Reporting standards for studies of diagnostic test accuracy in dementia: The STARDdem Initiative.

OBJECTIVE To provide guidance on standards for reporting studies of diagnostic test accuracy for dementia disorders. METHODS An international consensus process on reporting standards in dementia and cognitive impairment (STARDdem) was established, focusing on studies presenting data from which sensitivity and specificity were reported or could be derived. A working group led the initiative through 4 rounds of consensus work, using a modified Delphi process and culminating in a face-to-face consensus meeting in October 2012. The aim of this process was to agree on how best to supplement the generic standards of the STARD statement to enhance their utility and encourage their use in dementia research. RESULTS More than 200 comments were received during the wider consultation rounds. The areas at most risk of inadequate reporting were identified and a set of dementia-specific recommendations to supplement the STARD guidance were developed, including better reporting of patient selection, the reference standard used, avoidance of circularity, and reporting of test-retest reliability. CONCLUSION STARDdem is an implementation of the STARD statement in which the original checklist is elaborated and supplemented with guidance pertinent to studies of cognitive disorders. Its adoption is expected to increase transparency, enable more effective evaluation of diagnostic tests in Alzheimer disease and dementia, contribute to greater adherence to methodologic standards, and advance the development of Alzheimer biomarkers.

Multiple roles of complement MASP-1 at the interface of innate immune response and coagulation

MASP-1 is a versatile serine protease that cleaves a number of substrates in human blood. In recent years it became evident that besides playing a crucial role in complement activation MASP-1 also triggers other cascade systems and even cells to mount a more powerful innate immune response. In this review we summarize the latest discoveries about the diverse functions of this multi-faceted protease. Recent studies revealed that among MBL-associated serine proteases, MASP-1 is the one responsible for triggering the lectin pathway via its ability to rapidly autoactivate then cleave MASP-2, and possibly MASP-3. The crystal structure of MASP-1 explains its more relaxed substrate specificity compared to the related complement enzymes. Due to the relaxed specificity, MASP-1 interacts with the coagulation cascade and the kinin generating system, and it can also activate endothelial cells eliciting pro-inflammatory signaling.

Expanding the Mutation Spectrum Affecting αIIbβ3 Integrin in Glanzmann Thrombasthenia: Screening of the ITGA2B and ITGB3 Genes in a Large International Cohort.

We report the largest international study on Glanzmann thrombasthenia (GT), an inherited bleeding disorder where defects of the ITGA2B and ITGB3 genes cause quantitative or qualitative defects of the αIIbβ3 integrin, a key mediator of platelet aggregation. Sequencing of the coding regions and splice sites of both genes in members of 76 affected families identified 78 genetic variants (55 novel) suspected to cause GT. Four large deletions or duplications were found by quantitative real-time PCR. Families with mutations in either gene were indistinguishable in terms of bleeding severity that varied even among siblings. Families were grouped into type I and the rarer type II or variant forms with residual αIIbβ3 expression. Variant forms helped identify genes encoding proteins mediating integrin activation. Splicing defects and stop codons were common for both ITGA2B and ITGB3 and essentially led to a reduced or absent αIIbβ3 expression; included was a heterozygous c.1440-13_c.1440-1del in intron 14 of ITGA2B causing exon skipping in 7 unrelated families. Molecular modeling revealed how many missense mutations induced subtle changes in αIIb and β3 domain structure across both subunits thereby interfering with integrin maturation and/or function. Our study extends knowledge of Glanzmann thrombasthenia and the pathophysiology of an integrin. This article is protected by copyright. All rights reserved.

