Chung S.-K.,University of Swansea |
Bode A.,University of Queensland |
Cushion T.D.,University of Swansea |
Thomas R.H.,University of Swansea |
And 23 more authors.
Human Molecular Genetics | Year: 2013
Glycinergic neurotransmission is a major inhibitory influence in the CNS and its disruption triggers a paediatric and adult startle disorder, hyperekplexia. The postsynaptic α1-subunit (GLRA1) of the inhibitory glycine receptor (GlyR) and the cognate presynaptic glycine transporter (SLC6A5/GlyT2) are well-established genes of effect in hyperekplexia. Nevertheless, 52% of cases (117 from 232) remain gene negative and unexplained. Ligand-gated heteropentameric GlyRs form chloride ion channels that contain the a1 and b-subunits (GLRB) in a 2α1:3β configuration and they form the predominant population of GlyRs in the postnatal and adult human brain, brainstem and spinal cord. We screened GLRB through 117 GLRA1- and SLC6A5-negative hyperekplexia patients using a multiplex-polymerase chain reaction and Sanger sequencing approach. The screening identified recessive and dominant GLRB variants in 12 unrelated hyperekplexia probands. This primarily yielded homozygous null mutations, with nonsense (n=3), small indel (n=1), a large 95 kb deletion (n=1), frameshifts (n 5 1) and one recurrent splicing variant found in four cases. A further three cases were found with two homozygous and one dominant GLRB missense mutations. We provide strong evidence for the pathogenicity of GLRB mutations using splicing assays, deletion mapping, cell-surface biotinylation, expression studies and molecular modelling. This study describes the definitive assignment of GLRB as the third major gene for hyperekplexia and impacts on the genetic stratification and biological causation of this neonatal/paediatric disorder. Driven principally by consanguineous homozygosity of GLRB mutations, the study reveals long-term additive phenotypic outcomes for affected cases such as severe apnoea attacks, learning difficulties and developmental delay. © The Author 2012. Published by Oxford University Press. All rights reserved.
Gotzberger M.,Ludwig Maximilians University of Munich |
Rosch T.,UKE |
Geisenhof S.,Klinikum Dritter Orden |
Gulberg V.,Ludwig Maximilians University of Munich |
And 6 more authors.
Endoscopy | Year: 2011
Background and study aims: Training standards in gastrointestinal endoscopy are poorly defined even though different simulators are increasingly used for skills training. In 2001 a new training concept called GATE gastroenterological education training endoscopy was established, which provides a combination of background theory, video demonstrations, and simulator training. We aimed to evaluate the acceptance and training effect of this training model. Methods: In total, 98 physicians participating in four training courses were included. Data were collected on baseline characteristics, acceptance (5-point Likert scale), and pre- and post-course knowledge through a structured questionnaire (A-type and Pick-N multiple choice questions). A total of 13 trainees were randomly selected for additional simulator assessment of training effects on manual skills (5-point Likert scale). Results: A total of 78 trainees (80%) provided complete data sets. The evaluation showed a positive acceptance of the training program (value 1 and 2, Likert scale); for example, 88% of participants suggested the inclusion of the GATE course as an obligatory part of endoscopic education. There was a significant improvement in theoretical knowledge in the post-test set compared with the pre-test set (mean 3.27 ±1.30 vs. 1.69 ±1.01 points; P<0.001). The training effect on practical skill showed a significant reduction in time needed for a procedure (445 ±189s vs. 274 ±129s; P<0.01). The mean assessment rating for practical skills improved from 3.05 ±0.65 at baseline to 2.52 ±0.59 on Likert scale (P=0.085). Conclusions: The integrated GATE training improved theoretical knowledge and manual skill. The GATE courses have been accredited by the German Society of Gastroenterology, underlining the demand for implementing preclinical training courses in endoscopic training. © Georg Thieme Verlag KGStuttgart, New York.
Iesalnieks I.,University of Regensburg |
Machens A.,Martin Luther University of Halle Wittenberg |
Bures C.,Krankenanstalt Rudolfstiftung |
Krenz D.,Klinikum Dritter Orden |
And 15 more authors.
