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Human growth hormone (GH) causes a variety of physiological and metabolic effects in humans and plays a pivotal role in postnatal growth. In somatotroph cells of the anterior pituitary, GH is stored in concentrated forms in secretory granules to be rapidly released upon GH-releasing hormone stimulation. During the process of secretory granule biogenesis, self-association of GH occurs in the compartments of the early secretory pathway (endoplasmic reticulum and Golgi complex). Since this process is greatly facilitated by the presence of zinc ions, it is of importance to understand the potential role of zinc transporters that participate in the fine-tuning of zinc homeostasis and dynamics, particularly in the early secretory pathway. Thus, the role of zinc transporters in supplying the secretory pathway with the sufficient amount of zinc required for the biogenesis of GH-containing secretory granules is essential for normal secretion. This report, illustrated by a clinical case report on transient neonatal zinc deficiency, focuses on the role of zinc in GH storage in the secretory granules and highlights the role of specific zinc transporters in the early secretory pathway. © 2013 S. Karger AG, Basel.

Suboptimal dietary zinc (Zn(2+)) intake is increasingly appreciated as an important public health issue. Zn(2+) is an essential mineral, and infants are particularly vulnerable to Zn(2+) deficiency, as they require large amounts of Zn(2+) for their normal growth and development. Although term infants are born with an important hepatic Zn(2+) storage, adequate Zn(2+) nutrition of infants mostly depends on breast milk or formula feeding, which contains an adequate amount of Zn(2+) to meet the infants' requirements. An exclusively breast-fed 6 months old infant suffering from Zn(2+) deficiency caused by an autosomal dominant negative G87R mutation in the Slc30a2 gene (encoding for the zinc transporter 2 (ZnT-2)) in the mother is reported. More than 20 zinc transporters characterized up to date, classified into two families (Slc30a/ZnT and Slc39a/Zip), reflect the complexity and importance of maintaining cellular Zn(2+) homeostasis and dynamics. The role of ZnTs is to reduce intracellular Zn(2+) by transporting it from the cytoplasm into various intracellular organelles and by moving Zn(2+) into extracellular space. Zips increase intracellular Zn(2+) by transporting it in the opposite direction. Thus the coordinated action of both is essential for the maintenance of Zn(2+) homeostasis in the cytoplasm, and accumulating evidence suggests that this is also true for the secretory pathway of growth hormone.

Aims: To determine whether the current practice of sweat testing in Swiss hospitals is consistent with the current international guidelines., Methods: A questionnaire was mailed to all children's hospitals (n = 8), regional paediatric sections of general hospitals (n = 28), and all adult pulmonology centres (n = 8) in Switzerland which care for patients with cystic fibrosis (CF). The results were compared with published "guidelines 2000" of the American National Committee for Clinical Laboratory Standards (NCCLS) and the UK guidelines of 2003., Results: The response rate was 89%. All 8 children's hospitals and 18 out of 23 answering paediatric sections performed sweat tests but none of the adult pulmonology centres. In total, 1560 sweat tests (range: 5-200 tests/centre/year, median 40) per year were done. 88% (23/26) were using Wescor systems, 73% (19/26) the Macroduct system for collecting sweat and 31% (8/26) the Nanoduct system. Sweat chloride was determined by only 62% (16/26) of all centres; of these, only 63% (10/16) indicated to use the recommended diagnostic chloride-CF-reference value of >60 mmol/l. Osmolality was measured in 35%, sodium in 42% and conductivity in 62% of the hospitals. Sweat was collected for maximal 30-120 (median 55) minutes; only three centres used the maximal 30 minutes sample time recommended by the international guidelines., Conclusions: Sweat testing practice in Swiss hospitals was inconsistent and seldom followed the current international guidelines for sweat collection, analyzing method and reference values. Only 62% were used the chloride concentration as a diagnostic reference, the only accepted diagnostic measurement by the NCCLS or UK guidelines.

