[Algorithm for Choosing the Study Design in Systematic Reviews]. / Algorithmus zur Auswahl von Studientypen in systematischen Reviews.

Background: The Federal Joint Committee (Gemeinsamer Bundesausschuss) assigns the highest evidence level of Ia to systematic reviews of randomized controlled trials in evaluating the benefit of therapeutic interventions. Contradictory results among randomized and non-randomized studies may not always be caused by the study design. Methods: The objective of the study was to identify statements in systematic or non-systematic reviews about the choice of study designs in systematic reviews. Another objective was to develop an algorithm to facilitate the choice of appropriate study designs in systematic reviews. Results: The inclusion of non-randomized in addition to randomized study designs was supported by 85% of the 42 identified articles. A strong reason was the need to evaluate the possible treatment-associated harm. The developed algorithm included the 4 decision points of length of follow-up, frequency of events, outcomes, and study designs. Conclusions: If the benefit and the harm of a therapeutic intervention is planned to be evaluated, then often multiple study designs are required to be included. The algorithm provides guidance on which study designs should be considered for inclusion in systematic reviews.

Rapid COJEC Induction Therapy for High-risk Neuroblastoma Patients - Cochrane Review.

BACKGROUND: Neuroblastoma is a rare malignant disease and patients with high-risk neuroblastoma have a poor prognosis. Rapid COJEC induction chemotherapy means (almost) the same total doses given within a shorter time period. In theory, rapid COJEC could reduce the risk of drug resistance and it has been considered as a potential candidate for improving the outcome. METHODS: The objective was to evaluate effects of rapid COJEC compared to standard induction chemotherapy in patients with high-risk neuroblastoma. We searched the databases CENTRAL, MEDLINE, and EMBASE from inception to 11 November 2014 and included randomized controlled trials. RESULTS: We identified one relevant randomized controlled trial with 130 participants receiving rapid COJEC and 132 participants receiving standard OPEC/COJEC induction chemotherapy. There was no statistically significant difference between the treatment groups in complete response (risk ratio 0.99, 95% confidence interval 0.71 to 1.38, P=0.94) and treatment-related mortality (risk ratio 1.21, 95% confidence interval 0.33 to 4.39, P=0.77). A statistically significant difference in favor of the standard treatment arm was identified for the following early toxicities: febrile neutropenia, septicemia, and renal toxicity. CONCLUSION: The differences in complete response and treatment-related mortality between treatment alternatives were not statistically significantly different. Based on the currently available evidence, we are uncertain about the effects of rapid COJEC induction chemotherapy in patients with high-risk neuroblastoma.

Retinoic Acid for High-risk Neuroblastoma Patients after Autologous Stem Cell Transplantation - Cochrane Review.

BACKGROUND: Neuroblastoma is a rare malignant disease and patients with high-risk neuroblastoma have a poor prognosis. Retinoic acid has been shown to inhibit growth of human neuroblastoma cells and has been considered as a potential candidate for improving the outcome. METHODS: The objective was to evaluate effects of retinoic acid after consolidation with high-dose chemotherapy and bone marrow transplantation as compared to placebo or no further treatment in patients with high-risk neuroblastoma. We searched the databases CENTRAL, MEDLINE, and EMBASE from inception to 01 October 2014 and included randomized controlled trials. RESULTS: We identified one relevant randomized controlled trial with 50 participants receiving retinoic acid and 48 participants receiving no further therapy. There was no statistically significant difference between the treatment groups in overall survival (hazard ratio 0.87, 95% confidence interval 0.46-1.63, P=0.66) and event-free survival (hazard ratio 0.86, 95% confidence interval 0.50-1.49, P=0.59). We did not identify results for other outcomes, including toxicity. CONCLUSION: The difference in overall and event-free survival between treatment alternatives was not statistically significantly different. Based on the currently available evidence, we are uncertain about the effects of retinoic acid after bone marrow transplantation in patients with high-risk neuroblastoma.

Severe and prolonged sedation in five neonates due to persistence of active diazepam metabolites.

UNLABELLED: Five neonates who suffered from an unexpected long period of respiratory failure, muscular hypotonia, and drowsiness were observed in a retrospective study. Prior to this general depression, unusually high doses of diazepam were administered to all patients via intravenous bolus injection. Serum levels of diazepam and its active metabolites were substantially elevated in the course of the disease. The persistence of the very long-acting N-desmethyldiazepam with considerable extension in neonates and even more exaggerated in premature infants is emphasized due to the reduced capacity of the hepatic biotransformation system. CONCLUSION: The intravenous application of diazepam imposes a risk of marked and prolonged general depression in neonates. Pronounced adverse effects are to be expected for prematures even after a single diazepam intravenous bolus if the dosage is not appropriate. Diazepam should not be used for short sedation and is not the drug of choice for anticonvulsant therapy in neonates.

Clinical course and treatment of haemorrhagic cystitis associated with BK type of human polyomavirus in nine paediatric recipients of allogeneic bone marrow transplants.

UNLABELLED: Of a total of 117 bone marrow transplant (BMT) recipients in the period from August 1988 to November 1995, 9 (7.7%) developed haemorrhagic cystitis. This condition was characterized in all nine patients by late onset (day +24 to +50 post-BMT), long duration (1 to 7 weeks), and the excretion of BK virus in the urine, as confirmed by electron microscopy, DNA hybridization and PCR analysis. Adenovirus was not involved. The serological assessment of BK virus-specific IgM and IgG pre- and post-BMT is consistent with viral reactivation in all patients, although a primary infection cannot be absolutely excluded in a single patient. A significant correlation between the use of high-dose busulphan (16 mg/kg) in the preparative regimen and development of haemorrhagic cystitis (P = 0. 0003) was evident. The severe course of the disease in two patients resulted in bladder tamponade; bleeding could not be inhibited with coagulation and laser treatment. Deterioration was prevented by bladder irrigation via a suprapubic catheter. Remission occurred spontaneously in all patients. CONCLUSION: BK virus induced haemorrhagic cystitis in a paediatric bone marrow transplantation recipients is characterized by late onset, long duration, viral reactivation and correlates to high-dose busulphan. Severe bleeding could not be influenced by surgical intervention.

