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Introduction: Infantile oxalosis is the most severe form of primary hyperoxaluria type 1 (PH1), with onset of end-stage kidney disease (ESKD) during infancy. We aimed to analyze the outcome of these patients as our current understanding is limited owing to a paucity of reports. Methods: A retrospective registry study was conducted using data from the OxalEurope registry. All PH1 patients with ESKD onset at age

Nephronophthisis (NPH) is an autosomal-recessive ciliopathy representing one of the most frequent causes of kidney failure in childhood characterized by a broad clinical and genetic heterogeneity. Applied to one of the worldwide largest cohorts of patients with NPH, genetic analysis encompassing targeted and whole exome sequencing identified disease-causing variants in 600 patients from 496 families with a detection rate of 71%. Of 788 pathogenic variants, 40 known ciliopathy genes were identified. However, the majority of patients (53%) bore biallelic pathogenic variants in NPHP1. NPH-causing gene alterations affected all ciliary modules defined by structural and/or functional subdomains. Seventy six percent of these patients had progressed to kidney failure, of which 18% had an infantile form (under five years) and harbored variants affecting the Inversin compartment or intraflagellar transport complex A. Forty eight percent of patients showed a juvenile (5-15 years) and 34% a late-onset disease (over 15 years), the latter mostly carrying variants belonging to the Transition Zone module. Furthermore, while more than 85% of patients with an infantile form presented with extra-kidney manifestations, it only concerned half of juvenile and late onset cases. Eye involvement represented a predominant feature, followed by cerebellar hypoplasia and other brain abnormalities, liver and skeletal defects. The phenotypic variability was in a large part associated with mutation types, genes and corresponding ciliary modules with hypomorphic variants in ciliary genes playing a role in early steps of ciliogenesis associated with juvenile-to-late onset NPH forms. Thus, our data confirm a considerable proportion of late-onset NPH suggesting an underdiagnosis in adult chronic kidney disease.

BACKGROUND: Improved management of growth impairment might have resulted in less growth retardation after pediatric kidney transplantation (KT) over time. We aimed to analyze recent longitudinal growth data after KT in comparison to previous eras, its determinants, and the association with transplant outcome in a large cohort of transplanted children using data from the European Society for Paediatric Nephrology/European Renal Association and European Dialysis and Transplant Association Registry. METHODS: A total of 3492 patients transplanted before 18 years from 1990 to 2012 were included. Height SD scores (SDS) were calculated using recent national or European growth charts. We used generalized equation models to estimate the prevalence of growth deficit and linear mixed models to calculate adjusted mean height SDS. RESULTS: Mean adjusted height post-KT was -1.77 SDS. Height SDS was within normal range in 55%, whereas 28% showed moderate, and 17% severe growth deficit. Girls were significantly shorter than boys, but catch-up growth by 5 years post-KT was observed in both boys and girls. Children 12. CONCLUSIONS: Catch-up growth post-KT remains limited, height SDS did not improve over time, resulting in short stature in nearly half of transplanted children in Europe.

The Food Neophobia Scale (FNS) measures reluctance to try novel foods. In describing foods, the term complexity is not well defined. The objective of this work was to assess the acceptability of familiar and novel foods, with varying levels of flavor complexity in both salty and sweet foods, by food neophobics and neophilics and to assess the effect of expectation (frame-of-reference effect) and familiarity on the acceptability of foods. FNS was administered to 864 subjects, who were classified to neophobic, or neophilic based on their FNS scores. Experiment 1, which was replicated twice, focused on four familiar foods, prepared in two versions, an original version and a more flavorful version. Subjects rated foods on complexity, acceptability and expectation. Neophilics gave significantly higher acceptability ratings to complex foods than bland foods and vice versa for neophobics. The different versions of foods did not always meet panelists’ flavor expectations. Experiment 2 included eight commercial foods, four salty and four sweet, with two novel and two familiar foods used within each taste category/quality. One of the foods within the familiar or novel pairs was expected to be flavorful (e.g. chili is typically served as spicy) and the other expected to be bland. Subjects rated foods on complexity, acceptability, familiarity and expectation. Six out of the eight flavorful versions of foods were chosen by subjects as more complex. Significant factors were taste quality, novelty, expectation, and familiarity (p

Background and objectives The Wilms tumor suppressor gene 1 ( WT1 ) plays an essential role in urogenital and kidney development. Genotype/phenotype correlations of WT1 mutations with renal function and proteinuria have been observed in world-wide cohorts with nephrotic syndrome or Wilms tumor (WT). This study analyzed mid-European patients with known constitutional heterozygous mutations in WT1 , including patients without proteinuria or WT. Design, setting, participants & measurements Retrospective analysis of genotype, phenotype, and treatment of 53 patients with WT1 mutation from all pediatric nephrology centers in Germany, Austria, and Switzerland performed from 2010 to 2012. Results Median age was 12.4 (interquartile range [IQR], 6–19) years. Forty-four of 53 (83%) patients had an exon mutation (36 missense, eight truncating), and nine of 53 (17%) had an intronic lysine-threonine-serine (KTS) splice site mutation. Fifty of 53 patients (94%) had proteinuria, which occurred at an earlier age in patients with missense mutations (0.6 [IQR, 0.1–1.5] years) than in those with truncating (9.7 [IQR, 5.7–11.9]; P P= 0.004) mutations. Thirteen of 50 (26%) were treated with steroids and remained irresponsive, while three of five partially responded to cyclosporine A. Seventy-three percent of all patients required RRT, those with missense mutations significantly earlier (at 1.1 [IQR, 0.01–9.3] years) than those with truncating mutations (16.5 [IQR, 16.5–16.8]; P 0.001) and splice site mutations (12.3 [IQR, 7.9–18.2]; P =0.002). Diffuse mesangial sclerosis was restricted to patients with missense mutations, while focal segmental sclerosis occurred in all groups. WT occurred only in patients with exon mutations ( n =19). Fifty of 53 (94%) patients were karyotyped: Thirty-one (62%) had XY and 19 (38%) had XX chromosomes, and 96% of male karyotypes had urogenital malformations. Conclusions Type and location of WT1 mutations have predictive value for the development of proteinuria, renal insufficiency, and WT. XY karyotype was more frequent and associated with urogenital malformations in most cases.

