Prognostic factors in seminomas with special respect to HCG: Results of a prospective multicenter study

Objective: In a prospective multicenter trial, it was our intention to elucidate clinical prognostic factors of seminomas with special reference to the importance of human chorionic gonadotropin (HCG) elevations in histologically pure seminomas. Methods: Together with 96 participating urological departments in Germany, Austria, and Switzerland, we recruited 803 seminoma patients between 1986 and 1991. Out of 726 evaluable cases, 378 had elevated, while 348 had normal HCG values in the cubital vein. Histology was reviewed by two reference pathologists. HCG levels were determined in local laboratories and in a study laboratory. Standard therapy was defined as radiotherapy in stages I (30 Gy) and IIA/B (36 Gy) to the paraaortal and the ispilateral (stage I) and bilateral (stage IIA/B) iliac lymph nodes; higher stages received polychemotherapy and surgery in case of residual tumor masses. Statistics included chi-square tests, linear Cox regression, and log-rank test. Results: The HCG elevation is associated with a larger tumor mass (primary tumor and/or metastases). HCG-positive and HCG-negative seminomas had no different prognostic outcome after standard therapy. The overall relapse rate of 6% and the survival rate of 98% after 36 months (median) indicate an excellent prognosis. The calculation of the relative risk of developing a relapse discovered only stage of the disease and elevation of the lactate dehydrogenase concentration and its prolonged marker decay as independent prognostic factors for seminomas. A more detailed analysis of the prognostic significance of the stage revealed that the high relapse rate in stage IIB seminomas after radiotherapy (24%) is responsible for this result. Conclusions: We conclude that HCG-positive seminomas do not represent a special entity. Provided standard therapy is applied, HCG has no influence on the prognosis. Patients with stage IIB disease should be treated with chemotherapy because of the demonstrated higher relapse rate outside the retroperitoneum. Copyright (C) 1999 S. Karger AG. Basel

Constructing the Cubus simus and the Dodecaedron simum via paper folding

The archimedean solids Cubus simus (snub cube) and Dodecaedron simum (snub dodecahedron) cannot be constructed by ruler and compass. We explain that for general reasons their vertices can be constructed via paper folding on the faces of a cube, respectively dodecahedron, and we present explicit folding constructions. The construction of the Cubus simus is particularly elegant. We also review and prove the construction rules of the other Archimedean solids.Comment: 13 pages, 12 figures, v2: as published in Geometriae Dedicat

Board 317: Improving Undergraduate STEM Writing: A Collaboration Between Instructors and Writing Center Directors to Improve Peer-Writing Tutor Feedback

Undergraduate STEM writing skills, especially in engineering fields, need improvement. Yet students in engineering fields often do not value writing skills and underestimate the amount of writing they will do in their careers. University writing centers can be a helpful resource, but peer writing tutors need to be prepared for the differences between writing for the humanities and writing in STEM fields. The Writing Assignment Tutor Training in STEM (WATTS) model is designed to improve tutor confidence and student writing. In this innovative training, the writing center supervisor collaborates with the STEM instructor to create a one-hour tutor-training where the tutors learn about the assignment content, vocabulary, and expectations. This multidisciplinary collaborative project builds on previous investigative work to determine the impact of WATTS on students, tutors, and faculty and to identify its mitigating and moderating effects. Data has been collected and analyzed from pre- and post- training surveys, interviews, and focus groups. In addition, the project studies WATTS effects on student writing pre- and post-tutoring. The team will use these results to develop a replicable, sustainable model for future expansion to other institutions and fields. By systematically collecting data and testing WATTS, the investigators will be able to identify its mitigating and moderating effects on different stakeholders and contribute valuable knowledge to STEM fields. This approach assesses the elements of the model that have the most impact and the extent to which WATTS can be used to increase collaboration between engineering instructors and writing centers. The project enables the investigators to expand WATTS to additional engineering courses, test key factors with more instructors, refine the process, and position WATTS for dissemination to a broad audience. As the cost of higher education rises, institutions are pressured to graduate students in four years and engineering curricula are becoming more complex. WATTS presents an economical, effective method to improve student writing in the discipline. Several factors indicate that it has the potential for broad dissemination and impact and will provide a foundation for a sustainable model for future work, as instructors become trainers for their colleagues, allowing additional ongoing expansion and implementation. WATTS serves as a model for institutions (large or small) to capitalize on existing infrastructure and resources to achieve large-scale improvements to undergraduate STEM writing while increasing interdisciplinary collaboration and institutional support