Annals of Surgical Oncology | Year: 2015
Conclusions: Although significant improvement of local disease control in patients with thyroid metastases of RCC has been achieved during the last decade, overall outcome continues to be poor for patients with locally invasive thyroid metastases.Background: Most investigations of thyroidectomy for metastatic renal cell carcinoma (RCC) are case studies or small series. This study was conducted to determine the contribution of clinical and histopathologic variables to local recurrence in the neck and overall survival after thyroidectomy for RCC metastases.Methods: The medical records of 140 patients with thyroidectomy for metastatic RCC performed between 1979 and 2012 at 25 institutions in Germany and Austria were analyzed.Results: The median interval between nephrectomy and thyroidectomy was 120 months. Concurrence of thyroid and pancreatic metastases was present in 23 % of the patients and concurrence of thyroid and adrenal metastases in 13 % of the patients. Clinical outcome data were available for 130 patients with a median follow-up period of 34 months. The 5-year overall survival rate was 46 %, and 28 % of patients developed a local neck recurrence at a median of 12 months after thyroidectomy. Multivariate analysis showed that invasion of adjacent cervical structures (hazard ratio [HR] 3.2; p = 0.001), patient age exceeding 70 years (HR 2.5; p = 0.004), and current or past evidence of metastases to nonendocrine organs (HR 2.4; p = 0.003) were independent determinants of inferior overall survival. Conversely, invasion of adjacent cervical structures (HR 12.1; p < 0.0001) and year of thyroidectomy (HR 5.7 before 2000; p < 0.0001) were shown to be independently associated with local recurrence in the neck by multivariate analysis. © 2014, Society of Surgical Oncology.
Jacobs C.,Ludwig Maximilians University of Munich |
Duewell P.,Ludwig Maximilians University of Munich |
Heckelsmiller K.,Ludwig Maximilians University of Munich |
Wei J.,Ludwig Maximilians University of Munich |
And 10 more authors.
International Journal of Cancer | Year: 2011
Vaccines based on immune stimulatory complexes (ISCOM) induce T-cell responses against tumor antigen (Ag). However, immune responses are impaired in pancreatic cancer patients. We investigated the efficacy of an ISCOM vaccine in a murine pancreatic carcinoma model. Panc02 cells expressing OVA as a model Ag were induced subcutaneously or orthotopically in the pancreas of C57BL/6 mice. Treatment consisted of an OVA containing ISCOM vaccine, either used alone or in combination with the TLR9 agonist CpG. The ISCOM vaccine effectively induced Ag-specific CTL capable of killing tumor cells. However, in mice with established tumors CTL induction by the vaccine was inefficient and did not affect tumor growth. Lack of efficacy correlated with increased numbers of Treg. Depletion of Treg with anti-CD25 mAb restored CTL induction and prolonged survival. Adding low-dose CpG to the ISCOM vaccine reduced Treg numbers, enhanced CTL responses and induced regression of pancreatic tumors in a CD8 + T cell-dependent manner. Mice cured from the primary tumor mounted a memory T-cell response against wild-type Panc02 tumors, indicative of epitope spreading. Combining ISCOM vaccines with TLR agonists is a promising strategy for breaking tumor immune evasion and deserves further evaluation for the treatment of pancreatic carcinoma. Copyright © 2010 UICC.
Howard M.F.,University of Oxford |
Murakami Y.,Osaka University |
Pagnamenta A.T.,University of Oxford |
Daumer-Haas C.,Pranatal Medizin Munich |
And 22 more authors.
American Journal of Human Genetics | Year: 2014
Glycosylphophatidylinositol (GPI)-anchored proteins play important roles in many biological processes, and mutations affecting proteins involved in the synthesis of the GPI anchor are reported to cause a wide spectrum of intellectual disabilities (IDs) with characteristic additional phenotypic features. Here, we describe a total of five individuals (from three unrelated families) in whom we identified mutations in PGAP3, encoding a protein that is involved in GPI-anchor maturation. Three siblings in a consanguineous Pakistani family presented with profound developmental delay, severe ID, no speech, psychomotor delay, and postnatal microcephaly. A combination of autozygosity mapping and exome sequencing identified a 13.8 Mb region harboring a homozygous c.275G>A (p.Gly92Asp) variant in PGAP3 region 17q11.2-q21.32. Subsequent testing showed elevated serum alkaline phosphatase (ALP), a GPI-anchored enzyme, in all three affected children. In two unrelated individuals in a cohort with developmental delay, ID, and elevated ALP, we identified compound-heterozygous variants c.439dupC (p.Leu147Profs-16) and c.914A>G (p.Asp305Gly) and homozygous variant c.314C>G (p.Pro105Arg). The 1 bp duplication causes a frameshift and nonsense-mediated decay. Further evidence supporting pathogenicity of the missense mutations c.275G>A, c.314C>G, and c.914A>G was provided by the absence of the variants from ethnically matched controls, phylogenetic conservation, and functional studies on Chinese hamster ovary cell lines. Taken together with recent data on PGAP2, these results confirm the importance of the later GPI-anchor remodelling steps for normal neuronal development. Impairment of PGAP3 causes a subtype of hyperphosphatasia with ID, a congenital disorder of glycosylation that is also referred to as Mabry syndrome. © 2014 The American Society of Human Genetics.