Background: Controlled studies established the efficacy and good tolerability of pimecrolimus cream 1% for the treatment of atopic dermatitis but they may not reflect real-life use., Objective: To evaluate the efficacy, tolerability and cosmetic acceptance of a pimecrolimus-based regimen in daily practice in Switzerland., Methods: This was a 6-month, open-label, multicentre study in 109 patients (55% > or = 18 years) with atopic dermatitis. Pimecrolimus cream 1% was incorporated into patients' standard treatment protocols., Results: The pimecrolimus-based treatment was well tolerated and produced disease improvement in 65.7% of patients. It was particularly effective on the face (improvement rate: 75.0%). Mean pimecrolimus consumption decreased from 6.4 g/day (months 1-3) to 4.0 g/day (months 3-6) as disease improved. Most patients (74.1%) rated their disease control as 'complete' or 'good' and 90% were highly satisfied with the cream formulation., Conclusion: The use of a pimecrolimus-based regimen in everyday practice was effective, well tolerated and well accepted by patients., (Copyright (c) 2006 S. Karger AG, Basel.)

Classic purpura of Henoch-Schönlein is described in a seven years old girl. Prominent clinical markers of this disease entity are: cutaneous, non thrombozytopenic, purple skin lesions, swollen and painful joints, micro- or macrohematuria and abdominal pain. No causal therapy exists; for ambulatory control of painful symptoms non steoidal anti-inflammatory agents and steroids should not be prescribed (danger for intestinal hemorrage). Prognosis in childhood is good, development of chronic glomerulopathy can occur.

Introduction: Cystic fibrosis (CF) almost always leads to chronic airway infection with Pseudomonas aeruginosa. Despite advances in antibiotic therapy, after chronic infection rapid deterioration in lung function occurs, increasing morbidity and mortality. Prevention of infection by vaccination is desirable, but earlier trials produced disappointing results. The promising short term immunogenicity and safety of a new P. aeruginosa vaccine prompted us to evaluate its long term efficacy. We conducted a 10-year retrospective analysis of outcomes in a group of vaccinated patients., Materials and Methods: In 1989-1990, 30 young children with CF, mean age 7 years, with no prior history of infection with P. aeruginosa, were vaccinated against P. aeruginosa with a polyvalent conjugate vaccine. We report the follow-up of 26 of these patients from 1989 to 2001. The patients were given yearly vaccine boosters. Comparisons were made with a CF patient control group matched for gender, age and, where possible, genetic mutation. Vaccinated patients and controls were attending a single CF clinic and received the same clinical management throughout the study period. Main outcomes were time to infection, proportion of patients infected, development of P. aeruginosa mucoid phenotype, lung function and body weight., Results: The time to infection with P. aeruginosa was longer in the vaccination group than in the control group, and fewer vaccinated patients than controls became chronically infected (32% versus 72%; P < 0.001). The proportion of mucoid infections was higher in the control group (44%) than in the vaccinated group (25%). Patients >/=18 years of age at the end of the study had a lower mean forced expiratory volume at 1 s (FEV1) than did those 13-17 years of age, but this difference was small in the vaccinated group (73.6% versus 83.7%) compared with the controls (48.0% versus 78.7%). In the >/=18 year age category the mean FEV1% at 10 years was 73.6% (vaccinated) and 48.0% (controls) (P < 0.05). In the vaccinated group only 11 (44%) of 25 patients were underweight at the 10-year follow-up compared with 18 (72%) of 25 at the beginning of the study. In the control group 17 (68%) of 25 patients were underweight at 10-year follow-up compared with 16 (64%) of 25 at the beginning of the study., Conclusion: Regular vaccination of young CF patients for a period of 10 years with a polyvalent conjugate vaccine reduced the frequency of chronic infection with P. aeruginosa. This was associated with better preservation of lung function. Vaccinated patients gained more weight during the study period, a possible indication of an improved overall health status.

Survivin has received great attention due to its expression in many human tumors and its potential as a therapeutic target in cancer. Survivin expression has been described to be cell cycle-dependent and restricted to the G2-M checkpoint, where it inhibits apoptosis in proliferating cells. In agreement with this current view, we found that survivin expression was high in immature neutrophils, which proliferate during differentiation. In contrast with immature cells, mature neutrophils contained only little or no survivin protein. Strikingly, these cells reexpressed survivin upon granulocyte/macrophage colony-stimulating factor (CSF) or granulocyte CSF stimulation in vitro and under inflammatory conditions in vivo. Moreover, survivin-deficient mature neutrophils were unable to increase their lifespan after survival factor exposure. Together, our findings demonstrate the following: (a) overexpression of survivin occurs in primary, even terminally differentiated cells and is not restricted to proliferating cells; and (b) survivin acts as an inhibitor of apoptosis protein in a cell cycle-independent manner. Therefore, survivin plays distinct and independent roles in the maintenance of the G2-M checkpoint and in apoptosis control, and its overexpression is not restricted to proliferating cells. These data provide new insights into the regulation and function of survivin and have important implications for the pathogenesis, diagnosis, and treatment of inflammatory diseases and cancer.

