Friede T.,Universitatsmedizin Gottingen |
Statistics in Medicine | Year: 2010
Sample size estimation in clinical trials depends critically on nuisance parameters, such as variances or overall event rates, which have to be guessed or estimated from previous studies in the planning phase of a trial. Blinded sample size reestimation estimates these nuisance parameters based on blinded data from the ongoing trial, and allows to adjust the sample size based on the acquired information. In the present paper, this methodology is developed for clinical trials with count data as the primary endpoint. In multiple sclerosis such endpoints are commonly used in phase 2 trials (lesion counts in magnetic resonance imaging (MRI)) and phase 3 trials (relapse counts). Sample size adjustment formulas are presented for both Poisson-distributed data and for overdispersed Poisson-distributed data. The latter arise from sometimes considerable between-patient heterogeneity, which can be observed in particular in MRI lesion counts. The operation characteristics of the procedure are evaluated by simulations and recommendations on how to choose the size of the internal pilot study are given. The results suggest that blinded sample size reestimation for count data maintains the required power without an increase in the type I error. Copyright © 2010 John Wiley & Sons, Ltd.
Zautner A.E.,Universitatsmedizin Gottingen
BMC microbiology | Year: 2013
Campylobacter jejuni, the most common bacterial pathogen causing gastroenteritis, shows a wide genetic diversity. Previously, we demonstrated by the combination of multi locus sequence typing (MLST)-based UPGMA-clustering and analysis of 16 genetic markers that twelve different C. jejuni subgroups can be distinguished. Among these are two prominent subgroups. The first subgroup contains the majority of hyperinvasive strains and is characterized by a dimeric form of the chemotaxis-receptor Tlp7(m+c). The second has an extended amino acid metabolism and is characterized by the presence of a periplasmic asparaginase (ansB) and gamma-glutamyl-transpeptidase (ggt). Phyloproteomic principal component analysis (PCA) hierarchical clustering of MALDI-TOF based intact cell mass spectrometry (ICMS) spectra was able to group particular C. jejuni subgroups of phylogenetic related isolates in distinct clusters. Especially the aforementioned Tlp7(m+c)(+) and ansB+/ ggt+ subgroups could be discriminated by PCA. Overlay of ICMS spectra of all isolates led to the identification of characteristic biomarker ions for these specific C. jejuni subgroups. Thus, mass peak shifts can be used to identify the C. jejuni subgroup with an extended amino acid metabolism. Although the PCA hierarchical clustering of ICMS-spectra groups the tested isolates into a different order as compared to MLST-based UPGMA-clustering, the isolates of the indicator-groups form predominantly coherent clusters. These clusters reflect phenotypic aspects better than phylogenetic clustering, indicating that the genes corresponding to the biomarker ions are phylogenetically coupled to the tested marker genes. Thus, PCA clustering could be an additional tool for analyzing the relatedness of bacterial isolates.
Reiss J.,Universitatsmedizin Gottingen |
Hahnewald R.,Universitatsmedizin Gottingen
Human Mutation | Year: 2011
All molybdenum-containing enzymes other than the bacterial nitrogenase share an identical molybdenum cofactor (MoCo), which is synthesized via a conserved pathway in all organisms and therefore also is called "universal molybdenum cofactor." In humans, four molybdoenzymes are known: aldehyde oxidase, mitochondrial amidoxime reducing component (mARC), xanthine oxidoreductase, and sulfite oxidase. Mutations in the genes encoding the biosynthetic MoCo pathway enzymes abrogate the activities of all molybdoenzymes and result in the "combined" form of MoCo deficiency, which is clinically very similar to isolated sulfite oxidase deficiency, caused by mutations in the gene for the corresponding apoenzyme. Both deficiencies are inherited as an autosomal-recessive disease and result in progressive neurological damage and early childhood death in most cases. The majority of mutations leading to MoCo deficiency have been identified in the genes MOCS1 (type A deficiency), MOCS2 (type B deficiency), with one reported in GPHN. For type A deficiency an effective substitution therapy has been described recently. © 2010 Wiley-Liss, Inc.
Kiese-Himmel C.,Universitatsmedizin Gottingen
Kindheit und Entwicklung | Year: 2011
(Central) Auditory Processing Disorders [(C)APDs] are deficits in neural processing of auditory stimuli despite normal peripheral hearing and average intelligence. CAPDs may coexist with learning disabilities, developmental language disorders, dyslexia, or supramodal attention problems. The concept of CAPD can therefore be feasibly utilized to explain developmental and learning problems in spoken and literary language, behavioral disorders and pervasive developmental disorders. Because processing of speech acoustic stimuli differs from that of nonspeech acoustic stimuli, speech perception may be considered, at best, a special case of auditory perception. Hitherto, causal relations between impaired auditory functions and clinical disorders have not been proved satisfactorily. Studies backed by stronger levels of evidential support coupled with an untrained control group are therefore necessary. © Hogrefe Verlag, Göttingen 2011.
