Showing papers by "University of Erlangen-Nuremberg published in 2006"

Recommendations for chamber quantification

Abstract: Quantification of cardiac chamber size, ventricular mass and function ranks among the most clinically important and most frequently requested tasks of echocardiography. Over the last decades, echocardiographic methods and techniques have improved and expanded dramatically, due to the introduction of higher frequency transducers, harmonic imaging, fully digital machines, left-sided contrast agents, and other technological advancements. Furthermore, echocardiography due to its portability and versatility is now used in emergency rooms, operating rooms, and intensive care units. Standardization of measurements in echocardiography has been inconsistent and less successful, compared to other imaging techniques and consequently, echocardiographic measurements are sometimes perceived as less reliable. Therefore, the American Society of Echocardiography, working together with the European Association of Echocardiography, a branch of the European Society of Cardiology, has critically reviewed the literature and updated the recommendations for quantifying cardiac chambers using echocardiography. This document reviews the technical aspects on how to perform quantitative chamber measurements of morphology and function, which is a component of every complete echocardiographic examination.

Unbiased Recursive Partitioning: A Conditional Inference Framework

Abstract: Recursive binary partitioning is a popular tool for regression analysis. Two fundamental problems of exhaustive search procedures usually applied to fit such models have been known for a long time: overfitting and a selection bias towards covariates with many possible splits or missing values. While pruning procedures are able to solve the overfitting problem, the variable selection bias still seriously affects the interpretability of tree-structured regression models. For some special cases unbiased procedures have been suggested, however lacking a common theoretical foundation. We propose a unified framework for recursive partitioning which embeds tree-structured regression models into a well defined theory of conditional inference procedures. Stopping criteria based on multiple test procedures are implemented and it is shown that the predictive performance of the resulting trees is as good as the performance of established exhaustive search procedures. It turns out that the partitions and therefore the...

Controlling the Electronic Structure of Bilayer Graphene

Abstract: We describe the synthesis of bilayer graphene thin films deposited on insulating silicon carbide and report the characterization of their electronic band structure using angle-resolved photoemission. By selectively adjusting the carrier concentration in each layer, changes in the Coulomb potential led to control of the gap between valence and conduction bands. This control over the band structure suggests the potential application of bilayer graphene to switching functions in atomic-scale electronic devices.

Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): Standardized protocol and reference values

Abstract: The nationwide multicenter trials of the German Research Network on Neuropathic Pain (DFNS) aim to characterize the somatosensory phenotype of patients with neuropathic pain. For this purpose, we have implemented a standardized quantitative sensory testing (QST) protocol giving a complete profile for one region within 30 min. To judge plus or minus signs in patients we have now established age- and gender-matched absolute and relative QST reference values from 180 healthy subjects, assessed bilaterally over face, hand and foot. We determined thermal detection and pain thresholds including a test for paradoxical heat sensations, mechanical detection thresholds to von Frey filaments and a 64 Hz tuning fork, mechanical pain thresholds to pinprick stimuli and blunt pressure, stimulus/response-functions for pinprick and dynamic mechanical allodynia, and pain summation (wind-up ratio). QST parameters were region specific and age dependent. Pain thresholds were significantly lower in women than men. Detection thresholds were generally independent of gender. Reference data were normalized to the specific group means and variances (region, age, gender) by calculating z-scores. Due to confidence limits close to the respective limits of the possible data range, heat hypoalgesia, cold hypoalgesia, and mechanical hyperesthesia can hardly be diagnosed. Nevertheless, these parameters can be used for group comparisons. Sensitivity is enhanced by side-to-side comparisons by a factor ranging from 1.1 to 2.5. Relative comparisons across body regions do not offer advantages over absolute reference values. Application of this standardized QST protocol in patients and human surrogate models will allow to infer underlying mechanisms from somatosensory phenotypes.

Migrating cancer stem cells: An integrated concept of malignant tumor progression.

