Structural covariance of superficial white matter in mild Alzheimer's disease compared to normal aging.

INTRODUCTION: Interindividual variations in regional structural properties covary across the brain, thus forming networks that change as a result of aging and accompanying neurological conditions. The alterations of superficial white matter (SWM) in Alzheimer's disease (AD) are of special interest, since they follow the AD-specific pattern characterized by the strongest neurodegeneration of the medial temporal lobe and association cortices. METHODS: Here, we present an SWM network analysis in comparison with SWM topography based on the myelin content quantified with magnetization transfer ratio (MTR) for 39 areas in each hemisphere in 15 AD patients and 15 controls. The networks are represented by graphs, in which nodes correspond to the areas, and edges denote statistical associations between them. RESULTS: In both groups, the networks were characterized by asymmetrically distributed edges (predominantly in the left hemisphere). The AD-related differences were also leftward. The edges lost due to AD tended to connect nodes in the temporal lobe to other lobes or nodes within or between the latter lobes. The newly gained edges were mostly confined to the temporal and paralimbic regions, which manifest demyelination of SWM already in mild AD. CONCLUSION: This pattern suggests that the AD pathological process coordinates SWM demyelination in the temporal and paralimbic regions, but not elsewhere. A comparison of the MTR maps with MTR-based networks shows that although, in general, the changes in network architecture in AD recapitulate the topography of (de)myelination, some aspects of structural covariance (including the interhemispheric asymmetry of networks) have no immediate reflection in the myelination pattern.

Traitements des facteurs de risque cardiovasculaire et dépistage de la maladie coronarienne dans le diabète de type 2 [Treatments for cardiovascular risk factors and screening for coronary artery disease in type 2 diabetes mellitus]

The recent ACCORD and DIAD studies revealed results which could modify treatments and the screening of diabetes vascular complications. Indeed, ACCORD shows no benefit on the prevention of diabetes vascular complications by aggressive treatment of hypertension or the combined treatment of the dyslipidemia. The intensive treatment of the blood glucose, if associated with severe hypoglycemias, increases mortality. DIAD revealed 20% of silent myocardial ischaemia in diabetic patients but no beneficial effect on the cardiovascular mortality. A careful reading of these studies in the light of long term studies such as UKPDS and STENO reveals that these negative results are generated by a too short follow-up and too aggressive objectives. The long term studies reveal that more realistic objectives remain beneficial.

Facteurs de risque fracturaire, nouveaux traitements: comment evolue la prise en charge de l'ostéoporose de la personne agée [Fracture risk, new treatments: how does the management of the osteoporosis of elderly change?]

Osteoporosis of elderly is a growing medical, economic and health-care problem. It is due to the increase of the life expectancy and the number of osteoporotic fractures. With the new Swiss-specific tool FRAX and the development of inpatients fracture trajectory, we can better identify patients with high risk of fracture. An appropriate treatment can be proposed more quickly. The follow-up of bone markers increases the treatment efficiency. With a better identification, treatment and follow-up of osteoporosis of elderly patients, we can ameliorate the patient's quality of life and decrease the number of osteoporotic fractures with a good cost-effectiveness ratio.

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.

Superficial soft tissue sarcomas (S-STS): a study of 367 patients from the French Sarcoma Group (FSG) database.

AIM: The specific natural history of superficial soft tissue sarcomas (S-STS) has been rarely considered. We describe the clinical characteristics of a large series of S-STS (N=367) from the French Sarcoma Group (GSF-GETO) database and analyse the prognostic factors affecting outcome. METHODS: We performed univariate and multivariate analyses for overall survival (OS), metastasis-free survival (MFS) and local recurrence-free survival (LRFS). RESULTS: The median age was 59 years. Fifty-eight percent patients were female. Tumour locations were as follows: extremities, 55%; trunk wall, 35.4%; head and neck, 8% and unknown, 1.6%. Median tumour size was 3.0 cm. The most frequent tumour types were unclassified sarcoma (24.3%) and leiomyosarcoma (22.3%). Thirty-three percent of cases were grade 3. Median follow-up was 6.18 years. The 5-year OS, MFS and LRFS rates were 80.9%, 80.7% and 74.7%, respectively. Multivariate analysis retained histological type and wide resection for predicting LRFS and histological type and grade as prognostic factors of MFS. The factors influencing OS were age, histological type, grade and wide resection. STS with early invasion into but not through the underlying fascia had a significantly poorer MFS than with strict S-STS. CONCLUSION: S-STS represent a separate category characterised by a better outcome. Adequate surgery, i.e. wide resection, is essential in the management of S-STS.

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.

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.

Demyelination of superficial white matter in early Alzheimer's disease: a magnetization transfer imaging study.

Assuming selective vulnerability of short association U-fibers in early Alzheimer's disease (AD), we quantified demyelination of the surface white matter (dSWM) with magnetization transfer ratio (MTR) in 15 patients (Clinical Dementia Rating Scale [CDR] 0.5-1; Functional Assessment Staging [FAST]: 3-4) compared with 15 controls. MTRs were computed for 39 areas in each hemisphere. We found a bilateral MTR decrease in the temporal, cingulate, parietal, and prefrontal areas. With linear discriminant analysis, we successfully classified all the participants with 3 variates including the cuneus, parahippocampal, and superior temporal regions of the left hemisphere. The pattern of dSWM changed with the age of AD onset. In early onset patients, we found bilateral posterior demyelination spreading to the temporal areas in the left hemisphere. The late onset patients showed a distributed bilateral pattern with the temporal and cingulate areas strongly affected. A correlation with Mini Mental State Examination (MMSE), Lexis, and memory tests revealed the dSWM impact on cognition. A specific landscape of dSWM in early AD shows the potential of MTR imaging as an in vivo biomarker superior to currently used techniques.

Clinical assessment of fluorescence cytoscopy during transurethral bladder resection in superficial bladder cancer.

The prognosis of superficial bladder cancer in terms of recurrence and disease progression is related to bladder tumor multiplicity and the presence of concomitant "plane" tumors such as high-grade dysplasia and carcinoma in situ. This study in 33 patients aimed to demonstrate the role of fluorescence cystoscopy in transurethral resection of superficial bladder cancer. The method is based on the detection of protoporphyrin-IX-induced fluorescence in urothelial cancer cells by topical administration of 5-aminolevulinic acid. The sensitivity and the specificity of this procedure on apparently normal mucosa in superficial bladder cancer are estimated to be 82.9% and 81.3%, respectively. Thus, fluorescence cytoscopy is a simple and reliable method for mapping the bladder mucosa, especially in the case of multifocal bladder disease, and it facilitates the screening of occult dysplasia.

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.