Narayanan R.,Universitatsmedizin Gottingen |
Tuoc T.C.,Universitatsmedizin Gottingen
Cell and Tissue Research | Year: 2014
ATP-dependent BAF chromatin remodeling complexes play an essential role in the maintenance of the gene expression program by regulating the structure of chromatin. There is increasing evidence that BAF complexes based on the alternative ATPase subunits, Brg1 and Brm, control the differentiation of neural stem cells (NSCs) to generate distinct neural cell types and modulate trans-differentiation between cell types. The BAF complexes have dedicated functions at different stages of neural differentiation that appear to arise by combinatorial assembly of their subunits. Furthermore, the differentiation of NSCs is regulated by the tight interactions between the BAF chromatin remodeling complex and the transcriptional machinery. Here, we review recent insights into the functional interaction between BAF complexes and various transcription factors (TFs) in neural differentiation and cellular reprogramming. © 2014 Springer-Verlag.
Kiese-Himmel C.,Universitatsmedizin Gottingen
Kindheit und Entwicklung | Year: 2013
Expressing ideas by means of drawing is a basic childhood urge. Drawing is first and foremost thought to enhance sensory-motor development and spatial thinking, which are basic requirements for the development of further cognitive functions, particularly symbol-based ones. Drawing is thus regarded as an appropriate approach in early education of young children as it enables positive transfer effects to other areas. Because promotion early of development is becoming of increasing interest in education and politics, the question of the efficacy of our educational approach to drawing is of interest. In contrast to music education, drawing has received relatively little attention in Germany in non-school children. Therefore, an important opportunity for future research emerges. Methodological problems of evaluation result from the plethora of variables associated with the training effect.
Burckhardt G.,Universitatsmedizin Gottingen
Pharmacology and Therapeutics | Year: 2012
Common to all so far functionally characterized Organic Anion Transporters (OATs) is their broad substrate specificity and their ability to exchange extracellular against intracellular organic anions. Many OATs occur in renal proximal tubules, the site of active drug secretion. Exceptions are murine Oat6 (nasal epithelium), human OAT7 (liver), and rat Oat8 (renal collecting ducts). In human kidneys, OAT1, OAT2, and OAT3 are localized in the basolateral membrane, and OAT4, OAT10, and URAT1 in the apical cell membrane of proximal tubule cells, respectively. In rats and mice, Oat1 and Oat3 are located basolaterally, and Oat2, Oat5, Oat9, Oat10, and Urat1 apically. Several classes of drugs interact with human OAT1-3, including ACE inhibitors, angiotensin II receptor antagonists, diuretics, HMG CoA reductase inhibitors, β-lactam antibiotics, antineoplastic and antiviral drugs, and uricosuric drugs. For most drugs, interaction was demonstrated in vitro by inhibition of OAT-mediated transport of model substrates; for some drugs, transport by OATs was directly proven. Based on IC50 values reported in the literature, OAT1 and OAT3 show comparable affinities for diuretics, cephalosporins, and nonsteroidal anti-inflammatory drugs whereas OAT2 has a lower affinity to most of these compounds. Drug-drug interactions at OAT1 and OAT3 may retard renal drug secretion and cause untoward effects. OAT4, OAT10, and URAT1 in the apical membrane contribute to proximal tubular urate absorption, and OAT10 to nicotinate absorption. OAT4 is in addition able to release drugs, e.g. diuretics, into the tubule lumen. © 2012 Elsevier Inc.
Zautner A.E.,Universitatsmedizin Gottingen
Recent Patents on Inflammation and Allergy Drug Discovery | Year: 2012
Adenotonsillar disease (adenoiditis and recurrent tonsillitis) is a prevalent otolaryngologic disorder aetiologi-cally based on chronic inflammation triggered by a persistent bacterial infection. These bacteria, mostly Staphylococcus aureus, Haemophilus sp., and Streptococcus sp., persist predominantly intracellular and within mucosal biofilms. The recurrent or chronic inflammation of the adenoids and faucial tonsils leads to chronic activation of the cell-mediated and humoral immune response, resulting in hypertrophy of the lymphoid tonsillar tissue. This hypertrophic tissue is the cause for the prominent clinical symptoms: obstruction of the upper airways, snoring, and sleep apnea for adenoiditis or sore throat, dysphagia and halitosis for recurrent tonsillitis. Treatment strategies should target the persisting bacteria within their biofilm or intracellular shelter. Macrolide antibiotics like clarithromycin are able to modulate the immune system and to interfere in bacterial signaling within biofilms. Clindamycin, quinupristin-dalfopristin, and oritavancin are intracel-lular high active compounds. Surgical removal of the hypertrophic tissue by modern procedures like laser tonsil ablation, eliminates not only a mechanical obstacle of the airways, it removes also the basis for the aetiologic cause, the "biofilm carrier". This review summarizes the role of bacterial persistence in mucosal biofilms for the aetiology, diagnosis and treatment of adenotonsillar disease and relevant patents. © 2012 Bentham Science Publishers.