Interrater reliability of motor severity scales for hemifacial spasm

To compare the inter-rater reliability (IRR) of five clinical rating scales for video-based assessment of hemifacial spasm (HFS) motor severity. We evaluated the video recordings of 45 HFS participants recruited through the Dystonia Coalition. In Round 1, six clinicians with expertise in HFS assessed the participants\u27 motor severity with five scales used to measure motor severity of HFS: the Jankovic rating scale (JRS), Hemifacial Spasm Grading Scale (HSGS), Samsung Medical Center (SMC) grading system for severity of HFS spasms (Lee\u27s scale), clinical grading of spasm intensity (Chen\u27s scale), and a modified version of the Abnormal Involuntary Movement Scale (Tunc\u27s scale). In Round 2, clinicians rated the same cohort with simplified scale wording after consensus training. For each round, we evaluated the IRR using the intraclass correlation coefficient [ICC (2,1) single-rater, absolute-agreement, 2-way random model]. The scales exhibited IRR that ranged from poor to moderate ; the mean ICCs were 0.41, 0.43, 0.47, 0.43, and 0.65 for the JRS, HSGS, Lee\u27s, Chen\u27s, and Tunc\u27s scales, respectively, for Round 1. In Round 2, the corresponding IRRs increased to 0.63, 0.60, 0.59, 0.53, and 0.71. In both rounds, Tunc\u27s scale exhibited the highest IRR. For clinical assessments of HFS motor severity based on video observations, we recommend using Tunc\u27s scale because of its comparative reliability and because clinicians interpret the scale easily without modifications or the need for consensus training

BK polyomavirus microRNA levels in exosomes are modulated by non-coding control region activity and down-regulate viral replication when delivered to non-infected cells prior to infection

In immunosuppressed patients, BKPyV-variants emerge carrying rearranged non-coding control-regions (rr-NCCRs) that increase early viral gene region (EVGR) expression and replication capacity. BKPyV also encodes microRNAs, which have been reported to downregulate EVGR-encoded large T-antigen transcripts, to decrease viral replication in infected cells and to be secreted in exosomes. To investigate the interplay of NCCR and microRNAs, we compared archetype- and rr-NCCR-BKPyV infection in cell culture. We found that laboratory and clinical rr-NCCR-BKPyV-strains show higher replication rates but significantly lower microRNA levels than archetype virus intracellularly and in exosomes. To investigate whether rr-NCCR or increased EVGR activity modulated microRNA levels, we examined the (sp1-4)NCCR-BKPyV, which has an archetype NCCR-architecture but shows increased EVGR expression due to point mutations inactivating one Sp1 binding site. We found that microRNA levels following (sp1-4)NCCR-BKPyV infection were as low as in rr-NCCR-variants. Thus, NCCR rearrangements are not required for lower miRNA levels. Accordingly, Sp1 siRNA knock-down decreased microRNA levels in archetype BKPyV infection but had no effect on (sp1-4)- or rr-NCCR-BKPyV. However, rr-NCCR-BKPyV replication was downregulated by exosome preparations carrying BKPyV-microRNA prior to infection. To explore the potential relevance in humans, urine samples from 12 natalizumab-treated multiple sclerosis patients were analysed. In 7 patients, rr-NCCR-BKPyV were detected showing high urine BKPyV loads but low microRNAs levels, whereas the opposite was seen in 5 patients with archetype BKPyV. We discuss the results in a dynamic model of BKPyV replication according to NCCR activity and exosome regulation, which integrates immune selection pressure, spread to new host cells and rr-NCCR emergence

The CACNA1B R1389H variant is not associated with myoclonus-dystonia in a large European multicentric cohort.

