Loss of inhibition over master pathways of bone mass regulation results in osteosclerotic bone metastases in prostate cancer

Prostate cancer is the most common cancer among men in industrialised countries. Most patients with prostate cancer, however, will not die of it. As a result, many of them will experience symptomatic metastasis during the course of the disease. Prostate cancer has a high propensity to metastasize to bone. Unlike many other cancers prostate cancer cells induce a rather osteosclerotic than osteolytic reaction in the bone marrow by interfering with physiological bone remodelling. A proper understanding of the mechanisms of tumour cell-induced bone alterations and exaggerated bone deposition in prostate cancer may open new and urgently needed therapeutic approaches in the field of palliative care for affected patients. In this review we focus on the central role of two major regulators of bone mass, the wingless type integration site family members (WNTs) and the bone morphogenetic proteins (BMPs), in the development of osteosclerotic bone metastases.

BETASCAN: probable beta-amyloids identified by pairwise probabilistic analysis

Amyloids and prion proteins are clinically and biologically important beta-structures, whose supersecondary structures are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Recent work has indicated the utility of pairwise probabilistic statistics in beta-structure prediction. We develop here a new strategy for beta-structure prediction, emphasizing the determination of beta-strands and pairs of beta-strands as fundamental units of beta-structure. Our program, BETASCAN, calculates likelihood scores for potential beta-strands and strand-pairs based on correlations observed in parallel beta-sheets. The program then determines the strands and pairs with the greatest local likelihood for all of the sequence's potential beta-structures. BETASCAN suggests multiple alternate folding patterns and assigns relative a priori probabilities based solely on amino acid sequence, probability tables, and pre-chosen parameters. The algorithm compares favorably with the results of previous algorithms (BETAPRO, PASTA, SALSA, TANGO, and Zyggregator) in beta-structure prediction and amyloid propensity prediction. Accurate prediction is demonstrated for experimentally determined amyloid beta-structures, for a set of known beta-aggregates, and for the parallel beta-strands of beta-helices, amyloid-like globular proteins. BETASCAN is able both to detect beta-strands with higher sensitivity and to detect the edges of beta-strands in a richly beta-like sequence. For two proteins (Abeta and Het-s), there exist multiple sets of experimental data implying contradictory structures; BETASCAN is able to detect each competing structure as a potential structure variant. The ability to correlate multiple alternate beta-structures to experiment opens the possibility of computational investigation of prion strains and structural heterogeneity of amyloid. BETASCAN is publicly accessible on the Web at http://betascan.csail.mit.edu.

Hotshots, hot spots, and female preference: exploring lek formation models with a bower-building cichlid fish

In many animals, males congregate in leks that females visit for the sole purpose of mating. We observed male and female behavior on 3 different-sized leks of the bower-building cichlid fish Nyassachromis cf. microcephalus to test predictions of 3 prominent lek models: the "hotshot," "hot spot," and "female preference" models. In this system, we were able to refine these predictions by distinguishing between indirect mate choice, by which females restrict their set of potential mates in the absence of individual male assessment, and direct mate choice, by which females assess males and their territories through dyadic behavioral interactions. On no lek were males holding central territories favored by indirect or direct mate choice, contrary to the prediction of the hotshot model that leks form because inferior males establish territories surrounding hotshot males preferred by females. Average female encounter rate of males increased with lek size, a pattern typically interpreted as evidence that leks form through female preference for lekking males, rather than because males congregate in hot spots of high female density. Female propensity to engage in premating behavior once courted did not increase with lek size, suggesting female preference for males on larger leks operated through indirect choice rather than direct choice based on individual assessment. The frequency of male-male competitive interactions increased with lek size, whereas their foraging rate decreased, implying a cost to males maintaining territories on larger leks. Together these data most strongly support the female preference model, where females may benefit through indirect mate choice for males able to meet the competitive cost of occupying larger leks.

