Showing papers by "University of Erlangen-Nuremberg published in 2004"

Bioconductor: open software development for computational biology and bioinformatics

Abstract: The Bioconductor project is an initiative for the collaborative creation of extensible software for computational biology and bioinformatics. The goals of the project include: fostering collaborative development and widespread use of innovative software, reducing barriers to entry into interdisciplinary scientific research, and promoting the achievement of remote reproducibility of research results. We describe details of our aims and methods, identify current challenges, compare Bioconductor to other open bioinformatics projects, and provide working examples.

Preoperative versus Postoperative Chemoradiotherapy for Rectal Cancer

Abstract: background Postoperative chemoradiotherapy is the recommended standard therapy for patients with locally advanced rectal cancer. In recent years, encouraging results with preoperative radiotherapy have been reported. We compared preoperative chemoradiotherapy with postoperative chemoradiotherapy for locally advanced rectal cancer. methods We randomly assigned patients with clinical stage T3 or T4 or node-positive disease to receive either preoperative or postoperative chemoradiotherapy. The preoperative treatment consisted of 5040 cGy delivered in fractions of 180 cGy per day, five days per week, and fluorouracil, given in a 120-hour continuous intravenous infusion at a dose of 1000 mg per square meter of body-surface area per day during the first and fifth weeks of radiotherapy. Surgery was performed six weeks after the completion of chemoradiotherapy. One month after surgery, four five-day cycles of fluorouracil (500 mg per square meter per day) were given. Chemoradiotherapy was identical in the postoperative-treatment group, except for the delivery of a boost of 540 cGy. The primary end point was overall survival. results Four hundred twenty-one patients were randomly assigned to receive preoperative chemoradiotherapy and 402 patients to receive postoperative chemoradiotherapy. The overall five-year survival rates were 76 percent and 74 percent, respectively (P=0.80). The five-year cumulative incidence of local relapse was 6 percent for patients assigned to preoperative chemoradiotherapy and 13 percent in the postoperative-treatment group (P=0.006). Grade 3 or 4 acute toxic effects occurred in 27 percent of the patients in the preoperative-treatment group, as compared with 40 percent of the patients in the postoperative-treatment group (P=0.001); the corresponding rates of long-term toxic effects were 14 percent and 24 percent, respectively (P=0.01). conclusions Preoperative chemoradiotherapy, as compared with postoperative chemoradiotherapy, improved local control and was associated with reduced toxicity but did not improve overall survival.

Theoretical chemistry of gold.

Abstract: Gold is an element whose unique properties are strongly influenced by relativistic effects. A large body of appropriate calculations now exist and their main conclusions are summarized. The theoretical interpretation of the aurophilic attraction is discussed in detail.

Detection of Calcified and Noncalcified Coronary Atherosclerotic Plaque by Contrast-Enhanced, Submillimeter Multidetector Spiral Computed Tomography A Segment-Based Comparison With Intravascular Ultrasound

Abstract: Background— We investigated the ability of multidetector spiral computed tomography (MDCT) to detect atherosclerotic plaque in nonstenotic coronary arteries Methods and Results— In 22 patients without significant coronary stenoses, contrast-enhanced MDCT (075-mm collimation, 420-ms rotation) and intravascular ultrasound (IVUS) of one coronary artery were performed A total of 83 coronary segments were imaged by IVUS (left main, 19; left anterior descending, 51; left circumflex, 4; right coronary, 9) MDCT data sets were evaluated for the presence and volume of plaque in the coronary artery segments Results were compared with IVUS in a blinded fashion For the detection of segments with any plaque, MDCT had a sensitivity of 82% (41 of 50) and specificity of 88% (29 of 33) For calcified plaque, sensitivity was 94% (33 of 36) and specificity 94% (45 of 47) Coronary segments containing noncalcified plaque were detected with a sensitivity of 78% (35 of 45) and specificity of 87% (33 of 38), but presence o

Randomized study to evaluate Sirolimus-eluting stents implanted at coronary bifurcation lesions