Little is known about health-related quality of life (HRQoL) and mental health of parents having children with a history of hemolytic uremic syndrome (HUS). This study included 63 mothers and 58 fathers of a cohort of 63 HUS-affected children. At assessment, the mean time since a child experienced an acute episode of HUS was 6.4 years. Parental HRQoL, mental health and posttraumatic stress disorder (PTSD) were assessed with standardized self-report questionnaires. Medical data were extracted from patients’ hospital records. The HRQoL and mental health of both the mothers and fathers were not impaired compared to normative data. However, a shorter time since a child’s acute HUS episode was a significant predictor of lower HRQoL among the mothers, while no such effect was found among the fathers. Two fathers (3 %), but no mothers, met the criteria for a diagnosis of HUS-related full PTSD; one father (2 %) and four mothers (6 %) met the criteria for a diagnosis of HUS-related partial PTSD. Our study shows that most parents of our study sample were doing well in terms of HRQoL and mental health, although a small number met the criteria for full or partial PTSD diagnosis due to their child’s HUS. We therefore recommend that healthcare providers pay special attention to parents regarding PTSD symptoms during the clinical follow-up of a HUS-affected child since some parents may benefit from psychological support.

We investigate the influence of the interaction range of non-bonded monomers in an elastic, flexible polymer upon formation of structural phases. Massively parallel replica-exchange simulations of a generic, coarse-grained polymer model enable the construction of the structural phase diagram by means of microcanonical statistical analysis. Multiple solid phases, a liquid phase, and a gas-like phase can be identified. We find evidence for finite-size effects that cause the crossover of “collapse” and “freezing” transitions for very short interaction ranges.

Quantum adiabatic computations are designed to determine the ground state configurations of an classical problem Hamiltonian H3SAT within quantum theory and at imaginary time allow statistical mechanics studies for the computational e_ciency of the ground state search. We mention a recent determination of the quantum complexity, i.e. the mass-gap _mGAP for a specific ensemble of three-satisfiability (3SAT) problems with a unique satisfiability assignment, which shows an exponential increase of the gap correlation length _GAP with _GAP = 1=_mGAP. In 3SAT we present numerical data for the behavior of quantum Monte Carlo annealing cycles in search for the ground state. The findings show, that for the specific set of realizations quantum Monte Carlo searches in 3SAT fail above a sharp cut-o_ Kcut in the complexity K, which exemplifies the intractable nature of 3SAT.

Tobacco smoking, alcohol drinking, and occupational exposures to polycyclic aromatic hydrocarbons are the major proven risk factors for human head and neck squamous-cell cancer (HNSCC). Major research focus on gene-environment interactions concerning HNSCC has been on genes encoding enzymes of metabolism for tobacco smoke constituents and repair enzymes. To investigate the role of genetically determined individual predispositions in enzymes of xenobiotic metabolism and in repair enzymes under the exogenous risk factor tobacco smoke in the carcinogenesis of HNSCC, we conducted a case-control study on 312 cases and 300 noncancer controls. We focused on the impact of 22 sequence variations in CYP1A1, CYP1B1, CYP2E1, ERCC2/XPD, GSTM1, GSTP1, GSTT1, NAT2, NQO1, and XRCC1. To assess relevant main and interactive effects of polymorphic genes on the susceptibility to HNSCC we used statistical models such as logic regression and a Bayesian version of logic regression. In subgroup analysis of nonsmokers, main effects in ERCC2 (Lys751Gln) C/C genotype and combined ERCC2 (Arg156Arg) C/A and A/A genotypes were predominant. When stratifying for smokers, the data revealed main effects on combined CYP1B1 (Leu432Val) C/G and G/G genotypes, followed by CYP1B1 (Leu432Val) G/G genotype and CYP2E1 (-70G>T) G/T genotype. When fitting logistic regression models including relevant main effects and interactions in smokers, we found relevant associations of CYP1B1 (Leu432Val) C/G genotype and CYP2E1 (-70G>T) G/T genotype (OR, 10.84; 95% CI, 1.64-71.53) as well as CYP1B1 (Leu432Val) G/G genotype and GSTM1 null/null genotype (OR, 11.79; 95% CI, 2.18-63.77) with HNSCC. The findings underline the relevance of genotypes of polymorphic CYP1B1 combined with exposures to tobacco smoke.