Abstract: ED01-02 Most colorectal adenocarcinomas (CRC) have mutations in the APC gene leading to overexpression of the Wnt-pathway effector b-catenin. By acting as a transcriptional activator, nuclear b-catenin is decisively involved in two fundamental processes in embryonic development: epithelial to mesenchymal transition (EMT) and generation of stem cells (e.g. in intestine development). We have previously shown, that in particular tumor cells at the invasive front of CRCs accumulate nuclear b-catenin, undergo an EMT and aberrantly express EMT-associated transcriptional repressors, like ZEB1. The amount of these cells strongly correlates with clinical outcome and metastasis formation. We further showed that ZEB1 represses target genes involved in basement membrane formation and epithelial cell polarity. In contrast tumor cells in central tumor areas are differentiated and often show membranous, E-cadherin-bound b-catenin. Strikingly, also metastases show again a differentiated phenotype and lack nuclear b-catenin, indicating a regulatory role of the tumor environment for malignant progression. Based on the developmental functions of b-catenin and our data we propose, that the EMT-associated tumor cells at the invasive front act as "migrating cancer stem cells" which can re-differentiate and, depending on the range of dissemination, give raise to the primary carcinoma or metastases. In support of this hypothesis, we defined b-catenin target genes overexpressed in invading tumor cells: 1. A stem cell phenotype is supported by the b-catenin target genes hTERT and survivin. 2. Furthermore we identified target genes like uPA, MT1-MMP, and laminin5-g2 chain, which synergize to exert EMT and promigratory activity. We suggest that both primary tumors and metastases are derived from a pool of EMT-associated "migrating cancer stem cells" at the tumor host interface, which are defined by strong nuclear b-catenin accumulation and expression of its target genes. This gives these cells a feature, which drives malignant tumor progression including metastasis: the unusual combination of abilities allowing simultanously to migrate and behave as a cancer stem cell. Since ZEB1 might be the crucial mediator of EMT in tumor cells, it could be a promising therapeutic target to interfere with malignant tumor progression.

Hepatic platelet and leukocyte adherence during endotoxemia

Abstract: Introduction Liver microcirculation disturbances are a cause of hepatic failure in sepsis. Increased leukocyte-endothelial interaction, platelet adherence and impaired microperfusion cause hepatocellular damage. The time course and reciprocal influences of ongoing microcirculatory events during endotoxemia have not been clarified.

Engineered heart tissue grafts improve systolic and diastolic function in infarcted rat hearts

Abstract: The concept of regenerating diseased myocardium by implantation of tissue-engineered heart muscle is intriguing, but convincing evidence is lacking that heart tissues can be generated at a size and with contractile properties that would lend considerable support to failing hearts. Here we created large (thickness/diameter, 1-4 mm/15 mm), force-generating engineered heart tissue from neonatal rat heart cells. Engineered heart tissue formed thick cardiac muscle layers when implanted on myocardial infarcts in immune-suppressed rats. When evaluated 28 d later, engineered heart tissue showed undelayed electrical coupling to the native myocardium without evidence of arrhythmia induction. Moreover, engineered heart tissue prevented further dilation, induced systolic wall thickening of infarcted myocardial segments and improved fractional area shortening of infarcted hearts compared to controls (sham operation and noncontractile constructs). Thus, our study provides evidence that large contractile cardiac tissue grafts can be constructed in vitro, can survive after implantation and can support contractile function of infarcted hearts.

Reefs of the Deep: The Biology and Geology of Cold-Water Coral Ecosystems

Abstract: Coral reefs are generally associated with shallow tropical seas; however, recent deep-ocean exploration using advanced acoustics and submersibles has revealed unexpectedly widespread and diverse coral ecosystems in deep waters on continental shelves, slopes, seamounts, and ridge systems around the world. Advances reviewed here include the use of corals as paleoclimatic archives and their biogeological functioning, biodiversity, and biogeography. Threats to these fragile, long-lived, and rich ecosystems are mounting: The impacts of deep-water trawling are already widespread, and effects of ocean acidification are potentially devastating.

Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010

Abstract: As in previous years, the consensus group to consider the use of biological agents in the treatment of rheumatic diseases met during the 13th Annual Workshop on Advances in Targeted Therapies in April, 2011. The group consisted of rheumatologists from a number of universities among the continents of Europe, North America, South America, Australia and Asia. Pharmaceutical industry support was obtained from a number of companies for the annual workshop itself, but these companies had no part in the decisions about the specific programme or about the academic participants at this conference. Representatives of the supporting sponsors participated in the initial working groups to supply factual information. The sponsors did not participate in the drafting of the consensus statement. This consensus was prepared from the perspective of the treating physician. In view of the new data for abatacept, B cell-specific agents, interleukin 1 (IL-1) antagonists, tocilizumab (TCZ) and tumour necrosis factor α blocking agents (TNF inhibitors), an update of the previous consensus statement is appropriate. To allow ease of updating, the 2010 (data from March 2009 to January 2010) updates are incorporated into the body of the article, while 2011 updates (February 2010–January 2011) are separated and highlighted. The consensus statement is annotated to document the credibility of the data supporting it as much as possible. This annotation is that of Shekelle et al and is described in appendix 1.1 We have modified the Shekelle annotation by designating all abstracts as ‘category D evidence’, whether they describe well-controlled trials or not, as details of the study were often not available in the abstracts. Further, the number of possible references has become so large that reviews are sometimes included; if they contain category A references, they will be referred to as category A evidence. The rheumatologists and bioscientists who attended …

Germline KRAS mutations cause Noonan syndrome

Abstract: Noonan syndrome (MIM 163950) is characterized by short stature, facial dysmorphism and cardiac defects. Heterozygous mutations in PTPN11, which encodes SHP-2, cause approximately 50% of cases of Noonan syndrome. The SHP-2 phosphatase relays signals from activated receptor complexes to downstream effectors, including Ras. We discovered de novo germline KRAS mutations that introduce V14I, T58I or D153V amino acid substitutions in five individuals with Noonan syndrome and a P34R alteration in a individual with cardio-facio-cutaneous syndrome (MIM 115150), which has overlapping features with Noonan syndrome. Recombinant V14I and T58I K-Ras proteins show defective intrinsic GTP hydrolysis and impaired responsiveness to GTPase activating proteins, render primary hematopoietic progenitors hypersensitive to growth factors and deregulate signal transduction in a cell lineage-specific manner. These studies establish germline KRAS mutations as a cause of human disease and infer that the constellation of developmental abnormalities seen in Noonan syndrome spectrum is, in large part, due to hyperactive Ras.

Guidelines of the Pituitary Society for the diagnosis and management of prolactinomas

Abstract: In June 2005, an ad hoc Expert Committee formed by the Pituitary Society convened during the 9th International Pituitary Congress in San Diego, California. Members of this committee consisted of invited international experts in the field, and included endocrinologists and neurosurgeons with recognized expertise in the management of prolactinomas. Discussions were held that included all interested participants to the Congress and resulted in formulation of these guidelines, which represent the current recommendations on the diagnosis and management of prolactinomas based upon comprehensive analysis and synthesis of all available data.

The snoRNA HBII-52 Regulates Alternative Splicing of the Serotonin Receptor 2C

Abstract: The Prader-Willi syndrome is a congenital disease that is caused by the loss of paternal gene expression from a maternally imprinted region on chromosome 15. This region contains a small nucleolar RNA (snoRNA), HBII-52, that exhibits sequence complementarity to the alternatively spliced exon Vb of the serotonin receptor 5-HT2CR. We found that HBII-52 regulates alternative splicing of 5-HT2CR by binding to a silencing element in exon Vb. Prader-Willi syndrome patients do not express HBII-52. They have different 5-HT2CR messenger RNA (mRNA) isoforms than healthy individuals. Our results show that a snoRNA regulates the processing of an mRNA expressed from a gene located on a different chromosome, and the results indicate that a defect in pre-mRNA processing contributes to the Prader-Willi syndrome.