Myoclonus-dystonia (M-D) is a very rare movement disorder, caused in ∼30-50% of cases by mutations in SGCE. The CACNA1B variant c.4166G>A; (p.R1389H) was recently reported as the likely causative mutation in a single 3-generation Dutch pedigree with five subjects affected by a unique dominant M-D syndrome and cardiac arrhythmias. In an attempt to replicate this finding, we assessed by direct sequencing the frequency of CACNA1B c.4166G>A; (p.R1389H) in a cohort of 520 M-D cases, in which SGCE mutations had been previously excluded. A total of 146 cases (28%) had a positive family history of M-D. The frequency of the variant was also assessed in 489 neurologically healthy controls and in publicly available data sets of genetic variation (1000 Genomes, Exome Variant Server and Exome Aggregation Consortium). The variant was detected in a single sporadic case with M-D, but in none of the 146 probands with familial M-D. Overall, the variant was present at comparable frequencies in M-D cases (1 out of 520; 0.19%) and healthy controls (1 out of 489; 0.2%). A similar frequency of the variant was also reported in all publicly available databases. These results do not support a causal association between the CACNA1B c.4166G>A; (p.R1389H) variant and M-D

Methionine Sulfoxide Reductases Are Essential for Virulence of Salmonella Typhimurium

Production of reactive oxygen species represents a fundamental innate defense against microbes in a diversity of host organisms. Oxidative stress, amongst others, converts peptidyl and free methionine to a mixture of methionine-S- (Met-S-SO) and methionine-R-sulfoxides (Met-R-SO). To cope with such oxidative damage, methionine sulfoxide reductases MsrA and MsrB are known to reduce MetSOs, the former being specific for the S-form and the latter being specific for the R-form. However, at present the role of methionine sulfoxide reductases in the pathogenesis of intracellular bacterial pathogens has not been fully detailed. Here we show that deletion of msrA in the facultative intracellular pathogen Salmonella (S.) enterica serovar Typhimurium increased susceptibility to exogenous H2O2, and reduced bacterial replication inside activated macrophages, and in mice. In contrast, a ΔmsrB mutant showed the wild type phenotype. Recombinant MsrA was active against free and peptidyl Met-S-SO, whereas recombinant MsrB was only weakly active and specific for peptidyl Met-R-SO. This raised the question of whether an additional Met-R-SO reductase could play a role in the oxidative stress response of S. Typhimurium. MsrC is a methionine sulfoxide reductase previously shown to be specific for free Met-R-SO in Escherichia (E.) coli. We tested a ΔmsrC single mutant and a ΔmsrBΔmsrC double mutant under various stress conditions, and found that MsrC is essential for survival of S. Typhimurium following exposure to H2O2, as well as for growth in macrophages, and in mice. Hence, this study demonstrates that all three methionine sulfoxide reductases, MsrA, MsrB and MsrC, facilitate growth of a canonical intracellular pathogen during infection. Interestingly MsrC is specific for the repair of free methionine sulfoxide, pointing to an important role of this pathway in the oxidative stress response of Salmonella Typhimurium

Methionine Sulfoxide Reductase A (MsrA) Deficient Mycoplasma genitalium Shows Decreased Interactions with Host Cells

Mycoplasma genitalium is an important sexually transmitted pathogen that affects both men and women. In genital-mucosal tissues, it initiates colonization of epithelial cells by attaching itself to host cells via several identified bacterial ligands and host cell surface receptors. We have previously shown that a mutant form of M. genitalium lacking methionine sulfoxide reductase A (MsrA), an antioxidant enzyme which converts oxidized methionine (Met(O)) into methionine (Met), shows decreased viability in infected animals. To gain more insights into the mechanisms by which MsrA controls M. genitalium virulence, we compared the wild-type M. genitalium strain (G37) with an msrA mutant (MS5) strain for their ability to interact with target cervical epithelial cell lines (HeLa and C33A) and THP-1 monocytic cells. Infection of epithelial cell lines with both strains revealed that MS5 was less cytotoxic to HeLa and C33A cell lines than the G37 strain. Also, the MS5 strain was more susceptible to phagocytosis by THP-1 cells than wild type strain (G37). Further, MS5 was less able to induce aggregation and differentiation in THP-1 cells than the wild type strain, as determined by carboxyfluorescein diacetate succinimidyl ester (CFSE) labeling of the cells, followed by counting of cells attached to the culture dish using image analysis. Finally, MS5 was observed to induce less proinflammatory cytokine TNF-α by THP-1 cells than wild type G37 strain. These results indicate that MsrA affects the virulence properties of M. genitalium by modulating its interaction with host cells