Purpose: Outcomes in patients with brain metastases undergoing whole-brain radiotherapy (WBRT) are hardly encouraging, and an improvement in results is therefore needed. One possible approach is the addition of chemotherapeutics. However the data presented thus far are also disappointing. A promising substance in this setting could become topotecan, which is known to cross the blood–brain barrier and additionally offers radiosensitizing effects. Therefore we performed a phase I/II trial to evaluate the feasibility of a concurrent radiochemotherapy regimen. Methods and Materials: From January 1999 to July 2001, a total of 75 patients (10 in phase I and 65 in phase II) were included. The WBRT was applied with a fraction size of 2 Gy/day for a total of 40 Gy. Topotecan was administered as a 30-min infusion with 0.2 to 0.5 mg/m 2 /day for 5 days over 4 weeks within 2 h to radiation therapy. Results: Because of the higher toxic rates seen in patients receiving 0.5 mg/m 2 /day, the recommended dosage for phase II was 0.4 mg/m 2 /day. In this group Grade 3/4 hematologic and nonhematologic side effects occurred in 19% and 21% of the patients, respectively. The overall response rate was 72% with an overall survival of 17 weeks and 30 weeks among the responders. Conclusions: Based on the moderate toxicity profile presented here we recommend to perform a phase III trial to confirm the promising phase I/II data.

We report on a lattice investigation of heavy quark momentum diffusion within the pure SU(3) plasma above the deconfinement transition with the quarks treated to leading order in the heavy mass expansion. We measure the relevant "colour-electric" Euclidean correlator and based on several lattice spacing's perform the continuum extrapolation. This is necessary not only to remove cut-off effects but also the analytic continuation for the extraction of transport coefficients is well-defined only when a continuous function of the Euclidean time variable is available. We pay specific attention to scale setting in SU(3). In particular we present our determination for the critical temperature $T_c=1/({N_\tau}a) $ at values of $N_\tau \le 22$.

We explore a method developed in statistical physics which has been argued to have exponentially small finite-volume effects, in order to determine the critical temperature Tc of pure SU(3) gauge theory close to the continuum limit. The method allows us to estimate the critical coupling betac of the Wilson action for temporal extents up to Nt ~ 20 with < 0.1% uncertainties. Making use of the scale setting parameters r0 and sqrt{t0} in the same range of beta-values, these results lead to the independent continuum extrapolations Tc r0 = 0.7457(45) and Tc sqrt{t0} = 0.2489(14), with the latter originating from a more convincing fit. Inserting a conversion of r0 from literature (unfortunately with much larger errors) yields Tc / LambdaMSbar = 1.24(10)., 12 pages. v2: clarifications and references added, published version

In recent analytical work, Biskup et al. (Europhys. Lett., 60 (2002) 21) studied the behaviour of d-dimensional finite-volume liquid-vapour systems at a fixed excess δN of particles above the ambient gas density. By identifying a dimensionless parameter Δ(δN) and a universal constant Δc(d), they showed in the limit of large system sizes that for Δ Δc a droplet of the dense phase occurs ("condensed" system). Also the fraction λΔ of excess particles forming the droplet is given explicitly. Furthermore, they argue that the same is true for solid-gas systems. By making use of the well-known equivalence of the lattice-gas picture with the spin-(1/2) Ising model, we performed Monte Carlo simulations of the Ising model with nearest-neighbour couplings on a square lattice with periodic boundary conditions at fixed magnetisation, corresponding to a fixed particles excess. To test the applicability of the analytical results to much smaller, practically accessible system sizes, we measured the largest minority droplet, corresponding to the solid phase, at various system sizes (L = 40,...,640). Using analytic values for the spontaneous magnetisation m0, the susceptibility χ and the Wulff interfacial free energy density τW for the infinite system, we were able to determine λΔ numerically in very good agreement with the theoretical prediction.

Renal tubular dysgenesis is a clinical disorder that is observed in fetuses and characterized by the absence or poor development of proximal tubules, early onset and persistent oligohydramnios that leads to the Potter sequence, and skull ossification defects. It may be acquired during fetal development or inherited as an autosomal recessive disease. It was shown recently that autosomal recessive renal tubular dysgenesis is genetically heterogeneous and linked to mutations in the genes that encode components of the renin-angiotensin system. This study analyzed the clinical expression of the disease in 29 fetus/neonates from 18 unrelated families and evaluated changes in renal morphology and expression of the renin-angiotensin system. The disease was uniformly severe, with perinatal death in all cases as a result of persistent anuria and hypoxia related to pulmonary hypoplasia. Severe defects in proximal tubules were observed in all fetuses from 18 gestational weeks onward, and lesions also involved other tubular segments. They were associated with thickening of the renal arterial vasculature, from the arcuate to the afferent arteries. Renal renin expression was strikingly increased in 19 of 24 patients studied, from 13 families, whereas no renal renin was detected in four patients from three families. Angiotensinogen and angiotensin-converting enzyme were absent or present in only small amounts in the proximal tubule, in correlation with the severity of tubular abnormalities. No specific changes were detected in angiotensin II receptor expression. The severity and the early onset of the clinical and pathologic expression of the disease underline the major importance of this system in fetal kidney function and development in humans. The identification of the disease on the basis of precise histologic analysis and the research of the genetic defect now allow genetic counseling and early prenatal diagnosis.

