Appropriateness of therapy for active Crohn's disease: results of a multidisciplinary International Expert Panel (EPACT II)

Introduction: The development of novel therapies and the increasing number of trials testing management strategies for luminal Crohn's disease (CD) have not filled all the gaps in our knowledge. Thus, in clinical practice, many decisions for CD patients need to be taken without high quality evidence. For this reason, a multidisciplinary European expert panel followed the RAND method to develop explicit criteria for the management of individual patients with active, steroid-dependent (ST-D) and steroid-refractory (ST-R) CD. Methods: Twelve international experts convened in Geneva, Switzerland in December 2007, to rate explicit clinical scenarios, corresponding to real daily practice, on a 9-point scale according to the literature evidence and their own expertise. Median ratings were stratified into three categories: appropriate (7-9), uncertain (4-6) and inappropriate (1-3). Results: Overall, panelists rated 296 indications pertaining to mild-to-moderate, severe, ST-D, and ST-R CD. In anti-TNF naïve patients, budesonide and prednisone were found appropriate for mildmoderate CD, and infliximab (IFX) when those had previously failed or had not been tolerated. In patients with prior success with IFX, this drug with or without co-administration of a thiopurine analog was favored. Other anti-TNFs were appropriate in case of intolerance or resistance to IFX. High doses steroids, IFX or adalimumab were appropriate in severe active CD. Among 105 indications for ST-D or ST-R disease, the panel considered appropriate the thiopurine analogs, methotrexate, IFX, adalimumab and surgery for limited resection, depending on the outcome of prior therapies. Anti-TNFs were generally considered appropriate in ST-R. Conclusion: Steroids, including budesonide for mild-to-moderate CD, remain first-line therapies in active luminal CD. Anti-TNFs, in particular IFX with respect to the amount of available evidence, remain second-line for most indications. Thiopurine analogs are preferred to anti-TNFs when steroids are not appropriate, except when anti-TNFs were previously successful. These recommendations are available online (www.epact.ch). A prospective evaluation of these criteria in a large database in Switzerland in underway to validate these criteria.

Antigen binding to secretory immunoglobulin A results in decreased sensitivity to intestinal proteases and increased binding to cellular Fc receptors.

In intestinal secretions, secretory IgA (SIgA) plays an important sentinel and protective role in the recognition and clearance of enteric pathogens. In addition to serving as a first line of defense, SIgA and SIgA x antigen immune complexes are selectively transported across Peyer's patches to underlying dendritic cells in the mucosa-associated lymphoid tissue, contributing to immune surveillance and immunomodulation. To explain the unexpected transport of immune complexes in face of the large excess of free SIgA in secretions, we postulated that SIgA experiences structural modifications upon antigen binding. To address this issue, we associated specific polymeric IgA and SIgA with antigens of various sizes and complexity (protein toxin, virus, bacterium). Compared with free antibody, we found modified sensitivity of the three antigens assayed after exposure to proteases from intestinal washes. Antigen binding further impacted on the immunoreactivity toward polyclonal antisera specific for the heavy and light chains of the antibody, as a function of the antigen size. These conformational changes promoted binding of the SIgA-based immune complex compared with the free antibody to cellular receptors (Fc alphaRI and polymeric immunoglobulin receptor) expressed on the surface of premyelocytic and epithelial cell lines. These data reveal that antigen recognition by SIgA triggers structural changes that confer to the antibody enhanced receptor binding properties. This identifies immune complexes as particular structural entities integrating the presence of bound antigens and adds to the known function of immune exclusion and mucus anchoring by SIgA.

Traitements de fer: preuves de t'efficacité et bonne pratique clinique [Iron therapy: proof of efficacy and good clinical practice].

Efficacy of iron therapy, whether oral or intravenous, on biological markers of body iron stores is well recognized in medical literature, but current studies are heterogeneous, of sometimes dubious quality, and rarely address clinical outcomes. Precise practical guidelines appear available only for indications related to kidney disease. First-line intravenous use is reserved for situations comprising chronic renal failure, or patients presenting with malabsorption syndromes such as in inflammatory bowel disease. In all other situations, because of the non-negligible risk of hypersensitivity reactions, intravenous iron use is considered justified only in clinically sustained indications, for patients in whom oral administration of iron is unsatisfactory or impossible.

