[ZSE-DUO - dual guidance structure at the centre for rare diseases]. / ZSE-DUO ­ duale Lotsenstruktur im Zentrum für Seltene Erkrankungen.

BACKGROUND: Patients with an unclear diagnosis and suspected rare disease pose special challenges to physicians, among others. AIM OF THE STUDY (RESEARCH QUESTION): The ZSE-DUO project aims to establish whether patient care under the joint supervision of a somatic expert and a mental health expert can improve diagnostic efficacy and precision, as well as shorten the time to diagnosis. MATERIAL AND METHODS: ZSE-DUO has successfully recruited more than 1000 patients at eleven national centres for rare diseases in a control and an intervention group. The findings are being analysed by three evaluating institutions. RESULTS AND DISCUSSION: The study is currently in its final phase. The results will be published in further papers.

Non-contrast pulmonary perfusion MRI in patients with cystic fibrosis.

PURPOSE: This study aimed to assess the feasibility of Self-gated Non-Contrast-Enhanced Functional Lung (SENCEFUL) MRI for detection of pulmonary perfusion deficits in patients with cystic fibrosis. METHODS: Twenty patients with cystic fibrosis and 20 matched healthy controls underwent SENCEFUL-MRI at 1.5 T with reconstruction of perfusion and perfusion phase maps (i.e. comparable to pulse wave delays). Four blinded readers rated both types of maps separately followed by simultaneous assessment thereof. Perfusion phase data was plotted in histograms and a Peak-to-Offset ratio was calculated for comparison to subjective scoring and correlation (Spearman) to lung function parameters. Sensitivity, specificity and positive and negative predictive values were calculated for subjective scoring and Peak-to-Offset ratios. Intraclass correlation (ICC) was used to assess the interrater agreement. RESULTS: Readers attributed pathological ratings 2.2-3.5 times more frequently to the CF-group. The sensitivity with regard to a correct assignment to CF was similar between ratings (perfusion only vs. perfusions phase only vs. simultaneous assessment: 0.54-0.56), while specificity increased from 0.75 to 0.85 for simultaneous assessment. ICC was 0.77-0.84 for subjective scoring. ROC-analysis of Peak-to-Offset ratios on a mean per-subject basis revealed a sensitivity of 0.75 and specificity of 0.85 (PPV 0.83, NPV 0.77). Functional pulmonary parameters indicative of bronchial obstruction and Peak-to-Offset ratios showed positive correlation (FEV1: 0.77; FEF75: 0.76). CONCLUSIONS: SENCEFUL-MRI bears the potential for monitoring CF including disease-associated patterns of altered pulmonary perfusion. The proposed Peak-to-Offset ratio derived from pulmonary perfusion phase measurements could represent an objective future marker for perfusion impairment.

[CF Lung Disease - a German S3 Guideline: Module 2: Diagnostics and Treatment in Chronic Infection with Pseudomonas aeruginosa]. / S3-Leitlinie: Lungenerkrankung bei Mukoviszidose ­ Modul 2: Diagnostik und Therapie bei der chronischen Infektion mit Pseudomonas aeruginosa.

Cystic Fibrosis (CF) is the most common autosomal-recessive genetic disease affecting approximately 8000 people in Germany. The disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene leading to dysfunction of CFTR, a transmembrane chloride channel. This defect causes insufficient hydration of the epithelial lining fluid which leads to chronic inflammation of the airways. Recurrent infections of the airways as well as pulmonary exacerbations aggravate chronic inflammation, lead to pulmonary fibrosis and tissue destruction up to global respiratory insufficiency, which is responsible for the mortality in over 90 % of patients. The main aim of pulmonary treatment in CF is to reduce pulmonary inflammation and chronic infection. Pseudomonas aeruginosa (Pa) is the most relevant pathogen in the course of CF lung disease. Colonization and chronic infection are leading to additional loss of pulmonary function. There are many possibilities to treat Pa-infection. This is a S3-clinical guideline which implements a definition for chronic Pa-infection and demonstrates evidence-based diagnostic methods and medical treatment for Pa-infection in order to give guidance for individual treatment options.

[The Lymphoid Variant of HES (L-HES) as Differential Diagnose of Severe Asthma in Childhood]. / Ein T-Zell assoziiertes Hypereosinophilie-Syndrom (L-HES) als Differenzialdiagnose eines Asthma bronchiale.

