Clustering in an Object-Oriented Environment

This paper describes the incorporation of seven stand-alone clustering programs into S-PLUS, where they can now be used in a much more flexible way. The original Fortran programs carried out new cluster analysis algorithms introduced in the book of Kaufman and Rousseeuw (1990). These clustering methods were designed to be robust and to accept dissimilarity data as well as objects-by-variables data. Moreover, they each provide a graphical display and a quality index reflecting the strength of the clustering. The powerful graphics of S-PLUS made it possible to improve these graphical representations considerably. The integration of the clustering algorithms was performed according to the object-oriented principle supported by S-PLUS. The new functions have a uniform interface, and are compatible with existing S-PLUS functions. We will describe the basic idea and the use of each clustering method, together with its graphical features. Each function is briefly illustrated with an example.

Inflation, relative prices and nominal rigidities

This paper examines the distribution of Belgian consumer prices and its interaction with aggregate inflation over the period June 1976-September 2000. Given the fat-tailed nature of this distribution, both classical and robust measures of location, scale and skewness are presented. We found a positive short-run impact of the skewness of relative prices on aggregate inflation, irrespective of the average inflation rate. The dispersion of relative prices has also a positive impact on aggregate inflation in the short run and this impact is significantly lower in the sub-sample starting in 1988 than in the pre-1988 sub-sample, suggesting that the prevailing monetary policy regime has a substantial effect on this coefficient. The chronic right skewness of the distribution, revealed by the robust measures, is positively cointegrated with aggregate inflation, suggesting that it is largely dependent on the inflationary process itself and would disappear at zero inflation. These results have three important implications for monetary policy. First, as to the transmission of monetary policy, our results are in line with the predictions of menu cost models and therefore suggest that this type of friction can be an important factor behind the short run non-neutrality of monetary policy. Second, as to the design of robust estimators of core inflation, economic arguments based on menu cost models tend to highlight the importance of the absence of bias. We have proposed an unbiased estimator by taking the time-varying degree of chronic right skewness explicitly into account. Third, as to the optimal rate of inflation, the chronic right skewness found in the data provides no argument against price stability, as it appears as an endogenous response of optimising price setters and would disappear when targeting a zero inflation rate. This conclusion contrasts sharply with the implications of the exogenously assumed downward rigidity of Tobin (1972), which would justify targeting a sufficiently positive inflation rate in order to facilitate the adjustment of relative prices. Our empirical findings contradict the latter type of downward rigidity which implies a negative correlation between skewness and inflation. Therefore, the cross-sectional properties of Belgian inflation data do not provide strong arguments against a price stability-oriented monetary policy, such as the one pursued by the Eurosystem.

"Eingriffe in die Keimbahn sind für mich ein Tabu" : Gespräch mit dem Mediziner Hubert Serve und der Politikwissenschaftlerin Anja Karnein über die ethischen Grenzen der Zell- und Gentherapie

Je besser Forscher es verstehen, defekte Gene zu reparieren oder beliebige Körperzellen zu reprogrammieren, desto gefahrloser wird die Gen- und Stammzell-Therapie für Patienten, die an heute noch unheilbaren Krankheiten leiden. Gleichzeitig zeichnet sich damit die Möglichkeit ab, in ferner Zukunft vielleicht das Genom kommender Generationen zu verändern oder Menschen zu klonieren. Der Internist Prof. Hubert Serve und die Politikwissenschaftlerin Dr. Anja Karnein wagen im Gespräch mit den beiden Redakteurinnen des Wissenschaftsmagazins »Forschung Frankfurt« Dr. Anne Hardy und Ulrike Jaspers einen Ausblick jenseits aller aktuellen Debatten. Sie diskutieren aber auch über die Themen, die Patienten wie Wissenschaftler zurzeit unmittelbar berühren

Prostate Cancer Detection with mpMRI According to PI-RADS v2 Compared with Systematic MRI/TRUS-Fusion Biopsy: A Prospective Study

BACKGROUND: mpMRI assesses prostate lesions through their PI-RADS score. The primary goal of this prospective study was to demonstrate the correlation of PI-RADS v2 score and the volume of a lesion with the presence and clinical significance of prostate cancer (PCa). The secondary goal was to determine the extent of additionally PCa in inconspicuous areas. METHODS: All 157 patients underwent a perineal MRI/TRUS-fusion prostate biopsy. Targeted biopsies as well as a systematic biopsy were performed. The presence of PCa in the probes was specified by the ISUP grading system. RESULTS: In total, 258 lesions were biopsied. Of the PI-RADS 3 lesions, 24% were neoplastic. This was also true for 36.9% of the PI-RADS 4 lesions and for 59.5% of the PI-RADS 5 lesions. Correlation between ISUP grades and lesion volume was significant (p < 0.01). In the non-suspicious mpMRI areas carcinoma was revealed in 19.7% of the patients. CONCLUSIONS: The study shows that the PI-RADS v2 score and the lesion volume correlate with the presence and clinical significance of PCa. However, there are two major points to consider: First, there is a high number of false positive findings. Second, inconspicuous mpMRI areas revealed PCa

Differential activity of innate defense antimicrobial peptides against Nocardia species

