@article{VerruaFerranteFilopantietal.2014, author = {Verrua, Elisa and Ferrante, Emanuele and Filopanti, Marcello and Malchiodi, Elena and Sala, Elisa and Giavoli, Claudia and Arosio, Maura and Lania, Andrea Gerardo and Ronchi, Christina Lucia and Mantovani, Giovanna and Beck-Peccoz, Paolo and Spada, Anna}, title = {Reevaluation of Acromegalic Patients in Long-Term Remission according to Newly Proposed Consensus Criteria for Control of Disease}, series = {International Journal of Endocrinology}, journal = {International Journal of Endocrinology}, issn = {1687-8345}, doi = {10.1155/2014/581594}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-117790}, pages = {581594}, year = {2014}, abstract = {Acromegaly guidelines updated in 2010 revisited criteria of disease control: if applied, it is likely that a percentage of patients previously considered as cured might present postglucose GH nadir levels not adequately suppressed, with potential implications on management. This study explored GH secretion, as well as hormonal, clinical, neuroradiological, metabolic, and comorbid profile in a cohort of 40 acromegalic patients considered cured on the basis of the previous guidelines after a mean follow-up period of 17.2 years from remission, in order to assess the impact of the current criteria. At the last follow-up visit, in the presence of normal IGF-I concentrations, postglucose GH nadir was over 0.4 mu g/L in 11 patients (Group A) and below 0.4 mu g/L in 29 patients (Group B); moreover, Group A showed higher basal GH levels than Group B, whereas a significant decline of both GH and postglucose GH nadir levels during the follow-up was observed in Group B only. No differences in other evaluated parameters were found. These results seem to suggest that acromegalic patients considered cured on the basis of previous guidelines do not need a more intensive monitoring than patients who met the current criteria of disease control, supporting instead that the cut-off of 0.4 mcg/L might be too low for the currently used GH assay.}, language = {en} } @article{UnnewehrStich2015, author = {Unnewehr, Markus and Stich, August}, title = {Fighting Hepatitis B in North Korea: Feasibility of a Bi-modal Prevention Strategy}, series = {Journal of Korean Medical Science}, volume = {30}, journal = {Journal of Korean Medical Science}, doi = {10.3346/jkms.2015.30.11.1584}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-138773}, pages = {1584-1588}, year = {2015}, abstract = {In North Korea, the prevalence of hepatitis B is high due to natural factors, gaps in vaccination, and the lack of antiviral treatment. Aid projects are urgently needed, however impeded by North Korea's political and economical situation and isolation. The feasibility of a joint North Korean and German humanitarian hepatitis B prevention program was assessed. Part 1: Hepatitis B vaccination catch-up campaign. Part 2: Implementation of endoscopic ligation of esophageal varices (EVL) by trainings in Germany and North Korea. By vaccinating 7 million children between 2010 and 2012, the hepatitis B vaccination gap was closed. Coverage of 99.23\% was reached. A total of 11 hepatitis B-induced liver cirrhosis patients (mean age 41.1 yr) with severe esophageal varices and previous bleedings were successfully treated by EVL without major complications. A clinical standard operating procedure, a feedback system and a follow-up plan were developed. The bi-modal preventive strategy was implemented successfully. Parts of the project can serve as an example for other low-income countries, however its general transferability is limited due to the special circumstances in North Korea.}, language = {en} } @article{StrobelSickenbergerSchoenetal.2022, author = {Strobel, Katharina and Sickenberger, Christina and Schoen, Christoph and Kneitz, Hermann and Kolb-M{\"a}urer, Annette and Goebeler, Matthias}, title = {Diagnosis and therapy of Mycobacterium marinum: a single-center 21-year retrospective analysis}, series = {Journal der Deutschen Dermatologischen Gesellschaft}, volume = {20}, journal = {Journal der Deutschen Dermatologischen Gesellschaft}, number = {9}, doi = {10.1111/ddg.14847}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-318428}, pages = {1211 -- 1218}, year = {2022}, abstract = {Background and Objectives In Europe, infections with Mycobacterium (M.) marinum are rare. We conducted a