TNF-alpha blockers in inflammatory bowel diseases: practical consensus recommendations and a user's guide.

More than seventy years after their initial characterisation, the aetiology of inflammatory bowel diseases remains elusive. A recent review evaluating the incidence trends of the last 25 years concluded that an increasing incidence has been observed almost worldwide. A north-south gradient is still found in Europe. Genetic associations are variably reproduced worldwide and indicate a strong impact of environmental factors. Tumour necrosis factor alpha (TNF-alpha) has been shown to play a critical role in the pathogenesis of inflammatory bowel disease (IBD). TNF-alpha blockers are biological agents that specifically target this key cytokine in the inflammatory process and have become a mainstay in the therapy of inflammatory bowel diseases. This paper reviews the necessary investigations before using such agents, the use of such agents in pregnancy and lactation, the role of co-immunosuppression, how to monitor efficacy and safety, dose-adaptation, and the decision as to when to switch to another TNF-alpha blocker. Finally it gives recommendations for special situations. Currently there are three TNF-alpha blockers available for clinical use in IBD in Switzerland: infliximab (Remicade), adalimumab (Humira) and certolizumab pegol (Cimzia). Infliximab is a chimeric monoclonal antibody composed of a human IgG1 constant region and a murine variable region and is administered intravenously. Adalimumab is a humanised monoclonal antibody, with both human IgG1 constant and variable regions. Certolizumab pegol is a pegylated, humanised monoclonal anti-TNF fragment antigen binding fragment. Both adalimumab and certolizumab pegol are administered by subcutaneous injection. The efficacy and safety of TNF-alpha blockers in Crohn's disease has been reviewed. The authors conclude that the three above-mentioned agents are effective in luminal Crohn's disease. In fistulizing Crohn's disease, TNF-alpha blockers other than infliximab require additional investigation.

Targeting the intragraft microenvironment and the development of chronic allograft rejection.

In this review, we discuss a paradigm whereby changes in the intragraft microenvironment promote or sustain the development of chronic allograft rejection. A key feature of this model involves the microvasculature including (a) endothelial cell (EC) destruction, and (b) EC proliferation, both of which result from alloimmune leukocyte- and/or alloantibody-induced responses. These changes in the microvasculature likely create abnormal blood flow patterns and thus promote local tissue hypoxia. Another feature of the chronic rejection microenvironment involves the overexpression of vascular endothelial growth factor (VEGF). VEGF stimulates EC activation and proliferation and it has potential to sustain inflammation via direct interactions with leukocytes. In this manner, VEGF may promote ongoing tissue injury. Finally, we review how these events can be targeted therapeutically using mTOR inhibitors. EC activation and proliferation as well as VEGF-VEGFR interactions require PI-3K/Akt/mTOR intracellular signaling. Thus, agents that inhibit this signaling pathway within the graft may also target the progression of chronic rejection and thus promote long-term graft survival.

Caspase-3 Protects Stressed Organs against Cell Death.

The ability to generate appropriate defense responses is crucial for the survival of an organism exposed to pathogenesis-inducing insults. However, the mechanisms that allow tissues and organs to cope with such stresses are poorly understood. Here we show that caspase-3-knockout mice or caspase inhibitor-treated mice were defective in activating the antiapoptotic Akt kinase in response to various chemical and environmental stresses causing sunburns, cardiomyopathy, or colitis. Defective Akt activation in caspase-3-knockout mice was accompanied by increased cell death and impaired survival in some cases. Mice homozygous for a mutation in RasGAP that prevents its cleavage by caspase-3 exhibited a similar defect in Akt activation, leading to increased apoptosis in stressed organs, marked deterioration of their physiological functions, and stronger disease development. Our results provide evidence for the relevance of caspase-3 as a stress intensity sensor that controls cell fate by either initiating a RasGAP cleavage-dependent cell resistance program or a cell suicide response.

Programmes informatiques permettant l'adaptation des DRG aux statistiques médicales VESKA

Le présent cahier documente les différents programmes informatiques nécessaires à l'adaptation suisse des DRG.

