Hebestreit H.,Universitats Kinderklinik |
Sauer-Heilborn A.,Klinik fur Pneumologie |
Fischer R.,Medizinische Klinik Innenstadt |
Kading M.,Poliklinik Chemnitz GmbH |
Mainz J.G.,Jena University Hospital
Journal of Cystic Fibrosis | Year: 2013
Background: Recently, ivacaftor, a CFTR-potentiator, has been shown to be effective and safe in patients with cystic fibrosis carrying a G551D mutation and moderately impaired lung function. The objective of this retrospective study was to assess efficacy and safety of ivacaftor in severely ill patients with at least one G551D mutation. Methods: Data from 14 patients with a FEV1 < 40% predicted who received ivacaftor on a "named patient program" base in Germany were analyzed. Results: One patient took ivacaftor at a lower than recommended dose due to abundant mucus and a feeling to "suffocate." No additional severe adverse events were reported. One further patient stopped ivacaftor due to lung transplantation, one due to perceived poor effectiveness, one due to pregnancy, and one stopped standard therapy. The remaining patients took ivacaftor regularly and did not change other therapies. FEV1 increased by more than 5 %predicted in 5 of the 14 patients from baseline (average FEV1 during the year prior to ivacaftor). On average, FEV1 increased significantly by 5.2±5.6%predicted (p<0.01). The relative improvement in FEV1 was 19.7±22.1%. Conclusion: Ivacaftor was effective in many patients with poor lung function. The response was, however, variable. Although the drug appeared safe for most of these patients, increased bronchial secretions may warrant intensified physiotherapy and intravenous antibiotic treatment when ivacaftor is initiated. © 2013 European Cystic Fibrosis Society.
Clancy J.L.,Victor Chang Cardiac Research Institute |
Wei G.H.,Victor Chang Cardiac Research Institute |
Echner N.,Victor Chang Cardiac Research Institute |
Echner N.,Universitats Kinderklinik |
And 4 more authors.
RNA | Year: 2011
Reporter-based studies support inhibition of translation at the level of initiation as a substantial component of the miRNA mechanism, yet recent global analyses have suggested that they predominantly act through decreasing target mRNA stability. Cells commonly coexpress several processing isoforms of an mRNA, which may also differ in their regulatory untranslated regions (UTR). In particular, cancer cells are known to express high levels of short 3′ UTR isoforms that evade miRNA-mediated regulation, whereas longer 3′ UTRs predominate in nontransformed cells. To test whether mRNA isoform diversity can obscure detection of miRNA-mediated control at the level of translation, we assayed the responses of 11 endogenous let-7 targets to inactivation of this miRNA in HeLa cells, an intensively studied model system. We show that translational regulation in many cases appears to be modest when measuring the composite polysome profile of all extant isoforms of a given mRNA by density ultracentrifugation. In contrast, we saw clear effects at the level of translation initiation for multiple examples when selectively profiling mRNA isoforms carrying the 5′ or 3′ untranslated regions that were actually permissive to let-7 action, or when let-7 and a second targeting miRNA were jointly manipulated. Altogether, these results highlight a caveat to the mechanistic interpretation of data from global miRNA target analyses in transformed cells. Importantly, they reaffirm the importance of translational control as part of the miRNA mechanism in animal cells. Copyright © 2011 RNA Society.
Hulkova H.,Charles University |
Poupetova H.,Charles University |
Harzer K.,Universitats Kinderklinik |
Mistry P.,Yale University |
And 2 more authors.
Journal of Inherited Metabolic Disease | Year: 2010
Ultrastructural study of skin biopsies in two cases of Gaucher disease (GD) patients (types II and III) revealed hitherto unknown alteration of the blood capillary endothelial cells (ECs) featured by hypertrophy and numerous subplasmalemmal microvesicles underneath both the apical and basal membranes. There was also prominent apical membrane folding with formation of filiform and large cytoplasmic projections, with occasional transcapillary cytoplasmic bridges. Similar, though less frequently expressed, changes were manifested at the basal membrane by numerous cytoplasmic projections into the subendothelial space. Regressive changes with EC breakdown were rare. Lysosomal storage was always absent. Besides EC hypertrophy, there was also increased EC density in the capillary lumen, leading to pronounced changes in capillary architecture with loose or incomplete EC anchoring. There were also signs of EC sprouting. Some pericytes displayed an increase in size and number of cytoplasmic processes, which often extended into distant pericapillary regions. The spectrum of changes suggests that a significant positive growth effect on EC occurs in GD. The putative mechanisms triggered by GBA1 deficiency leading to EC involvement are discussed. The authors are well aware of the fact the results, based on a nontraditional type of bioptic samples, are preliminary, but they are worth following, as further ultrastructural and functional studies of blood endothelium in GD may open a novel field in molecular cell pathophysiology of the disorder: endothelial dysfunction.
