

Long-term follow-up of distal intestinal obstruction syndrome in cystic fibrosis.

AIM: To investigate the long-term follow-up of distal intestinal obstruction syndrome (DIOS) in Israeli cystic fibrosis (CF) patients. METHODS: This is a multi-center, comparative, retrospective study in which we reviewed the medical records of all CF patients from three major CF centers in Israel who were treated in the period from 1980 to 2012. Patients diagnosed with DIOS were defined as the study group. The patients were diagnosed with DIOS based on their clinical presentation and typical findings on either abdominal X-ray or computerized tomography scan. For the control group, CF patients with no DIOS were matched to the patients in the study group for age, sex, and cystic fibrosis transmembrane conductance regulator (CFTR) mutations. For both groups, the collected data included age, sex, CFTR genotype, weight, height, and body mass index. Clinical data included respiratory function tests in the last five years prior to the study, respiratory function test immediately before and after the DIOS event, number of hospitalizations, sputum culture results, and CF-related conditions diagnosed according to the CF clinical practice guidelines. In the study group, data on the DIOS treatment and tendency for DIOS recurrence were also analyzed. RESULTS: The medical charts for a total of 350 CF patients were reviewed. Of the 350 CF patients, 26 (7.4%) were diagnosed with DIOS. The control group included 31 CF patients with no DIOS diagnosis. The mean follow-up period was 21.6 ± 8.2 years. The total of DIOS episodes in the follow-up period was 60. The distribution of DIOS episodes was as follows: 6/26 (23.1%) study patients had one episode of DIOS in their lifetime, 7/26 (26.9%) had two episodes, 7/26 (26.9%) had three episodes, and 6/26 (23.1%) had four or more episodes. Compared to the control group, DIOS patients had a significantly higher incidence of meconium ileus in the past (65.4% vs 0%, respectively, P < 0.02), more Aspergillus spp. colonization (34.6% vs 3.2%, respectively, P < 0.02), and a higher number of hospitalizations due to respiratory exacerbations (8.6 vs 6.2 mean total hospitalizations per follow-up period, respectively, P < 0.02). No other significant differences were found between the control and study groups. The conservative treatment of DIOS, which mainly includes hydration and stool softeners, was successful in 82% of the episodes. The survival rate was similar for both groups. CONCLUSION: CF patients with DIOS suffer from recurrent hospitalizations and airway pathogen acquisition. Although recurrence of DIOS is common, conservative treatment is successful in most patients.

Evaluation of the intestinal current measurement method as a diagnostic test for cystic fibrosis.

BACKGROUND: The sweat test and nasal potential difference measurement are now established tools in the diagnostic work up of cystic fibrosis (CF). Intestinal current measurement (ICM) is under consideration as an aid in the diagnosis of CF especially in young children. The aim of this study is to evaluate the diagnostic reliability of ICM. METHODS: Rectal biopsies were obtained from three groups: CF patients, controls, and patients who were suspected for CF. ICMs were performed by mounting the rectal biopsy in an Ussing chamber and sequentially adding secretagogues while recording current changes. RESULTS: Twenty-one CF patients (aged 3.0 ± 3.8 years) and 16 controls (aged 15.6 ± 15.1 years) were examined and have remarkably different results (presented as µA/cm(2) ): carbachol 16.3 ± 6.9, histamine 13.2 ± 8.9, and cAMP/forskolin 4.8 ± 4.0 for control group and carbachol -1.5 ± 5.3 (P < 0.0001), histamine -1.5 ± 3.1 (P < 0.0001), and cAMP/forskolin 0.36 ± 0.67 (P < 0.0001) for the CF group. Our suggested reference values are: +5.40, +3.52, +2.19 for carbachol, histamine, and cAMP/forskolin, respectively. The combination parameter (the arithmetic sum of carbachol, histamine, and cAMP/forskolin) of +7.19 differentiates normal from abnormal (ROC curve analysis, area under the curve = 1.00, both sensitivity and specificity are 100%). This statistical model was applied to 71 patients suspected for CF and revealed that 66 patients had normal ICM results (combination >7.19) and five patients had abnormal ICM results (combination <7.19). CONCLUSION: We have shown that ICM tests may be useful to differentiate between patients suspected to have CF. These results require confirmation so that ICM may be included in diagnostic algorithms.

Ambulatory quantitative waking and sleeping cough assessment in patients with cystic fibrosis.

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.

Meconium ileus in patients with cystic fibrosis is not a risk factor for clinical deterioration and survival: the Israeli Multicenter Study.

OBJECTIVES: Patients with cystic fibrosis (CF) presenting with meconium ileus (MI) tend to have worse outcomes than those without MI. We evaluated the clinical characteristics and survival rates among Israeli patients with CF with and without MI after a prolonged follow-up (15-30 years). PATIENTS AND METHODS: A multicenter retrospective study. Forty-nine patients with CF, representing 13.8% of all patients with CF in Israel, presented with MI (current age 17.4 +/- 7.9 years) between 1975 and 2006. They were compared with 38 patients with CF (current age 19.3 +/- 6.5 years) without MI matched by sex and CF transmembrane conductance regulator mutation. RESULTS: A total of 66.2% of patients with MI and 73.6% without MI were followed for a prolonged period (24.9 +/- 2.7 years). Of the patients with MI, 31 were managed operatively, whereas 18 were treated successfully with gastrograffin enema, with similar clinical outcomes. Five patients in the MI group and 3 in the control group died during the study period. Bacterial colonization, z score of body mass index, and pulmonary function tests were similar in patients with and without MI in the long term. In younger patients, many clinical parameters were more prevalent in patients with MI (P = 0.004). However, these differences disappeared after the long-term follow-up (up to 31-years). CONCLUSIONS: Patients with CF presenting with MI had similar pulmonary function and nutritional status, as well as survival rates as did the control patients without MI. The distinct genetic mutation found in our population may explain in part the favorable results compared with other studies. In addition, it seems that early diagnosis and treatment of MI in patients with CF may be beneficial, subsequently lowering morbidity, and increasing survival.

