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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

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. Source

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. Source

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.

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. Source

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

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. Source

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

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. Source

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