Structural Validity of the Wechsler Intelligence Scale for Children (WISC-IV) in a French-speaking Swiss sample

The Wechsler Intelligence Scale for Children-fourth edition (i.e. WISC-IV) recognizes a four-factor scoring structure in addition to the Full Scale IQ (FSIQ) score: Verbal Comprehension (VCI), Perceptual Reasoning (PRI), Working Memory (WMI), and Processing Speed (PSI) indices. However, several authors suggested that models based on the Cattell-Horn-Carroll (CHC) theory with 5 or 6 factors provided a better fit to the data than does the current four-factor solution. By comparing the current four-factor structure to CHC-based models, this research aimed to investigate the factorial structure and the constructs underlying the WISC-IV subtest scores with French-speaking Swiss children (N = 249). To deal with this goal, confirmatory factor analyses (CFAs) were conducted. Results showed that a CHC-based model with five factors better fitted the French-Swiss data than did the current WISC-IV scoring structure. All together, these results support the hypothesis of the appropriateness of the CHC model with French-speaking children.

Current standards and progress in understanding and treatment of GIST.

Gastrointestinal stromal tumours (GIST), despite being rare, pose a relevant medical problem from the viewpoint of diagnosis and management. GIST are fragile, liable to metastasize and often located in delicate structures. Surgical options, therefore, are limited. In the last decade an improved understanding of the molecular mechanisms of the disease has resulted in novel modes of treatment. The introduction of systemic tyrosine kinase inhibitor therapy with imatinib has significantly improved the outcome of the disease and prolonged the survival of GIST patients. For many patients the acute threat of a deadly cancer has been transformed into a manageable chronic condition. Drug safety, tolerability and compliance, subjects of concern in all long-term therapies, have proven to be acceptable for the tyrosine kinase inhibitor imatinib. The present paper provides a compact overview of the epidemiology, pathophysiology and morphology of GIST, with special reference to the underlying molecular biology. Relevant aspects of diagnosis, therapy and monitoring of the disease are reviewed with particular emphasis on the available clinical evidence and recent guidelines.

Characterization and clinical evaluation of CD10+ stroma cells in the breast cancer microenvironment.

PURPOSE: There is growing evidence that interaction between stromal and tumor cells is pivotal in breast cancer progression and response to therapy. Based on earlier research suggesting that during breast cancer progression, striking changes occur in CD10(+) stromal cells, we aimed to better characterize this cell population and its clinical relevance. EXPERIMENTAL DESIGN: We developed a CD10(+) stroma gene expression signature (using HG U133 Plus 2.0) on the basis of the comparison of CD10 cells isolated from tumoral (n = 28) and normal (n = 3) breast tissue. We further characterized the CD10(+) cells by coculture experiments of representative breast cancer cell lines with the different CD10(+) stromal cell types (fibroblasts, myoepithelial, and mesenchymal stem cells). We then evaluated its clinical relevance in terms of in situ to invasive progression, invasive breast cancer prognosis, and prediction of efficacy of chemotherapy using publicly available data sets. RESULTS: This 12-gene CD10(+) stroma signature includes, among others, genes involved in matrix remodeling (MMP11, MMP13, and COL10A1) and genes related to osteoblast differentiation (periostin). The coculture experiments showed that all 3 CD10(+) cell types contribute to the CD10(+) stroma signature, although mesenchymal stem cells have the highest CD10(+) stroma signature score. Of interest, this signature showed an important role in differentiating in situ from invasive breast cancer, in prognosis of the HER2(+) subpopulation of breast cancer only, and potentially in nonresponse to chemotherapy for those patients. CONCLUSIONS: Our results highlight the importance of CD10(+) cells in breast cancer prognosis and efficacy of chemotherapy, particularly within the HER2(+) breast cancer disease.

Genome-wide linkage and association analyses to identify genes influencing adiponectin levels: the GEMS Study.