Procedure Guideline for Tumor Imaging with 18F-FDG PET/CT 1.0

Abstract: The purpose of these guidelines is to assist physicians in recommending, performing, interpreting, and reporting the results of 18F-FDG PET/CT for oncologic imaging of adult and pediatric patients. PET is a tomographic scintigraphic technique in which a computer-generated image of local radioactive

Ion Implantation and Annealing for an Efficient N-Doping of TiO2 Nanotubes

Abstract: Self-organized anodic titania nanotube layers were doped with nitrogen successfully using ion implantation. Photoelectrochemical measurements combined with XRD measurements show that the damage created by ion bombardment (that leads to a drastic decrease of the photoconversion efficiency) can be “annealed out” by an adequate heat treatment. This results in a N-doped crystalline anatase nanotube structure with strongly enhanced photocurrent response in both the UV and the visible range.

Tissue engineering of bone: the reconstructive surgeon's point of view

Abstract: Bone defects represent a medical and socioeconomic challenge. Different types of biomaterials are applied for reconstructive indications and receive rising interest. However, autologous bone grafts are still considered as the gold standard for reconstruction of extended bone defects. The generation of bioartificial bone tissues may help to overcome the problems related to donor site morbidity and size limitations. Tissue engineering is, according to its historic definition, an “interdisciplinary field that applies the principles of engineering and the life sciences toward the development of biological substitutes that restore, maintain, or improve tissue function”. It is based on the understanding of tissue formation and regeneration and aims to rather grow new functional tissues than to build new spare parts. While reconstruction of small to moderate sized bone defects using engineered bone tissues is technically feasible, and some of the currently developed concepts may represent alternatives to autologous bone grafts for certain clinical conditions, the reconstruction of largevolume defects remains challenging. Therefore vascularization concepts gain on interest and the combination of tissue engineering approaches with flap prefabrication techniques may eventually allow application of bone-tissue substitutes grown in vivo with the advantage of minimal donor site morbidity as compared to conventional vascularized bone grafts. The scope of this review is the introduction of basic principles and different components of engineered bioartificial bone tissues with a strong focus on clinical applications in reconstructive surgery. Concepts for the induction of axial vascularization in engineered bone tissues as well as potential clinical applications are discussed in detail.

Pyrimidine and Purine Biosynthesis and Degradation in Plants

Abstract: Nucleotide metabolism operates in all living organisms, embodies an evolutionarily ancient and indispensable complex of metabolic pathways and is of utmost importance for plant metabolism and development. In plants, nucleotides can be synthesized de novo from 5-phosphoribosyl-1-pyrophosphate and simple molecules (e.g., CO2, amino acids, and tetrahydrofolate), or be derived from preformed nucleosides and nucleobases via salvage reactions. Nucleotides are degraded to simple metabolites, and this process permits the recycling of phosphate, nitrogen, and carbon into central metabolic pools. Despite extensive biochemical knowledge about purine and pyrimidine metabolism, comprehensive studies of the regulation of this metabolism in plants are only starting to emerge. Here we review progress in molecular aspects and recent studies on the regulation and manipulation of nucleotide metabolism in plants.

Di(2-ethylhexyl)phthalate (DEHP): human metabolism and internal exposure-- an update and latest results.