retrospective single-center study to assess the clinical spectrum of M. marinum infection and its diagnosis, treatment and outcome under real-world conditions. Patients and Methods Eighteen patients presenting with M. marinum infections between 1998 and 2018 were identified in the data warehouse of the University Hospital W{\"u}rzburg and considered for detailed analysis. Results Twelve patients reported aquatic exposure. In 16/18 cases the upper extremities were affected. No invasive infections were detected. Mean time to diagnosis was 15 weeks. Histology revealed granulomatous inflammation in 14 patients while mycobacterial cultures were positive for M. marinum in 16 cases. Most patients received antibiotic monotherapy (14/18) while combination therapy was administered in four cases. Treatment (with a median duration of 10 weeks) was successful in 13 patients. Five patients were lost to follow-up. Conclusions Our retrospective analysis of M. marinum infections at a German tertiary referral center revealed a considerable diagnostic delay and the relevance of microbiological culture, PCR and histology for diagnosis. Monotherapy with clarithromycin (rather than doxycycline) appeared as a reasonable treatment option while immunosuppressed or -compromised patients and those with extended disease received combination therapy.}, language = {en} } @article{StebaniBlaimerZableretal.2023, author = {Stebani, Jannik and Blaimer, Martin and Zabler, Simon and Neun, Tilmann and Pelt, Dani{\"e}l M. and Rak, Kristen}, title = {Towards fully automated inner ear analysis with deep-learning-based joint segmentation and landmark detection framework}, series = {Scientific Reports}, volume = {13}, journal = {Scientific Reports}, doi = {10.1038/s41598-023-45466-9}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-357411}, year = {2023}, abstract = {Automated analysis of the inner ear anatomy in radiological data instead of time-consuming manual assessment is a worthwhile goal that could facilitate preoperative planning and clinical research. We propose a framework encompassing joint semantic segmentation of the inner ear and anatomical landmark detection of helicotrema, oval and round window. A fully automated pipeline with a single, dual-headed volumetric 3D U-Net was implemented, trained and evaluated using manually labeled in-house datasets from cadaveric specimen (N = 43) and clinical practice (N = 9). The model robustness was further evaluated on three independent open-source datasets (N = 23 + 7 + 17 scans) consisting of cadaveric specimen scans. For the in-house datasets, Dice scores of 0.97 and 0.94, intersection-over-union scores of 0.94 and 0.89 and average Hausdorf distances of 0.065 and 0.14 voxel units were achieved. The landmark localization task was performed automatically with an average localization error of 3.3 and 5.2 voxel units. A robust, albeit reduced performance could be attained for the catalogue of three open-source datasets. Results of the ablation studies with 43 mono-parametric variations of the basal architecture and training protocol provided task-optimal parameters for both categories. Ablation studies against single-task variants of the basal architecture showed a clear performance beneft of coupling landmark localization with segmentation and a dataset-dependent performance impact on segmentation ability.}, language = {en} } @article{SmithBrayHoffmanetal.2015, author = {Smith, Craig J. and Bray, Benjamin D. and Hoffman, Alex and Meisel, Andreas and Heuschmann, Peter U. and Wolfe, Charles D. A. and Tyrrell, Pippa J. and Rudd, Anthony G.}, title = {Can a novel clinical risk score improve pneumonia prediction in acute stroke care? A UK multicenter cohort study}, series = {Journal of the American Heart Association}, volume = {4}, journal = {Journal of the American Heart Association}, number = {1}, doi = {10.1161/JAHA.114.001307}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144602}, pages = {e001307}, year = {2015}, abstract = {Background Pneumonia frequently complicates stroke and has amajor impact on outcome. We derived and internally validated a simple clinical risk score for predicting stroke-associated pneumonia (SAP), and compared the performance with an existing score (A\(^{2}\)DS\(^{2}\)). Methods and Results We extracted data for patients with ischemic stroke or intracerebral hemorrhage from the Sentinel Stroke