992 resultados para Etiology.


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AIM: To document the feasibility and report the results of dosing darbepoetin-alpha at extended intervals up to once monthly (QM) in a large dialysis patient population. MATERIAL: 175 adult patients treated, at 23 Swiss hemodialysis centres, with stable doses of any erythropoiesis-stimulating agent who were switched by their physicians to darbepoetin-alpha treatment at prolonged dosing intervals (every 2 weeks [Q2W] or QM). METHOD: Multicentre, prospective, observational study. Patients' hemoglobin (Hb) levels and other data were recorded 1 month before conversion (baseline) to an extended darbepoetin-alpha dosing interval, at the time of conversion, and once monthly thereafter up to the evaluation point (maximum of 12 months or until loss to follow-up). RESULTS: Data for 161 evaluable patients from 23 sites were included in the final analysis. At 1 month prior to conversion, 73% of these patients were receiving darbepoetin-alpha weekly (QW) and 27% of the patients biweekly (Q2W). After a mean follow-up of 9.5 months, 34% received a monthly (QM) dosing regimen, 52% of the patients were receiving darbepoetin-alpha Q2W, and 14% QW. The mean (SD) Hb concentration at baseline was 12.3 +/- 1.2 g/dl, compared to 11.9 +/- 1.2 g/dl at the evaluation point. The corresponding mean weekly darbepoetin-alpha dose was 44.3 +/- 33.4 microg at baseline and 37.7 +/- 30.8 microg at the evaluation point. CONCLUSIONS: Conversion to extended darbepoetin-alpha dosing intervals of up to QM, with maintenance of initial Hb concentrations, was successful for the majority of stable dialysis patients.

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The incidence of basal cell carcinoma (BCC) has been related to ionizing radiation, particularly for exposure occurring at young age. In this study, we considered the incidence of second skin neoplasms in long-term survivors from childhood cancer. We considered second primary cancers occurring among 776 subjects (436 males, 340 females) with first primary cancer diagnosed before age 20 years, between 1974 and 2001, in the Swiss Cantons of Vaud and Neuchâtel (786,000 inhabitants). Five BCC were observed versus 0.43 expected (standardized incidence ratio: 11.6, 95% confidence interval: 3.7-27.1). No case of cutaneous squamous cell carcinoma, nor of malignant melanoma was observed. The estimated radiation doses at 1mm through the skin ranged between 7 and 27 Sv. These data confirm that BCC are strongly related to ionizing radiation exposure in childhood. All the BCC were located within the radiation field, thus indicating that ionizing radiation is the key aetiological factor, even in the absence of any meaningful interaction with UV.

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OBJECTIVE: Delirium is highly prevalent in general hospitals but remains underrecognized and undertreated despite its association with increased morbidity, mortality, and health services utilization. To enhance its management, we developed guidelines covering all aspects, from risk factor identification to preventive, diagnostic, and therapeutic interventions in adult patients. METHODS: Guidelines, systematic reviews, randomized controlled trials (RCT), and cohort studies were systematically searched and evaluated. Based on a synthesis of retrieved high-quality documents, recommendation items were submitted to a multidisciplinary expert panel. Experts scored the appropriateness of recommendation items, using an evidence-based, explicit, multidisciplinary panel approach. Each recommendation was graded according to this process' results. RESULTS: Rated recommendations were mostly supported by a low level of evidence (1.3% RCT and systematic reviews, 14.3% nonrandomized trials vs. 84.4% observational studies or expert opinions). Nevertheless, 71.1% of recommendations were considered appropriate by the experts. Prevention of delirium and its nonpharmacological management should be fostered. Haloperidol remains the first-choice drug, whereas the role of atypical antipsychotics is still uncertain. CONCLUSIONS: While many topics addressed in these guidelines have not yet been adequately studied, an explicit panel and evidence-based approach allowed the proposal of comprehensive recommendations for the prevention and management of delirium in general hospitals.