TNF-alpha plays a pivotal role in inflammation processes which are mainly regulated by endothelial cells. While TNF-alpha induces apoptosis of several cell types like tumor cells, endothelial cells are resistant to TNFa mediated cell death. The cytotoxic effects of TNF-alpha on most cells are only evident if RNA or protein synthesis is inhibited, suggesting that de novo RNA or protein synthesis protect cells from TNF-alpha cytotoxicity, presumably by NF-kappaB mediated induction of protective genes. However, the cytoprotective genes involved in NF-kappaB dependent endothelial cell survival have not been sufficiently identified. In the present study, the suppression subtractive hybridization (SSH) method was employed to identify rarely transcribed TNF-alpha inducible genes in human arterial endothelial cells related to cell survival and cell cycle. The TNF-alpha-induced expression of the RNA binding protein p54(nrb) and the 14-3-3 protein HS1 as shown here for the first time may contribute to the TNF-alpha mediated cell protection of endothelial cells. These genes have been shown to play pivotal roles in cell survival and cell cycle control in different experimental settings. The concerted expression of these genes together with other genes related to cell protection and cell cycle like DnaJ, p21(cip1) and the ubiquitin activating enzyme E1 demonstrates the identification of new genes in the context of TNF-alpha induced gene expression patterns mediating the prosurvival effect of TNF-alpha in endothelial cells.

Clinical consequences of PKHD1 mutations in 164 patients with autosomal-recessive polycystic kidney disease (ARPKD). Background ARPKD is associated with mutations in the PKHD1 gene on chromosome 6p12. Most cases manifest peri-/neonatally with a high mortality rate in the first month of life while the clinical spectrum of surviving patients is much more variable than generally perceived. Methods We examined the clinical course of 164 neonatal survivors (126 unrelated families) over a mean observation period of 6 years (range 0 to 35 years). PKHD1 mutation screening was done by denaturing high-performance liquid chromatography (DHPLC) for the 66 exons encoding the 4074 aa fibrocystin/polyductin protein. Results and Conclusion This is the first study that reports the long-term outcome of ARPKD patients with defined PKHD1 mutations. The 1- and 10-year survival rates were 85% and 82%, respectively. Chronic renal failure was first detected at a mean age of 4 years. Actuarial renal survival rates [end point defined as start of dialysis/renal transplantation (RTX) or by death due to end-stage renal disease (ESRD)] were 86% at 5 years, 71% at 10 years, and 42% at 20 years. All but six patients (92%) had a kidney length above or on the 97th centile for age. About 75% of the study population developed systemic hypertension. Sequelae of congenital hepatic fibrosis and portal hypertension developed in 44% of patients and were related with age. Positive correlations could further be demonstrated between renal and hepatobiliary-related morbidity suggesting uniform disease progression rather than organ-specific patterns. PKHD1 mutation analysis revealed 193 mutations (70 novel ones; 77% nonconservative missense mutations). No patient carried two truncating mutations corroborating that one missense mutation is indispensable for survival of newborns. We attempted to set up genotype-phenotype correlations and to categorize missense mutations. In 96% of families we identified at least one mutated PKHD1 allele (overall detection rate 76.6%) indicating that PKHD1 mutation screening is a powerful diagnostic tool in patients suspected with ARPKD.

Stromal cell-derived factor-1 (SDF-1), mainly known as a chemotactic factor for haematopoietic progenitor cells, also provides angiogenetic potency. Since the intracellular signalling of SDF-1-induced neovascularization remains unclear, we studied in human umbilical arterial endothelial cells (HUAEC) the influence of SDF-1alpha on induction of the genes of early growth response-1 (Egr-1) and VEGF, as well as the activation of extracellular regulated kinases (ERK) 1/2, which are all known to be involved in endothelial cell proliferation. We found a time-dependent induction of Egr-1 and VEGF mRNA expression and phosphorylation of ERK1/2 by SDF-1alpha. Furthermore, we demonstrated that Egr-1 expression is dependent on ERK 1/2 activation. Finally, we tried to confirm the relevance of the induced gene expression by detecting the [3H]thymidine incorporation as a marker for cell proliferation in HUAEC after stimulation with SDF-1alpha alone or together with VEGF. This particular test showed, that SDF-1alpha alone has no effect, but is able to significantly enhance VEGF induced DNA synthesis. In summary, SDF-1alpha is involved in different steps of endothelial cell proliferation, but, since Egr-1 and VEGF offer different functions, it may also play a so far undefined role on other conditions of the endothelium.

Multicanonical ensemble simulations for the simulation of first-order phase transitions suffer from exponential slowing down. Monte Carlo autocorrelation times diverge exponentially with free energy barriers ΔF, which in L d boxes grow as L d−1. We exemplify the situation in a study of the 2D Ising-model at temperature T/T c =0.63 for two different lattice manifolds, toroidal lattices, and surfaces of cubes. For both geometries the effect is caused by discontinuous droplet shape transitions between various classical crystal shapes obeying geometrical constraints. We use classical droplet theory and numerical simulations to calculate transition points and barrier heights. On toroidal lattices we determine finite size corrections to the droplet free energy, which are given by a linear combination of Gibbs–Thomson corrections, capillary wave fluctuation corrections, constant terms, and logarithmic terms in the droplet volume. Tolman corrections are absent. In addition, we study the finite size effects on the condensation phase transition, which occurs in infinite systems at the Onsager value of the magnetization. We find that this transition is of discontinuous order also. A combination of classical droplet theory and Gibbs–Thomson corrections yields a fair description for the transition point and for the droplet size discontinuity for large droplets. We also estimate the nucleation barrier that has to be surmounted in the formation of the stable droplet at coexistence.

