Couple and family treatments: study quality and level of evidence.

This paper examines the application of the guidelines for evidence-based treatments in family therapy developed by Sexton and collaborators to a set of treatment models. These guidelines classify the models using criteria that take into account the distinctive features of couple and family treatments. A two-step approach was taken: (1) The quality of each of the studies supporting the treatment models was assessed according to a list of ad hoc core criteria; (2) the level of evidence of each treatment model was determined using the guidelines. To reflect the stages of empirical validation present in the literature, nine models were selected: three models each with high, moderate, and low levels of empirical validation, determined by the number of randomized clinical trials (RCTs). The quality ratings highlighted the strengths and limitations of each of the studies that provided evidence backing the treatment models. The classification by level of evidence indicated that four of the models were level III, "evidence-based" treatments; one was a level II, "evidence-informed treatment with promising preliminary evidence-based results"; and four were level I, "evidence-informed" treatments. Using the guidelines helped identify treatments that are solid in terms of not only the number of RCTs but also the quality of the evidence supporting the efficacy of a given treatment. From a research perspective, this analysis highlighted areas to be addressed before some models can move up to a higher level of evidence. From a clinical perspective, the guidelines can help identify the models whose studies have produced clinically relevant results.

The role of climatic tolerances and seed traits in reduced extinction rates of temperate polygonaceae.

The latitudinal diversity gradient (LDG) is one of the most striking and consistent biodiversity patterns across taxonomic groups. We investigate the species richness gradient in the buckwheat family, Polygonaceae, which exhibits a reverse LDG and is, thus, decoupled from dominant gradients of energy and environmental stability that increase toward the tropics and confound mechanistic interpretations. We test competing age and evolutionary diversification hypotheses, which may explain the diversification of this plant family over the past 70 million years. Our analyses show that the age hypothesis, which posits that clade richness is positively correlated with the ecological and evolutionary time since clade origin, fails to explain the richness gradient observed in Polygonaceae. However, an evolutionary diversification hypothesis is highly supported, with diversification rates being 3.5 times higher in temperate clades compared to tropical clades. We demonstrate that differences in rates of speciation, migration, and molecular evolution insufficiently explain the observed patterns of differential diversification rates. We suggest that reduced extinction rates in temperate clades may be associated with adaptive responses to selection, through which seed morphology and climatic tolerances potentially act to minimize risk in temporally variable environments. Further study is needed to understand causal pathways among these traits and factors correlated with latitude.

Nouveautés en chirurgie vasculaire [New treatments in vascular diseases]

In superficial venous insufficiency, surgery remains the treatment of choice. Endovenous therapies are a minimal invasive alternative, whose long-term results are not demonstrated yet. In the treatment of abdominal aortic aneurysm, endovascular repair (EVAR) and laparoscopic approach are comparatively studied with open repair, to define their precise indications. In occlusive arterial disease, endovascular treatment offers inferior results in term of durability and patency, however with a decrease in morbidity and mortality.

Medical treatments and risk factors for resection surgery in Crohn's disease: results from the Swiss IBD Cohort Study

