Long-term effects of a partially supervised conditioning programme in cystic fibrosis.

Little is known about the long-term persistence of positive effects induced by a physical conditioning programme in cystic fibrosis. Therefore, this study determined the effects of a 6-month conditioning programme on peak oxygen uptake (primary outcome) and other markers of fitness, physical activity, anthropometry, lung function and quality of life (secondary outcomes), 18 and 24 months after the programme was initiated. Patients with cystic fibrosis aged 12-40 yrs were randomly assigned to an intervention (n = 23) and a control (n = 15) group. The intervention group consented to add 3 h of sports per week for > or =6 months to their previous activities. Controls were asked to maintain their level of activity for 12 months. Patients were seen at baseline and after 3, 6, 12, 18 and 24 months. There was no significant difference between groups at baseline. The intervention induced positive effects on peak oxygen uptake (difference in changes from baseline to the 18- and 24-month assessments between groups: 3.72+/-1.23 mL.min(-1).kg(-1); p<0.01), maximal workload (0.37+/-0.11 W.kg(-1); p<0.01), vigorous physical activity (1.63+/-0.82 h.week(-1); p<0.05), forced vital capacity (6.06+/-2.87% predicted; p<0.05) and perceived health (9.89+/-4.72; p<0.05). A home-based partially supervised physical conditioning programme can improve physical fitness, lung function and perceived health long after the intervention has ended.

Transient correction of the basic defect in sweat glands in an individual with cystic fibrosis carrying the complex CFTR allele F508del-R553Q.

The molecular pathology of mutant F508del CFTR is partially corrected in vitro by the secondary amino acid substitution R553Q in the ABC signature motif. An individual with the CFTR genotype R553X/F508del-R553Q showed the typical symptoms and electrophysiological anomalies of cystic fibrosis in the airways and intestine. Sweat chloride concentrations were normal early in life, but were later raised into the range that is diagnostic for cystic fibrosis, suggesting that R553Q could temporarily correct the basic defect in sweat glands. R553Q caused a delay in diagnosis because of false negative sweat tests but was not a disease reverting suppressor mutation as had been inferred from cellular models.

Tobramycin once- vs thrice-daily for elective intravenous antipseudomonal therapy in pediatric cystic fibrosis patients.

PURPOSE: We hypothesized that a single intravenous (iv) tobramycine infusion (treatment B) would have equivalent anti-infectious efficacy in chronic Pseudomonas aeruginosa (PA) infection in cystic fibrosis (CF) as the commonly performed treatment of three doses (treatment A) . Toxicity and practicability may even be improved in the single-dose regimen. METHODS: This was a randomized crossover study comparing outcome after 14 and 35 days. The primary end-point was a decrease in the leukocyte count, and the secondary end-points were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunoglobulin G, C-reactive protein) in serum. 30 patients (20 female, mean age 11.2 years, mean age range 1.7-18.1 years) received elective 14-day courses of treatments A or B, followed by the alternative treatment after a mean interval of 37 (+/- 21) weeks. RESULTS: With the exception of PA density, there were no significant differences between both treatment strategies after 14 days of treatment. After 35 days of treatment, there were no significant changes in the leukocyte count and inflammation markers. Both treatment strategies reduced the bacterial load in the airways, as reflected by a decreased PA density in sputum. Nephrotoxicity was equal in both groups, with a transient slight elevation of urinary N-acetyl-beta-glucosaminidase concentrations. Standard audiometry tests revealed no evidence of a hearing impairment in any patient following therapy. Mean body weight increased during the study period by 0.5 kg. Forced expiratory volume increased by approximately 5% of the predicted volume, forced vital capacity increased by 2% of predicted capacity, and forced mid expiratory flow rate increased by 7% (A) or 4% (B) of the predicted normal value, although these changes were not statistically significant. CONCLUSION: We conclude that tobramycin given in a daily single dose (with the advantage of being more practical in a home environment) has an efficacy equal to that of three daily doses in terms of elective antipseudomonal therapy in clinically stable patients with CF.

Continuous vs thrice-daily ceftazidime for elective intravenous antipseudomonal therapy in cystic fibrosis.