Neovascularization of the inflamed synovium and pannus is one of the hallmarks of chronic rheumatoid arthritis. It contributes to disease progression by supplying blood to the inflamed tissues and by recruiting immune competent and inflammatory cells. Angiogenesis is tightly regulated at several levels, but of significant importance is transcription. The Ets 1 transcription factor has been intimately linked to the regulation of angiogenesis under both physiological and pathological conditions and is induced in endothelial cells by vascular endothelial growth factor, the most important angiogenic factor in rheumatoid arthritis. We investigated Ets 1 expression in synovial membranes of joints in patients with active rheumatoid arthritis and compared the results to those obtained in patients with degenerative joint disease, which is characterized by significantly less neoangiogenesis. Using quantitative densitometric and real-time RT-PCR approaches, we found a significant upregulation of Ets 1 transcripts in rheumatic, compared to osteoarthritic, synovial membranes. Moreover, we were able to attribute both Ets 1 mRNA and Ets 1 protein to capillary endothelial cells of newly formed blood vessels by in situ hybridization and immunohistochemistry. Finally, our data suggest important roles of the Ets 1 transcription factor in the regulation of inflammatory angiogenesis in rheumatoid arthritis.

Aims The ATZ11 antibody has been well established for the identification of α1-anti-trypsin (AAT) molecule type PiZ (Z-AAT) in blood samples and liver tissue. In this study, we systematically analyzed the antibody for additional binding sites in human tissue. Methods and results Ultrastructural ATZ11 binding was investigated immunoelectron microscopically in human umbilical vein endothelial cells (HUVECs) and in platelets of a healthy individual. Human embryonic kidney (HEK293) cells were transiently transfected with Von Willebrand factor (VWF) and analyzed immunocytochemically using confocal microscopy and SDS-PAGE electrophoresis followed by western blotting (WB). Platelets and serum samples of VWF-competent and VWF-deficient patients were investigated using native PAGE and SDS-PAGE electrophoresis followed by WB. The specificity of the ATZ11 reaction was tested immunohistochemically by extensive antibody-mediated blocking of AAT- and VWF-antigens. ATZ11-positive epitopes could be detected in Weibel-Palade bodies (WPBs) of HUVECs and α-granules of platelets. ATZ11 stains pseudo-WBP containing recombinant wild-type VWF (rVWF-WT) in HEK293 cells. In SDS-PAGE electrophoresis followed by WB, anti-VWF and ATZ11 both identified rVWF-WT. However, neither rVWF-WT-multimers, human VWF-multimers, nor serum proteins of VWF-deficient patients were detected using ATZ11 by WB, whereas anti-VWF antibody (anti-VWF) detected rVWF-WT-multimers as well as human VWF-multimers. In human tissue specimens, AAT-antigen blockade using anti-AAT antibody abolished ATZ11 staining of Z-AAT in a heterozygous AAT-deficient patient, whereas VWF-antigen blockade using anti-VWF abolished ATZ11 staining of endothelial cells and megakaryocytes. Conclusions ATZ11 reacts with cellular bound and denatured rVWF-WT and human VWF as shown using immunocytochemistry and subsequent confocal imaging, immunoelectron microscopy, SDS-PAGE and WB, and immunohistology. These immunoreactions are independent of the binding of Z-AAT-molecules and non-Z-AAT complexes.

Objective: The objective of this retrospective study was to investigate the efficacy and safety of vinflunine monotherapy and the utility of second-line prognostic factors in patients with advanced or metastatic urothelial cancer relapsing/progressing during or after a prior platinum-containing regimen under daily routine clinical conditions in Germany. Methods: The selection was based on the marketing authorization indication and recommendations as well as on the evaluation of second-line prognostic factors issued from prior pivotal trials. Results: Eight centers across Germany provided a total of 21 patient records. Demographic and clinical characteristics were similar to the data previously reported in pivotal trials. Complete and partial response to vinflunine treatment was observed in 1 (4.8%) and 3 (14.3%) patients, respectively, resulting in an overall response rate of 19.1%. The disease control rate reached 47.7%. The median progression-free survival amounted to 4.4 months (95% CI 2.6-6.6), with a median overall survival of 6.2 months (95% CI 3.9-10.7). The observed toxicity profile was manageable and consistent with prior clinical trials: leukopenia (33.3%), neutropenia (9.5%), anemia (9.5%) and hyperglycemia (4.8%). The reported satisfaction rate with the treatment was 90.5 and 61.9% among patients and physicians, respectively. Conclusions: This retrospective study confirms that the clinical outcomes obtained from routine medical practice in Germany with vinflunine in the treatment of advanced/metastatic urothelial cancer are in line with the data observed in prior clinical trials.

We study with lattice Monte Carlo simulations the relation of global O(2) symmetry breaking in three dimensions to the properties of a geometrically defined vortex loop network. We find that different definitions of constructing a network lead to different results even in the thermodynamic limit, and that with typical definitions the percolation transition does not coincide with the thermodynamic phase transition. These results show that geometrically defined percolation observables need not display universal properties related to the critical behaviour of the system, and do not in general survive in the field theory limit., Comment: 14 pages; references added, version to appear in Phys.Lett.B

alpha1-Antitrypsin (AAT) deficiency is a common inherited cause of emphysema and cirrhotic liver disease. Current laboratory diagnosis of Pi (proteinase inhibitor) status by protein analysis depends on the availability of blood samples and has a limited accuracy. Single-strand conformational polymorphism (SSCP) analysis and direct DNA sequencing can be performed from blood cells or from tissue samples, but it is a time-consuming procedure not suitable for screening purposes. We used a Light-Cycler assisted PCR approach to identify the PiZ mutation and to determine hetero- and homozygous carrier status from whole blood and from paraffin-embedded archival tissue specimens. The results were compared to those obtained by standard PCR amplification followed by SSCP and direct DNA sequencing. Light-Cycler assisted PCR identified heterozygous PiZ mutations in 16 samples, a homozygous PiZ status in three cases, and wild-type PiM in five control samples. In all cases the results were confirmed by SSCP and direct DNA sequencing. Light-Cycler assisted PCR has a high detection rate for the PiZ mutation. It can be performed from blood or from fixed archival tissues, requires only small amounts of DNA, and allows a rapid diagnosis on a high output level.