Abstract: Background— A sirolimus-eluting stent (Cypher, Cordis Corp) has been reported to markedly decrease restenosis in selected lesions; higher-risk lesions, including coronary bifurcations, have not been studied. Methods and Results— This prospective study evaluated the safety and efficacy of sirolimus-eluting stents for treatment of coronary bifurcation lesions. Patients were randomly assigned to either stenting of both branches (group A) or stenting of the main branch with provisional stenting of the side branch (SB) (group B). Eighty-five patients (86 lesions) were enrolled. There was 1 case of unsuccessful delivery of any device at the bifurcation site. Given the high crossover, more lesions were treated with 2 stents (n=63) than with stent/balloon (n=22). Clinical follow-up at 6 months was completed in all patients and angiographic follow-up in 53 patients in group A (85.5%) and 21 in group B (95.4%). One patient died suddenly 4.5 months after the procedure. There were 3 cases of stent thrombosis (3.5%). ...

Reconstructing Mediatization as an Analytical Concept

Abstract: Mediatization relates to changes associated with communication media and their development. A basic assumption of mediatization is that the technological, semiotic and economic characteristics of mass media result in problematic dependencies, constraints and exaggerations. These are closely associated with three basic functions of the media in communication processes: (1) the relay function, grounded in the media’s technological capacities, serving to bridge spatial and temporal distances; (2) the semiotic function, making messages suitable for human information processing through encoding and formatting; and (3) the economic function, highlighting the standardization of media products as an outcome of mass production processes. The article looks at the analytical functions of mediatization and, finally, discusses three possible answers to the question whether the advent of new media might bring an end to mediatization.

Handbook of fluorous chemistry

Abstract: Preface.1. Fluorous Chemistry: Scope and Definition (I. Horvath, et al.).2. A Personal View of the History of Fluorous Chemistry (I. Horvath).3. Fluorous Solvents and Related Media (J. Gladysz & C. Emnet).4. Strategies for the Recovery of Fluorous Catalysts and Reagents: Design and Evaluation (J. Gladysz & R. Correa de Costa).5. Ponytails: Structural and Electronic Considerations (J. Gladysz).6. Partition Coefficients Involving Fluorous Solvents (J. Gladysz, et al.).7. Separations with Fluorous Silica Gel and Related Materials (D. Curran).8. Light Fluorous Chemistry-A User-s Guide (D. Curran).9. Getting Started in Synthesis: A Tabular Guide to Selected Monofunctional Fluorous Compounds (J. Rabai).10. Highlights of Applications in Synthesis and Catalysis.11. Preparations.12. Applications of Fluorous Compounds in Materials Chemistry.13. Fluorous Materials for Biomedical Uses (J. Riess).14. Fun and Games with Fluorous Chemistry (J. Rabai).Index.

Security of quantum key distribution with imperfect devices

Abstract: We prove the security of the Bennett-Brassard (BB84) quantum key distribution protocol in the case where the source and detector are under the limited control of an adversary. Our proof applies when both the source and the detector have small basis-dependent flaws, as is typical in practical implementations of the protocol. We derive a general lower bound on the asymptotic key generation rate for weakly basis-dependent eavesdropping attacks, and also estimate the rate in some special cases: sources that emit weak coherent states with random phases, detectors with basis-dependent efficiency, and misaligned sources and detectors.

Precoding in multiantenna and multiuser communications

Abstract: In this paper, Tomlinson-Harashima Precoding for multiple-input/multiple-output systems including multiple-antenna and multiuser systems is studied. It is shown that nonlinear preequalization offers significant advantages over linear preequalization which increases average transmit power. Moreover, it outperforms decision-feedback equalization at the receiver side which is applicable if joint processing at the receiver side is possible, and which suffers from error propagation. A number of aspects of practical importance are studied. Loading, i.e., the optimum distribution of transmit power and rate is discussed in detail. It is shown that the capacity of the underlying MIMO channel can be utilized asymptotically by means of nonlinear precoding.

GlyR alpha3: an essential target for spinal PGE2-mediated inflammatory pain sensitization.

Abstract: Prostaglandin E2 (PGE2) is a crucial mediator of inflammatory pain sensitization. Here, we demonstrate that inhibition of a specific glycine receptor subtype (GlyR alpha3) by PGE2-induced receptor phosphorylation underlies central inflammatory pain sensitization. We show that GlyR alpha3 is distinctly expressed in superficial layers of the spinal cord dorsal horn. Mice deficient in GlyR alpha3 not only lack the inhibition of glycinergic neurotransmission by PGE2 seen in wild-type mice but also show a reduction in pain sensitization induced by spinal PGE2 injection or peripheral inflammation. Thus, GlyR alpha3 may provide a previously unrecognized molecular target in pain therapy.