Based on a case report an overview on the differential diagnostic considerations with respect to blood hypereosinophilia (HE) and hypereosinophilic syndromes (HES) in childhood is given. A 13-year-old boy was admitted for the clarification of an asthma. In the blood count an increased HE with 3 500/µl (30%) was found along with elevated total serum IgE and IL-5 level (2 000 IU/ml and 17 pg/ml). Lung function showed an obstruction (FEV1 38%). Radiologically the picture of bronchiectasis and mucus pluggine appeared. In the BAL a HE (76%) with raised IL-5 level was apparent. Histologically asthma was diagnosed with mucostasis, hypertrophy of the bronchial wall musculature and a lung HE. Differential-diagnostically an ABPA, a Churg-Strauss-Syndrome, a parasitosis, drug associated HE, allergies and malignant disease could be excluded. An aberrant T-cell clone in peripheral blood was detected by flow cytometry and T-cell receptor clonal rearrangements by PCR, leading to the diagnosis of a lymphoid variant of HES (L-HES). Failure to detect the FIP1L1-PDGFRA gene fusion and a normal bone marrow examination could exclude a neoplastic HES (HESN). After steroid initiation, prompt decrease of blood eosinophilia with resolution of symptoms was observed. Steroid discontinuation led to eosinophilia recurrence associated with disease symptoms. As steroid-sparing agent the immunosuppressive azathioprine was additionally given; steroid doses could be decreased and stopped in the course. This case demonstrated the range of HE evaluation in infancy. With asthma one should also consider the possibility of a L-HES.

[The Hypereosinophilic Syndromes in Childhood]. / Die Hypereosinophilie-Syndrome (HES) im Kindesalter.

The hypereosinophilic syndromes are rare disorders in childhood and require extensive differential diagnostic considerations. In the last years the earlier "idiopathic HES" called syndromes could be differentiated into molecular biologically, immunophenotypically and clinically more characterized heterogeneous diseases with high therapeutic and prognostic relevance. Nowadays the term HES summarizes diseases, which go hand in hand with a local or systemic hypereosinophilia (HE) connected with an organ damage. Depending on the cause of the HE one differentiates primary/neoplastic HES (HESN) from secondary/reactive HES (HESR). The latter develops reactively in connection with allergies, parasitosis, medications, neoplasia or a clonal increase of T-lymphocytes among others. With HESN the HE results from a clonal increase of eosinophilic granulocytes. While for some subgroups of the HESN (among others FIP1L1-PDGFRA fusion gene) the administration of a tyrosine kinase inhibitor is a new and effective therapy option, glucocorticoids still represent the medication of first choice for many not PDGFRA associated variants. Different immunomodulatory drugs or cytostatic agents are necessary to allow dose reduction of glucocorticoids. The promising therapy with anti-IL-5 antibodies is still not approved in infancy, could however become a treatment option in the future. Due to the present lack of knowledge about the HES in infancy the establishment of a register should be aimed for the treatment of HES in infancy.

Erratum to "Practical guidelines: lung transplantation in patients with cystic fibrosis".

[This corrects the article DOI: 10.1155/2014/621342.].

Practical guidelines: lung transplantation in patients with cystic fibrosis.

There are no European recommendations on issues specifically related to lung transplantation (LTX) in cystic fibrosis (CF). The main goal of this paper is to provide CF care team members with clinically relevant CF-specific information on all aspects of LTX, highlighting areas of consensus and controversy throughout Europe. Bilateral lung transplantation has been shown to be an important therapeutic option for end-stage CF pulmonary disease. Transplant function and patient survival after transplantation are better than in most other indications for this procedure. Attention though has to be paid to pretransplant morbidity, time for referral, evaluation, indication, and contraindication in children and in adults. This review makes extensive use of specific evidence in the field of lung transplantation in CF patients and addresses all issues of practical importance. The requirements of pre-, peri-, and postoperative management are discussed in detail including bridging to transplant and postoperative complications, immune suppression, chronic allograft dysfunction, infection, and malignancies being the most important. Among the contributors to this guiding information are 19 members of the ECORN-CF project and other experts. The document is endorsed by the European Cystic Fibrosis Society and sponsored by the Christiane Herzog Foundation.

Contribution of physical education to overall physical activity.

For many children, physical activity (PA) during physical education (PE) lessons provides an important opportunity for being physically active. Although PA during PE has been shown to be low, little is known about the contribution of PA during PE to overall PA. The aim was therefore to assess children's PA during PE and to determine the contribution of PE to overall PA with special focus on overweight children. Accelerometer measurements were done in 676 children (9.3 ± 2.1 years) over 4-7 days in 59 randomly selected classes. Moderate-and-vigorous PA (MVPA; ≥ 2000 counts/min) during PE (MVPAPE), overall MVPA per day (MVPADAY), and a comparison of days with and without PE were calculated by a regression model with gender, grade, and weight status (normal vs overweight) as fixed factors and class as a random factor. Children spent 32.8 ± 15.1% of PE time in MVPA. Weight status was not associated to MVPAPE . MVPAPE accounted for 16.8 ± 8.5% of MVPADAY, and 17.5 ± 8.2% in overweight children. All children were more active on days with PE than on days without PE (differences: 16.1 ± 29.0 min of MVPADAY; P ≤ 0.001; 13.7 ± 28.0 min for overweight children). Although MVPAPE was low, PE played a considerable role in providing PA and was not compensated by reducing extracurricular MVPA.

