Assessment of the Matrix Degenerative Effects of MMP-3, ADAMTS-4 and HTRA1 injected into a bovine Intervertebral Disc Organ Culture Model

Study Design. In vitro study to develop an intervertebral disc degeneration (IDD) organ culture model, using coccygeal bovine intervertebral discs (IVDs) and injection of proteolytic enzymes MMP-3, ADAMTS-4 and HTRA1.Objective. This study aimed to develop an in-vitro model of enzyme-mediated IDD to mimic the clinical outcome in humans for investigation of therapeutic treatment options.Summary of Background Data. Bovine IVDs are comparable to human IVDs in terms of cell composition and biomechanical behavior. Researchers injected papain and trypsin into them to create an IDD model with a degenerated nucleus pulposus (NP) area. They achieved macroscopic cavities as well as a loss of glycosaminoglycans (GAGs). However, none of these enzymes are clinically relevant.Methods. Bovine IVDs were harvested maintaining the endplates. Active forms of MMP-3, ADAMTS-4 and HTRA1 were injected at a dose of 10μg/ml each. Phosphate buffered saline (PBS) was injected as a control. Discs were cultured for 8 days and loaded diurnally (day 1 to day 4 with 0.4 MPa for 16 h) and left under free swelling condition from day 4 to day 8 to avoid expected artifacts due to dehydration of the NP. Outcome parameters included disc height, metabolic cell activity, DNA content, glycosaminoglycan (GAG) content, total collagen content, relative gene expression and histological investigation.Results. The mean metabolic cell activity was significantly lower in the NP area of discs injected with ADAMTS-4 compared to the day 0 control discs. Disc height was decreased following injection with HTRA1, and was significantly correlated with changes in GAG/DNA of the NP tissue. Total collagen content tended to be lower in groups injected with ADAMTS4 and MMP-3.Conclusion. MMP-3, ADAMTS-4 and HTRA1 neither provoked visible matrix degradation nor major shifts in gene expression. However, cell activity was significantly reduced and HTRA1 induced loss of disc height which positively correlated with changes in GAG/DNA content. The use of higher doses of these enzymes or a combination thereof may therefore be necessary to induce disc degeneration

A non-coding genomic duplication at the HMX1 locus is associated with crop ears in highland cattle.

Highland cattle with congenital crop ears have notches of variable size on the tips of both ears. In some cases, cartilage deformation can be seen and occasionally the external ears are shortened. We collected 40 cases and 80 controls across Switzerland. Pedigree data analysis confirmed a monogenic autosomal dominant mode of inheritance with variable expressivity. All affected animals could be traced back to a single common ancestor. A genome-wide association study was performed and the causative mutation was mapped to a 4 Mb interval on bovine chromosome 6. The H6 family homeobox 1 (HMX1) gene was selected as a positional and functional candidate gene. By whole genome re-sequencing of an affected Highland cattle, we detected 6 non-synonymous coding sequence variants and two variants in an ultra-conserved element at the HMX1 locus with respect to the reference genome. Of these 8 variants, only a non-coding 76 bp genomic duplication (g.106720058_106720133dup) located in the conserved region was perfectly associated with crop ears. The identified copy number variation probably results in HMX1 misregulation and possible gain-of-function. Our findings confirm the role of HMX1 during the development of the external ear. As it is sometimes difficult to phenotypically diagnose Highland cattle with slight ear notches, genetic testing can now be used to improve selection against this undesired trait.

Die Entwicklung und Implementierung einer neuen staatlichen Schlussprüfung Humanmedizin am Beispiel Schweiz – Ergebnisse und Daten zur Prüfungsqualität der ersten 2 Kohorten sowie Überlegungen zur Qualitätssicherung und zur Weiterentwicklung der Prüfung