BACKGROUND/AIM: We hypothesized that a continuous 24-h infusion of 100 mg/kg per day ceftazidime (treatment C) would result in equivalent or even superior anti-infectious efficacy in chronic Pseudomonus aeruginosa (PA) infection in patients with cystic fibrosis (CF) in comparison to the usual application of 200 mg/kg per day ceftazidime in three doses (treatment T). METHODS: This was a randomized crossover study comparing outcome after 14 days and 35 days. Tobramycin administered once daily (10 mg/kg per day) was administered concomitantly in both groups. The primary end-point was a decrease in the leukocyte count, and the secondary endpoints were clinical and lung function parameters, Pseudomonas quantification in sputum, and inflammation markers (immunogloblulin [Ig] G, C-reactive protein [CRP]) in serum. All patients received antibiotics electively as 14-day courses on a regular basis, not for acute exacerbations. RESULTS: Fifty-six patients (29 females, mean patient age 14.4 years, age range 5-37) initially received treatments C or T, followed by the alternative treatment after a mean interval of 37 (+/- 21) weeks. After 2 weeks of antibiotic treatment, the overall study group showed significant improvements compared to baseline for body weight, leukocyte counts, CRP, forced expiratory volume in 1 s (FEV(1)), FVC (forced vital capacity), and bacterial load in the airways, with no significant differences between treatment groups. Both regimens were well tolerated. Three weeks after cessation of antimicrobial therapy, leukocytes and PA density had returned to pre-treatment values. CONCLUSION: We conclude that continuous or thrice-daily dosing of intravenous ceftazidime, both combined with once-daily tobramycin, are equally effective application regimens for elective antipseudomonal therapy in clinically stable patients with CF.

Respiratory viral infections within one year after pediatric lung transplant.

To characterize epidemiology and risk factors for respiratory viral infections (RVI) in pediatric lung transplant recipients within the first post-transplant year, a retrospective multicenter study of pediatric lung transplant recipients from 1988 to 2005 was conducted at 14 centers in the United States and Europe. Data were recorded for 1 year post transplant. Associations between RVI and continuous and categorical risk factors were assessed using Wilcoxon's rank-sum and chi(2) tests, respectively. Associations between time to RVI and risk factors or survival were assessed by multivariable Cox proportional hazards models. Of 576 subjects, 79 subjects (14%) had 101 RVI in the first year post transplant. Subjects with RVI were younger than those without RVI (median ages 9.7, 13; P<0.01). Viruses detected included adenovirus (n=25), influenza (n=9), respiratory syncytial virus (n=21), parainfluenza virus (n=19), enterovirus (n=4), and rhinovirus (n=22). In a multivariable model for time to first RVI, etiology other than cystic fibrosis (CF), younger age, and no induction therapy were independently associated with risk of RVI. Cytomegalovirus serostatus and acute rejection were not associated with RVI. RVI was independently associated with decreased 12-month survival (hazard ratio 2.6, 95% confidence interval 1.6-4.4). RVI commonly occurs after pediatric lung transplantation with risk factors including younger age and non-CF diagnosis. RVI is associated with decreased 1-year survival.

Diversity of the basic defect of homozygous CFTR mutation genotypes in humans.

BACKGROUND: Knowledge of how CFTR mutations other than F508del translate into the basic defect in cystic fibrosis (CF) is scarce due to the low incidence of homozygous index cases. METHODS: 17 individuals who are homozygous for deletions, missense, stop or splice site mutations in the CFTR gene were investigated for clinical symptoms of CF and assessed in CFTR function by sweat test, nasal potential difference and intestinal current measurement. RESULTS: CFTR activity in sweat gland, upper airways and distal intestine was normal for homozygous carriers of G314E or L997F and in the range of F508del homozygotes for homozygous carriers of E92K, W1098L, R553X, R1162X, CFTRdele2(ins186) or CFTRdele2,3(21 kb). Homozygotes for M1101K, 1898+3 A-G or 3849+10 kb C-T were not consistent CF or non-CF in the three bioassays. 14 individuals exhibited some chloride conductance in the airways and/or in the intestine which was identified by the differential response to cAMP and DIDS as being caused by CFTR or at least two other chloride conductances. DISCUSSION: CFTR mutations may lead to unusual electrophysiological or clinical manifestations. In vivo and ex vivo functional assessment of CFTR function and in-depth clinical examination of the index cases are indicated to classify yet uncharacterised CFTR mutations as either disease-causing lesions, risk factors, modifiers or neutral variants.

[Lung transplantation in cystic fibrosis--a position paper]. / Lungentransplantation bei Mukoviszidose--ein Positionspapier.