We use lattice Monte Carlo simulations to study non-perturbatively the tension, i.e. the free energy per unit length, of an infinitely long vortex in the three-dimensional U(1)+Higgs theory. This theory is the low-energy effective theory of high-temperature scalar electrodynamics, the standard framework for cosmic string studies. The vortex tension is measured as a function of the mass parameter at a large value of the Higgs self-coupling, where the transition between the phases is continuous. It is shown that the tension gives an order parameter that can distinguish between the two phases of the system. We argue that the vortex tension can describe the physics of long strings without lattice artifacts, unlike vortex network percolation., 18 pages, 7 figures

We explore the compact U(1) lattice gauge theory with staggered fermions and gauge field action -\sum_P [\beta \cos(\Theta_P) + \gamma \cos(2\Theta_P)], both for dynamical fermions and in the quenched approximation. (\Theta_P denotes the plaquette angle.) In simulations with dynamical fermions at various \gamma \le -0.2 on 6^4 lattices we find the energy gap at the phase transition of a size comparable to the pure gauge theory for \gamma \le 0 on the same lattice, diminishing with decreasing \gamma. This suggests a second order transition in the thermodynamic limit of the theory with fermions for \gamma below some finite negative value. Studying the theory on large lattices at \gamma = -0.2 in the quenched approximation by means of the equation of state we find non-Gaussian values of the critical exponents associated with the chiral condensate, \beta \simeq 0.32 and \delta \simeq 1.8, and determine the scaling function. Furthermore, we evaluate the meson spectrum and study the PCAC relation., Comment: 21 pages

Background. In several large studies an association between certain single-nucleotide polymorphisms (SNP) of the calpain-10 gene (CAPN10) with type 2 diabetes mellitus (T2D) has been identified. Since T2D and gestational diabetes mellitus (GDM) seem to be linked pathophysiologically, we examined the frequencies of CAPN10-polymorphisms in women with GDM. Methods. By using real-time PCR assisted melting curve analysis samples of 204 women with GDM and 297 controls were tested for variations of SNP-43, -44, -63 and Indel-19 of CAPN10. Results. Since the genotype frequencies found in SNP-44 among the controls did not meet the Hardy-Weinberg-Equilibrium, the further analysis was performed with SNP-43, -63 and Indel-19 only. Herein, the distribution of neither genotype nor allele nor haplogenotype-combination nor haplotype showed a significant difference between both groups. Conclusions. Variations of SNP-43, -63 and Indel-19 of CAPN10 were not associated with an increased risk of developing GDM.

Die Integration von leistungsgewandelten Mitarbeitern und Mitarbeitern mit Behinderung ist vor dem Hintergrund des demografischen Wandels eine der zentralen Herausforderungen fur die Automobilindustrie. Audi entwickelte in einer interdisziplinaren Arbeitsgruppe eine Systematik mit dem Ziel, diese Mitarbeitergruppe nachhaltig und produktiv zu integrieren. Grundsatzliche Idee ist es, in einem strukturierten, jahrlichen Prozess die Leistung des Mitarbeiters durch verschiedene Masnahmen wie z. B. ergonomische Verbesserungen so zu erhohen, dass der Mitarbeiter die geforderte Audi Standardleistung erbringen kann. Sollte dies nicht moglich sein, so wird die arbeitsplatzbezogene Differenz zur Audi Standardleistung (das sogenannte Leistungsdefizit) ermittelt und ausgewiesen, um die entstehenden Kosten transparent darzustellen.

We systematically investigate how the range of interaction between non-bonded monomers influences the formation of structural phases of elastic, flexible polymers. Massively parallel replica-exchange simulations of a generic, coarse-grained model, performed partly on graphics processing units and in multiple-gaussian modified ensembles, pave the way for the construction of the structural phase diagram, parametrized by interaction range and temperature. Conformational transitions between gas-like, liquid, and diverse solid (pseudo) phases are identified by microcanonical statistical inflection-point analysis. We find evidence for finite-size effects that cause the crossover of "collapse" and "freezing" transitions for very short interaction ranges.

The line of phase transitions, separating the confinement and the Coulomb phases in the four-dimensional pure compact U(1) gauge theory with extended Wilson action, is reconsidered. We present new numerical evidence that a part of this line, including the original Wilson action, is of second order. By means of a high precision simulation on homogeneous lattices on a sphere we find that along this line the scaling behavior is determined by one fixed point with distinctly non-Gaussian critical exponent nu = 0.365(8). This makes the existence of a nontrivial and nonasymptotically free four-dimensional pure U(1) gauge theory in the continuum very probable. The universality and duality arguments suggest that this conclusion holds also for the monopole loop gas, for the noncompact abelian Higgs model at large negative squared bare mass, and for the corresponding effective string theory., Comment: 11 pages, LaTeX, 2 figures