An eleven year old girl from Turkey was diagnosed to have a periodic fever syndrome. The diagnosis of familial mediterranean fever was made by molecular analysis of a mutation in the MEFV-Gen which codes for pyrin. The disease is well-known in the mediterranean area and belongs to the periodic fever syndromes. These syndromes are discussed for their differential diagnosis focused to childhood.

Background and Methods: In cystic fibrosis, growth and lung function have been identified as prognostic markers of both severity of pulmonary disease and survival. Cross-sectional studies in patients with cystic fibrosis (CF) including all genotypes have shown that in prepubertal patients with lifetime continuous care within a specialised CF centre, growth can normalise. No corresponding improvement in lung function has been found. We used a longitudinal design to determine whether normalisation of growth could be found in the genetic subgroup of prepubertal children with CF with the homozygous Delta F508 mutation, which is one of the known severe mutations., Methods: Data of all children born after 1980 with the homozygous Delta F508 mutation, diagnosed in early childhood at the specialised centre of the Children's Hospital of Berne were systematically assessed up to the age of 11 years and retrospectively analysed. Follow-up data of height, weight and BMI were compared to the Swiss reference population using z-scores. The correlations between lung function parameters (FEV1, MEF50, VC) and age, as well as lung function parameters and growth indices, were calculated. Additionally, the same correlations were examined in a cohort with the same mutation born 10 years earlier., Results: In the study, cohort growth (height, weight and BMI) was significantly below that of the normal Swiss population. A significant decline of lung function with age was also found, however, no association between lung function and growth could be seen. Compared to an earlier cohort, an improved growth over the last decade could be shown but no improvement on lung function could be detected. Lung function varied widely in both groups., Conclusion: In contrast to sequential cross-sectional studies of children with CF, the present longitudinal study of children with homozygous for the Delta F508 mutation failed to confirm normalisation of growth over time. However, compared to the data of children born in the previous decade, improved growth was observed.

This summary of the current knowledge of macrolide therapy serves as an example of recent progress in the therapeutic approach to treating patients with cystic fibrosis (CF). The benefit of macrolides in the treatment of patients with diffuse panbronchiolitis and Pseudomonas aeruginosa infections, as seen in Japan, was the rational behind trials in patients with CF. Thus far, the majority of reports of positive trends in the therapeutic potential of macrolides have studied azithromycin. The data presented in peer reviewed journals are, however, too sparse to already justify firm recommendations for the general use of azithromycin, erythromycin or clarithromycin on a long-term basis for the treatment of chronic lung disease in CF.

Up to 90% of patients with cystic fibrosis (CF) are chronically colonized with Pseudomonas aeruginosa, and 10% to 50% of CF patients are colonized with Aspergillus fumigatus. Despite an extensive inflammatory reaction, patients cannot eliminate the microorganisms. The present study demonstrates that an IL-10 mediated T-cell tolerance to major infectious agents A. fumigatus and P. aeruginosa plays an important role in the control of T-cell-mediated inflammatory responses in CF. Peripheral blood mononuclear cells of CF patients secreted significantly higher amounts of IL-10. T-cell response against recombinant A. fumigatus antigens rAsp f 3, rAsp f 4, rAsp f 6, and heat-inactivated P. aeruginosa was controlled by IL-10. Proliferation and interferon-gamma production was significantly increased when endogenous IL-10 was blocked in aspergillus and pseudomonas antigen-stimulated cells of CF patients. The role of IL-10 was further documented by increased spontaneous proliferation of peripheral blood mononuclear cells of CF patients after preincubation with antisense oligonucleotides blocking the synthesis of IL-10 receptor-associated kinases janus tyrosine kinase 1 and tyrosine kinase 2. Together, these data demonstrate an important role of IL-10-mediated peripheral T-cell tolerance to P. aeruginosa and A. fumigatus in the control of the intensity of the inflammatory T-cell response in CF.