Lung transplantation in cystic fibrosis is an established therapy, due to the fact that vast majority of adult CF patients will develop respiratory failure. Even adolescents and children can be transplanted successfully today. Lung transplantation in cystic fibrosis requires special consideration concerning candidate selection, surgery and postoperative follow-up care. Due to a donor shortage and increasing waiting time, early referral to transplant centres of potential candidates is crucial. In the process of candidate selection, assumed improvements in quality of life and survival benefit should be weighed against contraindications. Centre-based follow-up and close cooperation with local physicians are key factors for success. During follow-up care, the transplantation team should be contacted immediately in the case of any problem or change in medication.

Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings.

To investigate the impact of chloride (Cl(-)) permeability, mediated by residual activity of the cystic fibrosis transmembrane conductance regulator (CFTR) or by other Cl(-) channels, on the manifestations of cystic fibrosis (CF), we determined Cl(-) transport properties of the respiratory and intestinal tracts in Delta F508 homozygous twins and siblings. In the majority of patients, cAMP and/or Ca(2+)-regulated Cl(-) conductance was detected in the airways and intestine. Our finding of cAMP-mediated Cl(-) conductance suggests that, in vivo, at least some Delta F508 CFTR can reach the plasma membrane and affect Cl(-) permeability. In respiratory tissue, the expression of basal CFTR-mediated Cl(-) conductance, demonstrated by 30% of Delta F508 homozygotes, was identified as a positive predictor of milder CF disease. In intestinal tissue, 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid-insensitive (DIDS-insensitive) Cl(-) secretion, which is indicative of functional CFTR channels, correlated with a milder phenotype, whereas DIDS-sensitive Cl(-) secretion was observed mainly in more severely affected patients. The more concordant Cl(-) secretory patterns within monozygous twins compared with dizygous pairs imply that genes other than CFTR significantly influence the manifestation of the basic defect.

Binding of vasoactive intestinal polypeptide to dispersed enterocytes results in rapid removal of the NH2-terminal histidyl residue.

Specific binding sites for 125I-labelled vasoactive intestinal polypeptide (VIP) (half-maximal inhibition at 1.5 +/- 0.2 nM VIP) were identified on dispersed porcine enterocytes. Radioactivity bound to the cell surface was internalized. At 37 degrees C, a steady state was achieved after 45 min with a ratio of internalized to cell surface-bound radioactivity of approximately 1:2 but at 10 degrees C, no radioactivity appeared intracellularly. Incubation of VIP with cells in the absence of inhibitors of proteolysis for as short a time as 30 s at 37 degrees C led to the formation of [des-His1]VIP by the action of amastatin- and bestatin-sensitive aminopeptidase(s). This metabolite was formed in the presence of sodium azide and when incubations were performed at 10 degrees C suggesting that internalization was not a prerequisite for degradation. As [des-His1]-VIP has only 1% of the bioactivity of VIP, formation of this metabolite will effectivily terminate the action of VIP in the epithelial layer of the intestine.

Increased plasma membrane fluidity and decreased receptor availability of nonmuscle cells in myotonic dystrophy.

Plasma membrane fluidity of intact nonmuscle cells from patients with myotonic dystrophy (MyD) was determined by fluorescence anisotropy measurements. Anisotropy values of the probe diphenylhexatriene were decreased in patient mononuclear cells (0.163 +/- 0.017, n = 13) versus controls (0.181 +/- 0.013, n = 13, P less than 0.01) and in patient platelets (0.087 +/- 0.017, n = 9) versus controls (0.137 +/- 0.015, n = 9, P less than 0.001) indicating increased plasma membrane fluidity in patient nonmuscle cells. Vasopressin plasma concentrations were increased in patients (7.4 +/- 2.1 pg/ml, n = 12) versus controls (4.5 +/- 1.4 pg/ml, n = 22, P less than 0.0005), whereas serum osmolality was normal. These data are compatible with a decreased vasopressin sensitivity in MyD patients. Specific binding of 125I-labelled vasoactive intestinal peptide (VIP) was decreased in patient mononuclear cells (2.9 +/- 0.9%/10(6) cells, n = 8) versus controls (5.2 +/- 1.6%/10(6) cells, n = 9, P less than 0.005) and receptor affinity for VIP was decreased in patient mononuclear cells (Kd = 0.26 +/- 0.05 nM, n = 8) versus controls (Kd = 0.19 +/- 0.02 nM, n = 9, P less than 0.005). In nonmuscle cells of MyD patients, increased membrane fluidity correlated with decreased receptor availability. This might explain the various endocrine defects described in MyD patients.

Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis.

UNLABELLED: Inflammation is a hallmark in the pathogenesis of pulmonary destruction in cystic fibrosis (CF). There is no proven effective systemic anti-inflammatory treatment for CF patients with advanced pulmonary disease. Methotrexate (MTX) is known as an effective anti-inflammatory treatment in asthma and in juvenile rheumatoid arthritis. The question was: Is an improvement in pulmonary function achievable with low-dose MTX in patients with cystic fibrosis and advanced pulmonary disease.? METHODS: We treated five CF patients with advanced pulmonary disease, who deteriorated in spite of intensive conventional therapy on an individual basis with low-dose MTX. FEV1% and immunoglobulin G (IgG) serum levels were followed from the year before to the year after starting with MTX. RESULTS: In the year before starting with MTX, FEV1% decreased (median: 10% FEV1; range 9-15% FEV1; P<0.005) after starting with MTX, FEV1% increased (median: 9% FEV1; range: 2-15% FEV1; P<0.05). IgG changed (median: -2 g/l; range: 0.2 to -7.3 g/l) in the first year with MTX. CONCLUSION: These preliminary data suggest a beneficial effect of MTX even in advanced pulmonary disease in CF patients and supports the need for a controlled prospective study.

Prevention of coagulation during hemodialysis by a combination of the stable prostacyclin analogue CG 4203 and low-dose heparin.

In certain situations heparin used during hemodialysis can increase the risk of bleeding. Various groups have suggested that this bleeding risk can be reduced by using prostacyclin (PGI2). Since PGI2 is labile under physiological conditions and is thus difficult to use, we have used the stable PGI2 analogue CG 4203. This study in 5 chronic dialysis patients was designed to apply the following 5 different dialysis regimens with bicarbonate to each patient for 5 h: 1) conventional full heparinization; 2) CG 4203 (25 ng/kg/min) for the first 120 min, then full heparinization; 3) CG 4203 alone for 5 h (25 ng/kg/min); 4) initial bolus dose of heparin (500 IU), then continuous infusion of heparin (200 IU/h) and CG 4203 (25 ng/kg/min); 5) as 4) above but 35 ng/kg/min of CG 4203. Slight falls in thrombocytes and in some case substantial falls in leukocytes shortly after commencing the dialysis cannot be avoided when administering CG 4203 alone. Both 25 and 35 ng/kg/min doses of CG 4203 produced approx. 50% inhibition of the ADP-induced platelet aggregation for the entire 5 h administration period. At 30 min after dialysis the inhibition had fallen to approx. 20%. Although administering CG 4203 alone for 2 h produced no extracorporeal occlusion, administering CG 4203 alone for 5 h, some clots did occur after 3-5 h, which caused premature termination of the dialysis or made reinfusion impossible after 5 h. When 25 ng/kg/min was applied together with a continuous low dose of heparin for 5 h, only small clots were observed which did not impede dialysis or reinfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

Diabetes mellitus in patients with cystic fibrosis: the impact of diabetes mellitus on pulmonary function and clinical outcome.

In this multicenter study, the impact of CF-related diabetes mellitus (CFRD) on pulmonary function and clinical outcome has been investigated. To better characterize the relationship between insulin deficiency and clinical outcome we prospectively followed a group of 56 CF patients, 28 with CFRD (group 1) and 28 without diabetes (group 2) for 5 years. The clinical course of the patients was registered at each center. Data included were mortality, pulmonary function, body mass index, in-patient treatment, and CF-typical and diabetes typical complications. At the end of the study nearly twice the number of patients had died in group 1 as compared to group 2, however due to the low patient number this did not reach statistical significance. In patients with diabetes FEV1 and FVC declined significantly over the five year study period, whereas patients without diabetes did not show a significant decline during the study period. Retinopathy, nephropathy, and neuropathy were only observed in diabetic patients. In conclusion, the data presented in this prospective, multicenter study give evidence that insulin deficiency leads to a direct decline in pulmonary function suggesting a cause and effect relationship between insulin deficiency and lung disease.

Adaptation of the small intestine to induced maldigestion in rats. Experimental pancreatic atrophy and acarbose feeding.