<p>Abstract</p> <p>Background</p> <p>Members of the genus <it>Nocardia </it>are ubiquitous environmental saprophytes capable to cause human pulmonary, disseminated and cutaneous nocardiosis or bovine mastitis. Innate immunity appears to play an important role in early defense against <it>Nocardia </it>species. To elucidate the contribution of antimicrobial peptides (AMPs) in innate defense against <it>Nocardia</it>, the activity of human α-defensins human neutrophil peptides (HNPs) 1-3, human β-defensin (hBD)-3 and cathelicidin LL-37 as well as bovine β-defensins lingual and tracheal antimicrobial peptides (LAP, TAP) and bovine neutrophil-derived indolicidin against four important <it>Nocardia </it>species was investigated.</p> <p>Results</p> <p>Whereas <it>N. farcinica </it>ATCC 3318 and <it>N. nova </it>ATCC 33726 were found to be susceptible to all investigated human and bovine AMPs, <it>N. asteroides </it>ATCC 19247 was killed exclusively by neutrophil-derived human α-defensins HNP 1-3 and bovine indolicidin. <it>N. brasiliensis </it>ATCC 19296 was found to exhibit complete resistance to investigated human AMPs and to be susceptible only to bovine indolicidin.</p> <p>Conclusion</p> <p>Selected AMPs are capable to contribute to the first line of defense against <it>Nocardia</it>, yet, susceptibility appears to vary across different <it>Nocardia </it>species. Obtained results of neutrophil-derived AMPs to possess the broadest antinocardial spectrum are remarkable, since nocardiosis is characterized by a neutrophil-rich infiltrate <it>in vivo</it>.</p

Feasibility of azacitidine added to standard chemotherapy in older patients with acute myeloid leukemia - a randomised SAL pilot study

INTRODUCTION: Older patients with acute myeloid leukemia (AML) experience short survival despite intensive chemotherapy. Azacitidine has promising activity in patients with low proliferating AML. The aim of this dose-finding part of this trial was to evaluate feasibility and safety of azacitidine combined with a cytarabine- and daunorubicin-based chemotherapy in older patients with AML. TRIAL DESIGN: Prospective, randomised, open, phase II trial with parallel group design and fixed sample size. PATIENTS AND METHODS: Patients aged 61 years or older, with untreated acute myeloid leukemia with a leukocyte count of <20,000/µl at the time of study entry and adequate organ function were eligible. Patients were randomised to receive azacitidine either 37.5 (dose level 1) or 75 mg/sqm (dose level 2) for five days before each cycle of induction (7+3 cytarabine plus daunorubicine) and consolidation (intermediate-dose cytarabine) therapy. Dose-limiting toxicity was the primary endpoint. RESULTS: Six patients each were randomised into each dose level and evaluable for analysis. No dose-limiting toxicity occurred in either dose level. Nine serious adverse events occurred in five patients (three in the 37.5 mg, two in the 75 mg arm) with two fatal outcomes. Two patients at the 37.5 mg/sqm dose level and four patients at the 75 mg/sqm level achieved a complete remission after induction therapy. Median overall survival was 266 days and median event-free survival 215 days after a median follow up of 616 days. CONCLUSIONS: The combination of azacitidine 75 mg/sqm with standard induction therapy is feasible in older patients with AML and was selected as an investigational arm in the randomised controlled part of this phase-II study, which is currently halted due to an increased cardiac toxicity observed in the experimental arm

Ready for the OR? – Clinical anatomy and basic surgical skills for students in their preclinical education

Medical students’ first experience in the operating theatre often takes place during their electives and is therefore separated from the university’s medical curriculum. In the winter term 2009/10, the Institute of Anatomy and Cell Biology at the University of Ulm implemented an elective called “Ready for the OR” for 2nd year medical students participating in the dissection course. We attempted to improve learning motivation and examination results by transferring anatomical knowledge into a surgical setting and teaching basic surgical skills in preparation of the students’ first participation in the OR. Out of 69 online applicants, 50 students were randomly assigned to the Intervention Group (FOP) or the Control Group. In 5 teaching session students learned skills like scrubbing, stitching or the identification of frequently used surgical instruments. Furthermore, students visited five surgical interventions which were demonstrated by surgical colleagues on donated bodies that have been embalmed using the Thiel technique. The teaching sessions took place in the institute’s newly built “Theatrum Anatomicum” for an ideal simulation of a surgical setting. The learning outcomes were verified by OSPE. In a pilot study, an intervention group and a control group were compared concerning their examination results in the dissection course and their learning motivation through standardized SELLMO-test for students. Participants gained OSPE results between 60.5 and 92% of the maximum score. “Ready for the OR” was successfully implemented and judged an excellent add-on to anatomy teaching by the participants. However, we could not prove a significant difference in learning motivation or examination results. Future studies should focus on the learning orientation, the course’s long-term learning effects and the participants’ behavior in a real surgery setting

Phorbol-12-myristate-13-acetate is a potent enhancer of B cells with a granzyme B+ regulatory phenotype

IntroductionThe infusion of ex-vivo-generated regulatory B cells may represent a promising novel therapeutic approach for a variety of autoimmune and hyperinflammatory conditions including graft-versus-host disease.MethodsPreviously, we developed a protocol for the generation of a novel population of regulatory B cells, which are characterized by secretion of enzymatically active granzyme B (GraB cells). This protocol uses recombinant interleukin 21 (IL-21) and goat-derived F(ab)’2 fragments against the human B cell receptor (anti-BCR). Generally, the use of xenogeneic material for the manufacturing of advanced therapy medicinal products should be avoided to prevent adverse immune reactions as well as potential transmission of so far unknown diseases.ResultsIn the present work we demonstrated that phorbol-12-myristate-13-acetate (PMA/TPA), a phorbol ester with a particular analogy to the second messenger diacylglycerol (DAG), is a potent enhancer of IL-21-induced differentiation of pre-activated B cells into GraB cells. The percentage of GraB cells after stimulation of pre-activated B cells with IL-21 and PMA/TPA was not significantly lower compared to stimulation with IL-21 and anti-BCR.DiscussionGiven that PMA/TPA has already undergone encouraging clinical testing in patients with certain haematological diseases, our results suggest that PMA/TPA may be a safe and feasible alternative for ex-vivo manufacturing of GraB cells