21/2/20 [i.e. 22/2/20], anniversaire de Washington [statue équestre, place d'Iena] : [photographie de presse] / [Agence Rol]

Référence bibliographique : Rol, 58157

HLA Class I alleles associated with HCV polymorphisms and response to antiviral therapy in HCV genotype 1-infected patients

Aims: The adaptive immune response against hepatitis C virus (HCV) is significantly shaped by the host's composition of HLA alleles. Thus, the HLA phenotype is a critical determinant of viral evolution during adaptive immune pressure. Potential associations of HLA class I alleles with polymorphisms of HCV immune escape variants are largely unknown. Methods: Direct sequence analysis of the genes encoding the HCV proteins E2, NS3 and NS5B in a cohort of 159 patients with chronic HCV genotype 1 infection who were treated with pegylated interferon-alfa 2b and ribavirin in a prospective controlled trial for 48 weeks was exhibited. HLA class I genotyping was performed by strand-specific reverse hybridization with the INNO-LiPA line probe assays for HLA-A and HLA-B and by strand-specific PCR-SSP. We analyzed each amino acid position of HCV proteins using an extension of Fisher's exact test for associations with HLA alleles. In addition, associations of specific HLA alleles with inflammatory activity, liver fibrosis, HCV RNA viral load and virologic treatment outcome were investigated. Results: Separate analyses of HCV subtype 1a and 1b isolates revealed substantially different patterns of HLA-restricted polymorphisms between subtypes. Only one polymorphism within NS5B (V2758x) was significantly associated with HLA B*15 in HCV genotype 1b infected patients (adjusted p=0,048). However, a number of HLA class I-restricted polymorphisms within novel putative HCV CD8+ T cell epitopes (genotype 1a: HLA-A*11 GTRTIASPK1086-1094 [NS3], HLA-B*07 WPAPQGARSL1111-1120 [NS3]; genotype 1b: HLA-A*24 HYAPRPCGI488-496 [E2], HLA-B*44 GENETDVLL530-538 [E2], HLA-B*15 RVFTEAMTRY2757-2766 [NS5B]) were observed with high predicted epitope binding scores assessed by the web-based software SYFPEITHI (>21). Most of the identified putative epitopes were overlapping with already otherwise published epitopes, indicating a high immunogenicity of the accordant HCV protein region. In addition, certain HLA class I alleles were associated with inflammatory activity, stage of liver fibrosis, and sustained virologic response to antiviral therapy. Conclusions: HLA class I restricted HCV sequence polymorphisms are rare. HCV polymorphisms identified within putative HCV CD8+ T cell epitopes in the present study differ in their genomic distribution between genotype 1a and 1b isolates, implying divergent adaptation to the host's immune pressure on the HCV subtype level.

A threefold dose intensity treatment with ifosfamide, carboplatin, and etoposide for patients with small cell lung cancer: a randomized trial.

BACKGROUND: The dose intensity of chemotherapy can be increased to the highest possible level by early administration of multiple and sequential high-dose cycles supported by transfusion with peripheral blood progenitor cells (PBPCs). A randomized trial was performed to test the impact of such dose intensification on the long-term survival of patients with small cell lung cancer (SCLC). METHODS: Patients who had limited or extensive SCLC with no more than two metastatic sites were randomly assigned to high-dose (High, n = 69) or standard-dose (Std, n = 71) chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). High-ICE cycles were supported by transfusion with PBPCs that were collected after two cycles of treatment with epidoxorubicin at 150 mg/m(2), paclitaxel at 175 mg/m(2), and filgrastim. The primary outcome was 3-year survival. Comparisons between response rates and toxic effects within subgroups (limited or extensive disease, liver metastases or no liver metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, normal or abnormal lactate dehydrogenase levels) were also performed. RESULTS: Median relative dose intensity in the High-ICE arm was 293% (range = 174%-392%) of that in the Std-ICE arm. The 3-year survival rates were 18% (95% confidence interval [CI] = 10% to 29%) and 19% (95% CI = 11% to 30%) in the High-ICE and Std-ICE arms, respectively. No differences were observed between the High-ICE and Std-ICE arms in overall response (n = 54 [78%, 95% CI = 67% to 87%] and n = 48 [68%, 95% CI = 55% to 78%], respectively) or complete response (n = 27 [39%, 95% CI = 28% to 52%] and n = 24 [34%, 95% CI = 23% to 46%], respectively). Subgroup analyses showed no benefit for any outcome from High-ICE treatment. Hematologic toxicity was substantial in the Std-ICE arm (grade > or = 3 neutropenia, n = 49 [70%]; anemia, n = 17 [25%]; thrombopenia, n = 17 [25%]), and three patients (4%) died from toxicity. High-ICE treatment was predictably associated with severe myelosuppression, and five patients (8%) died from toxicity. CONCLUSIONS: The long-term outcome of SCLC was not improved by raising the dose intensity of ICE chemotherapy by threefold.