Hintergrund: Im Rahmen des neuen nationalen Medizinalberufegesetzes [http://www.admin.ch/ch/d/as/2007/4031.pdf], [http://www.bag.admin.ch/themen/berufe/07918/07919/index.html], der Entwicklung hin zu Kompetenz-basierten Curricula [1] und der Einführung der Bologna-Reform in den medizinischen Studiengängen [2] wurde in der Schweiz eine neue eidgenössische Schlussprüfung Humanmedizin unter Aufsicht des Bundes und in Zusammenarbeit mit den medizinischen Fakultäten in zwei Sprachen (D/F) entwickelt und 2011 erstmals durchgeführt. Projektbeschreibung: Im vorliegenden Beitrag werden die Rahmenbedingungen für die Implementierung aufgezeigt und die Entwicklung der Gesamtprüfung als Pass/Fail-Prüfung einschliesslich ihrer 2 Einzelprüfungen beschrieben. Die 1. Einzelprüfung besteht aus einer schriftlichen Prüfung (MCQ) an 2 Prüfungstagen zu je 4.5 h mit je 150 interdisziplinären, taxonomisch auf Anwendungswissen ausgerichteten Fragen. Die 2. Einzelprüfung umfasst eine strukturierte, klinisch-praktische CS-Prüfung (OSCE) mit insgesamt 12 Rotationsposten über je 13 min Dauer und je 2 min Rotationszeit zwischen den Posten. Zur Qualitätssicherung wurden zahlreiche Massnahmen ergriffen wie z.B. die Schulung der standardisierten Patienten anhand zentraler Standardisierungsvorlagen. Der Gesamtblueprint ist abgestimmt auf den Schweizer Lernzielkatalog Humanmedizin [http://sclo.smifk.ch] und beinhaltet die 2 Hauptdimensionen „General Objectives/CanMed Roles“ und „Problems as Starting Points“. Ergebnisse: Die Prüfung wurde an allen 5 Standorten 2011 und 2012 erfolgreich durchgeführt. Die Prüfungsresultate der ersten 2 Kohorten differenziert nach Gesamtprüfung und Einzelprüfungen zeigen in etwa die erwarteten Werte hinsichtlich der Bestehensquote. Die Metadaten zur Prüfungsqualität zeigen für beide Jahre, dass die angestrebte Messzuverlässigkeit der Prüfung mit einem Cronbach Alpha als Mass für die Reliabilität von im Mittel α=0.9 für die MCQ Einzelprüfung und von im Mittel α>0.8 für die CS-Einzelprüfung erreicht wurde. Diskussion und Schlussfolgerungen: Basierend auf den Erfahrungen und Daten der ersten 2 Prüfungskohorten kann gesagt werden, dass die Implementierung einer neuen nationalen Prüfung, die neben der neu ausgerichteten MCQ-Einzelprüfung erstmals mit einem strukturierten, objektivierbaren und national standardisierten Instrument klinische Fähigkeiten und Fertigkeiten misst, grundsätzlich gelungen ist. In diesem Kontext muss die Relevanz der intensiven Koordination und Abstimmung von der Gesetzgebung und den Verordnungsvorgaben bis hin zum Lernzielkatalog und dem korrespondierenden Gesamtblueprint der Prüfung hervorgehoben werden. Bezüglich der zukünftigen Entwicklung werden Aspekte der Qualitätssicherung und der Weiterentwicklung der Gesamtprüfung auch im Sinne von ergänzenden Prüfungsformaten diskutiert werden.

A retroperitoneal bronchogenic cyst mimicking a pancreatic or adrenal mass

Retroperitoneal location of bronchogenic cysts is extremely rare. Most commonly they are encountered in the posterior mediastinum. Bronchogenic cysts arise from developmental aberrations of the tracheobronchial tree in the early embryologic period. We report a 42-year-old female patient with a retroperitoneal bronchogenic cyst in the left adrenal region. She was admitted to our hospital with epigastric pain and subsequently underwent CT of the abdomen. The examination revealed a mass related to the left adrenal gland. Endocrine tests for adrenal hypersecretion were negative. Because of the uncertain entity, laparoscopic adrenalectomy was performed. Pathological examination revealed a bronchogenic cyst in proximity to an inconspicuous left adrenal gland. Although very rare, bronchogenic cysts should be considered in the differential diagnosis of retroperitoneal cystic lesions and surgical resection pursued for symptom resolution and to establish a definitive histology.