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BACKGROUND AND AIMS: In various populations, vitamin D deficiency is associated with chronic diseases and mortality. We examined the association between concentration of circulating 25-hydroxyvitamin D [25(OH)D], a marker of vitamin D status, and all-cause as well as cause-specific mortality. METHODS AND RESULTS: The study included 3404 participants of the general adult Swiss population, who were recruited between November 1988 and June 1989 and followed-up until the end of 2008. Circulating 25(OH)D was measured by protein-bound assay. Cox proportional hazards regression was used to examine the association between 25(OH)D concentration and all-cause and cause-specific mortality adjusting for sex, age, season, diet, nationality, blood pressure, and smoking status. Per 10 ng/mL increase in 25(OH)D concentration, all-cause mortality decreased by 20% (HR = 0.83; 95% CI 0.74-0.92). 25(OH)D concentration was inversely associated with cardiovascular mortality in women (HR = 0.68, 95% CI 0.46-1.00 per 10 ng/mL increase), but not in men (HR = 0.97; 95% CI 0.77-1.23). In contrast, 25(OH)D concentration was inversely associated with cancer mortality in men (HR = 0.72, 95% CI 0.57-0.91 per 10 ng/mL increase), but not in women (HR = 1.14, 95% CI 0.93-1.39). Multivariate adjustment only slightly modified the 25(OH)D-mortality association. CONCLUSION: 25(OH)D was similarly inversely related to all-cause mortality in men and women. However, we observed opposite effects in women and men with respect to cardiovascular and cancer mortality.

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OBJECTIVE: Inflammatory bowel diseases (IBDs), Crohn's disease, and ulcerative colitis (UC), are multifactorial disorders, characterized by chronic inflammation of the intestine. A number of genetic components have been proposed to contribute to IBD pathogenesis. In this case-control study, we investigated the association between two common vitamin D-binding protein (DBP) genetic variants and IBD susceptibility. These two single nucleotide polymorphisms (SNPs) in exon 11 of the DBP gene, at codons 416 (GAT>GAG; Asp>Glu) and 420 (ACG>AAG; Thr>Lys), have been previously suggested to play roles in the etiology of other autoimmune diseases. METHODS: Using TaqMan SNP technology, we have genotyped 884 individuals (636 IBD cases and 248 non-IBD controls) for the two DBP variants. RESULTS: On statistical analysis, we observed that the DBP 420 variant Lys is less frequent in IBD cases than in non-IBD controls (allele frequencies, P=0.034; homozygous carrier genotype frequencies, P=0.006). This inverse association between the DBP 420 Lys and the disease remained significant, when non-IBD participants were compared with UC (homozygous carrier genotype frequencies, P=0.022) or Crohn's disease (homozygous carrier genotype frequencies, P=0.016) patients separately. Although the DBP position 416 alone was not found to be significantly associated with IBD, the haplotype DBP_2, consisting of 416 Asp and 420 Lys, was more frequent in the non-IBD population, particularly notably when compared with the UC group (Odds ratio, 4.390). CONCLUSION: Our study adds DBP to the list of potential genes that contribute to the complex genetic etiology of IBD, and further emphasizes the association between vitamin D homeostasis and intestinal inflammation.

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The role of interferon-gamma in autoimmune diabetes was assessed by breeding a null mutation of the interferon-gamma receptor alpha chain into the nonobese diabetic mouse strain, as well as into a simplified T cell receptor transgenic model of diabetes. In contrast to a previous report on abrogation of the interferon-gamma gene, mutation of the gene encoding its receptor led to drastic effects on disease in both mouse lines. Nonobese diabetic mice showed a marked inhibition of insulitis-both the kinetics and penetrance-and no signs of diabetes; the transgenic model exhibited near-normal insulitis, but this never evolved into diabetes, either spontaneously or after experimental provocation. This failure could not be explained by perturbations in the ratio of T helper cell phenotypes; rather, it reflected a defect in antigen-presenting cells or in the islet beta cell targets.

