Medizin - Open Access LMU - Teil 15/22 Archiv

Background: The intermediate filament forming protein keratin 8 (K8) is a tumour-associated antigen, which was shown to be over-expressed in a variety of malignancies. Here, we present a study of K8 expression in squamous epithelia of the head and neck area, including normal mucosa, hyperplastic and dysplastic leukoplakia, carcinomas of different sub-localisations, and lymph node metastases. Methods: K8 expression was assessed upon immunohistochemistry with specific antibodies in cryosections of primary tumours of the head and neck area. Results: K8 expression was characteristic of transformed tissue and marked early stages of disease, i.e. dysplastic oral leukoplakia, but not normal or hyperplastic epithelium. With the exception of carcinomas of the larynx and the tongue, K8 expression also strictly differentiated carcinomas from normal epithelium of the same origin. Furthermore, K8(high) was characteristic of cells, which had detached from the sites of primary tumours and had been invading the surrounding tissue at the time point of surgery. Conclusion: K8 is an excellent marker for head and neck malignancies, which allows for early detection as well as for visualisation of potentially disseminating tumour cells in vivo.

Background: To establish an efficient prophylaxis of coronary artery disease reliable risk stratification is crucial, especially in the high risk population of patients suffering from diabetes mellitus. This prospective study determined the predictive value of coronary calcifications for future cardiovascular events in asymptomatic patients with diabetes mellitus. Methods: We included 716 patients suffering from diabetes mellitus (430 men, 286 women, age 55.2 +/- 15.2 years) in this study. On study entry all patients were asymptomatic and had no history of coronary artery disease. In addition, all patients showed no signs of coronary artery disease in ECG, stress ECG or echocardiography. Coronary calcifications were determined with the Imatron C 150 XP electron beam computed tomograph. For quantification of coronary calcifications we calculated the Agatston score. After a mean observation period of 8.1 +/- 1.1 years patients were contacted and the event rate of cardiac death (CD) and myocardial infarction (MI) was determined. Results: During the observation period 40 patients suffered from MI, 36 patients died from acute CD. The initial Agatston score in patients that suffered from MI or died from CD (475 +/- 208) was significantly higher compared to those without cardiac events (236 +/- 199, p < 0.01). An Agatston score above 400 was associated with a significantly higher annualised event rate for cardiovascular events (5.6% versus 0.7%, p < 0.01). No cardiac events were observed in patients with exclusion of coronary calcifications. Compared to the Framingham risk score and the UKPDS score the Agatston score showed a significantly higher diagnostic accuracy in the prediction of MI with an area under the ROC curve of 0.77 versus 0.68, and 0.71, respectively, p < 0.01. Conclusion: By determination of coronary calcifications patients at risk for future MI and CD could be identified within an asymptomatic high risk group of patients suffering from diabetes mellitus. On the other hand future events could be excluded in patients without coronary calcifications.

Background: Concerning surgical management experience with locking plates for proximal humeral fractures has been described with promising results. Though, distinct hardware related complaints after fracture union are reported. Information concerning the outcome after removal of hardware from the proximal humerus is lacking and most studies on hardware removal are focused on the lower extremity. Therefore the aim of this study was to analyze the functional short-term outcome following removal of locking plate fixation of the proximal humerus. Methods: Patients undergoing removal of a locking plate of the proximal humerus were prospectively followed. Patients were subdivided into the following groups: Group HI: symptoms of hardware related subacromial impingement, Group RD: persisting rotation deficit, Group RQ: patients with request for a hardware removal. The clinical (Constant-Murley score) and radiologic (AP and axial view) follow-up took place three and six months after the operation. To evaluate subjective results, the Medical Outcomes Study Short Form-36 (SF-36), was completed. Results: 59 patients were included. The mean length of time with the hardware in place was 15.2 +/- 3.81 months. The mean of the adjusted overall Constant score before hardware removal was 66.2 +/- 25.2% and increased significantly to 73.1 +/- 22.5% after 3 months; and to 84.3 +/- 20.6% after 6 months (p < 0.001). The mean of preoperative pain on the VAS-scale before hardware removal was 5.2 +/- 2.9, after 6 months pain in all groups decreased significantly (p < 0.001). The SF-36 physical component score revealed a significant overall improvement in both genders (p < 0.001) at six months. Conclusion: A significant improvement of clinical outcome following removal was found. However, a general recommendation for hardware removal is not justified, as the risk of an anew surgical and anesthetic procedure with all possible complications has to be carefully taken into account. However, for patients with distinct symptoms it might be justified.