The new licencing examination for human medicine: from concept to implementation

A new Swiss federal licencing examination for human medicine (FLE) was developed and released in 2011. This paper describes the process from concept design to the first results obtained on implementation of the new examination. The development process was based on the Federal Act on University Medical Professions and involved all national stakeholders in this venture. During this process questions relating to the assessment aims, the assessment formats, the assessment dimensions, the examination content and necessary trade-offs were clarified. The aims were to create a feasible, fair, valid and psychometrically sound examination in accordance with international standards, thereby indicating the expected knowledge and skills level at the end of undergraduate medical education. Finally, a centrally managed and locally administered examination comprising a written multiple-choice element and a practical “clinical skills” test in the objective structured clinical examination (OSCE) format was developed. The first two administrations of the new FLE show that the examination concept could be implemented as intended. The anticipated psychometric indices were achieved and the results support the validity of the examination. Possible changes to the format or content in the future are discussed.

Effect of comprehensive cardiac rehabilitation after heart valve surgery (CopenHeartVR): study protocol for a randomised clinical trial

Background Heart valve diseases are common with an estimated prevalence of 2.5% in the Western world. The number is rising due to an ageing population. Once symptomatic, heart valve diseases are potentially lethal, and heavily influence daily living and quality of life. Surgical treatment, either valve replacement or repair, remains the treatment of choice. However, post surgery, the transition to daily living may become a physical, mental and social challenge. We hypothesise that a comprehensive cardiac rehabilitation programme can improve physical capacity and self-assessed mental health and reduce hospitalisation and healthcare costs after heart valve surgery. Methods A randomised clinical trial, CopenHeartVR, aims to investigate whether cardiac rehabilitation in addition to usual care is superior to treatment as usual after heart valve surgery. The trial will randomly allocate 210 patients, 1:1 intervention to control group, using central randomisation, and blinded outcome assessment and statistical analyses. The intervention consists of 12 weeks of physical exercise, and a psycho-educational intervention comprising five consultations. Primary outcome is peak oxygen uptake (VO2 peak) measured by cardiopulmonary exercise testing with ventilatory gas analysis. Secondary outcome is self-assessed mental health measured by the standardised questionnaire Short Form 36. Also, long-term healthcare utilisation and mortality as well as biochemistry, echocardiography and cost-benefit will be assessed. A mixed-method design is used to evaluate qualitative and quantitative findings encompassing a survey-based study before the trial and a qualitative pre- and post-intervention study. Discussion The study is approved by the local regional Research Ethics Committee (H-1-2011-157), and the Danish Data Protection Agency (j.nr. 2007-58-0015).

Vascular cell adhesion molecule 1 expression by biliary epithelium promotes persistence of inflammation by inhibiting effector T-cell apoptosis

Chronic hepatitis occurs when effector lymphocytes are recruited to the liver from blood and retained in tissue to interact with target cells, such as hepatocytes or bile ducts (BDs). Vascular cell adhesion molecule 1 (VCAM-1; CD106), a member of the immunoglobulin superfamily, supports leukocyte adhesion by binding a4b1 integrins and is critical for the recruitment of monocytes and lymphocytes during inflammation. We detected VCAM-1 on cholangiocytes in chronic liver disease (CLD) and hypothesized that biliary expression of VCAM-1 contributes to the persistence of liver inflammation. Hence, in this study, we examined whether cholangiocyte expression of VCAM-1 promotes the survival of intrahepatic a4b1 expressing effector T cells. We examined interactions between primary human cholangiocytes and isolated intrahepatic T cells ex vivo and in vivo using the Ova-bil antigen-driven murine model of biliary inflammation. VCAM-1 was detected on BDs in CLDs (primary biliary cirrhosis, primary sclerosing cholangitis, alcoholic liver disease, and chronic hepatitis C), and human cholangiocytes expressed VCAM-1 in response to tumor necrosis factor alpha alone or in combination with CD40L or interleukin-17. Liver-derived T cells adhered to cholangiocytes in vitro by a4b1, which resulted in signaling through nuclear factor kappa B p65, protein kinase B1, and p38 mitogen-activated protein kinase phosphorylation. This led to increased mitochondrial B-cell lymphoma 2 accumulation and decreased activation of caspase 3, causing increased cell survival. We confirmed our findings in a murine model of hepatobiliary inflammation where inhibition of VCAM-1 decreased liver inflammation by reducing lymphocyte recruitment and increasing CD8 and T helper 17 CD4 Tcell survival. Conclusions: VCAM-1 expression by cholangiocytes contributes to persistent inflammation by conferring a survival signal to a4b1 expressing proinflammatory T lymphocytes in CLD.