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CONTEXT: Type 2 diabetes is associated with increased fracture risk but paradoxically greater bone mineral density (BMD). Trabecular bone score (TBS) is derived from the texture of the spine dual x-ray absorptiometry (DXA) image and is related to bone microarchitecture and fracture risk, providing information independent of BMD. OBJECTIVE: This study evaluated the ability of lumbar spine TBS to account for increased fracture risk in diabetes. DESIGN AND SETTING: We performed a retrospective cohort study using BMD results from a large clinical registry for the province of Manitoba, Canada. Patients: We included 29,407 women 50 years old and older with baseline DXA examinations, among whom 2356 had diagnosed diabetes. MAIN OUTCOME MEASURES: Lumbar spine TBS was derived for each spine DXA examination blinded to clinical parameters and outcomes. Health service records were assessed for incident nontraumatic major osteoporotic fractures (mean follow-up 4.7 years). RESULTS: Diabetes was associated with higher BMD at all sites but lower lumbar spine TBS in unadjusted and adjusted models (all P < .001). The adjusted odds ratio (aOR) for a measurement in the lowest vs the highest tertile was less than 1 for BMD (all P < .001) but was increased for lumbar spine TBS [aOR 2.61, 95% confidence interval (CI) 2.30-2.97]. Major osteoporotic fractures were identified in 175 women (7.4%) with and 1493 (5.5%) without diabetes (P < .001). Lumbar spine TBS was a BMD-independent predictor of fracture and predicted fractures in those with diabetes (adjusted hazard ratio 1.27, 95% CI 1.10-1.46) and without diabetes (hazard ratio 1.31, 95% CI 1.24-1.38). The effect of diabetes on fracture was reduced when lumbar spine TBS was added to a prediction model but was paradoxically increased from adding BMD measurements. CONCLUSIONS: Lumbar spine TBS predicts osteoporotic fractures in those with diabetes, and captures a larger portion of the diabetes-associated fracture risk than BMD.

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Context Heart failure (HF) is the most common complication of infective endocarditis. However, clinical characteristics of HF in patients with infective endocarditis, use of surgical therapy, and their associations with patient outcome are not well described.Objectives To determine the clinical, echocardiographic, and microbiological variables associated with HF in patients with definite infective endocarditis and to examine variables independently associated with in-hospital and 1-year mortality for patients with infective endocarditis and HF, including the use and association of surgery with outcome.Design, Setting, and Patients The International Collaboration on Endocarditis-Prospective Cohort Study, a prospective, multicenter study enrolling 4166 patients with definite native- or prosthetic-valve infective endocarditis from 61 centers in 28 countries between June 2000 and December 2006.Main Outcome Measures In-hospital and 1-year mortality.Results Of 4075 patients with infective endocarditis and known HF status enrolled, 1359 (33.4% [95% CI, 31.9%-34.8%]) had HF, and 906 (66.7% [95% CI, 64.2%-69.2%]) were classified as having New York Heart Association class III or IV symptom status. Within the subset with HF, 839 (61.7% [95% CI, 59.2%-64.3%]) underwent valvular surgery during the index hospitalization. In-hospital mortality was 29.7% (95% CI, 27.2%-32.1%) for the entire HF cohort, with lower mortality observed in patients undergoing valvular surgery compared with medical therapy alone (20.6% [95% CI, 17.9%-23.4%] vs 44.8% [95% CI, 40.4%-49.0%], respectively; P < .001). One-year mortality was 29.1% (95% CI, 26.0%-32.2%) in patients undergoing valvular surgery vs 58.4% (95% CI, 54.1%-62.6%) in those not undergoing surgery (P < .001). Cox proportional hazards modeling with propensity score adjustment for surgery showed that advanced age, diabetes mellitus, health care-associated infection, causative microorganism (Staphylococcus aureus or fungi), severe HF (New York Heart Association class III or IV), stroke, and paravalvular complications were independently associated with 1-year mortality, whereas valvular surgery during the initial hospitalization was associated with lower mortality.Conclusion In this cohort of patients with infective endocarditis complicated by HF, severity of HF was strongly associated with surgical therapy and subsequent mortality, whereas valvular surgery was associated with lower in-hospital and 1-year mortality.

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Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with a complex genetic etiology. We used high-resolution whole genome array-based comparative genomic hybridization (array-CGH) to screen 223 ASD patients for gene dose alterations associated with susceptibility for autism. Clinically significant copy number variations (CNVs) were identified in 18 individuals (8%), of which 9 cases (4%) had de novo aberrations. In addition, 20 individuals (9%) were shown to have CNVs of unclear clinical relevance. Among these, 13 cases carried rare but inherited CNVs that may increase the risk for developing ASDs, while parental samples were unavailable in the remaining seven cases. Classification of all patients into different phenotypic and inheritance pattern groups indicated the presence of different CNV patterns in different patient groups. Clinically relevant CNVs were more common in syndromic cases compared to non-syndromic cases. Rare inherited CNVs were present in a higher proportion of ASD cases having first- or second-degree relatives with an ASD-related neuropsychiatric phenotype in comparison with cases without reported heredity (P = 0.0096). We conclude that rare CNVs, encompassing potential candidate regions for ASDs, increase the susceptibility for the development of ASDs and related neuropsychiatric disorders giving us further insight into the complex genetics underlying ASDs.