Reference ranges for analytes of thyroid function in children.

Promptly detecting pediatric thyroid dysfunction requires age-appropriate reference ranges for serum thyroid-stimulating hormone (TSH), serum free thyroxine (FT4), and serum free triiodothyronine (FT3). We sought to establish such ranges, employing the widely-used Immulite® 2000 automated immunoluminometric assays in a large population. We assayed the analytes according to manufacturer's instructions in serum samples from 359 male and 297 female university hospital patients, aged between newborn to 18 years, without evidence of thyroid or pituitary dysfunction. As data were not normally distributed, the reference ranges were assumed to lie between the 2.5th and 97.5th percentiles. Curves for age-related changes in the reference ranges were calculated using the linearity, median and skewness method. TSH, FT4, and FT3 reference ranges showed a wide spread immediately after birth, rapidly decreasing within the first 2 years of life. Reference range width was fairly stable after about age 4 years. However, from that time, the ranges' lower and upper limits steadily declined, essentially reaching (FT3) or approximating (TSH, FT4) healthy adult values by age 18 years. Age-specific reference ranges should be used when measuring TSH, FT4, and FT3 in children. During very early life, values of these analytes range widely, making it challenging to interpret measurements in infants, and, especially, newborns.

Pulmonary function in children after open water SCUBA dives.

An increasing number of children and adolescents is diving with Self-Contained Underwater Breathing Apparatus (SCUBA). SCUBA diving is associated with health risks such as pulmonary barotrauma, especially in children and in individuals with airflow limitation. As no data has been published on the effects of open-water diving on pulmonary function in children, the objective of this study was to evaluate the effects of SCUBA dives on airflow in children. 16 healthy children aged 10-13 years underwent spirometry and a cycle-exercise challenge while breathing cold air. They subsequently performed dives to 1-m and 8-m depth in random order. Pulmonary function was measured before and after the exercise challenge and the dives. There were statistically significant decreases in FEV1, FVC, FEV1/FVC, MEF25 and MEF50 after the cold-air exercise challenge and the dives. Changes in lung function following the exercise challenge did not predict the responses to SCUBA diving. In 3 children the post-dive decrements in FEV1 exceeded 10%. These children had a lower body weight and BMI percentile. SCUBA diving in healthy children may be associated with relevant airflow limitation. A low body mass might contribute to diving-associated bronchoconstriction. In the majority of subjects, no clinically relevant airway obstruction could be observed.

Immune-mediated severe hemolytic crisis with a hemoglobin level of 1.6 g/dl caused by anti-piperacillin antibodies in a patient with cystic fibrosis.

We report a 23-year-old female patient with cystic fibrosis developing severe intravascular hemolysis with a minimal hemoglobin level of 1.6 g/dl after 7 days of treatment with piperacillin, consistent with an immune-mediated hemolytic crisis. Twenty days later, the patient could leave the hospital in good condition without any neurological deficit. To our knowledge, this is the lowest reported hemoglobin value caused by hemolytic anemia with intact survival. As piperacillin is commonly used in patients with cystic fibrosis, it is important to monitor the full-blood counts of patients during treatment with piperacillin and to be aware of the potential for hemolytic anemia to develop. Anti-piperacillin antibodies should be considered whenever these patients develop hemolytic anemia or a positive direct antiglobulin test (DAT). Furthermore, drug-fever under piperacillin application could be a warning sign for the development of hemolytic anemia.

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.

Is there a secular decline in motor skills in preschool children?

Current research seems to confirm a secular decline in movement skills in school children. Only few data are available for preschool children and no clear trend can be identified. In the year 2007, height, weight, and motor performance were determined in 726 preschool children [Prevention through Activity in Kindergarten Trial (PAKT)] and compared with historical samples from 1973, 1985, and 1989. There was no difference in height and weight between the samples of 1973 and 2007. Older boys of today were smaller and lighter than those of 1989. Regardless of age, PAKT children fared significantly better in standing long jump than those assessed in 1989. Compared with the sample of 1973, PAKT children did equally well in this task. There were no differences in performance in an obstacle course between children of 1989 and 2007. In balancing backwards, PAKT children performed significantly worse than those in 1985. Regarding target throwing only the PAKT 4-year-olds achieved significantly worse results than those in 1985.Therefore, in preschool children, a secular decline is only evident in some, but not all, motor skills, which may indicate a change in behavior activity over the last decades.