Naturalistic study on the effectiveness of psycho-oncological interventions in cancer patients and their partners

BACKGROUND There is evidence for the efficacy of psycho-oncological interventions (POI) in randomized controlled trials for cancer patients. Our objective was to explore, under naturalistic conditions (using propensity score matching), whether POI are effective to decrease anxiety, depression, distress and overall psychopathological symptoms within cancer patients and their partners. METHODS This study was conducted in the Oncology and Hematology Center of a University clinic in Switzerland with a group of 186 patients and 117 partners. Outcome measures of mental health were the Hospital Anxiety and Depression Scale and the Symptom Checklist (SCL-9-K). Repeated-measures ANOVAs were used to analyze change over time and group effects between individuals with POI vs. without POI. RESULTS Highly distressed patients and their partners participating in POI reported better mental health over time. Among moderately distressed patients, a decrease over time emerged in depression and distress independent of POI. No effectiveness of POI could be demonstrated in moderately distressed patients and partners. CONCLUSION Most of the highly distressed patients receive additional POI and therefore conclusions about the efficacy of POI are difficult. For moderately distressed individuals, POI as implemented in Switzerland does not improve mental health in such patients and their partners, which may be caused by very time limited POI treatments. Studies with more intense POI treatments are needed.

Impact of overlapping newer generation drug-eluting stents on clinical and angiographic outcomes: pooled analysis of five trials from the international Global RESOLUTE Program

BACKGROUND Overlapping first generation sirolimus- and paclitaxel-eluting stents are associated with persistent inflammation, fibrin deposition and delayed endothelialisation in preclinical models, and adverse angiographic and clinical outcomes--including death and myocardial infarction (MI)--in clinical studies. OBJECTIVES To establish as to whether there are any safety concerns with newer generation drug-eluting stents (DES). DESIGN Propensity score adjustment of baseline anatomical and clinical characteristics were used to compare clinical outcomes (Kaplan-Meier estimates) between patients implanted with overlapping DES (Resolute zotarolimus-eluting stent (R-ZES) or R-ZES/other DES) against no overlapping DES. Additionally, angiographic outcomes for overlapping R-ZES and everolimus-eluting stents were evaluated in the randomised RESOLUTE All-Comers Trial. SETTING Patient level data from five controlled studies of the RESOLUTE Global Clinical Program evaluating the R-ZES were pooled. Enrollment criteria were generally unrestrictive. PATIENTS 5130 patients. MAIN OUTCOME MEASURES 2-year clinical outcomes and 13-month angiographic outcomes. RESULTS 644 of 5130 patients (12.6%) in the RESOLUTE Global Clinical Program underwent overlapping DES implantation. Implantation of overlapping DES was associated with an increased frequency of MI and more complex/calcified lesion types at baseline. Adjusted in-hospital, 30-day and 2-year clinical outcomes indicated comparable cardiac death (2-year overlap vs non-overlap: 3.0% vs 2.1%, p=0.36), major adverse cardiac events (13.3% vs 10.7%, p=0.19), target-vessel MI (3.9% vs 3.4%, p=0.40), clinically driven target vessel revascularisation (7.7% vs 6.5%, p=0.32), and definite/probable stent thrombosis (1.4% vs 0.9%, p=0.28). 13-month adjusted angiographic outcomes were comparable between overlapping and non-overlapping DES. CONCLUSIONS Overlapping newer generation DES are safe and effective, with comparable angiographic and clinical outcomes--including repeat revascularisation--to non-overlapping DES.

Genetic in long QT syndromes

The long QT syndrome (LQTS) is a genetic disorder characterized by prolongation of the QT interval in the electrocardiogram (ECG) and a propensity to "torsades de pointes" ventricular tachycardia frequently leading to syncope, cardiac arrest, or sudden death usually in young otherwise healthy individuals. LQTS caused by mutations of predominantly potassium and sodium ion channel genes or channel-interacting proteins leading to positive overcharge of myocardial cell with consequent heterogeneous prolongation of repolarization in various layers and regions of myocardium. These conditions facilitate the early after-depolarization and reentry phenomena underlying development of polymorphic ventricular tachycardia observed in patients with LQTS. Obtaining detailed patient history regarding cardiac events in the patient and his/her family members combined with careful interpretation of standard 12-lead ECG (with precise measurement of QT interval in all available ECGs and evaluation of T-wave morphology) usually is sufficient to diagnose the syndrome. The LQTS show great genetic heterogeneity and has been identified more than 500 mutations distributed in 10 genes: KCNQ1, HERG, SCN5A, KCNE1, KCNE2, ANKB, KCNJ2, CACNA1A, CAV3 and SCN4B. Despite advances in the field, 25-30% of patients remain undiagnosed genetic. Genetic testing plays an important role and is particularly useful in cases with nondiagnostic or borderline ECG findings.