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Excessive salt intake increases the risk of developing hypertension and cardiovascular disease. Sodium intake remains high both in developed and emerging countries. The Swiss Federal Office of Public Health has ordered a national survey on the salt intake in Switzerland, realized in different centers. This article presents the results of the awareness of the Swiss population concerning the relationship between excessive salt intake and health. This survey reveals a lack of knowledge regarding the association between high salt intake and cardiovascular disease, the sodium content of usual food, and the recommended daily value of sodium intake. Strategies to reduce salt consumption need to be reinforced by collaborations between health authorities and health care professionals.

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To determine the role of Chlamydia trachomatis in miscarriage, we prospectively collected serum, cervicovaginal swab specimens, and placental samples from 386 women with and without miscarriage. Prevalence of immunoglobulin G against C. trachomatis was higher in the miscarriage group than in the control group (15.2% vs. 7.3%; p = 0.018). Association between C. trachomatis-positive serologic results and miscarriage remained significant after adjustment for age, origin, education, and number of sex partners (odds ratio 2.3, 95% confidence interval 1.1-4.9). C. trachomatis DNA was more frequently amplified from products of conception or placenta from women who had a miscarriage (4%) than from controls (0.7%; p = 0.026). Immunohistochemical analysis confirmed C. trachomatis in placenta from 5 of 7 patients with positive PCR results, whereas results of immunohistochemical analysis were negative in placenta samples from all 8 negative controls tested. Associations between miscarriage and serologic/molecular evidence of C. trachomatis infection support its role in miscarriage.