[Oxygen-enhanced functional MR lung imaging]. / Sauerstoffverstärkte funktionelle MR-Lungenbildgebung.

Current diagnostic tools for the assessment of lung function are limited by global measurements or the need for radioactive tracers. Ideally, these tools should allow quantitative, regional distinct analyses without exposure to radiation. The current paper presents oxygen-enhanced functional MRI for assessment of lung ventilation. First applied in humans in 1996, a considerable amount of experience is now available on 1.5T scanners. The generation of quantitative T1-maps shows a high clinical potential. Low-field MR scanners, which are mostly open-designed, are especially interesting for functional lung imaging. The open design has advantages in respect to patient comfort by lower noise production and easy access to the patients and the costs are lower (no need for helium cooling). Lower signal-to-noise ratios can be overcome by changing the relaxation times. New navigator techniques allow further compensations. This article focuses on the presentation of low-field scanners and the application of T1 and T2(*) maps is described for healthy volunteers and first patients.

Applicability of an allometric power equation to children, adolescents and young adults of extreme body size.

AIM: The aim of this study was to assess the applicability of a regression model for peak power (PP) and total mechanical work (TMW) for healthy children, adolescents and young adults especially in the extreme ranges of stature, mass, and body mass index (BMI). METHODS: A total of 454 children, adolescents and young adults aged 6-20 years volunteered for the study. Subjects, whose stature, mass and BMI were between the 10(th) and the 90(th) centile, were selected to calculate the prediction equation: 267 subjects fulfilled these criteria. Each subject performed two unilateral Wingate tests (ULWAnT), one with each leg. PP (Watts) and TMW (Joules) of the left and right leg were averaged for each individual. Ln(mass), in(stature), age, age(2), gender, and age x gender were used as predictors for in(PP) and ln(TMW). The applicability of the prediction equation was tested on individuals who were less than the 10(th) centile or greater than the 90(th) centile for stature, body mass and BMI. RESULTS: All independent variables were statistically significant (P<0.05) predictors of in(PP), adjusted R(2)=0.93 and all but gender were significant predictors for in(TMW), adjusted R(2)=0.95. However, measured in(PP) and in(TMW) were significantly lower than predicted in(PP) and in(TMW) for subjects >90th centile for stature, body mass, or BMI. CONCLUSIONS: the prediction equations overestimated PP and TMW in children, adolescents and young adults who were heavier than the reference subjects, as indicated by a relatively high body mass or high BMI for age or were taller than the reference subjects. The findings might reflect a deficit in anaerobic capacity in children, adolescents and young adults with relatively large body size for their age.

Physical activity is independently related to aerobic capacity in cystic fibrosis.

It is unclear whether a relationship between physical activity (PA) and maximal oxygen uptake (V'(O2,max)) exists in cystic fibrosis (CF) and, if so, whether the relationship reflects a direct effect or is mediated by the effects of confounding variables, such as pulmonary or muscle function. The objective of the present study was to determine the relationship between PA and V'(O2,max) in CF while adjusting for possible influences of confounding factors. In total, 36 female and 35 male patients with CF from Germany and Switzerland (aged 12-40 yrs, forced expiratory volume in one second (FEV1) 25-107% predicted) were studied. A Wingate test was employed to measure muscle power. PA was monitored for 7 days and expressed in two ways: 1) average daily accelerometer count (ADAC) and 2) time spent in moderate-to-vigorous PA (MVPA). V'(O2,max) was determined during an incremental cycle exercise test to volitional fatigue. PA was positively related to V'(O2,max). In a multiple linear regression analysis, height, sex, FEV1, muscle power and ADAC (additionally explained variance 2.5%) or time spent in MVPA (additionally explained variance 3.7%) were identified as independent predictors of V'(O2,max). In conclusion, high levels of physical activity in addition to good muscular and pulmonary functions are associated with a high aerobic capacity in cystic fibrosis.

Follow-up of acute pulmonary complications in cystic fibrosis by magnetic resonance imaging: a pilot study.

UNLABELLED: The aim of this pilot study was to obtain information on the value of MRI in the follow-up of atelectasis and pneumonic infiltrates in cystic fibrosis (CF). Six patients aged 5-15 y were initially examined using chest X-ray and magnetic resonance imaging (MRI). Both methods provided identical information. During follow-up, MRI proved suitable to monitor pulmonary complications. CONCLUSION: MRI of the lung is feasible and valuable in the follow-up of atelectasis and pulmonary infiltrates in CF.