The RYR2-encoded ryanodine receptor/calcium release channel in patients diagnosed previously with either catecholaminergic polymorphic ventricular tachycardia or genotype negative, exercise-induced long QT syndrome: a comprehensive open reading frame mutational analysis.

OBJECTIVES This study was undertaken to determine the spectrum and prevalence of mutations in the RYR2-encoded cardiac ryanodine receptor in cases with exertional syncope and normal corrected QT interval (QTc). BACKGROUND Mutations in RYR2 cause type 1 catecholaminergic polymorphic ventricular tachycardia (CPVT1), a cardiac channelopathy with increased propensity for lethal ventricular dysrhythmias. Most RYR2 mutational analyses target 3 canonical domains encoded by <40% of the translated exons. The extent of CPVT1-associated mutations localizing outside of these domains remains unknown as RYR2 has not been examined comprehensively in most patient cohorts. METHODS Mutational analysis of all RYR2 exons was performed using polymerase chain reaction, high-performance liquid chromatography, and deoxyribonucleic acid sequencing on 155 unrelated patients (49% females, 96% Caucasian, age at diagnosis 20 +/- 15 years, mean QTc 428 +/- 29 ms), with either clinical diagnosis of CPVT (n = 110) or an initial diagnosis of exercise-induced long QT syndrome but with QTc <480 ms and a subsequent negative long QT syndrome genetic test (n = 45). RESULTS Sixty-three (34 novel) possible CPVT1-associated mutations, absent in 400 reference alleles, were detected in 73 unrelated patients (47%). Thirteen new mutation-containing exons were identified. Two-thirds of the CPVT1-positive patients had mutations that localized to 1 of 16 exons. CONCLUSIONS Possible CPVT1 mutations in RYR2 were identified in nearly one-half of this cohort; 45 of the 105 translated exons are now known to host possible mutations. Considering that approximately 65% of CPVT1-positive cases would be discovered by selective analysis of 16 exons, a tiered targeting strategy for CPVT genetic testing should be considered.

Participation in Further Education over the Life Course: a longitudinal study of three birth cohorts in the Federal Republic of Germany

In this paper we address the issue of who is most likely to participate in further training, for what reasons and at what stage of the life course. Special emphasis is given to the impact of labour-market policies to encourage further education and a person's individual or cohort possibilities to participate in further education. We apply a Cox proportional hazard model to data from the West German Life History Study, separately for women and men, within and outside the firm. Younger cohorts show not only higher proportions of participation in further education and training at early stages of the life course, they also continue to participate in higher numbers during later stages of the life course. General labour-force participation reduces and tenure with the same firm increases the propensity to participate in further education and training. Contrary to expectations, in Germany labour-market segmentation has been enhanced rather than reduced by further education and training policies, since in the firm-specific labour-market segment, i.e. skilled jobs in large firms, and in the public sector both women and men had a higher probability of participation. Particularly favourable conditions for participation in further education outside the firm prevailed during the first years of the labour promotion act (Arbeitsförderungsgesetz) between 1969 and 1974, but women did not benefit to the same extent as men. Training policies are, therefore, in need of continuous assessment based on a goal-achievement evaluation to avoid any unintended effects of such policies.