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RÉSUMÉ La sclérose en plaques (SEP) est une maladie démyélinisante du système nerveux central (SNC) qui touche le plus souvent de jeunes femmes. Bien qu'elle ait été décrite pour la première fois il y a plus de 200 ans, son étiologie n'est pas encore complètement comprise. Contrairement à d'autres maladies purement génétiques, l'épidémiologie de la SEP ne peut être que partiellement expliquée par des facteurs génétiques. Ceci suggère que des facteurs environnementaux pourraient être impliqués dans la pathogenèse de la SEP. Parmi ceux-ci, le virus d'Epstein-Barr (EBV) est un excellent candidat, comme cela a été démontré par de larges études séroépidémiologiques ainsi que pax l'évaluation de la réponse cellulaire dans le sang. Bien que le SNC soit en fait la cible des réponses immunitaires anormales dans la SEP, peu d'études ont été accomplies sur les réponses immunitaires spécifiques à EBV dans ce compartiment. Ceci est particulièrement vrai chez des patients vivants chez lesquels des biopsies sont rarement effectuées, ainsi que pour les réponses cellulaires car très peu de cellules immunitaires peuvent être obtenues du SNC. Nous avons donc développé des conditions de cultures et un readout nous permettant d'étudier le nombre réduit de cellules disponibles dans le liquide céphalo-rachidien (LCR), qui représente le seul matériel pouvant être obtenu du SNC de patients SEP vivants. Nous avons trouvé que les réponses cellulaires et humorales spécifiques à EBV étaient augmentées dans le LCR des patients SEP comparé à du sang pairé, ainsi que par rapport à des patients avec d'autres maladies neurologiques inflammatoires et noninflammatoires. Afin de déterminer si les réponses immunitaires augmentées contre EBV étaient spécifiques à ce virus ou si elles reflétaient simplement une hyperactivation immunitaire aspécifique, nous avons comparé les réponses spécifiques à EBV avec celles spécifiques au cytomegalovirus (CNN). En effet, comme EBV, CNN est un herpesvirus neurotropique qui peut établir des infections latentes, mais ce dernier n'est pas considéré comme étant associé à la SEP. De façon intéressante, les réponses immunitaires spécifiques à CNN trouvées dans le LCR étaient plus basses que dans le sang, et ceci dans toutes les catégories de patients. Ces données suggèrent qu'une réactivation d'EBV pourrait avoir lieu dans le SNC des patients SEP à un stade précoce de la maladie et renforcent fortement l'hypothèse qu'EBV pourrait avoir un rôle déclencheur dans cette maladie. Ainsi, il pourrait être intéressant d'explorer si un traitement ou un vaccin efficace contre EBV peut prévenir le développement de la SEP. On ne connaît toujours pas la raison pour laquelle les réponses immunitaires spécifiques à EBV sont augmentées chez les patients SEP. Une hypothèse est que la réponse immunitaire est qualitativement différente chez les patients SEP par rapports aux contrôles. Pour examiner ceci, nous avons évalué le profile cytokinique de lymphocytes T CD4+ et CD8+ stimulés par EBV, mais nous n'avons pas pu mettre en évidence de différence remarquable entre patients SEP et sujets sains. Cette question reste donc ouverte et d'autres études sont justifiées. Il n'existe pas de marqueur fiable de la SEP. Ici, nous avons trouvé que la cytokine IL-26, récemment décrite, était augmentée dans les lymphocytes T CD8+ des patients avec une SEP secondairement progressive comparé à des patients SEP en poussée, des patients avec une SEP primairement progressive, des patients avec d'autres maladies neurologiques inflammatoires, ou des sujets sains. De plus, nous avons identifié des types de cellules dérivées du cerveau (astrocytes, oligodendrocytes et neurones) qui exprimaient le récepteur de l'IL-26. Ceci ouvre la voie à d'autres études afin de mieux comprendre la fonction de l'II.-26 et son interaction avec la. SEP. SUMMARY : Multiple sclerosis (MS) is a demyelinating disease affecting the central nervous system (CNS), mostly in young female adults. Although it was first described 200 years ago, its etiology is still not completely understood. Contrary to other purely genetic diseases, genetics can explain only part of MS epidemiology. Therefore, environmental factors that might be involved in MS pathogenesis were searched for. Among them, Epstein-Barr virus (EBV) is a strong potential candidate, such as shown by large seroepidemiological studies and cellular immune response assessments in the blood. Although the CNS is the actual target of abnormal immune responses in MS, few studies have been performed on EBV-specific immune responses in this compartment. This is particularly true for live patients, from which biopsy material is almost never available, and for cellular immune responses, since very few immune cells are available from the CNS. We therefore developed culture conditions and a readout that were compatible with the study of the reduced number of cells found in the cerebrospinal fluid (CSF), the only readily available material from the CNS of live ' MS patients. We found that EBV-specific cellular and humoral immune responses were increased in the CSF of MS patients as compared with paired blood, as well as compared with the CSF of patients with other inflammatory and non-inflammatory neurological diseases. To determine whether the enhanced immune responses against EBV were specific of this virus or simply reflected an aspecific immune hyperactivation, we compared the EBV- with the cytomegalovirus (CMV)-specific immune responses. Indeed, like EBV, CMV is a neurotrophic herpesvirus that can establish latent infections, but the latter is not considered to be associated with MS. Interestingly, CSF CMV-specific immune responses were lower than blood ones and this, in all patient categories. These findings suggest that EBV reactivation may be taking place in the CNS of patients at the early stages of MS and strengthen the hypothesis that EBV may have a triggering role in this disease. Therefore, it might be interesting to explore whether an efficient anti-EBV drug or vaccine is able to prevent MS development. The reason why EBV-specific immune responses are increased in MS patients is still missing. One hypothesis might be that the immune response against EBV is qualitatively different in MS patients as compared with controls. To examine this, we assessed the cytokine mRNA profile of EBV-stimulated CD4+ and CD8+ T cells, but could not find any remarkable difference between MS patients and healthy controls. Therefore, this question remains open and fiirther studies are warranted. Reliable disease markers are lacking for MS. Here, we found that the recently described cytokine IL-26 was increased in CD8+ T cells of patients with secondary progressive MS as compared with relapsing MS, primary progressive MS, other inflammatory neurological diseases and healthy controls. Moreover, we identified brain cell types (astrocytes, oligodendrocytes and neurons) that expressed the IL-26 receptor, paring the way for further studies to understand IL-26 function and its interaction with MS.