Die zweite Generation der Tibeter in der Schweiz: Identitätsaushandlungen und Formen buddhistischer Religiosität

Schon vor über fünfzig Jahren kamen die ersten tibetischen Migrantinnen und Migranten in die Schweiz. Einige Studien widmeten sich dem Prozess, wie diese erste Generation ihre kulturellen und religiösen Traditionen fortführte und sich zugleich den Erwartungen und Bedingungen der Aufnahmegesellschaft anpasste. Die vorliegende Studie schliesst daran nun mit der aktuellen Frage an, wie die zweite Generation der Tibeter in der Schweiz ihre tibetische Herkunft wie auch ihren Bezug zum Buddhismus auffasst und gestaltet. Wie verändert sich die individuelle Religiosität bei den Tibetern in der Schweiz angesichts des Generationenwechsels und der umgreifenden gesellschaftlichen Veränderungsprozesse, namentlich der religiösen Pluralisierung, der Individualisierung und der wieder erstarkenden religiösen Identitätspolitik im Zeitalter der Globalisierung -

Increase of Caffeine and Decrease of Corticosteroids for Extremely Low Birthweight Infants with Respiratory Failure from 1997 to 2011

AIM To compare treatment strategies for respiratory failure in extremely low birth weight (ELBW) infants in Germany in 1997 to Germany, Austria and Switzerland in 2011. METHODS A detailed questionnaire about treatment strategies for ELBW infants was sent to all German centres treating ELBW infants in 1997. A follow-up survey was conducted in 2011 in Germany, Austria and Switzerland. RESULTS In 1997 and 2011, 63.6% and 66.2% of the hospitals responded. In 2011 the response rate was higher in Switzerland than in Germany, and in university hospitals versus non-university hospitals. Treatment strategies did not differ between university and non-university hospitals as well as NICUs of different sizes in 2011. Differences between Germany, Austria and Switzerland were minimal. Administration of caffeine increased significantly, whereas theophylline and doxapram declined (all p<0.001). While the use of dexamethasone decreased and the use of hydrocortisone increased, the overall use of corticosteroids declined (all p<0.001). Between 1997 and 2011 therapy with inhalations and mucolytics decreased (both p<0.001) whereas the use application of diuretics did not change significantly. In mechanically ventilated infants the application of muscle relaxants and sedation declined significantly (p=0.009 and p<0.001), whereas analgesia use did not change. CONCLUSION Treatment strategies for respiratory failure in ELBW infants have changed significantly between 1997 and 2011. This article is protected by copyright. All rights reserved.

Wohlbefinden in der Schule

Das Wohlbefinden von Kindern und Jugendlichen in der Schule ist zu einem ernsthaften Anliegen geworden, obwohl bisher noch weitgehend unklar ist, was darunter zu verstehen ist und was zum Wohlbefinden in der Schule beiträgt. In diesem Buch werden theoretische Grundlagen zum psychologischen Konzept ́Wohlbefinden in der Schule ́ gelegt und anhand eines Forschungsprojekts mit über 2000 Schüler/-innen der Sekundarstufe I (Klassenstufe 7-9) überprüft. Der Schwerpunkt der Studien bestand darin, aus der Perspektive der Schüler/-innen relevante Quellen des Wohlbefindens in der Schule zu identifizieren. Anhand von qualitativen und quantitativen Forschungsarbeiten werden Alternativen zu programmatischen pädagogischen Ausführungen vorgeschlagen, und es wird eine empirisch abgestützte Basis für Schulreformen vorgelegt.