Neuhauser C.,Center Hospitalier Of Luxembourg |
Wagner B.,Universitats Kinderklinik |
Heckmann M.,Universitats klinikum Giessen and Marburg |
Weigand M.A.,Universitatsklinikum Giessen and Marburg |
Zimmer K.-P.,Universitats klinikum Giessen and Marburg
Deutsches Arzteblatt | Year: 2010
Background: Painful procedures on children and adolescents often have to be performed with the aid of analgesia and sedation in order to prevent pain and emotional distress. Moreover, many procedures can be performed more rapidly and more effectively in a relaxed patient. Because the combination of analgesia and sedation can cause serious or even life-threatening complications, it must be accompanied by the same safety precautions as a general anesthetic. Methods: Selective review of the literature. Results: A high level of safety can be achieved by adherence to the published guidelines of the societies for anesthesiology and pediatrics. The depth of sedation during procedures performed under combined analgesia and sedation is often equivalent to that resulting from general anesthesia. Therefore, in order to avoid serious complications, combined analgesia and sedation should only be administered by physicians trained in pediatric anesthesia or pediatric critical care. This is particularly so when propofol is used, because it has a narrow therapeutic range and can cause cardiorespiratory respiratory problems without warning. As long as the appropriate safety precautions are followed, nonanesthesiologists can also administer propofol in combination with an analgesic, such as ketamine, to children and adolescents. Conclusion: In children and adolescents, the combination of analgesia and sedation can prevent the emotional trauma that would result from a painful procedure, while often enhancing the quality of the procedure itself. This method should be considered a variant of general anesthesia. Accordingly, any non-anesthesiologist employing this method must be as well versed as an anesthesiologist in the management of its specific side effects and complications.
Muller-Wiefel D.E.,University of Hamburg |
Frisch H.,Universitats Kinderklinik |
Tulassay T.,Semmelweis University |
Bell L.,Montreal Childrens Hospital |
Zadik Z.,Kaplan Medical Center
Clinical Nephrology | Year: 2010
Aims: To assess long-term efficacy and safety of recombinant human growth hormone (GH) in childrenwith chronic kidney disease (CKD). Methods: An open-label, international, multicenter study. Children with CKD and growth failure received GH (0.35 mg/kg/week). The primary efficacy endpoint was a significant change in height velocity (HV) and height standard deviation score (SDS) versus baseline after 12months of treatment, extended to 24 months, then to 5 years. Results: In total, 81 patients enrolled (CKD Stage 4 - 5 = 37, on dialysis = 27, post-transplant = 17). After 12 and 24 months of treatment, increases were seen in mean (SD) HV (4.6 (3.1) to 9.0 (3.6) cm/year and 4.5 (3.3) to 7.5 (2.9) cm/year, respectively; both p < 0.001), mean (SD) height SDS (-3.7 (1.7) to -3.0 (1.7) and -3.6 (1.5) to -2.5 (1.5), respectively; both p < 0.001) and mean (SD) HV SDS (-2.4 (2.5) to 3.8 (4.5) and -2.4 (2.2) to 1.1 (3.8), respectively; both p < 0.001). A normal height SDS was seen in 1% of children at baseline, 17%after 12months and 43% after 24months of treatment. Improvementswere similar across CKD subgroups with the greatest improvements in CKD Stage 4 - 5. Among 31 patients who completed about 5 years of treatment, four reached final height. There was no undue bone age acceleration and no deterioration of kidney function. Ten adverse events were related to GH treatment. Conclusions: In this long-term study, GH treatment was associated with significant improvements in growth and height in children with CKD and growth failure, and was well tolerated. ©2010 Dustri-Verlag Dr. K. Feistle.