National Audit Programme multicenter UK registry. The data were randomly allocated into derivation (n=11 551) and validation (n=11 648) samples. A multivariable logistic regression model was fitted to the derivation data to predict SAP in the first 7 days of admission. The characteristics of the score were evaluated using receiver operating characteristics (discrimination) and by plotting predicted versus observed SAP frequency in deciles of risk (calibration). Prevalence of SAP was 6.7\% overall. The final 22-point score (ISAN: prestroke Independence [modified Rankin scale], Sex, Age, National Institutes of Health Stroke Scale) exhibited good discrimination in the ischemic stroke derivation (C-statistic 0.79; 95\% CI 0.77 to 0.81) and validation (C-statistic 0.78; 95\% CI 0.76 to 0.80) samples. It was well calibrated in ischemic stroke and was further classified into meaningful risk groups (low 0 to 5, medium6 to 10, high 11 to 14, and very high >= 15) associated with SAP frequencies of 1.6\%, 4.9\%, 12.6\%, and 26.4\%, respectively, in the validation sample. Discrimination for both scores was similar, although they performed less well in the intracerebral hemorrhage patients with an apparent ceiling effect. Conclusions The ISAN score is a simple tool for predicting SAP in clinical practice. External validation is required in ischemic and hemorrhagic stroke cohorts.}, language = {en} } @article{SchreiberSchneideratKressetal.2013, author = {Schreiber, Olivia and Schneiderat, Peter and Kress, Wolfram and Rautenstrauss, Bernd and Senderek, Jan and Schoser, Bendikt and Walter, Maggie C.}, title = {Facioscapulohumeral muscular dystrophy and Charcot-Marie-Tooth neuropathy 1A-evidence for "double trouble" overlapping syndromes}, series = {BMC Medical Genetics}, volume = {14}, journal = {BMC Medical Genetics}, number = {92}, issn = {1471-2350}, doi = {10.1186/1471-2350-14-92}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-121963}, year = {2013}, abstract = {Background: We report on a patient with genetically confirmed overlapping diagnoses of CMT1A and FSHD. This case adds to the increasing number of unique patients presenting with atypical phenotypes, particularly in FSHD. Even if a mutation in one disease gene has been found, further genetic testing might be warranted in cases with unusual clinical presentation. Case presentation: The reported 53 years old male patient suffered from walking difficulties and foot deformities first noticed at age 20. Later on, he developed scapuloperoneal and truncal muscle weakness, along with atrophy of the intrinsic hand and foot muscles, pes cavus, claw toes and a distal symmetric hypoesthesia. Motor nerve conduction velocities were reduced to 20 m/s in the upper extremities, and not educible in the lower extremities, sensory nerve conduction velocities were not attainable. Electromyography showed both, myopathic and neurogenic changes. A muscle biopsy taken from the tibialis anterior muscle showed a mild myopathy with some neurogenic findings and hypertrophic type 1 fibers. Whole-body muscle MRI revealed severe changes in the lower leg muscles, tibialis anterior and gastrocnemius muscles were highly replaced by fatty tissue. Additionally, fatty degeneration of shoulder girdle and straight back muscles, and atrophy of dorsal upper leg muscles were seen. Taken together, the presenting features suggested both, a neuropathy and a myopathy. Patient's family history suggested an autosomal dominant inheritance. Molecular testing revealed both, a hereditary motor and sensory neuropathy type 1A (HMSN1A, also called Charcot-Marie-Tooth neuropathy 1A, CMT1A) due to a PMP22 gene duplication and facioscapulohumeral muscular dystrophy (FSHD) due to a partial deletion of the D4Z4 locus (19 kb). Conclusion: Molecular testing in hereditary neuromuscular disorders has led to the identification of an increasing number of atypical phenotypes. Nevertheless, finding the right diagnosis is crucial for the patient in order to obtain adequate medical care and appropriate genetic counseling, especially in the background of arising curative therapies.