Teachers' Acculturation Attitudes and their Classroom Management: an empirical study among fifth-grade primary school teachers in Switzerland

This article investigates the influence of attitudes towards acculturation of 180 primary school teachers on their classroom management. The results indicate that teachers with integrative attitudes towards immigrant students' acculturation have a high propensity to punish students for disruptive behaviour, but they also demonstrate high levels of diagnostic expertise in social areas. Teachers with assimilative attitudes are also likely to punish students for misbehaviour, but tend to have a deficiency in the ability to diagnose social tensions among students. Teachers with assimilative attitudes who report high levels of disruptive behaviour in their classroom have the strongest tendency to punish and the lowest level of diagnostic expertise in social areas.

Group size adjustment to ecological demand in a cooperative breeder

Environmental factors can determine which group size will maximize the fitness of group members. This is particularly important in cooperative breeders, where group members often serve different purposes. Experimental studies are yet lacking to check whether ecologically mediated need for help will change the propensity of dominant group members to accept immigrants. Here, we manipulated the perceived risk of predation for dominant breeders of the cooperatively breeding cichlid fish Neolamprologus pulcher to test their response to unrelated and previously unknown immigrants. Potential immigrants were more readily accepted if groups were exposed to fish predators or egg predators than to herbivorous fish or control situations lacking predation risk. Our data are consistent with both risk dilution and helping effects. Egg predators were presented before spawning, which might suggest that the fish adjust acceptance rates also to a potential future threat. Dominant group members of N. pulcher apparently consider both present and future need of help based on ecological demand. This suggests that acceptance of immigrants and, more generally, tolerance of group members on demand could be a widespread response to ecological conditions in cooperatively breeding animals.

Daptomycin versus vancomycin for osteoarticular infections due to methicillin-resistant Staphylococcus aureus (MRSA): a nested case-control study

Vancomycin is the standard antibiotic for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. While daptomycin is approved for MRSA bacteremia, its effectiveness in osteoarticular infections (OAIs) has not been established. A 1:2 nested case-control study of adult patients with MRSA OAIs admitted to an academic center from 2005 to 2010 was carried out. Clinical outcomes and drug toxicity in patients treated with daptomycin versus vancomycin were compared. Twenty patients with MRSA OAIs treated with daptomycin were matched to 40 patients treated with vancomycin. The median age of the patients was 52 years (range, 25-90), and 40 (67 %) were male. Most patients had osteomyelitis (82 %), predominantly from a contiguous source (87 %). Forty percent were diabetics. Diabetic patients were more likely to receive vancomycin than daptomycin [20 (50 %) vs. 4 (20 %); p = 0.03]. Vancomycin was more often combined with antibiotics other than daptomycin [22 (55 %) vs. 5 (25 %); p = 0.03]. The median total antibiotic treatment duration was 48 (daptomycin) vs. 46 days (vancomycin) (p = 0.5). Ninety percent of daptomycin-treated patients had previously received vancomycin for a median of 14.5 days (range, 2-36). Clinical success rates were similar between daptomycin and vancomycin at 3 months [15 (75 %) vs. 27 (68 %); p = 0.8] and 6 months [14 (70 %) vs. 23 (58 %); p = 0.5], even after propensity score-based adjustment for antibiotic assignment. The frequency of adverse events was similar between treatment groups [1 (5 %) vs. 7 (18 %); p = 0.2]. Daptomycin and vancomycin achieved similar rates of clinical success and drug tolerability. Daptomycin is a reasonable alternative for treating MRSA OAIs, particularly in patients where therapy with vancomycin has not been well tolerated.

Do Integration Policies Affect Immigrants' Voluntary Engagement? An Exploration at Switzerland's Subnational Level

This paper investigates whether integration policies influence immigrants' propensity to volunteer, the latter being an important element of immigrants' integration into the host society. By distinguishing different categories of integration policies at Switzerland's subnational level and applying a Bayesian multilevel approach, our results suggest varying policy effects: while policies fostering socio-structural rights enhance immigrants' propensity to volunteer, we observe a negative curvilinear relationship between cultural rights and obligations and immigrants' volunteerism implying that a combination of cultural entitlements and obligations is most conducive to immigrants' civic engagement.