Die Rolle des Benefit-Finding für die Qualität der Anpassung an das Leben nach dem Spitzensport

Die Lebensereignisforschung postuliert, dass die Anpassung an eine durch ein kritisches Ereignis veränderte Situation durch Benefit-Finding gefördert wird, indem Menschen Gewinnbringendes für ihr Leben erkennen (Filipp & Aymanns, 2010). Während in der frühen Forschung zum oft als kritisches Lebensereignis beschriebenen Karriereende im Spitzensport Benefit-Finding mitbedacht wurde, wird es in der aktuellen Forschung nur punktuell berücksichtigt (z.B. Curtis & Ennis, 1988, Wippert, 2011). Basierend auf dem Konzept Kritisches Lebensereignis (Filipp, 1995) untersucht die vorliegende Studie die Rolle des Benefit-Finding für die kurz-, mittel- und langfristige Qualität der Anpassung an das Karriereende. Methods: 290 Schweizer Spitzenathleten (Frauenanteil: 32.8%) aus 64 Sportarten wurden etwa 7.46 Jahre nach ihrem Karriereende mittels Fragebogen zum Benefit-Finding, Erleben des Karriereendes, zur Dauer und subjektiven Qualität der Anpassung an das Karriereende sowie zum psychischen Wohlbefinden befragt. Die Datenauswertung erfolgte mittels Strukturgleichungsmodellierung. Results: Das Modell zur Vorhersage der langfristigen Anpassungsqualität (psychische Wohlbefinden) an das Karriereende mit einer Varianzaufklärung von R2 = .26 passt recht gut zu den Daten (χ2 = 114.764, p ≤ .001, df = 56, CFI = .93, SRMR = .06, RMSEA = .06; AGFI = .91). Wie postuliert, hat das Ausmass von Benefit-Finding einen – über die kurz- und mittelfristige Anpassungsqualität (positive Emotionen, Anpassungsdauer und subjektive Anpassungsqualität) – vermittelten Effekt auf das psychische Wohlbefinden im Leben nach dem Spitzensport. Discussion/Conclusion: Das Konzept Kritisches Lebensereignis kristallisierte sich als zielführender Ansatz für die Analyse von zusammenwirkenden Faktoren hinsichtlich Qualität der Anpassung an das Leben nach dem Spitzensport heraus. Die Befunde indizieren, dass sportpsychologische Interventionen mit Fokus auf Benefit-Finding, zusammen mit anderen Elementen der gängigen Career-Assistance-Programme, kurzfristig für eine gelingende Transition und langfristig ein günstiges psychisches Wohlbefinden sinnvoll sind. References: Curtis, J. & Ennis, R. (1988). Negative consequences of leaving competitive sport? Comparative findings for former elite-level hockey players. Sociology of Sport Journal, 5, 87-106. Filipp, S.-H. (Hrsg.) (1995). Kritische Lebensereignisse (3. Aufl.). Weinheim: Beltz. Filipp, S.-H. & Aymanns, P. (2010). Kritische Lebensereignisse und Lebenskrisen. Vom Umgang mit den Schattenseiten des Lebens. Stuttgart: Kohlhammer. Wippert, P.-M. (2011). Kritische Lebensereignisse in Hochleistungsbiografien. Untersuchungen an Spitzensportlern, Tänzern und Musikern. Lengerich: Pabst.

Development of a specific tracer for metabolic imaging of alveolar echinococcosis: A preclinical study

Positron emission tomography (PET)-computed tomography (CT) using [18F]-fluorodeoxyglucose (FDG) (FDG-PET/CT) is a valuable method for initial staging and follow up of patients with alveolar echinococcosis (AE). However, the cells responsible for FDG uptake have not been clearly identified. The main goal of our study was to evaluate the uptake of PET tracers by the cells involved in the host-parasite reaction around AE lesions as the first step to develop a specific PET tracer that would allow direct assessment of parasite viability in AE. Candidate molecules ([18F]-fluorotyrosine (FET), [18F]-fluorothymidine (FLT), and [18F]-fluorometylcholine (FMC), were compared to FDG by in vitro studies on human leukocytes and parasite vesicles. Our results confirmed that FDG was mainly consumed by immune cells and showed that FLT was the best candidate tracer for parasite metabolism. Indeed, parasite cells exhibited high uptake of FLT. We also performed PET/CT scans in mice infected intraperitoneally with E. multilocularis metacestodes. PET images showed no FDG or FLT uptake in parasitic lesions. This preliminary study assessed the metabolic activity of human leukocytes and AE cells using radiolabeling. Future studies could develop a specific PET tracer for AE lesions to improve lesion detection and echinococcosis treatment in patients. Our results demonstrated that a new animal model is needed for preclinical PET imaging to better mimic human hepatic and/or periparasitic metabolism.