Weight loss, day-time sleep and loss of appetite were leading symptoms in a thirteen years old girl, in whom consecutively the diagnosis of Crohn's disease of the stomach and the duodenum was made after endoscopy and biopsy were performed. There were no complaints of diarrhea, abdominal pain or other symptoms suspicious for this chronic inflammatory bowel disease.

Genotype-phenotype association in cystic fibrosis (CF) is difficult because of heterogeneous disease expression. The genotype-phenotype correlation for the 3905insT mutation in comparison to deltaF508 was studied here. Thirty CF patients compound heterozygous for 3905insT were compared to clinical presentation of matched patients homozygous for deltaF508 (1960-1997). Sweat tests, age at diagnosis, at death and at onset of Pseudomonas aeruginosa colonization were analysed. Chrispin-Norman scores and pulmonary function forced expiratory volume in one second (FEV1) determined severity of lung disease. Twenty-five of the patients with 3905insT had deltaF508 as a second mutation and five had another rare mutation. At the age of 15 yrs, 60% of patients with 3905insT had an FEV1 < 60% predicted in comparison to 25% of patients with deltaF508 (p<0.05). Age at death and cumulative survival rate was significantly lower (p<0.05) in the 3905insT than in the deltaF508 group (20.3 and 24.0 yrs, respectively). Age at onset of P. aeruginosa colonization was not different in the study groups. Sweat chloride concentrations were lower in patients homozygous for deltaF508 (105.63+/-15.3 mmol L(-1)) than in patients with 3905insT (119.9+/-22.1 mmol x L(-1)) (p<0.05). Patients compound heterozygous for 3905insT have similar high morbidity and mortality to patients homozygous for deltaF508.

The Swiss Registry for Cystic Fibrosis (SRCF) was designed to collect demographic, clinical and therapeutic data from patients with cystic fibrosis (CF) in Switzerland. It was designed, programmed and implemented for standalone application in Swiss cystic fibrosis centres. It is part of the European Registry for Cystic Fibrosis (ERCF), which has been implemented in Europe to collect data on the use and safety of dornase alpha (Pulmozyme) in the treatment of cystic fibrosis. At the time of first evaluation 245 cystic fibrosis patients are registered, their mean age is 13 years, and 17% are over 18. In larger databases in Germany or North America we observe comparable demographic data, similar degrees of severity and similar therapeutic approaches to those in Swiss cystic fibrosis patients. The aim of the Swiss Registry is to cover the maximum possible number of cystic fibrosis patients from this country.

Unlabelled: Although bacterial colonisation of bronchi may occur from early childhood onwards, infections extending beyond the lungs are uncommon in patients with cystic fibrosis. A 12-year-old boy with cystic fibrosis, receiving oral corticosteroids for 3 weeks because of allergic bronchopulmonary aspergillosis, experienced pneumonia and septicaemia caused by Staphylococcus aureus. He was treated with flucloxacillin, ticarcillin-clavulanate, aztreonam, cefazolin and rifampin according to resistance testing of S. aureus cultured from the blood. On day 25 the patient finally had recovered., Conclusion: Systemic steroid therapy for allergic bronchopulmonary aspergillosis may favour life-threatening systemic bacterial infection which is rare in the immunocompetent patient with cystic fibrosis.

Inhibition of carbonic anhydrase in general or specific inhibition of one the different isoenzymes results in a significant metabolic acidosis due to renal bicarbonate loss. The increase of arterial pCO2 stimulates central and peripheral chemoreceptors and enhances ventilation. The inhibition of carbonic anhydrase as a respiratory stimulant is an accepted measure for the prevention of acute mountain sickness, has been used for a restricted number of subjects with sleep-disordered breathing or chronic hypoxaemic lung disease. The few indications and the narrow therapeutic index restrict the use of carbonic anhydrase blockers as stimulants for ventilation.