Continuous Positive Airway Pressure Treatment Rapidly Improves Insulin Sensitivity in Patients with Obstructive Sleep Apnea Syndrome

Abstract: The obstructive sleep apnea syndrome is typically associated with conditions known to increase insulin resistance as hypertension, obesity, and diabetes. We investigated whether obstructive sleep apnea itself is an independent risk factor for increased insulin resistance and whether continuous positive airway pressure (CPAP) treatment improves insulin sensitivity. Forty patients (apnea-hypopnea index > 20) were treated with CPAP. Before, 2 days after, and after 3 months of effective CPAP treatment, hyperinsulinemic euglycemic clamp studies were performed. Insulin sensitivity significantly increased after 2 days (5.75 +/- 4.20 baseline versus 6.79 +/- 4.91 micromol/kg.min; p = 0.003) and remained stable after 3 months of treatment. The improvement in insulin sensitivity after 2 days was much greater in patients with a body mass index less than 30 kg/m2 than in more obese patients. The improved insulin sensitivity after 2 nights of treatment may reflect a decreasing sympathetic activity, indicating that sleep apnea is an independent risk factor for increased insulin resistance. The effect of CPAP on insulin sensitivity is smaller in obese patients than in nonobese patients, suggesting that in obese individuals insulin sensitivity is mainly determined by obesity and, to a smaller extent, by sleep apnea.

Sympathetic augmentation in hypertension: role of nerve firing, norepinephrine reuptake, and Angiotensin neuromodulation.

Abstract: There is growing evidence that essential hypertension is commonly neurogenic and is initiated and sustained by sympathetic nervous system overactivity. Potential mechanisms include increased central sympathetic outflow, altered norepinephrine (NE) neuronal reuptake, diminished arterial baroreflex dampening of sympathetic nerve traffic, and sympathetic neuromodulation by angiotensin II. To address this issue, we used microneurography and radiotracer dilution methodology to measure regional sympathetic activity in 22 hypertensive patients and 11 normotensive control subjects. The NE transport inhibitor desipramine was infused to directly assess the potential role of impaired neuronal NE reuptake. To evaluate possible angiotensin sympathetic neuromodulation, the relation of arterial and coronary sinus plasma concentrations of angiotensin II to sympathetic activity was investigated. Hypertensive patients displayed increased muscle sympathetic nerve activity and elevated total systemic, cardiac, and renal NE spillover. Cardiac neuronal NE reuptake was decreased in hypertensive subjects. In response to desipramine, both the reduction of fractional transcardiac 3[H]NE extraction and the increase in cardiac NE spillover were less pronounced in hypertensive patients. DNA sequencing analysis of the NE transporter gene revealed no mutations that could account for reduced transporter activity. Arterial baroreflex control of sympathetic nerve traffic was not diminished in hypertensive subjects. Angiotensin II plasma concentrations were similar in both groups and were not related to indexes of sympathetic activation. Increased rates of sympathetic nerve firing and reduced neuronal NE reuptake both contribute to sympathetic activation in hypertension, whereas a role for dampened arterial baroreflex restraint on sympathetic nerve traffic and a peripheral neuromodulating influence of angiotensin II appear to be excluded.

Functional analysis of Sox8 and Sox9 during sex determination in the mouse.

Abstract: Sex determination in mammals directs an initially bipotential gonad to differentiate into either a testis or an ovary. This decision is triggered by the expression of the sex-determining gene Sry, which leads to the activation of male-specific genes including the HMG-box containing gene Sox9. From transgenic studies in mice it is clear that Sox9 is sufficient to induce testis formation. However, there is no direct confirmation for an essential role for Sox9 in testis determination. The studies presented here are the first experimental proof for an essential role for Sox9 in mediating a switch from the ovarian pathway to the testicular pathway. Using conditional gene targeting, we show that homozygous deletion of Sox9 in XY gonads interferes with sex cord development and the activation of the male-specific markers Mis and P450scc, and leads to the expression of the female-specific markers Bmp2 and follistatin. Moreover, using a tissue specific knock-out approach, we show that Sox9 is involved in Sertoli cell differentiation, the activation of Mis and Sox8, and the inactivation of Sry. Finally, double knock-out analyses suggest that Sox8 reinforces Sox9 function in testis differentiation of mice.