}, language = {en} } @phdthesis{Schaefer2014, author = {Schaefer, Frauke}, title = {Diagnosis and therapy of malaria under the conditions of a developing country - the example of Burkina Faso}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-102863}, school = {Universit{\"a}t W{\"u}rzburg}, year = {2014}, abstract = {Malaria is a challenging infection with increasing and wide-spread treatment failure risk due to resistance. With a estimated death toll of 1-3 Million per year, most cases of Malaria affect children under the age of five years in Sub-Saharan Africa. In this thesis, I analyse the current status of malaria control (focussing on diagnosis and therapy) in Burkina Faso to show how this disease burdens public health in endemic countries and to identify possible approaches to improvement. MB is discussed as a therapeutic option under these circumstances. Burkina Faso is used as a representative example for a country in Sub-Saharan Africa with high endemicity for malaria and is here portrayed, its health system characterised and discussed under socioeconomic aspects. More than half of this country's population live in absolute poverty. The burden that malaria, especially treatment cost, poses on these people cannot be under-estimated. A retrospective study of case files from the university pediatric hospital in Burkina Faso's capital, Ouagadougou, shows that the case load is huge, and especially the specific diagnosis of severe malaria is difficult to apply in the hospital's daily routine. Treatment policy as proposed by WHO is not satisfactorily implemented neither in home treatment nor in health services, as data for pretreatment clearly show. In the face of growing resistance in malaria parasites, pharmacological combination therapies are important. Artemisinins currently are the last resort of malaria therapy. As I show with homology models, even this golden bullet is not beyond resistance development. Inconsidered mass use has rendered other drugs virtually useless before. Artemisinins should thus be protected similar to reserve antibiotics against multi-resistant bacteria. There is accumulating evidence that MB is an effective drug against malaria. Here the biological effects of both MB alone and in combination therapy is explored via modeling and experimental data. Several different lines of MB attack on Plasmodium redox defense were identified by analysis of the network effects. Next, CQ resistance based on Pfmdr1 and PfCRT transporters as well as SP resistance were modeled in silico. Further modeling shows that MB has a favorable synergism on antimalarial network effects with these commonly used antimalarial drugs, given their correct application. Also from the economic point of view MB shows great potential: in terms of production price, it can be compared to CQ, which could help to diminuish the costs of malaria treatment to affordable ranges for those most affected and struk by poverty. Malaria control is feasible, but suboptimal diagnosis and treatment are often hindering the achievment of this goal. In order to achieve malaria control, more effort has to be made to implement better adjusted and available primary treatment strategies for uncomplicated malaria that are highly standardised. Unfortunately, campaigns against malaria are chronically underfinanced. In order to maximize the effect of available funds, a cheap treatment option is most important, especially as pharmaceuticals represent the biggest single matter of expense in the fight against malaria.}, subject = {Malaria}, language = {en} } @article{RickmanLachAbhyankaretal.2015, author = {Rickman, Kimberly A. and Lach, Francis P. and Abhyankar, Avinash and Donovan, Frank X. and Sanborn, Erica M. and Kennedy, Jennifer A. and Sougnez, Carrie and Gabriel, Stacey B. and Elemento, Olivier and Chandrasekharappa, Settara C. and Schindler, Detlev and Auerbach, Arleen D. and Smogorzewska, Agata}, title = {Deficiency of UBE2T, the E2 Ubiquitin Ligase Necessary for FANCD2 and FANCI Ubiquitination, Causes FA-T Subtype of Fanconi Anemia}, series = {Cell Reports}, volume = {12}, journal = {Cell Reports}, doi = {10.1016/j.celrep.2015.06.014}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151525}, pages = {35 -- 41}, year = {2015}, abstract = {Fanconi anemia (FA) is a rare bone marrow failure and cancer predisposition syndrome resulting from pathogenic mutations in genes encoding proteins participating in the repair of DNA interstrand crosslinks (ICLs). Mutations in 17 genes (FANCA-FANCS) have been identified in FA patients, defining 17 complementation groups. Here, we describe an individual presenting with typical FA features who is deficient for the ubiquitin-conjugating enzyme (E2), UBE2T. UBE2T is known to interact with FANCL, the E3 ubiquitin-ligase component of the multiprotein FA core complex, and is necessary for the monoubiquitination of FANCD2 and FANCI. Proband fibroblasts do not display FANCD2 and FANCI monoubiquitination, do not form FANCD2 foci following treatment with mitomycin C, and are hypersensitive to crosslinking agents. These cellular defects are complemented by expression of wild-type UBE2T, demonstrating that deficiency of the protein UBE2T can lead to Fanconi anemia. UBE2T gene gains an alias of FANCT.