MASP-1 of the complement system promotes clotting via prothrombin activation.

Mannan-binding lectin-associated serine protease-1 (MASP-1), a protein of the complement lectin pathway, resembles thrombin in terms of structural features and substrate specificity, and it has been shown to activate coagulation factors. Here we studied the effects of MASP-1 on clot formation in whole blood (WB) and platelet-poor plasma (PPP) by thrombelastography and further elucidated the underlying mechanism. Cleavage of prothrombin by MASP-1 was investigated by SDS-PAGE and N-terminal sequencing of cleavage products. Addition of MASP-1 or thrombin to WB and PPP shortened the clotting time and clot formation time significantly compared to recalcified-only samples. The combination of MASP-1 and thrombin had additive effects. In a purified system, MASP-1 was able to induce clotting only in presence of prothrombin. Analysis of MASP-1-digested prothrombin confirmed that MASP-1 cleaves prothrombin at three cleavage sites. In conclusion, we have shown that MASP-1 is able to induce and promote clot formation measured in a global setting using the technique of thrombelastography. We further confirmed that MASP-1-induced clotting is dependent on prothrombin. Finally, we have demonstrated that MASP-1 cleaves prothrombin and identified its cleavage sites, suggesting that MASP-1 gives rise to an alternative active form of thrombin by cleaving at the cleavage site R393.

Plasma Levels of MASP-1 and MASP-2 are Elevated in Type 1 Diabetes and Correlate with Glycaemic Control

There is increasing evidence that the complement system plays an important role in diabetes and the development of diabetic vascular complications. In particular, mannan-binding lectin (MBL) levels are elevated in diabetes patients, and diabetes patients with diabetic nephropathy have higher MBL levels than diabetes patients with normal renal function. The MBL-associated serine proteases (MASPs) MASP-1, MASP-2, and MASP-3, and MBL-associated protein MAp44 have not yet been studied in diabetes patients. We therefore measured plasma levels of MASP-1, MASP-2, MASP-3, and MAp44 in 30 children with type 1 diabetes mellitus (T1DM) and 17 matched control subjects, and in 45 adults with T1DM and 31 matched control subjects. MASP-1 and MASP-2 levels were significantly higher in children and adults with T1DM than in their respective control groups, whereas MASP-3 and MAp44 levels did not differ between patients and controls. MASP-1 and MASP-2 levels correlated with HbA1c, and MASP levels decreased when glycaemic control improved. Since MASP-1 and MASP-2 have been shown to directly interact with blood coagulation, elevated levels of these proteins may play a role in the enhanced thrombotic environment and consequent vascular complications in diabetes.

Comparative proteomic analysis of lung tissue from guinea pigs with leptospiral pulmonary haemorrhage syndrome (LPHS) reveals a decrease in abundance of host proteins involved in cytoskeletal and cellular organization