Lung Function in Childhood and Adolescence: Influence of Prematurity and Bronchopulmonary Dysplasia [Lungenfunktion in Kindheit und Adoleszentenalter: Einfluss von Frühgeburtlichkeit und bronchopulmonaler Dysplasie]
Segerer F.J.H.,Universitats Kinderklinik |
Speer C.P.,Universitats Kinderklinik
Zeitschrift fur Geburtshilfe und Neonatologie | Year: 2016
Introduction: The introduction of prenatal steroids, surfactant replacement therapy and gentle ventilation modes has reduced short term respiratory morbidity and increased survival of very preterm infants. However, there is some evidence that prenatal factors, the extend of prematurity and bronchopulmonary dysplasia (BPD) may affect pulmonary function in childhood and adolescence. Methods: We have performed a comprehensive review on the outcome of pulmonary function after premature birth before 32 weeks of gestation in the era of surfactant replacement therapy and tried to evaluate the influence of chorioamnionitis, intrauterine growth retardation (IUGR), maternal metabolic syndrome, prematurity and BPD on long term pulmonary function. Results: Some children and adolescents born very preterm may experience significant airflow reduction. The bronchial obstruction in these patients is not entirely reversible by inhalative ß2-mimetics. The degree of pulmonary function impairment is partly correlated with the degree of BPD. Abnormalities in pulmonary diffusion capacity may occur after extreme prematurity, but also in patients with moderate and severe BPD. IUGR may have a negative impact on later pulmonary function in very children. There is insufficient data to assess the preterm impact of chorioamnionitis or maternal metabolic syndrome on later lung function. Conclusion: Infants born before 32 weeks of gestational age in the surfactant era still carry an increased risk to suffer an impaired pulmonary function in childhood and adolescence, particularly if they survived with BPD. Long term pulmonary care for these patients should take place in specialized centers. Copyright © 2016, Georg Thieme Verlag KG. All rights reserved.
Beck M.,Universitats Kinderklinik
Tagliche Praxis | Year: 2012
In the past management of lysosomal storage disorders mainly consisted of supportive care and treatment of complications. The situation promptly changed when enzyme replacement therapy became available for Gaucher disease 20 years ago. Because orphan drug regulations in the USA and Europe incited pharmaceutical companies to develop drugs for rare disorders, enzyme replacement therapy has become achievable also for Fabry disease, mucopolysaccharidosis type I, II and VI and Pompe disease. The intravenously applied enzymes, however, do not have any effect on the clinical manifestations of the central nervous system as they are notable to enter the brain because of the blood-brainbarrier. The enzymes are no more effective if irreversible organ damage has already occurred. In addition, the formation of neutralizing antibodies may diminish enzyme activity. To cirumvent these limitations of enzyme replacement therapy new drugs are under development. Enzyme activity, for example, can be increased by small molecules, called chaperones. Other substances have been detected that are able to inhibit the synthesis of the storage material ("Substrate deprivation"). A great number of genetherapeutic experiments are being performed in animal models. A cure, however, can be achieved in none of the lysosomal storage disorder until now, therefore of greatest importance are supportive care, prevention of complications and the care by a physician who is experienced in this field.
Comparison of five video laryngoscopes and conventional direct laryngoscopy: Investigations on simple and simulated difficult airways on the intubation trainer [Vergleich von fünf Videolaryngoskopen und direkter konventioneller Laryngoskopie: Untersuchung des einfachen und simulierten schwierigen Atemweg am Intubationstrainer]
Ruetzler K.,Outcome Research Consortium |
Ruetzler K.,Universitats Klinik Zurich |
Imach S.,Universitats Kinderklinik |
Weiss M.,Universitats Kinderklinik |
And 3 more authors.