Intestinal adaptation has been studied in rats with pancreatic atrophy induced by feeding a copper-deficient diet and penicillamine and in rats with carbohydrate maldigestion induced by feeding of an alpha-glucosidase inhibitor (acarbose). Pancreatic atrophy led to a significant increase of weight, protein, and DNA content as well as specific activities and total amounts of the enzymes sucrase and maltase in the distal but not in the proximal part of the small intestine. Plasma levels of CCK and GIP were significantly higher in rats with pancreatic atrophy, whereas plasma levels of gastrin and insulin were lower. Tissue concentrations of gastrin in the antrum and GIP in duodenum and jejunum were unchanged. Duodenal CCK and jejunal substance P, somatostatin, and VIP and ileal substance P and somatostatin were significantly decreased in rats with acinar atrophy. Glucosidase inhibition by acarbose feeding led to weight increase of the small intestine and cecum. This was more marked when acarbose was fed together with a fiber-free diet. Under these conditions the protein and DNA content also increased significantly in both gut segments and maltase and sucrase content predominantly in the distal part. Insulin plasma concentration decreased significantly in the acarbose-fed groups, whereas GIP, gastrin, and CCK plasma concentrations remained unchanged. After fiber-rich diet tissue concentrations of gastrin in the antrum and insulin in the pancreas were significantly higher and GIP concentrations in the duodenum and jejunum significantly lower than after fiber-free diet. Acarbose increased the pancreatic insulin concentration only in the fiber-free group and did not influence gastrin and GIP concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

A novel sidestream ultrasonic flow sensor for multiple breath washout in children.

OBJECTIVE: Inert gas multiple breath washout (MBW) for measuring Lung Clearance Index using mass spectrometry and 4% sulfur hexafluoride (SF(6)) as the tracer gas has been shown to be sensitive for detecting early Cystic Fibrosis (CF) lung disease. However, mass spectrometry requires bulky equipment and is expensive to buy and maintain. A novel sidestream ultrasonic device may overcome this problem. The aims of this study were to assess the feasibility and clinical validity of measuring lung volume (functional residual capacity, FRC) and the LCI using the sidestream ultrasonic flow sensor in children and adolescents with CF in relation to spirometry and plain chest radiographs. PATIENTS AND METHODS: MBW using the sidestream ultrasonic device and conventional spirometry were performed in 26 patients with CF and 22 healthy controls. RESULTS: In the controls (4.7-17.7 years) LCI was similar to that reported using mass spectrometry (mean (SD) 6.7 (0.5)). LCI was elevated in 77% of the CF children (6.8-18.9 years), whereas spirometry was abnormal in only 38.5%, 61.5%, and 26.9% for FEV(1), MEF(25), and FEV(1)/FVC, respectively. This was more marked in children <10 years. LCI correlated with the Crispin-Norman score, whereas FEV(1) did not. CONCLUSIONS: Sidestream ultrasonic MBW is a valid and simple alternative to mass spectrometry for assessing ventilation homogeneity in children.

Cystic fibrosis in 65- and 67-year-old siblings. Clinical feature and nasal potential difference measurement in patients with genotypes F508del and 2789+5G-->A.

Cystic fibrosis (CF) is a recessive genetic disease caused by defects of the cystic fibrosis trans-membrane regulator (CFTR) gene with a median survival of less than 35 years. This work reports on the oldest living German siblings with CF. Besides clinical history, CF genotype and nasal potential difference (NPD) measurement results, the remarkably high exercise activity of the siblings is discussed as a disease-modifying factor. Both male patients have an overall mild pulmonary manifestation. They have suffered from abdominal symptoms since their early childhood, including recurrent pancreatitis and diffuse symptoms leading to partial gastric resection. They were diagnosed as having CF with positive sweat tests at the advanced ages of 45 and 43 years, respectively. Later on genotyping revealed compound heterozygosity for F508del and 2789+5G-->A. Using NPD we demonstrated a CF-typical inhibition of the NPD by the Na channel blocker amiloride, although in both siblings the remaining CFTR function and alternate chloride channel function were detected during superfusion of the nasal epithelium with isoproterenol and ATP. Long-term survival with CF is basically influenced by the CFTR genotype. The patients' genotype was discussed as a mild one with remaining CFTR function. We demonstrated this residual CFTR function in both siblings using NPD. Additionally the siblings' continuous healthy lifestyle and their engagement in a remarkably high level of exercise activities from early childhood to the present possibly have an important effect on the long-term outcome of CF as disease-modifying factors. In this regard this report can encourage CF patients to maintain a high level of physical activity in their daily lives.