Adiponectin has a variety of metabolic effects on obesity, insulin sensitivity, and atherosclerosis. To identify genes influencing variation in plasma adiponectin levels, we performed genome-wide linkage and association scans of adiponectin in two cohorts of subjects recruited in the Genetic Epidemiology of Metabolic Syndrome Study. The genome-wide linkage scan was conducted in families of Turkish and southern European (TSE, n = 789) and Northern and Western European (NWE, N = 2,280) origin. A whole genome association (WGA) analysis (500K Affymetrix platform) was carried out in a set of unrelated NWE subjects consisting of approximately 1,000 subjects with dyslipidemia and 1,000 overweight subjects with normal lipids. Peak evidence for linkage occurred at chromosome 8p23 in NWE subjects (lod = 3.10) and at chromosome 3q28 near ADIPOQ, the adiponectin structural gene, in TSE subjects (lod = 1.70). In the WGA analysis, the single-nucleotide polymorphisms (SNPs) most strongly associated with adiponectin were rs3774261 and rs6773957 (P < 10(-7)). These two SNPs were in high linkage disequilibrium (r(2) = 0.98) and located within ADIPOQ. Interestingly, our fourth strongest region of association (P < 2 x 10(-5)) was to an SNP within CDH13, whose protein product is a newly identified receptor for high-molecular-weight species of adiponectin. Through WGA analysis, we confirmed previous studies showing SNPs within ADIPOQ to be strongly associated with variation in adiponectin levels and further observed these to have the strongest effects on adiponectin levels throughout the genome. We additionally identified a second gene (CDH13) possibly influencing variation in adiponectin levels. The impact of these SNPs on health and disease has yet to be determined.

Complete longitudinal analyses of the randomized, placebo-controlled, phase III trial of sunitinib in patients with gastrointestinal stromal tumor following imatinib failure.

PURPOSE: To analyze final long-term survival and clinical outcomes from the randomized phase III study of sunitinib in gastrointestinal stromal tumor patients after imatinib failure; to assess correlative angiogenesis biomarkers with patient outcomes. EXPERIMENTAL DESIGN: Blinded sunitinib or placebo was given daily on a 4-week-on/2-week-off treatment schedule. Placebo-assigned patients could cross over to sunitinib at disease progression/study unblinding. Overall survival (OS) was analyzed using conventional statistical methods and the rank-preserving structural failure time (RPSFT) method to explore cross-over impact. Circulating levels of angiogenesis biomarkers were analyzed. RESULTS: In total, 243 patients were randomized to receive sunitinib and 118 to placebo, 103 of whom crossed over to open-label sunitinib. Conventional statistical analysis showed that OS converged in the sunitinib and placebo arms (median 72.7 vs. 64.9 weeks; HR, 0.876; P = 0.306) as expected, given the cross-over design. RPSFT analysis estimated median OS for placebo of 39.0 weeks (HR, 0.505, 95% CI, 0.262-1.134; P = 0.306). No new safety concerns emerged with extended sunitinib treatment. No consistent associations were found between the pharmacodynamics of angiogenesis-related plasma proteins during sunitinib treatment and clinical outcome. CONCLUSIONS: The cross-over design provided evidence of sunitinib clinical benefit based on prolonged time to tumor progression during the double-blind phase of this trial. As expected, following cross-over, there was no statistical difference in OS. RPSFT analysis modeled the absence of cross-over, estimating a substantial sunitinib OS benefit relative to placebo. Long-term sunitinib treatment was tolerated without new adverse events.

Angiogenesis in Wounds Treated by Microdeformational Wound Therapy.