Background: Surgery has been previously reported to be necessary in up to 80% of Crohn's disease (CD) patients, and up to 65% of patients needed reoperation after 10 years. Prevention of surgery is therefore a particularly important issue for these patients. Treatment options are controversial and data on them are scarce. This study reports medical treatments and main clinical risk factors in CD patients having undergone one or several surgeries. Risks for being free from surgery were also assessed. Methods: Retrospective cohort study, using data from patients included in the Swiss IBD cohort study from November 2006 to July 2011. History of resective surgeries, clinical characteristics and drug regimens were collected through detailed medical records. Univariate and multivariate analyses for clinical and therapeutic factors were performed. Cox regression was made to estimate free-of-surgery risks for different phenotypes and drugs. Results: Out of 1138 CD patients in the cohort, 721 (63.4%) were free of surgery at inclusion; 203 (17.8%) had 1 surgery and 214 (18.8%) >1 surgery. Main risk factors for surgery were disease duration 5-10 years (OR=2.92; p<0.001) and >10 years (OR=10.45; p<0.001), as well as stricturing (OR=8.33; p<0.001) or fistulizing disease (OR=7.34; p<0.001). Risk factors for repeated surgery was disease duration >10 years (OR=2.55; p=0.006) or fistulizing disease (OR=3.79; p<0.001). At inclusion, 107 patients (25.7%) had at least one anti-TNF alpha, 168 (40.3%) at least one immunosuppressive agent, and 41 (9.8%) at least 5-ASA or antibiotics. 64 (15.3%) were not exposed to any medical treatment. Kaplan-Meier curves showed that the risk of being free of surgery was 65% after 10 years, 42% after 20 years and 23% after 40 years. Surgical risks were four resp. five time higher for fistulizing and stricturing phenotypes (Hazard ratio (HR) =4.2; p<0.001; resp. HR=4.7; p<0.001) compared to inflammatory phenotype. Surgical risk was 4 times lower (HR=0.27; p=0.063) in CD patients under anti-TNF alpha compared to those under other or no drugs. Conclusion: The risk of having resective surgery was confirmed to be very high for CD in our cohort. Duration of disease, fistulizing and stricturing disease pattern enhance the risk of surgery. Anti-TNF alpha tends to lower this risk.

Why human islets die? analysis of death signaling pathways during isolation and following cytokine treatments