Les inflammasomes et les maladies humaines

The understanding of the innate immunity, the first line of the host defence, was significantly modified following the sequential discovery of innate immune receptors such as the Toll-like receptors (TLRs) and the NOD-like receptors (NLRs). In response to recognition of microbial patterns or danger signals, some NLRs assemble a multimolecular platform termed as the inflammasome. Inflammasome assembly leads to the activation of the proinflammatory caspase-1. Consequently, an inflammatory immune response is mounted along with a programmed cell death, called pyroptosis. This review summarizes recent advances in the knowledge of the inflammasome and its role in auto-inflammatory diseases, autoimmune diseases, and most common metabolic, cardiovascular or rheumatic diseases.

Public-health and individual approaches to antiretroviral therapy: township South Africa and Switzerland compared.

BACKGROUND: The provision of highly active antiretroviral therapy (HAART) in resource-limited settings follows a public health approach, which is characterised by a limited number of regimens and the standardisation of clinical and laboratory monitoring. In industrialized countries doctors prescribe from the full range of available antiretroviral drugs, supported by resistance testing and frequent laboratory monitoring. We compared virologic response, changes to first-line regimens, and mortality in HIV-infected patients starting HAART in South Africa and Switzerland. METHODS AND FINDINGS: We analysed data from the Swiss HIV Cohort Study and two HAART programmes in townships of Cape Town, South Africa. We included treatment-naïve patients aged 16 y or older who had started treatment with at least three drugs since 2001, and excluded intravenous drug users. Data from a total of 2,348 patients from South Africa and 1,016 patients from the Swiss HIV Cohort Study were analysed. Median baseline CD4+ T cell counts were 80 cells/mul in South Africa and 204 cells/mul in Switzerland. In South Africa, patients started with one of four first-line regimens, which was subsequently changed in 514 patients (22%). In Switzerland, 36 first-line regimens were used initially, and these were changed in 539 patients (53%). In most patients HIV-1 RNA was suppressed to 500 copies/ml or less within one year: 96% (95% confidence interval [CI] 95%-97%) in South Africa and 96% (94%-97%) in Switzerland, and 26% (22%-29%) and 27% (24%-31%), respectively, developed viral rebound within two years. Mortality was higher in South Africa than in Switzerland during the first months of HAART: adjusted hazard ratios were 5.90 (95% CI 1.81-19.2) during months 1-3 and 1.77 (0.90-3.50) during months 4-24. CONCLUSIONS: Compared to the highly individualised approach in Switzerland, programmatic HAART in South Africa resulted in similar virologic outcomes, with relatively few changes to initial regimens. Further innovation and resources are required in South Africa to both achieve more timely access to HAART and improve the prognosis of patients who start HAART with advanced disease.

Urologie [Urology]

In prostatic cancer, PSA velocity is a reliable sign of cancer agressivity. In the metastatic prostatic cancer, there is no difference on survival between an early and late hormonal treatment. In the invasive bladder cancer néo-adjuvant chemotherapy offers a light advantage. In the kidney cancer, anti-angiogenic agents increase the survival. In the non neurogenic overactive bladder, no studies have led to relevant results in using antimuscarinic agent in the first line. The 5 phophodiesterase inhibitors used in the treatment of erectile dysfunction are also effective in the treatment of trouble induced by benign prostatic hyperplasia.

Evaluation of clinician-operated sonography and fine-needle aspiration in the assessment of salivary gland tumours.

OBJECTIVES: To evaluate the combination of ultrasound (US) + fine-needle aspiration (FNA) in the assessment of salivary gland tumours in the hands of the otolaryngologist. DESIGN: A retrospective review of case notes was performed. SETTING: Two university teaching hospitals in Switzerland. PARTICIPANTS: One hundred and three patients with a total of 106 focal masses of the salivary glands were included. Clinician-operated US + FNA were the first line of investigation for these lesions. All patients underwent surgical excision of the lesion, which allowed for confirmation of diagnosis by histopathology in 104 lesions and by laboratory testing in two lesions. MAIN OUTCOME MEASURES: Primary--diagnostic accuracy in identifying true salivary gland neoplasms and detecting malignancy. Secondary--predicting an approximate and specific diagnosis in these tumours. RESULTS: The combination of US + FNA achieved a diagnostic accuracy of 99% in identifying and differentiating true salivary gland neoplasms from tumour-like lesions. In detecting malignancy, this combination permitted an accuracy of 98%. An approximate diagnosis was possible in 89%, and a specific diagnosis in 69% of our patients. CONCLUSIONS: Due to economic factors and a high diagnostic accuracy, the combination of US + FNA represents the investigation method of choice for most salivary gland tumours. We suggest that the otolaryngologist be employed in carrying out these procedures, as is already the rule in other medical specialties, while computed tomography and magnetic resonance imaging should be reserved to those few lesions, which cannot be delineated completely by sonography.