}, language = {en} } @article{ReimannStopperPolaketal.2020, author = {Reimann, Hauke and Stopper, Helga and Polak, Thomas and Lauer, Martin and Herrmann, Martin J. and Deckert, J{\"u}rgen and Hintzsche, Henning}, title = {Micronucleus frequency in buccal mucosa cells of patients with neurodegenerative diseases}, series = {Scientific Reports}, volume = {10}, journal = {Scientific Reports}, doi = {10.1038/s41598-020-78832-y}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-231430}, year = {2020}, abstract = {Neurodegenerative diseases show an increase in prevalence and incidence, with the most prominent example being Alzheimer's disease. DNA damage has been suggested to play a role in the pathogenesis, but the exact mechanisms remain elusive. We enrolled 425 participants with and without neurodegenerative diseases and analyzed DNA damage in the form of micronuclei in buccal mucosa samples. In addition, other parameters such as binucleated cells, karyolytic cells, and karyorrhectic cells were quantified. No relevant differences in DNA damage and cytotoxicity markers were observed in patients compared to healthy participants. Furthermore, other parameters such as lifestyle factors and diseases were also investigated. Overall, this study could not identify a direct link between changes in buccal cells and neurogenerative diseases, but highlights the influence of lifestyle factors and diseases on the human buccal cytome.}, language = {en} } @article{LitovkinVanEyndeJoniauetal.2015, author = {Litovkin, Kirill and Van Eynde, Aleyde and Joniau, Steven and Lerut, Evelyne and Laenen, Annouschka and Gevaert, Thomas and Gevaert, Olivier and Spahn, Martin and Kneitz, Burkhard and Gramme, Pierre and Helleputte, Thibault and Isebaert, Sofie and Haustermans, Karin and Bollen, Mathieu}, title = {DNA Methylation-Guided Prediction of Clinical Failure in High-Risk Prostate Cancer}, series = {PLoS ONE}, volume = {10}, journal = {PLoS ONE}, number = {6}, doi = {10.1371/journal.pone.0130651}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-151705}, pages = {e0130651}, year = {2015}, abstract = {Background Prostate cancer (PCa) is a very heterogeneous disease with respect to clinical outcome. This study explored differential DNA methylation in a priori selected genes to diagnose PCa and predict clinical failure (CF) in high-risk patients. Methods A quantitative multiplex, methylation-specific PCR assay was developed to assess promoter methylation of the APC, CCND2, GSTP1, PTGS2 and RARB genes in formalin-fixed, paraffin-embedded tissue samples from 42 patients with benign prostatic hyperplasia and radical prostatectomy specimens of patients with high-risk PCa, encompassing training and validation cohorts of 147 and 71 patients, respectively. Log-rank tests, univariate and multivariate Cox models were used to investigate the prognostic value of the DNA methylation. Results Hypermethylation of APC, CCND2, GSTP1, PTGS2 and RARB was highly cancer-specific. However, only GSTP1 methylation was significantly associated with CF in both independent high-risk PCa cohorts. Importantly, trichotomization into low, moderate and high GSTP1 methylation level subgroups was highly predictive for CF. Patients with either a low or high GSTP1 methylation level, as compared to the moderate methylation groups, were at a higher risk for CF in both the training (Hazard ratio [HR], 3.65; 95\% CI, 1.65 to 8.07) and validation sets (HR, 4.27; 95\% CI, 1.03 to 17.72) as well as in the combined cohort ( HR, 2.74; 95\% CI, 1.42 to 5.27) in multivariate analysis. Conclusions Classification of primary high-risk tumors into three subtypes based on DNA methylation can be combined with clinico-pathological parameters for a more informative risk-stratification of these PCa patients.}, language = {en} }