Neutrophil leukocytes have been shown to be the predominant cells in inflammatory airway infiltrates of cystic fibrosis (CF) patients. The aim of this study was to investigate the effect of rehabilitation on neutrophil surface antigen expression and lung function in healthy controls and stable CF patients with moderately severe disease. The absolute number of neutrophils and the level of surface marker expression on neutrophils were elevated in 12 CF patients compared with eight healthy controls. The level of neutrophil surface marker expression was similar in bronchoalveolar lavage fluid from CF patients who underwent bronchoscopy for diagnostic or therapeutic reasons. After 3 weeks' rehabilitation, there was a significant reduction in the expression of CD11b (complement receptor type 3), CD13 (aminopeptidase N), CD32 (low-affinity Fc gamma chain receptor II), and CD35 (complement receptor type 1) in only the CF patients. At the same time, lung function improved significantly. The increase in forced vital capacity correlated significantly with the decrease in CD32 level. These results demonstrate that rehabilitation in a specialized clinic can reduce the neutrophil-dominated inflammation and improve the lung function of stable CF patients with moderately severe disease even without changing any medications.

Complex interactions between nutrition, skeletal and respiratory muscle function and energy expenditure in cystic fibrosis patients exist. Malnutrition significantly contributes to muscle weakness in patients with chronic obstructive pulmonary disease of the adult or in cystic fibrosis in childhood. Together with a measurable increase in resting energy expenditure the malnutrition, as a consequence of pancreatic insufficiency, leads to pulmonary deterioration. Whether pulmonary disease, pancreatic insufficiency, increased energy expenditure or insufficient intake of nutrition are the starters for the destructive circle or whether the basic defect is responsible for some of the components interacting with each other remains to be determined., (Copyright 2000 Harcourt Publishers Ltd.)

Neutrophils are important effector cells in immunity to microorganisms, particularly bacteria. Here, we show that the process of neutrophil apoptosis is delayed in several inflammatory diseases, suggesting that this phenomenon may represent a general feature contributing to the development of neutrophilia, and, therefore, in many cases to host defense against infection. The delay of neutrophil apoptosis was associated with markedly reduced levels of Bax, a pro-apoptotic member of the Bcl-2 family. Such Bax-deficient cells were also observed upon stimulation of normal neutrophils with cytokines present at sites of neutrophilic inflammation, such as granulocyte and granulocyte-macrophage colony-stimulating factors, in vitro. Moreover, Bax-deficient neutrophils generated by using Bax antisense oligodeoxynucleotides demonstrated delayed apoptosis, providing direct evidence for a role of Bax as a pro-apoptotic molecule in these cells. Interestingly, the Bax gene was reexpressed in Bax-deficient neutrophils under conditions of cytokine withdrawal. Thus, both granulocyte expansion and the resolution of inflammation appear to be regulated by the expression of the Bax gene in neutrophils.

The association between long-term exposure to ambient air pollution and respiratory symptoms was investigated in a cross-sectional study in random population samples of adults (aged 18 to 60 yr, n = 9,651) at eight study sites in Switzerland. Information on respiratory symptoms was obtained with an extended version of the European Community Respiratory Health Survey questionnaire. The impact of annual mean concentrations of air pollutants was analyzed separately for never-, former, and current smokers. After controlling for age, body mass index, gender, parental asthma, parental atopy, low education, and foreign citizenship, we found positive associations between annual mean concentrations of NO2, total suspended particulates, and particulates of less than 10 micrometers in aerodynamic diameter (PM10) and reported prevalences of chronic phlegm production, chronic cough or phlegm production, breathlessness at rest during the day, breathlessness during the day or at night, and dyspnea on exertion. We found no associations with wheezing without cold, current asthma, chest tightness, or chronic cough. Among never-smokers, the odds ratio (95% confidence interval) for a 10 micrograms/ m3 increase in the annual mean concentration of PM10 was 1. 35 (1.11 to 1.65) for chronic phlegm production, 1.27 (1.08 to 1.50) for chronic cough or phlegm production, 1.48 (1.23 to 1.78) for breathlessness during the day, 1.33 (1.14 to 1.55) for breathlessness during the day or at night, and 1.32 (1.18 to 1.46) for dyspnea on exertion. No associations were found with annual mean concentrations of O3. Similar associations were also found for former and current smokers, except for chronic phlegm production. The observed associations remained stable when further control was applied for environmental tobacco smoke exposure, past and current occupational exposures, atopy, and early childhood respiratory infections when restricting the analysis to long-term residents and to non- alpine areas, and when excluding subjects with physician-diagnosed asthma. The high correlation between the pollutants makes it difficult to sort out the effect of one single pollutant. This study provides further evidence that long-term exposure to air pollution of rather low levels is associated with higher prevalences of respiratory symptoms in adults.