RESUME Le diabète de type 1 se définit comme un désordre métabolique d'origine auto-immune qui aboutit à la destruction progressive et sélective de la cellule ß-pancréatique sécrétrice d'insuline. Cette maladie représente 10 % des cas de diabète enregistrés dans la population mondiale, et touche les jeunes de moins de 20 ans. Le traitement médical par insulinothérapie corrige le manque d'hormone mais ne prévient pas les nombreuses complications telles que les atteintes cardiaques, neurologiques, rénales, rétiniennes, et les amputations que la maladie provoque. Le remplacement de la cellule ß par transplantation d'îlots de Langerhans est une alternative prometteuse au traitement médical du diabète de type 1. Cependant la greffe d'îlots est encore un traitement expérimental et ne permet pas un contrôle efficace de la glycémie au long terme chez les patients transplantés, et les raisons de cet échec restent mal comprises. L'obstacle immédiat qui se pose est la purification d'un nombre suffisant d'îlots viables et la perte massive de ces îlots dans les premières heures suite à la greffe. Cette tendance presque systématique de la perte fonctionnelle du greffon immédiatement après la transplantation est connue sous le terme de « primary graft non-function » (PNF). En effet, la procédure d'isolement des îlots provoque la destruction des composantes cellulaires et non cellulaires du tissu pancréatique qui jouent un rôle déterminant dans le processus de survie de l'îlot. De plus, la transplantation elle-même expose les cellules à différents stress, notamment le stress par les cytokines inflammatoires qui encourage la mort cellulaire par apoptose et provoque par la suite le rejet de la greffe. L'ensemble de ces mécanismes aboutit a une perte de la masse d'îlot estimée a plus de 60%. Dans ce contexte, nous nous sommes intéressés à définir les voies majeures de stress qui régissent cette perte massive d'îlot par apoptose lors du processus d'isolement et suite à l'exposition immédiate aux cytokines. L'ensemble des résultats obtenus indique que plusieurs voies de signalisation intracellulaire sont recrutées qui s'activent de manière maximale très tôt lors des premières phases de l'isolement. La mise en culture des îlots deux jours permet aux voies activées de revenir aux taux de base. De ce fait nous proposons une stratégie dite de protection qui doit être 1) initiée aussitôt que possible lors de l'isolement des îlots pancréatiques, 2) devrait probablement bloquer l'activation de ces différentes voies de stress mis en évidence lors de notre étude et 3) devrait inclure la mise en culture des îlots purifiés deux jours après l'isolement et avant la transplantation. RESUME LARGE PUBLIC Le diabète est une maladie qui entraîne un taux anormalement élevé de sucre (glucose) dans le sang du à une insuffisance du pancréas endocrine à produire de l'insuline, une hormone qui régule la glycémie (taux de glucose dans le sang). On distingue deux types majeurs de diabètes; le diabète de type 1 ou juvénile ou encore appelé diabète maigre qui se manifeste souvent pendant l'enfance et qui se traduit par une déficience absolue en insuline. Le diabète de type 2 ou diabète gras est le plus fréquent, et touche les sujets de plus de 40 ans qui souffrent d'obésité et qui se traduit par une dysfonction de la cellule ß avec une incapacité à réguler la glycémie malgré la production d'insuline. Dans le diabète de type 1, la destruction de la cellule ß est programmée (apoptose) et est majoritairement provoquée par des médiateurs inflammatoires appelés cytokines qui sont produites localement par des cellules inflammatoires du système immunitaire qui envahissent la cellule ß-pancréatiques. Les cytokines activent différentes voies de signalisation parmi lesquelles on distingue celles des Mitogen-Activated Protein Kinase (MAPKs) composées de trois familles de MAPKs: ERK1/2, p38, et JNK, et la voie NF-κB. Le traitement médical par injections quotidiennes d'insuline permet de contrôler la glycémie mais ne prévient pas les nombreuses complications secondaires liées à cette maladie. La greffe d'îlots de Langerhans est une alternative possible au traitement médical, considérée avantageuse comparée a la greffe du pancréas entier. En effet l'embolisation d'îlots dans le foie par injection intraportale constitue une intervention simple sans complications majeures. Néanmoins la technique de préparation d'îlots altère la fonction endocrine et cause la perte massive d'îlots pancréatiques. De plus, la transplantation elle-même expose la cellule ß à différents stress, notamment le stress par les cytokines inflammatoires qui provoque le rejet de greffon cellulaire. Dans la perspective d'augmenter les rendements des îlots purifiés, nous nous sommes intéressés à définir les voies majeures de stress qui régissent cette perte massive d'îlot lors du processus d'isolement et suite à l'exposition immédiate aux cytokines après transplantation. L'ensemble de ces résultats indique que le stress induit lors de l'isolement des îlots et celui des cytokines recrute différentes voies de signalisation intracellulaire (JNK, p38 et NF-κB) qui s'additionnent entre-elles pour altérer la fonction et la viabilité de l'îlot. De ce fait une stratégie doit être mise en place pour bloquer toute action synergique entre ces différentes voies activées pour améliorer la viabilité et la fonction de la cellule ß lors du greffon cellulaire. SUMMARY Type 1 diabetes mellitus (T1DM) is an autoimmune disease characterized by the progressive and selective destruction of the pancreatic ß-cells that secrete insulin, leading to absolute insulin deficiency. T1DM accounts for about 10% of all diabetes cases, affecting persons younger than 20 years of age. Medical treatment using daily exogenous insulin injection corrects hormone deficiency but does not prevent devastating complications such as heart attack, neuropathy, kidney failure, blindness, and amputation caused by the disease. Pancreatic islet transplantation (PIT) is one strategy that holds promise to cure patients with T1DM, but purified pancreatic islet grafts have failed to maintain long-term glucose homeostasis in human recipients, the reasons for this failure being still poorly understood. There is however a more immediate problem with islet grafting that is dependent upon poor islet recovery from donors and early islet loss following the first hours of grafting. This tendency of islet grafts to fail to function within a short period after transplantation is termed primary graft non-function (PNF). Indeed, the islet isolation procedure itself destroys cellular and non-cellular components of the pancreas that may play a role in supporting islet survival. Further, islet transplantation exposes cells to a variety of stressful stimuli, notably pro-inflammatory cytokines that encourage ß-cell death by apoptosis and lead to early graft failure. Altogether these mechanisms lead to an estimated loss of 60% of the total islet mass. Here, we have mapped the major intracellular stress signaling pathways that may mediate human islet loss by apoptosis during isolation and following cytokine attack. We found that several stress pathways are maximally activated from the earliest stages of the isolation procedure. Culturing islet for two days allow for the activated pathways to return to basal levels. We propose that protective strategies should 1) be initiated as early as possible during isolation of the islets, 2) should probably target the activated stress pathways that we uncovered during our studies and 3) should include culturing islets for two days post-isolation and prior transplantation.

p27 and Skp2 immunoreactivity and its clinical significance with endocrine and chemo-endocrine treatments in node-negative early breast cancer.