The present study investigated the metabolism of glyceryl trinitrate by washed human platelets as compared to that by rat vascular smooth muscle cells. Possible changes in metabolism after induction of nitrate tolerance were also studied in both systems. Incubation of the cells with glyceryl trinitrate (0.1 mM) resulted in a time-dependent release of nitrite (NO2-) amounting to 6.30 +/- 0.63 nmol mg protein-1 h-1 in vascular smooth muscle cells and 0.61 +/- 0.08 nmol mg protein-1 h-1 for platelets, respectively. The nitric oxide (NO) scavenger, oxyhemoglobin (10 microM), significantly reduced NO2- generation in both cell types studied. Nitrate tolerance was induced by incubation of the cells with glyceryl trinitrate (2 mM) for 2 h. In tolerant vascular smooth muscle cells as well as in tolerant platelets, NO2- release was significantly reduced. The inhibitory capacity of glyceryl trinitrate on ADP (6 microM)-induced platelet aggregation and on intracellular Ca2+ signals was significantly reduced in tolerant platelets. The data show a direct metabolism of glyceryl trinitrate by human blood platelets which is subject to a type of tolerance development similar to that in vascular smooth muscle cells.

We present results for 2D and 4D systems on lattices with topology homotopic to the surface of a (hyper) sphere $S^2$ or $S^4$. Finite size scaling is studied in situations with phase transitions of first and second order type. The Ising and Potts models exhibit the expected behaviour; for the 4D pure gauge $U(1)$ theory we find consistent scaling indicative of a second order phase transition with critical exponent $\nu\simeq 0.36(1)$., Comment: 4 pages, LaTeX, 3 POSTSCRIPT figures (uuencoded)

The C-terminal peptide of thrombospondin (4N1-1) stimulates distinct signalling pathways but induces an activation-independent platelet aggregation. This study demonstrates inhibitory effects of epigallocatechin gallate (EGCG), a major flavonoid component of green tea, on 4N1-1-induced aggregation of washed human platelets. Thrombin (0.1 U/ml)-induced platelet aggregation was completely inhibited by prostaglandin E1 (PGE1, 300 nM). In contrast, platelet aggregation induced by 4N1-1 (100 microM) was not affected by PGE1. However, epigallocatechin gallate (EGCG), but not other catechins from green tea, concentration-dependently inhibited 4N1-1-induced platelet aggregation. Thus, dietary components, such as EGCG, may inhibit platelet function even under conditions, when 'classical' platelet inhibitors, such as cAMP-elevating agents, are not effective.

We study the phase structure and the chiral limit of $4d$ compact lattice QED with Wilson fermions (both dynamical and quenched). We use the standard Wilson gauge action and also a modified one suppressing lattice artifacts. Different techniques and observables to locate the chiral limit are discussed., Comment: 17 pages, 14 figures attached as compressed postscript files, preprint DESY and HU Berlin-IEP-94/13

Tyrosine kinase inhibitors (TKI) play a pivotal role in the modern treatment of patients with metastatic renal cell carcinoma (mRCC). Depending on the course and the response, the targeted therapy may last for years. Thus the question arises, if a successful treatment leading to a complete response or at least a stable disease after a partial remission, may be discontinued.Here we present 3 patients with mRCC treated with sunitinib for at least one year, resulting in a partial response, followed by a stable disease for several years. In these patients, the treatment was interrupted for different medical reasons.After a period of 20, 33 and 34 months, respectively, the metastases of the renal cell cancer showed no signs of progression, neither clinically nor in computed tomography scans, but the side effects of TKI or the medical problem leading to treatment interruption resolved in all patients within a few weeks.The discontinuation of the treatment for mRCC with TKI seems to be possible, even in those patients with a partial response only, but no complete remission has been achieved before.

Thymoma and thymic carcinoma are rare neoplasms of the mediastinum, arising from the epithelial cells of the thymus. While surgical resection is the treatment of choice in early stages, platin-based chemotherapy is mainly used in patients with advanced or metastatic disease; however, the prognosis is poor. Here we present the case of a 54 year old female patient suffering from a CD117-negative thymic carcinoma with widespread metastases. After several courses of different kinds of chemotherapy, finally these approaches failed to be effective. Thus we initiated a treatment with sorafenib, an inhibitor of several receptor tyrosine kinases. The treatment was tolerated very well, and within a few weeks the general condition of the patient improved significantly. A CT-scan, performed 3 months after therapy with sorafenib started, showed a 50 % reduction of tumor size, and this effect lasted for 15 months. When the carcinoma relapsed again, we administered another course of chemotherapy and, because of lacking success, we even tried to use sunitinib. However, the patient died in a septic shock, based on progressive disease. In summary, we present a patient with metastastic thymic carcinoma, in which sorafenib led to a tumor-control for 18 months.

Persistent and intractable hiccups are a rather rare, but distressing gastrointestinal symptom found in palliative care patients. Although several recommendations for treatment are given, hiccups often persist.We describe a new pharmacological approach for successfully treating hiccups in four cancer patients. In the first patient, chronic and intractable hiccups lasted for more than 18 months, but disappeared immediately after swallowing a viscous 2 % lidocaine solution for treatment of mucositis. Based on this experience, we successfully treated three further patients suffering from singultus using a lidocaine-containing gel. To our knowledge, this is the first report about managing hiccups by oral application of a lidocaine solution.