Abstract: Di(2-ethylhexyl)phthalate (DEHP) is a reproductive and developmental toxicant in animals and a suspected endocrine modulator in humans. There is widespread exposure to DEHP in the general population. Patients can be additionally exposed through DEHP-containing medical devices. Toxicokinetic and metabolic knowledge on DEHP in humans is vital not only for the toxicological evaluation of DEHP but also for exposure assessments based on human biomonitoring data. Secondary oxidized DEHP metabolites like mono-(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono-(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP), mono-(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP) and mono-[2-(carboxymethyl)hexyl]phthalate (2cx-MMHP) are most valuable biomarkers of DEHP exposure. They represent the major share of DEHP metabolites excreted in urine (about 70% for these four oxidized metabolites vs. about 6% for MEHP); they are immune to external contamination and possibly the ultimate developmental toxicants. Long half-times of elimination make 5cx-MEPP and 2cx-MMHP excellent parameters to measure the time-weighted body burden to DEHP. 5OH-MEHP and 5oxo-MEHP more reflect the short-term exposure. We calculated the daily DEHP intake for the general population (n = 85) and for children (n = 254). Children were significantly higher exposed to DEHP than adults. Exposures at the 95th percentile (21 and 25 microg/kg/day, respectively) scooped out limit values like the Reference Dose (RfD, 20 microg/kg/day) and the Tolerable Daily Intake (TDI, 20-48 microg/kg/day) to a considerable degree. Up to 20-fold oversteppings for some children give cause for concern. We also detected significant DEHP exposures for voluntary platelet donors (n = 12, 38 microg/kg/apheresis, dual-needle technique). Premature neonates (n = 45) were exposed to DEHP up to 100 times above the limit values depending on the intensity of medical care (median: 42 microg/kg/day; 95th percentile: 1,780 microg/kg/day).

Usefulness of Multidetector Row Spiral Computed Tomography With 64- × 0.6-mm Collimation and 330-ms Rotation for the Noninvasive Detection of Significant Coronary Artery Stenoses

Abstract: Eighty-four patients with suspected coronary artery disease were studied to determine the accuracy of noninvasive coronary angiography using a multidetector computed tomographic scanner with 64- x 0.6-mm collimation and 330-ms gantry rotation. All coronary artery segments with a diameter >1.5 mm were assessed with respect to stenoses >50% decreased diameter. Results were compared with quantitative coronary angiographic findings. After exclusion of unevaluable coronary segments (4%), multidetector computed tomography demonstrated a sensitivity of 93%, a specificity of 97%, and a negative predictive value of 100% in a per-segment analysis. In a per-artery analysis, 15 of 336 arteries (4%) were unevaluable. Sensitivity and specificity in evaluable arteries were 95% and 93%, respectively. In a per-patient analysis (81 of 84 patients included), sensitivity and specificity were 96% and 91%, respectively.

Global rules and private actors: Toward a new role of the transnational corporation in global governance

Abstract: Economic activities require the existence of rules and their enforcement as preconditions that the market cannot generate itself. Property rights, and contractual rights and obligations, are minimal prerequisites for modern societies that are provided and enforced by the state. Without such prerequisites, the market cannot flourish. The state thus determines regulations and delineates the sphere of private freedom, within which individual citizens and private institutions are entitled to conclude contracts with one another, to which the system of property and contractual rights compels obedience. In the development of modern nation states, the state has not only been the guarantor of civil rights, e. g. the right to own property, to enter into private contracts, and to engage in market activity. In its role as a democratic constitutional state, it has also been the guarantor of political participation rights, the right of the citizen to take part in the processes that determine public rules and issues of public concern. Finally, in its role as a welfare state, it has provided social rights for citizens, such as the right to education, to health care, and to other forms of welfare (Marshall 1965). The combination of state-guaranteed civil, political, and social rights has provided legitimacy, solidarity, and welfare to modern society, thereby contributing to peaceful, stable communities of anonymous individuals (Habermas 2001). Following Matten and Crane (Matten/Crane 2005) we refer to this triad of rights as citizenship rights.

Presenilin clinical mutations can affect gamma-secretase activity by different mechanisms.