In this paper, we present results from the SAPALDIA study (Swiss Study on Air Pollution and Lung Diseases in Adults) regarding associations between lung function [forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1)], as assessed during the cross-sectional study in 1991, and average levels of NO2 exposure within the eight study communities. We distinguished average home outdoor exposure and average personal exposure to NO2 and obtained exposure estimates by computing regional averages of passive sampler measurements performed by a random subsample of SAPALDIA participants in 1993. Previous analyses had revealed associations between average lung function and average air pollution levels between communities. The present results show that such associations may also be seen within communities: a 10-micrograms per m3 increase in average home outdoor and personal exposure to NO2 between zones of residence of the same community was associated with a change in average FVC by -0.59% [95% confidence limits (CL) = 0.01, -1.19] and -0.74% (95% CL = -0.07, -1.41), respectively. These values, however, are smaller than the ones found for the corresponding associations between study communities: -1.67% (95% CL = -1.01, -2.33) and -2.93% (95% CL = -2.11, -3.75), respectively. The different magnitudes of these two types of associations might be explained by differences in spatial variation between various components of air pollution.

Allergic bronchopulmonary aspergillosis (ABPA), an intense inflammatory reaction to Aspergillus in the lung, is recognized as a severe complication in patients with cystic fibrosis (CF). The diagnosis of ABPA in CF patients sensitized to Aspergillus fumigatus is complicated by interfering laboratory and clinical findings shared by the diseases. We have used cDNA encoding A. fumigatus allergens which were cloned from a cDNA library displayed on phage surface to produce recombinant proteins in Escherichia coli. Differential IgE responses to the allergens in A. fumigatus-sensitized CF patients with or without ABPA and CF controls without sensitization to A. fumigatus were demonstrated. A secreted ribotoxin (rAsp f 1) and a peroxisomal protein (rAsp f 3) were recognized by sera from A. fumigatus-sensitized CF-patients with or without ABPA. An intracellular manganese superoxide dismutase (rAsp f 6) and rAsp f 4, a protein with unknown function, were recognized exclusively by IgE from sera of CF patients with ABPA. Therefore, Asp f 4 and Asp f 6 represent specific markers for ABPA and allow a sensitive, fully specific diagnosis of the disease. The data suggest distinct IgE responses to colonization of the bronchial tree in CF patients with ABPA or A. fumigatus allergy and therefore a differential recognition of the pathogen in the two IgE-related inflammatory diseases.

Physical exercise can improve sputum clearance in patients with cystic fibrosis (CF). To set up individual training protocols it is desirable to know the anaerobic threshold (AT). Established methods such as blood lactate measurements and ergometry can only be performed in specialized centers. Conconi showed that the heart rate threshold (HRT), i.e., the deflection point from the linear relationship between work load and heart rate, correlated significantly with the AT in healthy adults. To assess the reliability of the HRT in CF, we performed ergometry in 32 CF patients (mean age, 21.0 +/- 5.5 years; mean Shwachman score, 77.8 +/- 12.0) according to the Conconi protocol. The HRT was compared with the aerobic threshold (AeT) as determined by the V-slope method and with two turn points in the lactate performance curve (LTP1, LTP2). An HRT could be obtained in only 17 of the 32 patients (53%). In these 17 patients there was a significant correlation between HRT and the other thresholds, but the absolute values for the AT differed considerably: The mean HRT was 132% higher than the AeT according to Beaver, 107% higher than LTP1, and 19% higher than LTP2. Exercise protocols that rely solely on the HRT in CF will lead to excessive exertion during exercise training programs in these patients. According to these results the HRT of Conconi is not a suitable method to determine appropriate exercise levels in CF training programs and might even be harmful in CF patients. These results also indicate the need to test the reliability of a diagnostic procedure that has been developed only for healthy people.