Leptospiral pulmonary haemorrhage syndrome (LPHS) is a particularly severe form of leptospirosis. LPHS is increasingly recognized in both humans and animals and is characterized by rapidly progressive intra-alveolar haemorrhage leading to high mortality. The pathogenic mechanisms of LPHS are poorly understood which hampers the application of effective treatment regimes. In this study a 2-D guinea pig proteome lung map was created and used to investigate the pathogenic mechanisms of LPHS. Comparison of lung proteomes from infected and non-infected guinea pigs via differential in-gel electrophoresis revealed highly significant differences in abundance of proteins contained in 130 spots. Acute phase proteins were the largest functional group amongst proteins with increased abundance in LPHS lung tissue, and likely reflect a local and/or systemic host response to infection. The observed decrease in abundance of proteins involved in cytoskeletal and cellular organization in LPHS lung tissue further suggests that infection with pathogenic Leptospira induces changes in the abundance of host proteins involved in cellular architecture and adhesion contributing to the dramatically increased alveolar septal wall permeability seen in LPHS. BIOLOGICAL SIGNIFICANCE The recent completion of the complete genome sequence of the guinea pig (Cavia porcellus) provides innovative opportunities to apply proteomic technologies to an important animal model of disease. In this study, the comparative proteomic analysis of lung tissue from experimentally infected guinea pigs with leptospiral pulmonary haemorrhage syndrome (LPHS) revealed a decrease in abundance of proteins involved in cellular architecture and adhesion, suggesting that loss or down-regulation of cytoskeletal and adhesion molecules plays an important role in the pathogenesis of LPHS. A publically available guinea pig lung proteome map was constructed to facilitate future pulmonary proteomics in this species.

A 2-D guinea pig lung proteome map

Guinea pigs represent an important model for a number of infectious and non-infectious pulmonary diseases. The guinea pig genome has recently been sequenced to full coverage, opening up new research avenues using genomics, transcriptomics and proteomics techniques in this species. In order to further annotate the guinea pig genome and to facilitate future pulmonary proteomics in this species we constructed a 2-D guinea pig proteome map including 486 protein identifications and post translational modifications (PTMs). The map has been up-loaded to the UCD 2D-PAGE open access database (http://proteomics-portal.ucd.ie/). Transit peptides, N-terminal acetylations and other PTMs are available via Peptideatlas (ftp://PASS00619:NM455hi@ftp.peptideatlas.org/). This dataset is associated with a research article published in the Journal of Proteomics [1].

The effects of benefit finding on athletes’ quality of adjustment to career termination

Retirement from elite sports requires athletes to cope with adjustments on an occupational, financial, physical, social or emotional level. Research on critical life events (e.g., Filipp & Aymanns, 2010) suggests that benefit finding, defined as “the process of deriving positive growth from adversity” (Cassidy et al., 2014), may have a positive impact on this transition. The present study examined the effects of benefit finding on the quality of adjustment to career termination in the short, middle and long term. Former Swiss elite athletes (N = 290) completed a written survey collecting information on a) their emotional reaction to career termination, b) the amount of adjustment in various respects, c) situational characteristics of their career termination, d) the duration and quality of the transition, and e) their subjective well-being. Using Latent Variable Modelling, finding benefit in career termination was found to have both a direct and an indirect effect on long-term well-being (γ=.18). It predicts favorable emotional reactions to career termination (γ = .53) and less adjustment (γ = -.38) which in turn shortens the transition duration (β = -.15 and β = .55, respectively) and quality (β = -.15), and finally augments well-being (β = .41). The data suggest that a focus on benefit finding in both crisis-prevention and crisis-coping interventions may prove useful to prevent crisis transitions.

The potential of female immigrants' integration into sport by intercultural clubs in Switzerland

Sport participation means a privileged access to participate in the sport system and the opportunities of actual integration into sport (Seiberth et al., 2013). The access to sport activities is often restricted for female immigrants. The function of sport participation concerning exercise offers of social associations is not a common theme in research on migration or on sports-related integration. Research on boundaries (Lamont & Molnár, 2002) suggest that gender-related and ethnic boundaries are stable behavioural and cognitive patterns leading to unequal social opportunities. The present study examined the potential of a Swiss intercultural club regarding female immigrants’ integration into sport by focussing on gender-related and ethnic boundaries. Ten interviews with female immigrants and conductress of an intercultural club plus a group discussion were held. Using qualitative content analysis and documentary method, findings reveal multifaceted, interwoven boundaries, e.g. maternal devotion, exclusive exercise offers for women, language learning devotion, religious need of headscarf. Otherwise resources to overcome boundaries are provided: Deploying competent employees; offering childcare, exercise offers suited to mothers‘ time schedule and language lessons; equitable, on integration focussed club-life. Thus, intercultural clubs might help to overcome boundaries and facilitate access to exercise for female immigrants and integrate them more successfully into sport than many sport clubs. A boundary focus and present data may open new perspectives for sport organisation and integration research. Further investigations of social associations offering exercise are advised.