BACKGROUND: Low p27 and high Skp2 immunoreactivity are associated with a poor prognosis and other poor prognostic features including resistant phenotypes and antiestrogen drug resistance. We investigated these proteins in two International Breast Cancer Study Group trials studying node-negative early breast cancer. PATIENTS AND METHODS: Trial VIII compared chemotherapy followed by goserelin with either modality alone in premenopausal patients. Trial IX compared chemotherapy followed by tamoxifen with tamoxifen alone in postmenopausal patients. Central Pathology Office assessed p27 and Skp2 expression in the primary tumor by immunohistochemistry among 1631 (60%) trial patients. RESULTS: p27 and Skp2 were inversely related; 13% of tumors expressed low p27 and high Skp2. Low p27 and high Skp2 were associated with unfavorable prognostic factors including larger size and higher grade tumors, absence of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 overexpression and high Ki-67 (each P < 0.05). Low p27 and high Skp2 were not associated with disease-free survival (P = 0.42 and P = 0.48, respectively). The relative effects of chemo-endocrine versus endocrine therapy were similar regardless of p27 or Skp2. CONCLUSIONS: We confirm the association of low p27 and high Skp2 with other poor prognostic features, but found no predictive or prognostic value, and therefore do not recommend routine determination of p27 and Skp2 for node-negative breast cancer.

Spatially and genetically distinct control of seed germination by phytochromes A and B.

Phytochromes phyB and phyA mediate a remarkable developmental switch whereby, early upon seed imbibition, canopy light prevents phyB-dependent germination, whereas later on, it stimulates phyA-dependent germination. Using a seed coat bedding assay where the growth of dissected embryos is monitored under the influence of dissected endosperm, allowing combinatorial use of mutant embryos and endosperm, we show that canopy light specifically inactivates phyB activity in the endosperm to override phyA-dependent signaling in the embryo. This interference involves abscisic acid (ABA) release from the endosperm and distinct spatial activities of phytochrome signaling components. Under the canopy, endospermic ABA opposes phyA signaling through the transcription factor (TF) ABI5, which shares with the TF PIF1 several target genes that negatively regulate germination in the embryo. ABI5 enhances the expression of phytochrome signaling genes PIF1, SOMNUS, GAI, and RGA, but also of ABA and gibberellic acid (GA) metabolic genes. Over time, weaker ABA-dependent responses eventually enable phyA-dependent germination, a distinct type of germination driven solely by embryonic growth.

Nouveaux traitements de l'hépatite C: aspects pharmacologiques et potentiel d'interaction [New hepatitis C treatments: pharmacological considerations and potential for drug interactions].

Progress in the understanding of the hepatitis C virus life cycle allowed the development of new, very promising antiviral therapies. Although these new drugs have a favourable profile in terms of efficacy, tolerance and interaction potential, their prescription in the setting of comedication and impaired renal or hepatic function remains a challenge. Here, we provide a summary of pharmacological considerations, focusing on sofosbuvir, simeprevir and daclatasvir. A better understanding of their metabolic pathways and transporters may help the prescriber to identify and manage drug interactions especially in patients under immunosuppressive or anti-HIV therapy. Recommendations for the prescription of these drugs in specific situations are also discussed.

Outcome evaluation of ankle osteoarthritis treatments: plantar pressure analysis during relatively long-distance walking.

Background : This study aimed to use plantar pressure analysis in relatively long-distance walking for objective outcome evaluation of ankle osteoarthritis treatments, i.e., ankle arthrodesis and total ankle replacement.Methods : Forty-seven subjects in four groups: three patient groups and controls, participated in the study. Each subject walked twice in 50-m trials. Plantar pressure under the pathological foot was measured using pressure insoles. Six parameters: initial contact time, terminal contact time, maximum force time, peak pressure time, maximum force and peak pressure were calculated and averaged over trials in ten regions of foot. The parameters in each region were compared between patient groups and controls and their effect size was estimated. Besides, the correlations between pressure parameters and clinical scales were calculated.Findings : We observed based on temporal parameters that patients postpone the heel-off event, when high force in forefoot and high ankle moment happens. Also based on maximum force and peak pressure, the patients apply smoothened maximum forces on the affected foot. In ten regions, some parameters showed improvements after total ankle replacement, some showed alteration of foot function after ankle arthrodesis and some others showed still abnormality after both surgical treatments. These parameters showed also significant correlation with clinical scales in at least two regions of foot.Interpretation : Plantar pressure parameters in relatively long-distance trials showed to be strong tools for outcome evaluation of ankle osteoarthritis treatments. (C) 2010 Elsevier Ltd. All rights reserved.