The demands of family caregivers of elderly individuals with dementia

The purpose of this cross-sectional observational study was to identify characteristics of caregivers of elderly people with dementia, types of care demands and to relate demands to the stage of dementia. The study was carried out in 2004 with 104 older adults and 90 caregivers in Ribeirão Preto, state of São Paulo. The OARS instrument was utilized and a questionnaire answered by caregivers. Among older adults, 66.3% were female, aged 75.5 years in average and 86.5% had caregivers. Eighty percent of the caregivers were women family members, aged 52.3 years in average. They spent 15.10 hours/day with care, without help. An important relationship was observed between caregiver's burden, physical and emotional effort and stage of dementia. Emotional overburden was higher at dementia early and late stages, this difference was statistically non-significant. Results reveal the urgent need to plan formal and informal support strategies to caregivers of Brazilian elderly people with dementia.

A Genetic Validation Study Reveals a Role of Vitamin D Metabolism in the Response to Interferon-Alfa-Based Therapy of Chronic Hepatitis C.

BACKGROUND: To perform a comprehensive study on the relationship between vitamin D metabolism and the response to interferon-α-based therapy of chronic hepatitis C. METHODOLOGY/PRINCIPAL FINDINGS: Associations between a functionally relevant polymorphism in the gene encoding the vitamin D 1α-hydroxylase (CYP27B1-1260 rs10877012) and the response to treatment with pegylated interferon-α (PEG-IFN-α) and ribavirin were determined in 701 patients with chronic hepatitis C. In addition, associations between serum concentrations of 25-hydroxyvitamin D(3) (25[OH]D(3)) and treatment outcome were analysed. CYP27B1-1260 rs10877012 was found to be an independent predictor of sustained virologic response (SVR) in patients with poor-response IL28B genotypes (15% difference in SVR for rs10877012 genotype AA vs. CC, p = 0.02, OR = 1.52, 95% CI = 1.061-2.188), but not in patients with favourable IL28B genotype. Patients with chronic hepatitis C showed a high prevalence of vitamin D insufficiency (25[OH]D(3)<20 ng/mL) during all seasons, but 25(OH)D(3) serum levels were not associated with treatment outcome. CONCLUSIONS/SIGNIFICANCE: Our study suggests a role of bioactive vitamin D (1,25[OH](2)D(3), calcitriol) in the response to treatment of chronic hepatitis C. However, serum concentration of the calcitriol precursor 25(OH)D(3) is not a suitable predictor of treatment outcome.

Serum ferritin levels are associated with a distinct phenotype of chronic hepatitis C poorly responding to pegylated interferon-alpha and ribavirin therapy.

Elevated serum ferritin levels may reflect a systemic inflammatory state as well as increased iron storage, both of which may contribute to an unfavorable outcome of chronic hepatitis C (CHC). We therefore performed a comprehensive analysis of the role of serum ferritin and its genetic determinants in the pathogenesis and treatment of CHC. To this end, serum ferritin levels at baseline of therapy with pegylated interferon-alpha and ribavirin or before biopsy were correlated with clinical and histological features of chronic hepatitis C virus (HCV) infection, including necroinflammatory activity (N = 970), fibrosis (N = 980), steatosis (N = 886), and response to treatment (N = 876). The association between high serum ferritin levels (> median) and the endpoints was assessed by logistic regression. Moreover, a candidate gene as well as a genome-wide association study of serum ferritin were performed. We found that serum ferritin ≥ the sex-specific median was one of the strongest pretreatment predictors of treatment failure (univariate P < 0.0001, odds ratio [OR] = 0.45, 95% confidence interval [CI] = 0.34-0.60). This association remained highly significant in a multivariate analysis (P = 0.0002, OR = 0.35, 95% CI = 0.20-0.61), with an OR comparable to that of interleukin (IL)28B genotype. When patients with the unfavorable IL28B genotypes were stratified according to high versus low ferritin levels, SVR rates differed by > 30% in both HCV genotype 1- and genotype 3-infected patients (P < 0.001). Serum ferritin levels were also independently associated with severe liver fibrosis (P < 0.0001, OR = 2.67, 95% CI = 1.68-4.25) and steatosis (P = 0.002, OR = 2.29, 95% CI = 1.35-3.91), but not with necroinflammatory activity (P = 0.3). Genetic variations had only a limited impact on serum ferritin levels. Conclusion: In patients with CHC, elevated serum ferritin levels are independently associated with advanced liver fibrosis, hepatic steatosis, and poor response to interferon-alpha-based therapy.

Greenstick fractures of the middle third of the forearm. A prospective multi-centre study.