Migrantinnen in interkulturellen Vereinen: Perspektiven zur Integration in den Sport

Im deutschsprachigen Raum wird ein hoher Anteil an Migrantinnen, die sportlich inaktiv und in Sportvereinen unterrepräsentiert sind, konstatiert (Burrmann et al., 2015; Lamprecht et al., 2014). Migrantinnen ist der Zugang zu Sportaktivitäten häufig erschwert aufgrund von Diskriminierung, Konflikten und Grenzziehungsprozessen, denen Aspekte betreffend des Geschlechts und der Ethnizität inhärent sind. Vor diesem Hintergrund wurde bislang häufig das Potenzial der Integration in den Sport bzw. Sozialisation zum Sport von Migrantinnen in (ethnischen) Sportvereinen und im Schulsport untersucht. Wie jedoch die Integration in den Sport in interkulturellen Vereinen, welche Sportangebote offerieren, funktioniert, ist weder in der Migrations- noch in der sportbezogenen Integrationsforschung ein gängiges Thema. Basierend auf dem theoretischen Ansatz Boundary Work (Lamont & Molnár, 2002) untersucht die vorliegende Studie geschlechtsbezogene und ethnische Grenzziehungsprozesse hinsichtlich der Sportpartizipation von Migrantinnen in einem interkulturellen Verein sowie vereinsbezogene Möglichkeiten, welche die Integration in den Sport fördern. Es wurden halbstrukturierte Interviews mit acht Migrantinnen verschiedener Herkunft und zwei Leiterinnen eines interkulturellen Vereins in der deutschsprachigen Schweiz durchgeführt. Zusätzlich erfolgte eine Gruppendiskussion mit sechs Migrantinnen. Mittels qualitativer Inhaltsanalyse und dokumentarischer Methode wurden geschlechtsbezogene und ethnische Grenzen sowie Möglichkeiten für eine Sportpartizipation durch den Verein abgeleitet. Hinsichtlich der erschwerten Sportpartizipation indizieren die Resultate vielfältige, miteinander verschränkte, sich überlagernde und durchlässige Grenzen, die das Geschlecht und die Ethnizität allgemein betreffen. Im Speziellen wirken migrationsbedingt und lebensphasenspezifisch geprägte Haltungen gegenüber „mütterlichen“ Verpflichtungen, sprachlichen- und beruflichen Aus- bzw. Weiterbildungspflichten sowie Praktiken der Körperverhüllung. Die jeweilige Struktur der Grenzverschränkungen wirkt z.T. mehrfach restriktiv und prägt zugleich die verfügbare Zeit und finanzielle Mittel der Migrantinnen, was eine Dilemma artige Situation hervorruft. Zur Überwindung der Grenzen bietet der interkulturelle Verein insbesondere professionelle Mitarbeiterinnen; Kinderbetreuung; niederschwellige, kosten- und zeitgünstige Sportangebote exklusiv für Frauen; und eine wohlwollende Atmosphäre mit gleichberechtigtem Zusammensein. Interkulturelle Vereine können somit den Zugang zu Sportangeboten für Migrantinnen erleichtern und die Integration in den Sport bzw. die Sozialisation zum Sport fördern. Dies geschieht z.B. infolge bedarfsgerechter Vereinsangebote, unverbindlicher Teilnahmebedingungen und einer integrationsorientierten Vereinskultur. Der auf Grenzziehung fokussierte theoretische Ansatz und die vorliegenden Resultate eröffnen neue Forschungsperspektiven im Bereich Sport und Sozialisation sowie Integration.