Background: For the last eight years, microarray-based classification has been a major topic in statistics, bioinformatics and biomedicine research. Traditional methods often yield unsatisfactory results or may even be inapplicable in the so-called "p >> n" setting where the number of predictors p by far exceeds the number of observations n, hence the term "ill-posed-problem". Careful model selection and evaluation satisfying accepted good-practice standards is a very complex task for statisticians without experience in this area or for scientists with limited statistical background. The multiplicity of available methods for class prediction based on high-dimensional data is an additional practical challenge for inexperienced researchers. Results: In this article, we introduce a new Bioconductor package called CMA (standing for "Classification for MicroArrays") for automatically performing variable selection, parameter tuning, classifier construction, and unbiased evaluation of the constructed classifiers using a large number of usual methods. Without much time and effort, users are provided with an overview of the unbiased accuracy of most top-performing classifiers. Furthermore, the standardized evaluation framework underlying CMA can also be beneficial in statistical research for comparison purposes, for instance if a new classifier has to be compared to existing approaches. Conclusion: CMA is a user-friendly comprehensive package for classifier construction and evaluation implementing most usual approaches. It is freely available from the Bioconductor website at http://bioconductor.org/packages/2.3/bioc/html/CMA.html.

Background: Despite the increase of mobile phone use in the last decade and the growing concern whether mobile telecommunication networks adversely affect health and well-being, only few studies have been published that focussed on children and adolescents. Especially children and adolescents are important in the discussion of adverse health effects because of their possibly higher vulnerability to radio frequency electromagnetic fields. Methods: We investigated a possible association between exposure to mobile telecommunication networks and wellbeing in children and adolescents using personal dosimetry. A population-based sample of 1.498 children and 1.524 adolescents was assembled for the study (response 52%). Participants were randomly selected from the population registries of four Bavarian (South of Germany) cities and towns with different population sizes. During a Computer Assisted Personal Interview data on participants' well-being, socio-demographic characteristics and potential confounder were collected. Acute symptoms were assessed three times during the study day (morning, noon, evening). Using a dosimeter (ESM-140 Maschek Electronics), we obtained an exposure profile over 24 hours for three mobile phone frequency ranges (measurement interval 1 second, limit of determination 0.05 V/ m) for each of the participants. Exposure levels over waking hours were summed up and expressed as mean percentage of the ICNIRP (International Commission on Non-Ionizing Radiation Protection) reference level. Results: In comparison to non-participants, parents and adolescents with a higher level of education who possessed a mobile phone and were interested in the topic of possible adverse health effects caused by mobile telecommunication network frequencies were more willing to participate in the study. The median exposure to radio frequency electromagnetic fields of children and adolescents was 0.18% and 0.19% of the ICNIRP reference level respectively. Conclusion: In comparison to previous studies this is one of the first to assess the individual level of exposure to mobile telecommunication networks using personal dosimetry, enabling objective assessment of exposure from all sources and longer measurement periods. In total, personal dosimetry was proofed to be a well accepted tool to study exposure to mobile phone frequencies in epidemiologic studies including health effects on children and adolescents.

Background: Epidemiological studies have shown that microalbuminuria is an important risk factor for arteriosclerosis, coronary heart disease and other vascular diseases in persons with type 2 diabetes. In the present study we examined the prevalence and risk factors for micro- and macroalbuminuria and examined glycemic control as well as treatment of modifiable cardiovascular risk factors in persons with known type 2 diabetes in Germany. Methods: The presented data were derived from the `KORA Augsburg Diabetes Family Study', conducted between October 2001 and September 2002. Participants were adults aged 29 years and older with previously diagnosed type 2 diabetes (n = 581). Microalbuminuria was defined as an albumin-creatinine ratio of 30 to 300 mg/g, and macroalbuminuria as an albumin-creatinine ratio of more than 300 mg/g. Results: Microalbuminuria was revealed in 27.2% and macroalbuminuria in 9.0% of the 581 included diabetic persons. Multivariable regression analysis identified HBA1c, duration of diabetes, systolic blood pressure, serum creatinine, smoking and waist circumference as independent risk factors associated with albuminuria (micro- or macroalbuminuria). Relatively few persons with type 2 diabetes achieved treatment targets of HbA1c < 7% (46.6%), total cholesterol < 200 mg/dl (44.1%), and LDL cholesterol < 100 mg/dl (16.0%). Optimal HDL cholesterol values (> 45 mg/ dl in men, > 55 mg/ dl in women) were found in 55.8%, and blood pressure values < 130 and < 85 mmHg in 31.3% of the persons Conclusion: Albuminuria is common among German persons with known type 2 diabetes. Despite evidence-based guidelines, only a small proportion of type 2 diabetic persons achieved the recommended levels of glycemic control and control of cardiovascular risk factors.