Phase measuring deflectometry: a new approach to measure specular free-form surfaces

Abstract: We present a new method to measure specular free-form surfaces within seconds. We call the measuring principle `Phase Measuring Deflectometry' (PMD). With a stereo based enhancement of PMD we are able to measure both the height and the slope of the surface. The basic principle is to project sinusoidal fringe patterns onto a screen located remotely from the surface under test and to observe the fringe patterns reflected via the surface. Any slope variations of the surface lead to distortions of the patterns. Using well-known phase-shift algorithms, we can precisely measure these distortions and thus calculate the surface normal in each pixel. We will deduce the method's diffraction-theoretical limits and explain how to reach them. A major challenge is the necessary calibration. We solved this task by combining various photogrammetric methods. We reach a repeatability of the local slope down to a few arc seconds and an absolute accuracy of a few arc minutes. One important field of application is the measurement of the local curvature of progressive eyeglass lenses. We will present experimental results and compare these results with the theoretical limits.

Cortical reorganization during recovery from complex regional pain syndrome

Abstract: Objective: To characterize reorganization of the primary somatosensory cortex (S1) during healing process in complex regional pain syndrome (CRPS). Background: Recently, the authors showed extensive reorganization of the S1 cortex contralateral to the CRPS affected side. Predictors for these plastic changes were CRPS pain and the extent of mechanical hyperalgesia. It is unclear how these S1 changes develop following successful therapy. Methods: The authors used magnetic source imaging to explore changes in the cortical representation of digits (D) 1 and 5 in relation to the lower lip on the unaffected and affected CRPS side in 10 patients during a year or more of follow-up. Results: Cortical reorganization reversed coincident with clinical improvement. A reduction of CRPS pain correlated with recovery from cortical reorganization. Conclusions: Changes of the somatotopic map within the S1 cortex may depend on CRPS pain and its recovery.

Predictive Value of 16-Slice Multidetector Spiral Computed Tomography to Detect Significant Obstructive Coronary Artery Disease in Patients at High Risk for Coronary Artery Disease: Patient- Versus Segment-Based Analysis

Abstract: Background— In this study, we investigated the diagnostic value and limitations of multidetector computed tomography (MDCT)–based noninvasive detection of significant obstructive coronary artery disease (CAD) in a consecutive high-risk patient population with inclusion of all coronary segments. Methods and Results— In a prospective, blinded, standard cross-sectional technology assessment, a cohort of 33 consecutive patients with a positive stress test result underwent 16-slice MDCT and selective coronary angiography for the detection of significant obstructive CAD. We assessed the diagnostic accuracy of MDCT in a segment-based and a patient-based model and determined the impact of stenosis location and the presence of calcification on diagnostic accuracy in both models. Analysis of all 530 coronary segments demonstrated moderate sensitivity (63%) and excellent specificity (96%) with a moderate positive predictive value of 64% and an excellent negative predictive value (NPV) of 96% for the detection of sig...

Molecular mechanism for distinct neurological phenotypes conveyed by allelic truncating mutations.

Abstract: The molecular mechanisms by which different mutations in the same gene can result in distinct disease phenotypes remain largely unknown. Truncating mutations of SOX10 cause either a complex neurocristopathy designated PCWH or a more restricted phenotype known as Waardenburg-Shah syndrome (WS4; OMIM 277580). Here we report that although all nonsense and frameshift mutations that cause premature termination of translation generate truncated SOX10 proteins with potent dominant-negative activity, the more severe disease phenotype, PCWH, is realized only when the mutant mRNAs escape the nonsense-mediated decay (NMD) pathway. We observe similar results for truncating mutations of MPZ that convey distinct myelinopathies. Our experiments show that triggering NMD and escaping NMD may cause distinct neurological phenotypes.

Defective suppressor function of human CD4+ CD25+ regulatory T cells in autoimmune polyglandular syndrome type II.