It is demonstrated that the canonical distribution for a subsystem of a closed system follows directly from the solution of the time-reversible Newtonian equation of motion in which the total energy is strictly conserved. It is shown that this conclusion holds for both integrable or nonintegrable systems even though the whole system may contain as little as a few thousand particles. In other words, we demonstrate that the canonical distribution holds for subsystems of experimentally relevant sizes and observation times., Comment: Comment are welcome

Background: Most patients (pts) diagnosed with Acute Myeloid Leukemia (AML) are older than 60 years. Although intensive induction chemotherapy in medically fit pts is still the standard practice and a prerequisite for long-term survival, elderly pts have a higher risk of treatment related morbidity and lower remission rates than younger AML pts. An optimized induction treatment would combine high complete remission (CR) rates with tolerable toxicity. The combination of intermediate-dose cytarabine plus mitoxantrone (IMA) has been reported to result in high CR rates (73.5%) with acceptable toxicity in 86 elderly AML pts (Niederwieser et al., Blood 2002, abstr. 1337). We present the mature final results of a randomized-controlled trial comparing efficacy and tolerability of IMA with the standard 7+3 induction regimen consisting of daunorubicin plus cytarabine (DA). Patients and Methods: In the 60+ trial of the Study Alliance Leukemia (SAL), AML pts >60 years and medically fit for chemotherapy were randomized to receive either intermediate-dose cytarabine (1000 mg/m2 BID days 1,3,5,7) plus mitoxantrone (10 mg/m2 days 1-3) (IMA) or standard induction therapy with cytarabine (100 mg/m2 continuously days 1-7) plus daunorubicin (45 mg/m2 days 3-5) (DA). All pts in CR after DA received intermediate-dose cytarabine plus amsacrine (MAMAC) as consolidation treatment, whereas pts in CR after IMA were consolidated with standard-dose cytarabine plus mitoxantrone (2+5). Primary study endpoint was the CR rate with an expected difference of 15% in favor of IMA. Secondary endpoints were the incidence of serious adverse events (SAEs), time to relapse (TTR), relapse-free survival (RFS), and overall survival (OS). Results: Between February 2005 and October 2009, 852 pts were screened for study inclusion and 485 pts started study treatment, of which 241 pts were randomized for treatment arm A (DA) and 244 for treatment arm B (IMA). The median age was 69 years. Pt characteristics were equally distributed between the two arms. According to a strict definition, all patients with early death, study drop-out, or failed remission assessment were categorized as being not in CR. The CR rate amongst all 485 pts treated in the study was 47%. The CR rate after DA was 39% (95%-CI; 33-45) versus 55% (95%-CI; 49-61) after IMA (OR 1.89, p=0.001). If all first CRs were taken into account including those achieved after trial discontinuation, the CR rates after DA versus IMA induction were 55% versus 64% (p=0.043). Separate analyses addressing age, cytogenetics, de novo AML, NPM1 and FLT3-ITD confirmed higher CR rates after IMA induction throughout these subgroups. Six-week mortality was 14% in both arms. The median duration of ≥ grade 3 neutropenia was 23 days after DA I and 25 days after IMA (p=0.031). The median duration of thrombocytopenia ≥ grade 3 was 16 versus 20 days after DA I and IMA I, respectively (p In the course of treatment, 11 pts in each arm (5%) received allogeneic stem cell transplantation. After a median follow-up of 66 months, RFS curves are superimposable in the first year with a similar median RFS of 11 months and 10 months after DA and IMA, respectively. However, a separation of RFS curves developed with longer follow up, resulting in 1-year RFS rates of 45% versus 46%, but 3-year RFS rates of 29% versus 14% in the DA versus IMA arms, respectively (p=0.042). The median OS for all randomized pts was 10 months in both arms; 1-year and 3-year OS rates were 45% and 19% after DA versus 44% and 19% after IMA (p=0.513). Conclusion: The results indicate that elderly AML pts benefit from a dose escalation of cytarabine in induction therapy by significantly higher CR rates and similar toxicity compared to a standard 7+3 approach. In our trial, this did not translate into a survival advantage, most likely due to differences in consolidation treatment of the respective treatment arms. In combination with an effective consolidation strategy such as high-dose cytarabine or allogeneic transplantation, our current results favor the use of intermediate dose cytarabine in induction for pts with a curative AML treatment approach. Figure 1. CR rates depending on induction treatment Figure 1. CR rates depending on induction treatment Disclosures Einsele: Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Amgen/Onyx: Consultancy, Honoraria, Speakers Bureau. Thiede:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AgenDix GmBH: Equity Ownership. Platzbecker:Amgen, Inc.: Honoraria; GlaxoSmithKline: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Honoraria. Ehninger:Cellex GmbH: Equity Ownership.

We estimate the momentum diffusion coefficient of a heavy quark within a pure SU(3) plasma at a temperature of about 1.5Tc. Large-scale Monte Carlo simulations on a series of lattices extending up to 192^3*48 permit us to carry out a continuum extrapolation of the so-called colour-electric imaginary-time correlator. The extrapolated correlator is analyzed with the help of theoretically motivated models for the corresponding spectral function. Evidence for a non-zero transport coefficient is found and, incorporating systematic uncertainties reflecting model assumptions, we obtain kappa = (1.8 - 3.4)T^3. This implies that the "drag coefficient", characterizing the time scale at which heavy quarks adjust to hydrodynamic flow, is (1.8 - 3.4) (Tc/T)^2 (M/1.5GeV) fm/c, where M is the heavy quark kinetic mass. The results apply to bottom and, with somewhat larger systematic uncertainties, to charm quarks., Comment: 18 pages. v2: clarifications added