Clinical response to chemotherapy in oesophageal adenocarcinoma patients is linked to defects in mitochondria

Chemotherapeutic drugs kill cancer cells, but it is unclear why this happens in responding patients but not in non-responders. Proteomic profiles of patients with oesophageal adenocarcinoma may be helpful in predicting response and selecting more effective treatment strategies. In this study, pretherapeutic oesophageal adenocarcinoma biopsies were analysed for proteomic changes associated with response to chemotherapy by MALDI imaging mass spectrometry. Resulting candidate proteins were identified by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and investigated for functional relevance in vitro. Clinical impact was validated in pretherapeutic biopsies from an independent patient cohort. Studies on the incidence of these defects in other solid tumours were included. We discovered that clinical response to cisplatin correlated with pre-existing defects in the mitochondrial respiratory chain complexes of cancer cells, caused by loss of specific cytochrome c oxidase (COX) subunits. Knockdown of a COX protein altered chemosensitivity in vitro, increasing the propensity of cancer cells to undergo cell death following cisplatin treatment. In an independent validation, patients with reduced COX protein expression prior to treatment exhibited favourable clinical outcomes to chemotherapy, whereas tumours with unchanged COX expression were chemoresistant. In conclusion, previously undiscovered pre-existing defects in mitochondrial respiratory complexes cause cancer cells to become chemosensitive: mitochondrial defects lower the cells' threshold for undergoing cell death in response to cisplatin. By contrast, cancer cells with intact mitochondrial respiratory complexes are chemoresistant and have a high threshold for cisplatin-induced cell death. This connection between mitochondrial respiration and chemosensitivity is relevant to anticancer therapeutics that target the mitochondrial electron transport chain.

Individual socialization or politocultural context? The cultural roots of volunteering in Switzerland

Volunteering rates in Switzerland vary substantially across language regions. In this article, we investigate the cultural roots of this variation by presenting and empirically testing two different conceptualizations of how linguistic culture is related to individual volunteering. Whereas the first perspective perceives the individual as belonging to a particular language community and its norms and values as crucial for individual volunteering, the other sees the linguistic culture mainly as an important context in which an individual lives and which therefore influences individual volunteering. Empirically, we base our analysis on new survey data from 60 Swiss communes and apply a Bayesian multi-level analysis in order to disentangle the linguistic group from contextual effects. Our analysis supports the view that cultural patterns of civic self-organization can indeed explain regional volunteering behaviour in Switzerland. Whereas the propensity to volunteer is generally highest in German-speaking Switzerland, our findings reveal that it is the group of French speakers that exhibits the highest propensity to volunteer when controlling for language region.

Comparison of pain-resilient working individuals to population-based case controls with/without momentary low back pain

Background: Few studies have examined the 20% of individuals who never experience an episode of low back pain (LBP). To date, no investigation has been undertaken that examines a group who claim to have never experienced LBP in their lifetime in comparison to two population-based case–control groups with and without momentary LBP. This study investigates whether LBP-resilient workers between 50 and 65 years had better general health, demonstrated more positive health behaviour and were better able to achieve routine activities compared with both case–control groups. Methods: Forty-two LBP-resilient participants completed the same pain assessment questionnaire as a population-based LBP sample from a nationwide, large-scale cross-sectional survey in Switzerland. The LBP-resilient participants were pairwise compared to the propensity score-matched case controls by exploring differences in demographic and work characteristics, and by calculating odds ratios (ORs) and effect sizes. A discriminant analysis explored group differences, while the multiple logistic regression analysis specified single indicators which accounted for group differences. Results: LBP-resilient participants were healthier than the case controls with momentary LBP and achieved routine activities more easily. Compared to controls without momentary LBP, LBP-resilient participants had a higher vitality, a lower workload, a healthier attitude towards health and behaved more healthily by drinking less alcohol. Conclusions: By demonstrating a difference between LBP-resilient participants and controls without momentary LBP, the question that arises is what additional knowledge can be attained. Three underlying traits seem to be relevant about LBP-resilient participants: personality, favourable work conditions and subjective attitudes/attributions towards health. These rationales have to be considered with respect to LBP prevention.