Knochenanabole Therapie mit Teriparatid [Bone anabolic treatment with Teriparatide].

The recombinant amino-terminal fragment of human parathyroid hormone (Teriparatide) is a bone anabolic agent which reduces fracture risk by increasing bone mass and improving bone microarchitecture. Teriparatide reduces vertebral fracture risk by 65 % and non-vertebral by 50 %. Its efficacy is higher as bisphosphonates to prevent corcicosteroid-induced osteoporosis. Teriparatide may also have a direct effect on bone pain. Teriparatide may be initiating immediately after an anticatabolic agent. However, it is not recommended to associate both treatments. At the end of teripatide treatment, an anticatabolic agent may be given. According to cost-effectiveness studies, Teriparatide should be considered as first line treatment for postmenopausal women and for men with severe osteoporosis.

THE USEFUL SIDE OF AMBIVALENCE: Ambivalent attitudes can be adaptive and socially valued

En s'inspirant de la littérature récente qui a dépeint l'ambivalence comme étant adaptative et en lien avec des comportements stratégiques, cette thèse examine le versant utile des attitudes ambivalentes. Elle met tout d'abord en évidence que son expression peut-être sciemment contrôlée et mise en avant pour des raisons d'auto-présentation. De plus, elle démontre que les individus peuvent présenter une attitude ambivalente afin de gagner l'approbation sociale sur un objet d'attitude controversé alors que l'inverse a été observé sur des objets consensuels (Première ligne de recherche). Cette thèse a également révélé que l'expression d'attitudes ambivalentes pouvait amener à être valorisé socialement. En effet, contrairement à des attitudes plus tranchées (pro-normatives ou contre-normatives), les attitudes ambivalentes ont été évaluées de façon plus importante sur la dimension de l'utilité sociale (une dimension qui indique la compétence d'autrui ou encore la propension à évoluer dans la hiérarchie sociale). La valorisation de l'ambivalence n'est apparue que sur la dimension de l'utilité sociale et non sur la dimension de la désirabilité sociale (une dimension qui indique la sympathie d'autrui ainsi que la propension à être apprécié socialement). De plus, ce résultat a été observé sur des thèmes controversés et non sur des thèmes consensuels (Seconde ligne de recherche). Dans l'ensemble cette thèse soutient une approche de l'ambivalence comme donnant lieu à des bénéfices. Elle peut également ouvrir la voie à l'étude de l'ambivalence en lien avec la pensée critique. - Drawing on the recent literature that portrayed ambivalence as being adaptive and linked with strategic behaviors, this thesis examines the useful side of ambivalent attitudes. It first revealed that the expression of ambivalent attitudes could be controlled and purposely displayed for self-presentational concerns. Furthermore, it demonstrated that people could put ambivalence forward to gain social approval when expressing it on controversial social issues, whereas the opposite was true on consensual social issues (First line of research). The thesis also revealed that the expression of ambivalent attitudes could lead to be socially valued. Indeed, contrary to clear-cut attitudes (either pro-normative or counter-normative attitudes), ambivalent attitudes have been evaluated the highest on the social utility dimension (a dimension indicating people's competence as well as the extent to which they are likely to climb in social hierarchy). The valorization of ambivalent attitudes only appeared on social utility and not on social desirability (a dimension indicating people's niceness as well as the extent to which they are likely to be socially appreciated). This effect was true on controversial social issues but not on consensual ones (Second line of research). Overall, this thesis provides support for an approach that conceives attitudinal ambivalence as leading to benefits. It also may open avenues for the study of ambivalence in relation with critical thinking.

Mutations in ALDH1A3 represent a frequent cause of microphthalmia/anophthalmia in consanguineous families.

Anophthalmia or microphthalmia (A/M), characterized by absent or small eye, can be unilateral or bilateral and represent developmental anomalies due to the mutations in several genes. Recently, mutations in aldehyde dehydrogenase family 1, member A3 (ALDH1A3) also known as retinaldehyde dehydrogenase 3, have been reported to cause A/M. Here, we screened a cohort of 75 patients with A/M and showed that mutations in ALDH1A3 occurred in six families. Based on this series, we estimate that mutations in ALDH1A3 represent a major cause of A/M in consanguineous families, and may be responsible for approximately 10% of the cases. Screening of this gene should be performed in a first line of investigation, together with SOX2.

Allergologie: 2. Mastocytose systémique--nouvelles stratégies thérapeutiques [Systemic mastocytosis--new therapeutic strategies].