BACKGROUND:: Mechanical forces play an important role in tissue neovascularization and are a constituent part of modern wound therapies. The mechanisms by which vacuum assisted closure (VAC) modulates wound angiogenesis are still largely unknown. OBJECTIVE:: To investigate how VAC treatment affects wound hypoxia and related profiles of angiogenic factors as well as to identify the anatomical characteristics of the resultant, newly formed vessels. METHODS:: Wound neovascularization was evaluated by morphometric analysis of CD31-stained wound cross-sections as well as by corrosion casting analysis. Wound hypoxia and mRNA expression of HIF-1α and associated angiogenic factors were evaluated by pimonidazole hydrochloride staining and quantitative reverse transcription-polymerase chain reaction (RT-PCR), respectively. Vascular endothelial growth factor (VEGF) protein levels were determined by western blot analysis. RESULTS:: VAC-treated wounds were characterized by the formation of elongated vessels aligned in parallel and consistent with physiologically function, compared to occlusive dressing control wounds that showed formation of tortuous, disoriented vessels. Moreover, VAC-treated wounds displayed a well-oxygenated wound bed, with hypoxia limited to the direct proximity of the VAC-foam interface, where higher VEGF levels were found. By contrast, occlusive dressing control wounds showed generalized hypoxia, with associated accumulation of HIF-1α and related angiogenic factors. CONCLUSIONS:: The combination of established gradients of hypoxia and VEGF expression along with mechanical forces exerted by VAC therapy was associated with the formation of more physiological blood vessels compared to occlusive dressing control wounds. These morphological changes are likely a necessary condition for better wound healing.

Diagnostic et prise en charge de la thrombocytopénie immune primaire

La thrombocytopénie immune primaire (ITP) est une affection auto-immune acquise avec diminution de la survie des plaquettes et perturbation de la production plaquettaire. Il n'existe aucun test clinique simple permettant de prouver la nature auto-immune de l'affection. Pour cette raison, il s'agit presque toujours d'un diagnostic par exclusion d'autres causes. Bien que les plaquettes soient souvent inférieures à 10 x 109/l lors de la présentation initiale, la tendance hémorragique est étonnamment modérée chez la majorité des patients. Le traitement initial fait toujours appel aux corticostéroïdes, combinés à des immunoglobulines intraveineuses et à des transfusions de plaquettes dans les formes compliquées avec hémorragies significatives. Chez l'enfant, la maladie est souvent induite par des infections virales et son évolution est bénigne et spontanément régressive dans la majorité des cas. Chez l'adulte, la maladie est plus souvent persistante ou chroniquement récidivante, et le taux de plaquettes se situe souvent à un taux suffisant pour prévenir des hémorragies spontanées. Seule une faible proportion de patients souffre d'une thrombocytopénie sévère prolongée accompagnée de saignements réguliers avec risque d'hémorragies potentiellement fatales. C'est probablement ce groupe de patients restreint qui tirera surtout profit des nouvelles options thérapeutiques telles que les agonistes du récepteur de la thrombopoïétine. A la lumière de ces nouvelles possibilités, un groupe d'hématologues suisses s'est réuni pour élaborer des directives concernant la prise en charge de l'ITP conformément aux besoins et aux habitudes de notre pays.

Compliance im öffentlichen Sektor : Untersuchung über den allfälligen Nutzen eines Compliance-Management-Systems in der öffentlichen Verwaltung am Beispiel des Bundesamtes für Gesundheit

Par Compliance, on entend l'ensemble des mesures organisationnelles d'une entreprise qui visent à assurer le respect des règles par l'entreprise et ses collaborateurs. Dans le secteur privé - surtout dans les banques et les assurances - la Compliance est un concept bien établi et le poste du Compliance Officer apparaît clairement dans l'organigramme des entreprises. Ce terme apparaît aussi de temps à autre au sein de l'administration fédérale, en relation avec la politique de gestion des risques et le système de contrôle interne (SCI) ; mais une introduction effective de la Compliance n'y a pas encore eu lieu (jusqu'ici). Les Américains ont l'habitude de dire « if you think compliance is expensive, try non compliance ». Cette déclaration, apparemment valable pour le secteur privé, peut-elle cependant être transposée telle quelle au secteur public ? L'introduction d'un système de management tel que la Compliance apporterait-elle effectivement une plus-value par rapport aux systèmes existants afin d'éviter les risques engendrant des conséquences juridiques ou causant une mauvaise réputation suite au non-respect de règles par des collaborateurs ? La présente étude se penche sur ces questions et analyse, sur la base de documents et d'interviews, quels éléments de la Compliance existent au niveau de la Confédération et au sein de l'Office fédéral de la santé publique (OFSP) et s'ils sont propres à atteindre les objectifs visés par la Compliance. Dans plusieurs domaines, on a pu constater des défauts et, par conséquent, un gros potentiel d'amélioration. Le problème principal est l'absence d'organisation au niveau de la Compliance. Cela complique la vue d'ensemble des risques juridiques et de ceux pouvant causer une mauvaise réputation qui existent au niveau de la Confédération et à l'OFSP et rend impossible un management homogène de ces risques. En conséquence et dans l'état actuel des choses, il pourrait s'avérer difficile d'éviter de manière durable la réalisation des risques susmentionnés au moyen des systèmes existants. D'un autre côté, la politique de gestion des risques au sein de la Confédération et l'introduction d'un système de contrôle interne (SCI) ont représenté les premiers pas en direction d'un système de gestion des risques intégré. La Compliance serait un complément idéal et pourrait - dans la mesure où la direction de l'Office la soutient et donne le bon exemple - contribuer à la réduction des risques décrits ci-dessus non seulement au niveau de la Confédération mais encore au sein de l'OFSP. La présente étude ne vise pas pour autant à critiquer les systèmes établis, mais bien plus à montrer le potentiel d'amélioration dont on pourrait tirer profit.