Urological treatment and clinical course of BK polyomavirus-associated hemorrhagic cystitis in children after bone marrow transplantation.

Hemorrhagic cystitis (HC) is a major complication of bone marrow transplantation (BMT). We describe the clinical course and urological management of BK polyomavirus-associated HC in children after bone marrow transplantation. From 8/88 to 11/95, a total of 117 consecutive pediatric patients received BMT. Nine patients (7. 7%) developed HC after transplantation. HC in all 9 patients was characterized by late onset (day +24 to +50 post-BMT), long duration (1-7 weeks) and the excretion of BK polyomavirus in the urine as confirmed by electron microscopy, DNA hybridization and PCR techniques. Six children developed mild HC (grade 1-2) and were treated successfully by hyperhydration. In 3 patients, severe HC (grade 3-4) over 6 weeks required surgical interventions. In these 3 patients, cystoscopy revealed circumscript papulous tumors as the source of hematuria. Severe and persistent hematuria required blood transfusions, insertion of large suprapubic catheters and permanent bladder irrigation because of recurrent blood clot retention. Attempts to stop the hematuria in 2 of these patients by coagulation and laser vaporization (Nd:YAG) failed to stop the bleeding. Differential diagnosis of hematuria after BMT includes urinary tract infection, cyclophosphamide-induced chemical cystitis and bleeding due to BMT-induced thrombocytopenia. With the increasing number of BMTs in children, urologists may be confronted with BK polyomavirus-associated HC and must consider this in the differential diagnosis of hematuria after BMT.

Import rate of the E1beta subunit of human branched chain alpha-ketoacid dehydrogenase is a limiting factor in the amount of complex formed in the mitochondria.

Components of the mitochondrial branched chain alpha-ketoacid dehydrogenase multienzyme complex are all encoded by nuclear genes. The functional complex is formed with a known stoichiometric relationship of subunits, but how they enter the mitochondria and form the complex is not defined. Although cytosolic precursors for several of the proteins have been identified, the requirements for import and processing have not been described. Here we demonstrate the similar requirements for in vitro import and processing of the three catalytic subunits unique the this complex. Import was not affected by the amount of endogenous BCKD within the mitochondria. No cooperativity or competition among the subunits for import was found when subunits were used in combination. The relative rates of entry are E1alpha>E2>/=E1beta, making E1beta the limiting component supporting previously reported observations.

Molecular genetic characterization of maple syrup urine disease in European families.

Maple syrup urine disease results from defects in the branched chain alpha-ketoacid dehydrogenase complex. Cells from seven German, three Turkish, and two Italian families including five consanguineous matings were analyzed for the causative mutations. Enzyme assays were used to confirm the initial clinical diagnosis of all probands. Immunoblots of mitochondrial proteins from these probands revealed reduced expression of the E1 alpha and beta proteins of the complex. Previous studies showed that interaction of alpha and beta was necessary to stabilize both proteins so that defects in either protein can result in decreased presence of both. The E1 alpha Y393N mutation common in the Mennonite population that results in diminished amounts of both alpha and beta proteins was not the cause of the reduction in these European patients.

Prenatal deletion detection in a sporadic case of Duchenne muscular dystrophy without genotype information from the affected individual.

We describe the application of deletion screening by amplification of deletion-prone exons via polymerase chain reaction (PCR) in a family with a sporadic case of Duchenne muscular dystrophy (DMD). No DNA was available from the affected patient who died 12 years beforehand at the age of 18 years. Material obtained prenatally from two male fetuses exhibited an identical deletion. These findings effectively transformed a sporadic case into a familial case and a numerical carrier risk was substituted by obligate carrier status. Additionally an indirect genotype analysis was replaced by the possibility of direct DNA analysis. Genetic counselling, formerly based upon incomplete data, can now be aided by precise risk assessment.

A novel human multi-locus DNA family detected by pJU78 (DF31).

pJU78 is a 2.9-kb cloned human DNA segment derived from Xq24-q26. When used as a hybridization probe, it detects some 25 related sequences dispersed over the genome, including several autosomes and the X and Y chromosomes. Several pJU78-related sequences were chromosomally allocated and five different restriction fragment length polymorphisms detected and partially characterized in population and family studies. This sequence family was not found in non-primate species. The sequence appears to lack CpG-island character and is not detectably expressed in a variety of human tissues.

[Principles of DNA diagnosis exemplified by cystic fibrosis]. / Grundlagen der DNA-Diagnostik am Beispiel der zystischen Fibrose.

Principles of genetic disease analysis using molecular genetic techniques are illustrated. Direct and indirect genotyping is described with cystic fibrosis as an example. The possibilities to combine genetic markers for "full informativity" are included.

Frequency of the F508 deletion in the CFTR gene in Turkish cystic fibrosis patients.

The F508 deletion in the cystic fibrosis transmembrane conductance regulator (CFTR) gene was found in 8 out of 30 Turkish cystic fibrosis (CF) chromosomes (27%). Five Turkish delta F508 CF chromosomes were associated with the risk haplotype B in KM19 (2 allele)/XV2c (1 allele). In the Turkish population, cystic fibrosis is predominantly caused by mutations other than the F508 deletion.