Frosch S.,Universitatsmedizin Gottingen
Zeitschrift für Orthopädie und Unfallchirurgie | Year: 2011
The diagnosis and treatment of patellar dislocation is very complex. The aim of this study is to give an overview of the biomechanics of the patellofemoral joint and to point out the latest developments in diagnosis and treatment of patellar dislocation. The authors electronically searched Medline, Cochrane and Embase for studies on the biomechanics of the patellofemoral joint and for conservative and surgical treatments after patellar dislocation. We extracted baseline demographics, biomechanical, conservation and surgical details. Understanding the biomechanics of the patellofemoral joint is necessary to understand the pathology of patellar dislocation. The patellofemoral joint consists of a complex system of static, active and passive stabilising factors. Patellar instability can result from osseous and soft-tissue abnormalities, such as trochlear dysplasia, patella alta, a high tibial tuberosity trochlear groove (TTTG) distance, weaknesses of the vastus medialis obliquus or a lesion of the medial retinaculum. Recent studies have focused on the medial patellofemoral ligament (MPFL) and have shown that the MPFL is the most significant passive stabiliser of the patella. Following patellar dislocation, an MRI should be standard practice to detect an MPFL rupture, osteochondral lesions or other risk factors for redislocation. An acute first-time patellar dislocation without osteochondral lesions and without severe risk factors for a redislocation should follow a conservative treatment plan. If surgical treatment is required, the best postoperative results occur when the MPFL is reconstructed, leading to a redislocation rate of 5%, this includes cases that have a dysplastic trochlea. Duplication of the medial retinaculum show very inconsistent results in the literature, possibly due to the fact that the essential pathomorphology of patellar dislocation is not addressed. Addressing the exact location of the rupture of the MPFL with a suture is possibly more convenient, especially after first-time dislocation with associated risk factors for a redislocation. Recent literature does not encourage the use of lateral release, since this can increase patellar instability. Indications for lateral release include persistent patellar instability or pain reduction in an older arthritic subject. For correcting a patellofemoral malalignment, the TTTG distance should be measured and a medial transposition of the anterior tibial tubercle hinged on a distal periosteal attachment should be considered. Cartilage lesions on the medial facet of the patella are a contra-indication for medial tubercle transposition. For cartilage lesions of the lateral facet, antero-medialization of the tibial tubercle can be successful. A tubercle osteotomy can be efficiently combined with MPFL reconstruction. We believe that patients with open epiphyseal plates should be treated with duplication of the medial retinaculum. In the presence of patellar maltracking, an additional subperiostal soft tissue release with medialisation of the distal part of the patellar tendon can be performed. It seems that the predominating factors for patellar dislocation are heterogenic morphology in combination with individual predisposition. Non-surgical treatment is typically recommended for primary patellar dislocation without any osteochondral lesions and in the absence of significant risk factors for redislocation. If surgical treatment is deemed necessary, addressing the essential pathomorphology has become the primary focus. © Georg Thieme Verlag KG Stuttgart · New York.
Sedation in palliative medicine: Guidelines for the use of sedation in palliative care. European Association for Palliative Care (EAPC) [Sedierung in der Palliativmedizin Leitlinie für den Einsatz sedierender Maßnahmen in der Palliativversorgung European Association for Palliative Care (EAPC)]
Alt-Epping B.,Universitatsmedizin Gottingen
Schmerz | Year: 2010
The European Association for Palliative Care (EAPC) considers sedation to be an important and necessary therapy option in the care of selected palliative care patients with otherwise refractory distress. Prudent application of this approach requires due caution and good clinical practice. Inattention to potential risks and problematic practices can lead to harmful and unethical practice which may undermine the credibility and reputation of the responsible clinicians and institutions as well as the discipline of pal Native medicine more generally. Procedural guidelines are helpful to educate medical providers, set standards for best practice, promote optimal care and convey the important message to staff, patients and families that palliative sedation is an accepted, ethical practice when used in appropriate situations. EAPC aims to facilitate the development of such guidelines by presenting a 10-point framework that is based on the pre-existing guidelines and literature and extensive peer review. © Deutsche Gesellschaft zum Studium des Schmerzes.