Effectiveness of PTC124 treatment of cystic fibrosis caused by nonsense mutations: a prospective phase II trial.

BACKGROUND: In about 10% of patients worldwide and more than 50% of patients in Israel, cystic fibrosis results from nonsense mutations (premature stop codons) in the messenger RNA (mRNA) for the cystic fibrosis transmembrane conductance regulator (CFTR). PTC124 is an orally bioavailable small molecule that is designed to induce ribosomes to selectively read through premature stop codons during mRNA translation, to produce functional CFTR. METHODS: This phase II prospective trial recruited adults with cystic fibrosis who had at least one nonsense mutation in the CFTR gene. Patients were assessed in two 28-day cycles. During the first cycle, patients received PTC124 at 16 mg/kg per day in three doses every day for 14 days, followed by 14 days without treatment; in the second cycle, patients received 40 mg/kg of PTC124 in three doses every day for 14 days, followed by 14 days without treatment. The primary outcome had three components: change in CFTR-mediated total chloride transport; proportion of patients who responded to treatment; and normalisation of chloride transport, as assessed by transepithelial nasal potential difference (PD) at baseline, at the end of each 14-day treatment course, and after 14 days without treatment. The trial was registered with who.int/ictrp, and with clinicaltrials.gov, number NCT00237380. FINDINGS: Transepithelial nasal PD was evaluated in 23 patients in the first cycle and in 21 patients in the second cycle. Mean total chloride transport increased in the first treatment phase, with a change of -7.1 (SD 7.0) mV (p<0.0001), and in the second, with a change of -3.7 (SD 7.3) mV (p=0.032). We recorded a response in total chloride transport (defined as a change in nasal PD of -5 mV or more) in 16 of the 23 patients in the first cycle's treatment phase (p<0.0001) and in eight of the 21 patients in the second cycle (p<0.0001). Total chloride transport entered the normal range for 13 of 23 patients in the first cycle's treatment phase (p=0.0003) and for nine of 21 in the second cycle (p=0.02). Two patients given PTC124 had constipation without intestinal obstruction, and four had mild dysuria. No drug-related serious adverse events were recorded. INTERPRETATION: In patients with cystic fibrosis who have a premature stop codon in the CFTR gene, oral administration of PTC124 to suppress nonsense mutations reduces the epithelial electrophysiological abnormalities caused by CFTR dysfunction.

Nasal potential difference in non-classic cystic fibrosis-long term follow up.

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.

Multicenter cross-sectional study of nontuberculous mycobacterial infections among cystic fibrosis patients, Israel.

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.

Hemoptysis in Israeli CF patients--prevalence, treatment, and clinical characteristics.

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.

Vitamins A and E and pulmonary exacerbations in patients with cystic fibrosis.

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.

Reproducibility of nasal potential difference measurements in cystic fibrosis.

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.

Paternal isodisomy of chromosome 7 with cystic fibrosis and overgrowth.

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.

Long term nutritional rehabilitation by gastrostomy in Israeli patients with cystic fibrosis: clinical outcome in advanced pulmonary disease.

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.

Effect of low altitude at the Dead Sea on exercise capacity and cardiopulmonary response to exercise in cystic fibrosis patients with moderate to severe lung disease.

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.

Familial concordance of phenotype and microbial variation among siblings with CF.

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.

Gentamicin-induced correction of CFTR function in patients with cystic fibrosis and CFTR stop mutations.

BACKGROUND: Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene containing a premature termination signal cause a deficiency or absence of functional chloride-channel activity. Aminoglycoside antibiotics can suppress premature termination codons, thus permitting translation to continue to the normal end of the transcript. We assessed whether topical administration of gentamicin to the nasal epithelium of patients with cystic fibrosis could result in the expression of functional CFTR channels. METHODS: In a double-blind, placebo-controlled, crossover trial, patients with stop mutations in CFTR or patients homozygous for the DeltaF508 mutation received two drops containing gentamicin (0.3 percent, or 3 mg per milliliter) or placebo in each nostril three times daily for two consecutive periods of 14 days. Nasal potential difference was measured at base line and after each treatment period. Nasal epithelial cells were obtained before and after gentamicin treatment from patients carrying stop mutations, and the C-terminal of surface CFTR was stained. RESULTS: Gentamicin treatment caused a significant reduction in basal potential difference in the 19 patients carrying stop mutations (from -45+/-8 to -34+/-11 mV, P=0.005) and a significant response to chloride-free isoproterenol solution (from 0+/-3.6 to -5+/-2.7 mV, P<0.001). This effect of gentamicin on nasal potential difference occurred both in patients who were homozygous for stop mutations and in those who were heterozygous, but not in patients who were homozygous for DeltaF508. After gentamicin treatment, a significant increase in peripheral and surface staining for CFTR was observed in the nasal epithelial cells of patients carrying stop mutations. CONCLUSIONS: In patients with cystic fibrosis who have premature stop codons, gentamicin can cause translational "read through," resulting in the expression of full-length CFTR protein at the apical cell membrane, and thus can correct the typical electrophysiological abnormalities caused by CFTR dysfunction.