Systemic mastocytosis is characterized by an excessive proliferation of mast cells and their accumulation in different organs. Avoidance of trigger factors leading to anaphylaxis is a general measure valid for all forms of mastocytosis. A premedication is necessary in case of surgery, anesthesia or administration of radiocontrast agents. Symptomatic treatment comprises antihistamines, anti-leukotrienes, proton pump inhibitors and topical corticosteroids. Indolent mastocytosis with refractory symptoms, the rare cases of aggressive mastocytosis with organ dysfunction and the even rarer mast cell leukemia require cytoreductive therapy. First-line agents are interferon alpha 2b and imatinib, a tyrosine kinase inhibitor. To date there is no curative treatment.

The role of neutrophils upon leishmania major infection

Les neutrophiles constituent la première ligne de défense contre un grand nombre de pathogènes. Après infection avec Leishmania major, les neutrophiles migrent rapidement et massivement au site d'infection par le parasite. Les neutrophiles sont d'importants acteurs dans l'orchestration de la réponse anti-Leishmania, via la sécrétion de nombreuses cytokines, chimiokines et composés stockés dans leurs granules. De plus, les neutrophiles interagissent avec les cellules présentatrices d'antigènes, telles que les cellules dendritiques et en conséquences contribuent au développement de la réponse adaptative. A ce jour, l'impact des neutrophiles sur 1'activation des cellules dendritiques et les possibles conséquences de l'interaction neutrophiles avec ces dernières sur l'évolution de la maladie suite à l'infection avec L. major reste peu connu. Ainsi, nous avons dans un premier temps investigué l'influence des neutrophiles sur 1'activation des cellules dendritiques in vitro. Suite à cela, nous avons analysé le rôle des neutrophiles sur 1'activation des cellules dendritiques présentes au site d'infection et dans les ganglions drainants in vivo, après inoculation intra-dermale de L. major dans le pavillon auriculaire de souris de souche C57BL/6 et BALB/c, ainsi que les conséquences de la déplétion des neutrophiles sur l'évolution de la maladie. Nous avons pu démontrer que les neutrophiles ont un impact négatif sur l'activation des cellules dendritiques exposées à L. major in vitro, via des mécanismes impliquant la sécrétion de Prostaglandines par les neutrophiles et la séquestration des parasites. La déplétion des neutrophiles dans les souris BALB/c durant les premiers jours après infection avec L. major dans le derme de l'oreille résulte en une augmentation de l'expression de marqueurs d'activation des cellules dendritiques présentes dans les ganglions drainants, mais pas au site d'infection. De plus, les souris BALB/c transitoirement déplétées en neutrophiles développent des lésions significativement plus petites, une réponse de type Th2 diminuée et une charge parasitaire plus faible au site d'infection que les souris non déplétées. La déplétion des neutrophiles dans les souris C57BL/6 n'a pas d'influence détectable sur l'activation des cellules dendritiques que ce soit au niveau des ganglions drainants ou au site d'infection. La progression de la lésion et la charge parasitaire ne sont pas affectées par la déplétion des neutrophiles, malgré le développement d'une réponse Th2 diminuée par rapport aux souris non déplétées. En résumé, dans les premières heures après infection, les neutrophiles ont un effet négatif sur l'activation des cellules dendritiques et sur la réponse anti-Leishmania dans les souris BALB/c tandis que leur rôle paraît moins important dans les souris C57BL/6. Ces résultats peuvent avoir d'importantes implications en terme de développement de nouveaux vaccins contre Leishmania. - Neutrophils constitute the first line of defense against a variety of pathogens. Following Leihmania major infection neutrophils migrate rapidly and massively to the site of parasite inoculation. They are important players in the orchestration of the anti-leishmania response through the release of a plethora of cytokines, chemokines and granular components. In addition, neutrophils interact with antigen-presenting cells such as dendritic cells (DCs) and thereby contribute to the development of the adaptive immune response. However, the impact of neutrophils on the activation of DCs and possible consequences on disease progression following L. major infection are poorly understood. Therefore, we first investigated the influence of neutrophils on DC activation in vitro. Next we analyzed the role of neutrophils on the activation of DCs present at the site of infection and in the draining lymph node (dLN) following inoculation of L. major in the ear pinna of C57BL/6 and BALB/c mice and analyzed the consequences of early neutrophil depletion on disease progression. We could demonstrate that neutrophils had a negative impact on the activation of DCs exposed to L. major in vitro through mechanisms involving neutrophil-derived prostaglandins and sequestration of parasites. In BALB/c mice, depletion of neutrophils during the first days of infection with L. major in the ear dermis increased the expression of activation markers on dLN DCs but not on DCs present at the site of infection. In addition, BALB/c mice transiently depleted of neutrophils developed significantly smaller lesions, a decreased Th2 immune response and harbored fewer parasites at the site of infection compared to non-depleted littermates. In C57BL/6, mice early depletion of neutrophils had no detectable impact on the activation of DCs both at the site of infection and in the dLN following L. major inoculation. Furthermore, depletion of neutrophils had no major effect on lesion evolution and parasite loads despite the development of a decreased Th2 immune response compared to non- depleted littermates. In summary, at the onset of infection, neutrophils are detrimental for DC activation and the anti-leishmania response in BALB/c mice while their role appears to be less important in C57BL/6 mice. These findings could have important implications for the design of new vaccination strategies.