Notch tumor suppressor function

Cancer development results from deregulated control of stem cell populations and alterations in their surrounding environment. Notch signaling is an important form of direct cell-cell communication involved in cell fate determination, stem cell potential and lineage commitment. The biological function of this pathway is critically context dependent. Here we review the pro-differentiation role and tumor suppressing function of this pathway, as revealed by loss-of-function in keratinocytes and skin, downstream of p53 and in cross-connection with other determinants of stem cell potential and/or tumor formation, such as p63 and Rho/CDC42 effectors. The possibility that Notch signaling elicits a duality of signals, involved in growth/differentiation control and cell survival will be discussed, in the context of novel approaches for cancer therapy

Peut-on exclure l'hypothèse d'une imitation parfaite de signature?

L'expert, en présence d'une signature contestée qu'il juge authentique, peut être confronté à l'argument selon lequel il pourrait s'agir d'une imitation parfaite. Les différents facteurs pouvant avoir un impact sur cette possibilité sont inventoriés et discutés dans cet article. Il s'agit principalement d'éléments liés soit à la signature en tant que telle, par exemple sa complexité et son degré de variation, soit à l'imitateur putatif, en particulier ses compétences. Pour répondre à la question d'un magistrat sur la possibilité de se trouver face à une imitation parfaite, l'expert sera armé pour écarter la simple explication que représente l'imitation parfaite au profit d'une discussion des résultats balancée et cohérente, où l'ensemble de ces facteurs sont discutés dans un cadre d'évaluation probabiliste.

Admissions of patients with alcohol intoxication in the Emergency Department: a growing phenomenon.

QUESTION UNDER STUDY: To investigate the change over time in the number of ED admissions with positive blood alcohol concentration (BAC) and to evaluate predictors of BAC level. METHODS: We conducted a single site retrospective study at the ED of a tertiary referral hospital (western part of Switzerland) and obtained all the BAC performed from 2002 to 2011. We determined the proportion of ED admissions with positive BAC (number of positive BAC/number of admissions). Regression models assessed trends in the proportion of admissions with positive BAC and the predictors of BAC level among patients with positive BAC. RESULTS: A total of 319,489 admissions were recorded and 20,021 BAC tests were performed, of which 14,359 were positive, divided 34.5% female and 65.5% male. The mean (SD) age was 41.7(16.8), and the mean BAC was 2.12(1.04) permille (g of ethanol/liter of blood). An increase in the number of positive BAC was observed, from 756 in 2002 to 1,819 in 2011. The total number of admissions also increased but less: 1.2 versus 2.4 times more admissions with positive BAC. Being male was independently associated with a higher (+0.19 permille) BAC, as was each passing year (+0.03). A significant quadratic association with age indicated a maximum BAC at age 53. CONCLUSION: We observed an increase in the percentage of admissions with positive BAC that was not limited to younger individuals. Given the potential consequences of alcohol intoxication, and the large burden imposed on ED teams, communities should be encouraged to take measures aimed at reducing alcohol intoxication.