BACKGROUND: Greenstick fractures suffered during growth have a high risk for refracture and posttraumatic deformity, particularly at the forearm diaphysis. The use of a preemptive completion of the fracture by manipulation of the concave cortex is controversial and data supporting this approach are few. AIM: Aim of this study was to determine the factors which predispose to refracture and deformities, and to define therapeutic strategies. METHODS: We prospectively gathered clinical and radiographic data over a period of one year on greenstick fractures of the middle third of the forearm in children as part of a multi-centre study. Endpoint was a follow-up visit at one year. Radiographic deformity, state of consolidation at resumption of physical activities and refracture rate were analysed statistically (ANOVA, Student's t-test and Pearson's chi-square test) with regard to patient age, gender, fracture type, therapy and time in plaster. RESULTS: We collected the data of 103 patients (63 boys, 40 girls), average age 6.6 years (1.3-14.5 years), the vast majority of whom had a combined greenstick fracture of the radius and ulna. 6.7% of the patients sustained a refracture within 49 days (29-76) after plaster removal. They were significantly older (p=0.017) with a significantly higher incidence of manual completion of the fracture with radiographic signs of partial consolidation (p=0.025). Residual deformities were significantly smaller after completion of the fracture compared to reduction without completion (p=0.019) or plaster fixation alone (p<0.005). CONCLUSIONS: Completion of a greenstick fracture does not prevent refracture. Nevertheless, it diminishes the extent of secondary deformities in cases where the primary angulation exceeds the remodelling capacity. Prevention of refracture should include a routine radiographic follow-up 4-6 weeks after injury with continuation of plaster fixation in cases of partial consolidation.

Klassenkampf und Klassenkompromiss : Arbeit, Kapital und Staat in den Niederlanden und der Schweiz

Les Pays-Bas et la Suisse sont souvent décrits comme ayant des relations entre travail et capital similaires, marquées par des négociations et le compromis. La conviction est courante dans les deux pays qu'il y a une tendance constante au consensus et au compromis dans l'histoire nationale. Cette thèse livre une comparaison historique du développement des relations de classe dans la 1ers moitié du 20eme siècle. Une attention particulière est donnée aux confrontations sévères et partiellement violentes entre les classes qui ont eu lieu pendant et juste après la Première Guerre Mondiale. Dans la crise des années trente, les deux pays ont longtemps maintenu l'attachement à une politique de déflation, ce qui a mené à une nouvelle accentuation des tensions sociales. Dans ce contexte, loin d'être prêts à faire des concessions au mouvement ouvrier, d'importantes composantes du patronat néerlandais et suisse sympathisaient avec un corporatisme autoritaire comme il était prôné par les mouvements et régimes fascistes. Des alliances entre le mouvement ouvrier socialiste et des fractions importantes des classes moyennes étaient capables d'arrêter cette dérive autoritaire, sans avoir assez de force pour imposer leurs propres alternatives. C'est seulement après l'affaiblissement de la droite dure entre la deuxième moitié des années trente et l'immédiat après-guerre que des premiers fondements pour un compromis de classe stable ont été établis. Généralement, l'approche comparée de la thèse permet de mieux saisir les histoires nationales dans leur contexte européen et global et permet donc de dépasser une vue de l'histoire nationale comme «cas spécial».¦Die Beziehungen zwischen Arbeit und Kapital in Niederlande und die Schweiz werden oft als âhnlich und stark von Verhandlungen und von Kompromissen geprâgt beschrieben. In beiden Lândern ist die Auffassung weitverbreitet, dass es in der nationalen Geschichte eine konstante Tendenz zum Konsens und zum Kompromiss gebe. Diese Dissertation bietet einen historischen Vergleich der Entwicklung der Klassenbeziehungen in der ersten Hâlfte des 20. Jahrhunderts. Thematisiert werden insbesondere die ernsthaften und teilweise gewalttàtigen Zusammenstôsse zwischen den Klassen, die sich wàhrend und unmittelbar nach dem Ersten Weltkrieg ereigneten. In der Krise der Dreissigerjahre hielten beide Staaten lange an der Deflationspolitik fest, was erneut zu einer Verschârfung der sozialen Spannungen fïïhrte. Vor diesem Hintergrund lehnten weite Teile der schweizerischen und niederlândischen Grossunternehmer Konzessionen gegenuber der Arbeiterbewegung ab. Vielmehr sympathisierten sie mit einem autoritàren Korporatismus, wie er von den faschistischen Bewegungen und Regimes vertreten wurde. Allianzen zwischen der sozialistischen Arbeiterbewegung und Teilen der Mittelschichten gelang es zwar, diese autoritàren Tendenzen aufzuhalten, nicht aber ihre eigenen Alteraativkonzepte durchzusetzen. Erst nach der Schwâchung der radikalen Rechten in der Zeit zwischen der zweiten Hàlfte der 1930er Jahre und der unmittelbaren Nachkriegszeit nach dem Zweiten Weltkrieg fand sich eine¦Grundlage fur einen stabilen Klassenkompromiss. Generell ermôglicht es der vergleichende Ansatz der Dissertation, die nationale Geschichte in ihrem europâischen und globalen Kontext zu sehen und so eine Sicht auf die Geschichte eines einzelnen Landes als ,,Sonderfall" zu uberwinden.