Benzodiazepine overtreatment in status epilepticus is related to higher need of intubation and longer hospitalization.

Benzodiazepine (BDZ), a widely recognized first-line status epilepticus (SE) treatment, may lead to respiratory depression. This cohort study investigates the effect of BDZ doses in SE patients in terms of morbidity and mortality. It considers incident SE episodes from a prospective registry (2009-2012), comparing patients receiving standard BDZ dose to those receiving exceeding doses (>30% above recommended dose), in terms of likelihood to receive intubation, morbidity, and mortality. Duration of hospitalization was assessed for subjects needing intubation for airways protection (not for refractory SE treatment) versus matched subjects not admitted to the intensive care unit (ICU). We identified 29 subjects receiving "excessive" and 173 "standard" BDZ dose; 45% of the overtreated patients were intubated for airways protection, but only 8% in the standard-dose group (p < 0.001). However, both groups presented similar clinical outcomes: 50% returned to baseline, 40% acquired a new handicap, and 10% died. Orotracheal intubation due to airways protection was associated with significantly longer hospitalization (mean 2 weeks vs. 1 week, p = 0.008). In conclusion, although administration of excessive BDZ doses in SE treatment does not seem to influence outcome, it is related to higher respiratory depression risk and longer hospitalization, potentially exposing patients to additional complications and costs.

Genome-wide association study of virologic response with efavirenz-containing or abacavir-containing regimens in AIDS clinical trials group protocols.

BACKGROUND: Efavirenz and abacavir are components of recommended first-line regimens for HIV-1 infection. We used genome-wide genotyping and clinical data to explore genetic associations with virologic failure among patients randomized to efavirenz-containing or abacavir-containing regimens in AIDS Clinical Trials Group (ACTG) protocols. PARTICIPANTS AND METHODS: Virologic response and genome-wide genotype data were available from treatment-naive patients randomized to efavirenz-containing (n=1596) or abacavir-containing (n=786) regimens in ACTG protocols 384, A5142, A5095, and A5202. RESULTS: Meta-analysis of association results across race/ethnic groups showed no genome-wide significant associations (P<5×10) with virologic response for either efavirenz or abacavir. Our sample size provided 80% power to detect a genotype relative risk of 1.8 for efavirenz and 2.4 for abacavir. Analyses focused on CYP2B genotypes that define the lowest plasma efavirenz exposure stratum did not show associations nor did analysis limited to gene sets predicted to be relevant to efavirenz and abacavir disposition. CONCLUSION: No single polymorphism is associated strongly with virologic failure with efavirenz-containing or abacavir-containing regimens. Analyses to better consider context, and that minimize confounding by nongenetic factors, may show associations not apparent here.

Treatment Options in the Management of Status Epilepticus

Status epilepticus treatment involves the use of several pharmacologic compounds, which are conceptually divided into three successive and additional lines of action. Because of their rapid onset of action, benzodiazepines represent the first approach; these are followed by classic antiepileptic drugs that are administered intravenously. In refractory episodes, pharmacologic coma induction with an appropriate anesthetic is advocated. Apart from first-line compounds, the level of evidence for medications used in status epilepticus is extremely limited. It is important to specifically address etiology in order to maximize the impact of the antiepileptic therapy. Fine-tuning of the treatment strategy, mainly regarding the choice of whether to induce coma, should be approached by balancing the benefits of rapid control of the status epilepticus with the risks of adverse effects. Although each status epilepticus episode should be treated as rapidly as possible, it appears advisable to reserve coma induction for those forms, such as generalized convulsive status, that have been shown to present a consistent risk of neurologic sequelae.