Abstract: In autoimmune polyglandular syndromes (APS), several organ-specific autoimmune diseases are clustered. Although APS type I is caused by loss of central tolerance, the etiology of APS type II (APS-II) is currently unknown. However, in several murine models, depletion of CD4+ CD25+ regulatory T cells (Tregs) causes a syndrome resembling human APS-II with multiple endocrinopathies. Therefore, we hypothesized that loss of active suppression in the periphery could be a hallmark of this syndrome. Tregs from peripheral blood of APS-II, control patients with single autoimmune endocrinopathies, and normal healthy donors showed no differences in quantity (except for patients with isolated autoimmune diseases), in functionally important surface markers, or in apoptosis induced by growth factor withdrawal. Strikingly, APS-II Tregs were defective in their suppressive capacity. The defect was persistent and not due to responder cell resistance. These data provide novel insights into the pathogenesis of APS-II and possibly human autoimmunity in general.

DC-SIGN and DC-SIGNR Interact with the Glycoprotein of Marburg Virus and the S Protein of Severe Acute Respiratory Syndrome Coronavirus

Abstract: The lectins DC-SIGN and DC-SIGNR can augment viral infection; however, the range of pathogens interacting with these attachment factors is incompletely defined. Here we show that DC-SIGN and DC-SIGNR enhance infection mediated by the glycoprotein (GP) of Marburg virus (MARV) and the S protein of severe acute respiratory syndrome coronavirus and might promote viral dissemination. SIGNR1, a murine DC-SIGN homologue, also enhanced infection driven by MARV and Ebola virus GP and could be targeted to assess the role of attachment factors in filovirus infection in vivo.

The Structure of a Mycobacterial Outer-Membrane Channel

Abstract: Mycobacteria have low-permeability outer membranes that render them resistant to most antibiotics. Hydrophilic nutrients can enter by way of transmembrane-channel proteins called porins. An x-ray analysis of the main porin from Mycobacterium smegmatis, MspA, revealed a homooctameric goblet-like conformation with a single central channel. This is the first structure of a mycobacterial outer-membrane protein. No structure-related protein was found in the Protein Data Bank. MspA contains two consecutive β barrels with nonpolar outer surfaces that form a ribbon around the porin, which is too narrow to fit the thickness of the mycobacterial outer membrane in contemporary models.

Di(2-ethylhexyl)phthalate (DEHP) metabolites in human urine and serum after a single oral dose of deuterium-labelled DEHP

Abstract: Human metabolism of di(2-ethylhexyl)phthalate (DEHP) was studied after a single oral dose of 48.1 mg to a male volunteer. To avoid interference by background exposure the D4-ring-labelled DEHP analogue was dosed. Excretion of three metabolites, mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP) and mono(2-ethylhexyl)phthalate (MEHP), was monitored for 44 h in urine and for 8 h in serum. Peak concentrations of all metabolites were found in serum after 2 h and in urine after 2 h (MEHP) and after 4 h (5OH-MEHP and 5oxo-MEHP). While the major metabolite in serum was MEHP, the major metabolite in urine was 5OH-MEHP, followed by 5oxo-MEHP and MEHP. Excretion in urine followed a multi-phase elimination model. After an absorption and distribution phase of 4 to 8 h, half-life times of excretion in the first elimination phase were approximately 2 h with slightly higher half-life times for 5OH- and 5oxo-MEHP. Half-life times in the second phase-beginning 14 to 18 h post dose-were 5 h for MEHP and 10 h for 5OH-MEHP and 5oxo-MEHP. In the time window 36 to 44 h, no decrease in excreted concentrations of 5OH- and 5oxo-MEHP was observed. In the first elimination phase (8 to 14 h post dose), mean excretion ratios of MEHP to 5oxo-MEHP and MEHP to 5OH-MEHP were 1 to 1.8 and 1 to 3.1. In the second elimination phase up to 24 h post dose mean excretion ratios of MEHP to 5oxo-MEHP to 5OH-MEHP were 1 to 5.0 to 9.3. The excretion ratio of 5OH-MEHP to 5oxo-MEHP remained constant through time at 1.7 in the mean. After 44 h, 47% of the DEHP dose was excreted in urine, comprising MEHP (7.3%), 5OH-MEHP (24.7%) and 5oxo-MEHP (14.9%).