Experimental design on the simplex

Optimum experimental designs depend on the design criterion, the model andthe design region. The talk will consider the design of experiments for regressionmodels in which there is a single response with the explanatory variables lying ina simplex. One example is experiments on various compositions of glass such asthose considered by Martin, Bursnall, and Stillman (2001).Because of the highly symmetric nature of the simplex, the class of models thatare of interest, typically Scheff´e polynomials (Scheff´e 1958) are rather differentfrom those of standard regression analysis. The optimum designs are also ratherdifferent, inheriting a high degree of symmetry from the models.In the talk I will hope to discuss a variety of modes for such experiments. ThenI will discuss constrained mixture experiments, when not all the simplex is availablefor experimentation. Other important aspects include mixture experimentswith extra non-mixture factors and the blocking of mixture experiments.Much of the material is in Chapter 16 of Atkinson, Donev, and Tobias (2007).If time and my research allows, I would hope to finish with a few comments ondesign when the responses, rather than the explanatory variables, lie in a simplex.ReferencesAtkinson, A. C., A. N. Donev, and R. D. Tobias (2007). Optimum ExperimentalDesigns, with SAS. Oxford: Oxford University Press.Martin, R. J., M. C. Bursnall, and E. C. Stillman (2001). Further results onoptimal and efficient designs for constrained mixture experiments. In A. C.Atkinson, B. Bogacka, and A. Zhigljavsky (Eds.), Optimal Design 2000,pp. 225–239. Dordrecht: Kluwer.Scheff´e, H. (1958). Experiments with mixtures. Journal of the Royal StatisticalSociety, Ser. B 20, 344–360.1

High-dose sequential chemotherapy (ICE) under circulating progenitor cells (CPC) protection in patients with small cell lung carcinoma (SCLC). Preliminary report on a multicentric study

Starting in February 1994, 20 patients (pt) with a median age of 50 years(range 41-63) from 7 European centers have been included. Completedata were obtained in 16 patients so far. CPC were mobilized with chemo(Epirubicine 75 mg/m2 /d, 01 + 02) followed by G-CSF 5 p.gfkg/d for14 days. HD chemo consisted in 3 sequential courses of ICE regimen(UOs. 10 g/m2 , Carbo. 1200 mg/m2 and Etop. 1200 mg/m2 ) underCPC protection and G-CSF 5 p.g/kg/d. Out of the 16 pt, 12 completedfull program (3 cycles). One pt died of septic shock before receivingany ICE course. One pt died during the first ICE of renal insufficiency.Two pt had only 2 courses because of toxicity. Among the 16 pt, responserate (RR) was: 7 CR, 6 PR, 1 PO; 3 pt are not evaluable dueto early withdrawal (overall RR: 13/16 = 81 %). Thirty-nine cycles ofHD chemo were given with a median hematological recovery of 9 days(range 7-12) until neutro. counts> 1.0 x 109 /1 and 9 days (range 717)until thrombo. > 20 x 109 /1. No cumulative, hematological toxicitywas seen. Accrual of patients is still ongoing and updated results will bepresented.

Shared knowledge

Agents use their knowledge on the history of the economy in orderto choose what is the optimal action to take at any given moment of time,but each individual observes history with some noise. This paper showsthat the amount of information available on the past evolution of theeconomy is an endogenous variable, and that this leads to overconcentrationof the investment, which can be interpreted as underinvestment in research.It presents a model in which agents have to invest at each period in one of$K$ sectors, each of them paying an exogenous return that follows a welldefined stochastic path. At any moment of time each agent receives an unbiasednoisy signal on the payoff of each sector. The signals differ across agents,but all of them have the same variance, which depends on the aggregate investmentin that particular sector (so that if almost everybody invests in it theperceptions of everybody will be very accurate, but if almost nobody doesthe perceptions of everybody will be very noisy). The degree of hetereogeneityacross agents is then an endogenous variable, evolving across time determining,and being determined by, the amount of information disclosed.As long as both the level of social interaction and the underlying precisionof the observations are relatively large agents behave in a very preciseway. This behavior is unmodified for a huge range of informational parameters,and it is characterized by an excessive concentration of the investment ina few sectors. Additionally the model shows that generalized improvements in thequality of the information that each agent gets may lead to a worse outcomefor all the agents due to the overconcentration of the investment that thisproduces.