Cost limitation through constrained oviposition site in a plant-pollinator/seed predator mutualism

Mutualism often involves reciprocal exploitation due to individual selection for increased benefits even at the expense of the partner. Therefore, stability and outcomes of such interactions crucially depend on cost limitation mechanisms. In the plant, pollinator /seed predator interaction between Silene latifolia (Caryophyllaceae) and Hadena bicruris (Lepidoptera: Noctuidae), moths generate pollination benefits as adults but impose seed predation costs as larvae. We examined whether floral morphology limits over-exploitation by constraining oviposition site. Oviposition site varies naturally inside vs. outside the corolla tube, but neither its determinants nor its effect on the interaction have been investigated. In a common garden with plants originating from eight populations, corolla tube length predicted oviposition site, but not egg presence or pollination efficiency, suggesting that long corolla tubes constrain the moth to lay eggs on petals. Egg position was also predicted by the combined effect of corolla tube and moth ovipositor lengths, with shorter ovipositor than corolla tube resulting in higher probability for eggs outside. Egg position on a given plant was repeatable over different exposure nights. When egg position was experimentally manipulated, eggs placed on the petal resulted in significantly fewer successful fruit attacks compared with eggs placed inside the corolla tube, suggesting differences in egg/larval mortality. Egg position also differently affected larval mass, fruit mass and fruit development. Our results indicate that constraining oviposition site through a long corolla tube reduces seed predation costs suffered by the plant without negatively affecting pollination efficiency and, hence may act to limit over-exploitation. However, the net effects of corolla tube depth variation on this interaction may fluctuate with extrinsic factors affecting egg mortality, and with patterns of gene flow affecting trait matching between the interacting species. The intermediate fitness costs incurred by both plant and insect associated with the different egg positions may reduce selective pressures for this interaction to evolve towards antagonism, favouring instead a mutualistic outcome. While a role for oviposition site variation in cost limitation is a novel finding in this system, it may apply more generally also to other mutualisms involving pollinating seed predators.

Seed-specific silencing of OsMRP5 reduces seed phytic acid and weight in rice.

Phytic acid (PA) is poorly digested by humans and monogastric animals and negatively affects human/animal nutrition and the environment. Rice mutants with reduced PA content have been developed but are often associated with reduced seed weight and viability, lacking breeding value. In the present study, a new approach was explored to reduce seed PA while attaining competitive yield. The OsMRP5 gene, of which mutations are known to reduce seed PA as well as seed yield and viability, was down-regulated specifically in rice seeds by using an artificial microRNA driven by the rice seed specific promoter Ole18. Seed PA contents were reduced by 35.8-71.9% in brown rice grains of transgenic plants compared to their respective null plants (non-transgenic plants derived from the same event). No consistent significant differences of plant height or number of tillers per plant were observed, but significantly lower seed weights (up to 17.8% reduction) were detected in all transgenic lines compared to null plants, accompanied by reductions of seed germination and seedling emergence. It was observed that the silencing of the OsMRP5 gene increased the inorganic P (Pi) levels (up to 7.5 times) in amounts more than the reduction of PA-P in brown rice. This indicates a reduction in P content in other cellular compounds, such as lipids and nucleic acids, which may affect overall seed development. Put together, the present study demonstrated that seed specific silencing of OsMRP5 could significantly reduce the PA content and increase Pi levels in seeds; however, it also significantly lowers seed weight in rice. Discussions were made regarding future directions towards producing agronomically competitive and nutritionally valuable low PA rice.