Background: The aim of this study was to establish and validate a practical method to disperse nanoparticles in physiological solutions for biological in vitro and in vivo studies. Results: TiO(2) (rutile) dispersions were prepared in distilled water, PBS, or RPMI 1640 cell culture medium. Different ultrasound energies, various dispersion stabilizers (human, bovine, and mouse serum albumin, Tween 80, and mouse serum), various concentrations of stabilizers, and different sequences of preparation steps were applied. The size distribution of dispersed nanoparticles was analyzed by dynamic light scattering and zeta potential was measured using phase analysis light scattering. Nanoparticle size was also verified by transmission electron microscopy. A specific ultrasound energy of 4.2 x 10(5) kJ/m(3) was sufficient to disaggregate TiO(2) (rutile) nanoparticles, whereas higher energy input did not further improve size reduction. The optimal sequence was first to sonicate the nanoparticles in water, then to add dispersion stabilizers, and finally to add buffered salt solution to the dispersion. The formation of coarse TiO(2) (rutile) agglomerates in PBS or RPMI was prevented by addition of 1.5 mg/ml of human, bovine or mouse serum albumin, or mouse serum. The required concentration of albumin to stabilize the nanoparticle dispersion depended on the concentration of the nanoparticles in the dispersion. TiO(2) (rutile) particle dispersions at a concentration lower than 0.2 mg/ml could be stabilized by the addition of 1.5 mg/ml albumin. TiO(2) (rutile) particle dispersions prepared by this method were stable for up to at least 1 week. This method was suitable for preparing dispersions without coarse agglomerates (average diameter < 290 nm) from nanosized TiO(2) (rutile), ZnO, Ag, SiO(x), SWNT, MWNT, and diesel SRM2975 particulate matter. Conclusion: The optimized dispersion method presented here appears to be effective and practicable for preparing dispersions of nanoparticles in physiological solutions without creating coarse agglomerates.

The chance of an intrathyroidal occurrence of a parathyroid gland is about 1-3%. Among the causes of hyperparathyroidism, parathyroid cases occur in less than 1% of patients. Here we present the case of a 63 year old Saudi female suffering from an intrathryroidal parathyroid carcinoma. The suspicion coming from the clinical investigations that the removed tumor tissue may be a parathyroid carcinoma could be confirmed by histology. Additionally non-radioactive in situ hybridization to localize mRNA transcripts for Cyclin D1 and immunohistochemical localization of Cyclin D1 was performed. Although parathyroid adenoma and carcinoma have disparate natural history, it can be difficult to differentiate between the two entities. Clinical presentation, operative findings may raise suspicion, but may not be conclusive especially if there is no evidence of invasion or metastasis, especially if the gland was intrathyroidal.