Anaesthesist | Year: 2015
Introduction: Securing the airway with a tracheal tube is essential in emergency situations, in the intensive care setting as well as during anesthesia for surgery and other interventions. Current methods of airway assessment are poor screening tests for predicting difficult direct laryngoscopy due to a generally low positive predictive value; therefore, successful endotracheal intubation requires a high level of expertise, regular training and practice and sometimes additional tools. Currently, several video laryngoscopes (VL) with different designs are commercially available and have been investigated in a wide variety of settings. To our knowledge there is no prospective study evaluating and comparing performance among these three groups of VL; therefore, the aim of this study was to compare performance of five VL and conventional direct laryngoscopy in an intubation manikin model, both in a normal and simulated difficult intubation setting. Methods: In this study 10 residents, 12 senior staff physicians and 5 anesthesia nurses, all experienced in conventional direct laryngoscopy and inexperienced with VL underwent theoretical and hands-on training with all VL lasting 60 min. Afterwards participants performed intubation with all 5 VL and conventional direct laryngoscopy in a randomized sequence using an intubation manikin with normal intubation settings. Thereafter participants performed intubation in a simulated difficult intubation setting using the same intubation manikin with a neck collar to immobilize the cervical spine. In this study, the C-MAC® with Macintosh blade size 3, GlideScope® size 3, McGrath® series 5, King Vision® and Airtraq® size 2 were used. Time to intubation served as primary outcome and time to glottis visualization, number of intubation attempts, success rate and subjective evaluation of difficulty served as secondary outcomes. Results: In the normal intubation setting, time to intubation ranged from 16.0 s (conventional direct laryngoscopy) to 34.3 s (McGrath). GlideScope and conventional direct laryngoscopy were successful in 100 % followed by C-MAC (96.7 %), Airtraq (88.9 %), King Vision (77.8 %) and McGrath VL (44.4 %). In the simulated difficult intubation setting, time to intubation ranged between 20.3 s (Airtraq) and 26.7 s (McGrath). Success rate with C-MAC was 100 %, followed by GlideScope (96.7 %), Airtraq (85.2 %), conventional direct laryngoscopy (85.2 %), King Vision (81.5 %) and McGrath VL (70.4 %). Conclusion: In the manikin with normal intubation setting, conventional direct laryngoscopy using a Macintosh blade was convincing and superior to any VL used in this study. During simulated difficult intubation, a blade with video transmission, such as C-MAC and the GlideScope were superior compared to conventional direct laryngoscopy and any other VL tested. © 2015, Springer-Verlag Berlin Heidelberg.
Weber S.,Universitats Kinderklinik
Nieren- und Hochdruckkrankheiten | Year: 2011
Congenital anomalies of the kidney and urinary tract (CAKUT) are among the most frequent organ malformations. They are a relevant cause of chronic renal failure in children. Besides isolated forms of CAKUT, more than 500 syndromes have been described that are characterized by combined defects of the kidney and other organ systems. Familial aggregation of renal malformations in approximatively 10% of patients suggests that genetic events might be involved. Mutations in different renal developmental genes seem to contribute to this accumulation. The mutation detection rate is low, however, it is significantly higher for HNF1β, a relevant genetic cause of cystic dysplasia of the kidney. Modifier effects and oligogenic influences seem to be important for the pathogenesis of CAKUT, complicating genetic counseling of affected families in many cases. On the contrary, genetic counseling is of high relevance for patients affected by autosomal dominant CAKUT disorders which are frequently complicated by extrarenal symptoms. © 2011 Dustri-Verlag Dr. Karl Feistle.
PubMed | Universitats Kinderklinik
Type: Journal Article | Journal: Zeitschrift fur Geburtshilfe und Neonatologie | Year: 2016
The introduction of prenatal steroids, surfactant replacement therapy and gentle ventilation modes has reduced short term respiratory morbidity and increased survival of very preterm infants. However, there is some evidence that prenatal factors, the extend of prematurity and bronchopulmonary dysplasia (BPD) may affect pulmonary function in childhood and adolescence.We have performed a comprehensive review on the outcome of pulmonary function after premature birth before 32 weeks of gestation in the era of surfactant replacement therapy and tried to evaluate the influence of chorioamnionitis, intrauterine growth retardation (IUGR), maternal metabolic syndrome, prematurity and BPD on long term pulmonary function.Some children and adolescents born very preterm may experience significant airflow reduction. The bronchial obstruction in these patients is not entirely reversible by inhalative 2-mimetics. The degree of pulmonary function impairment is partly correlated with the degree of BPD. Abnormalities in pulmonary diffusion capacity may occur after extreme prematurity, but also in patients with moderate and severe BPD. IUGR may have a negative impact on later pulmonary function in very children. There is insufficient data to assess the preterm impact of chorioamnionitis or maternal metabolic syndrome on later lung function.Infants born before 32 weeks of gestational age in the surfactant era still carry an increased risk to suffer an impaired pulmonary function in childhood and adolescence, particularly if they survived with BPD. Long term pulmonary care for these patients should take place in specialized centers.