Abstract: Mutations in human presenilin (PS) genes cause aggressive forms of familial Alzheimer's disease. Presenilins are polytopic proteins that harbour the catalytic site of the gamma-secretase complex and cleave many type I transmembrane proteins including beta-amyloid precursor protein (APP), Notch and syndecan 3. Contradictory results have been published concerning whether PS mutations cause 'abnormal' gain or (partial) loss of function of gamma-secretase. To avoid the possibility that wild-type PS confounds the interpretation of the results, we used presenilin-deficient cells to analyse the effects of different clinical mutations on APP, Notch, syndecan 3 and N-cadherin substrate processing, and on gamma-secretase complex formation. A loss in APP and Notch substrate processing at epsilon and S3 cleavage sites was observed with all presenilin mutants, whereas APP processing at the gamma site was affected in variable ways. PS1-Delta9 and PS1-L166P mutations caused a reduction in beta-amyloid peptide Abeta40 production whereas PS1-G384A mutant significantly increased Abeta42. Interestingly PS2, a close homologue of PS1, appeared to be a less efficient producer of Abeta than PS1. Finally, subtle differences in gamma-secretase complex assembly were observed. Overall, our results indicate that the different mutations in PS affect gamma-secretase structure or function in multiple ways.

Predictors of joint damage in patients with early rheumatoid arthritis treated with high‐dose methotrexate with or without concomitant infliximab: Results from the ASPIRE trial

Abstract: Objective To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with infliximab plus MTX. Methods Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54. Results C-reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX-only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (≥3 mg/dl) and ESR (≥52 mm/hour) tertiles in the MTX-only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS ≥10.5) showed less progression with infliximab plus MTX compared with MTX alone (−0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab. Conclusion High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.

Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation.

Abstract: The underlying cause of mental retardation remains unknown in up to 80% of patients. As chromosomal aberrations are the most common known cause of mental retardation, several new methods based on FISH, PCR, and array techniques have been developed over recent years to increase detection rate of subtle aneusomies initially of the gene rich subtelomeric regions, but nowadays also genome wide. As the reported detection rates vary widely between different reports and in order to compare the diagnostic yield of various investigations, we analyzed the diagnostic yield of conventional karyotyping, subtelomeric screening, molecular karyotyping, X-inactivation studies, and dysmorphological evaluation with targeted laboratory testing in unselected patients referred for developmental delay or mental retardation to our cytogenetic laboratory (n = 600) and to our genetic clinic (n = 570). In the cytogenetic group, 15% of patients showed a disease-related aberration, while various targeted analyses after dysmorphological investigation led to a diagnosis in about 20% in the genetic clinic group. When adding the patients with a cytogenetic aberration to the patient group seen in genetic clinic, an etiological diagnosis was established in about 40% of the combined study group. A conventional cytogenetic diagnosis was present in 16% of combined patients and a microdeletion syndrome was diagnosed in 5.3%, while subtelomeric screening revealed only 1.3% of causes. Molecular karyotyping with a 10 K SNP array in addition revealed 5% of underlying causes, but 29% of all diagnoses would have been detectable by molecular karyotyping. In those patients without a clear diagnosis, 5.6% of mothers of affected boys showed significant (>95%) skewing of X-inactivation suggesting X-linked mental retardation. The most common diagnoses with a frequency of more than 0.5% were Down syndrome (9.2%), common microdeletion 22q11.2 (2.4%), Williams-Beuren syndrome (1.3%), Fragile-X syndrome (1.2%), Cohen syndrome (0.7%), and monosomy 1p36.3 (0.6%). From our data, we suggest the following diagnostic procedure in patients with unexplained developmental delay or mental retardation: (1) Clinical/dysmorphological investigation with respective targeted analyses; (2) In the remaining patients without an etiological diagnosis, we suggest conventional karyotyping, X-inactivation screening in mothers of boys, and molecular karyotyping, if available. If molecular karyotyping is not available, subtelomeric screening should be performed.