Background: The aim of this study, conducted in Europe, was to develop a validated risk factor based model to predict RSV-related hospitalisation in premature infants born 33-35 weeks' gestational age (GA). Methods: The predictive model was developed using risk factors captured in the Spanish FLIP dataset, a case-control study of 183 premature infants born between 33-35 weeks' GA who were hospitalised with RSV, and 371 age-matched controls. The model was validated internally by 100-fold bootstrapping. Discriminant function analysis was used to analyse combinations of risk factors to predict RSV hospitalisation. Successive models were chosen that had the highest probability for discriminating between hospitalised and non-hospitalised infants. Receiver operating characteristic (ROC) curves were plotted. Results: An initial 15 variable model was produced with a discriminant function of 72% and an area under the ROC curve of 0.795. A step-wise reduction exercise, alongside recalculations of some variables, produced a final model consisting of 7 variables: birth +/- 10 weeks of start of season, birth weight, breast feeding for = 2 years, family members with atopy, family members with wheeze, and gender. The discrimination of this model was 71% and the area under the ROC curve was 0.791. At the 0.75 sensitivity intercept, the false positive fraction was 0.33. The 100-fold bootstrapping resulted in a mean discriminant function of 72% (standard deviation: 2.18) and a median area under the ROC curve of 0.785 (range: 0.768-0.790), indicating a good internal validation. The calculated NNT for intervention to treat all at risk patients with a 75% level of protection was 11.7 (95% confidence interval: 9.5-13.6). Conclusion: A robust model based on seven risk factors was developed, which is able to predict which premature infants born between 33-35 weeks' GA are at highest risk of hospitalisation from RSV. The model could be used to optimise prophylaxis with palivizumab across Europe.

Background: The incidence of tick-borne encephalitis showed a dramatic spike in several countries in Europe in 2006, a year that was unusually cold in winter but unusually warm and dry in summer and autumn. In this study we examine the possible causes of the sudden increase in disease: more abundant infected ticks and/or increased exposure due to human behaviour, both in response to the weather. Methods: For eight countries across Europe, field data on tick abundance for 2005-2007, collected monthly from a total of 41 sites, were analysed in relation to total annual and seasonal TBE incidence and temperature and rainfall conditions. Results: The weather in 2006-2007 was exceptional compared with the previous two decades, but neither the very cold start to 2006, nor the very hot period from summer 2006 to late spring 2007 had any consistent impact on tick abundance. Nor was the TBE spike in 2006 related to changes in tick abundance. Countries varied in the degree of TBE spike despite similar weather patterns, and also in the degree to which seasonal variation in TBE incidence matched seasonal tick activity. Conclusion: The data suggest that the TBE spike was not due to weather-induced variation in tick population dynamics. An alternative explanation, supported by qualitative reports and some data, involves human behavioural responses to weather favourable for outdoor recreational activities, including wild mushroom and berry harvest, differentially influenced by national cultural practices and economic constraints.

Background: Chemokines immobilized on endothelial cells play a central role in the induced firm adhesion and transendothelial migration of leukocytes. Activation of platelets at sites of vascular injury is considered to support leukocyte adhesion and extravasation. However, activated platelets also secrete soluble glycosaminoglycans that can interfere with immobilization of chemokines. We therefore analyzed the impact of platelet derived glycosaminoglycans on the immobilization of the chemokine CCL5 (RANTES) on human microvascular endothelial cells and their influence on CCL5-CCR5 interactions. Results: We confirm that undiluted serum in contrast to plasma decreases binding of CCL5 to endothelial cells. However, when lower concentrations of serum were used, CCL5-presentation on endothelial cells was markedly enhanced. This enhancement was neutralized if serum was digested with chondroinitase ABC. Using different chondroitinsulfate-subtypes we demonstrate that chondroitinsulfate A mediates the enhanced presentation of CCL5 on endothelial cells, whereas chondroitinsulfate B/C even at low concentrations block CCL5 binding. CCR5 downregulation on CCR5-transfected CHO cells or human monocytes is increased by preincubation of CCL5 with serum or chondroitinsulfate A. Conclusion: We show that chondroitinsulfate A released from platelets increases the binding of chemokines to endothelial cells and supports receptor internalization in a dose dependent manner. These data help to understand the proinflammatory effects of activated platelets.

During the last 200 years, the social, scientific, and religious framework in which homeopathy is taught and practiced has changed tremendously. Various different forms of homeopathy have been advocated. To avoid being misled by the prevailing pluralism as a standard of reference for assessing new concepts, Hahnemann's original ideas and attitude toward medicine, philosophy, and ethics are discussed. Hahnemann's hierarchisation of values appears to consist primarily in striving for a world view in which he could conceive of himself as a spiritual and moral being, secondly in a yearning for scientific advancement, and thirdly in his need to earn a living. Homeopaths are challenged to match this hierarchisation and be aware that homeopathy comprises dimensions other than just science and economics.