Influence of IL28B polymorphisms on response to a lower-than-standard dose peg-IFN-α 2a for genotype 3 chronic hepatitis C in HIV-coinfected patients.

BACKGROUND Data on which to base definitive recommendations on the doses and duration of therapy for genotype 3 HCV/HIV-coinfected patients are scarce. We evaluated the efficacy of a lower peginterferon-α 2a dose and a shorter duration of therapy than the current standard of care in genotype 3 HCV/HIV-coinfected patients. METHODS AND FINDINGS Pilot, open-label, single arm clinical trial which involved 58 Caucasian HCV/HIV-coinfected patients who received weekly 135 µg peginterferon-α 2a plus ribavirin 400 mg twice daily during 20 weeks after attaining undetectable viremia. The relationships between baseline patient-related variables, including IL28B genotype, plasma HCV-RNA, ribavirin dose/kg, peginterferon-α 2a and ribavirin levels with virological responses were analyzed. Only 4 patients showed lack of response and 5 patients dropped out due to adverse events related to the study medication. Overall, sustained virologic response (SVR) rates were 58.3% by intention-to-treat and 71.4% by per protocol analysis, respectively. Among patients with rapid virologic response (RVR), SVR and relapses rates were 92.6% and 7.4%, respectively. No relationships were observed between viral responses and ribavirin dose/kg, peginterferon-α 2a concentrations, ribavirin levels or rs129679860 genotype. CONCLUSIONS Weekly 135 µg pegIFN-α 2a could be as effective as the standard 180 µg dose, with a very low incidence of severe adverse events. A 24-week treatment duration appears to be appropriate in patients achieving RVR, but extending treatment up to just 20 weeks beyond negativization of viremia is associated with a high relapse rate in those patients not achieving RVR. There was no influence of IL28B genotype on the virological responses.

Anthropogenic influence on the distribution, abundance and diversity of sandfly species (Diptera: Phlebotominae: Psychodidae), vectors of cutaneous leishmaniasis in Panama

In Panama, species of the genus Lutzomyia are vectors of American cutaneous leishmaniasis (ACL). There is no recent ecological information that may be used to develop tools for the control of this disease. Thus, the goal of this study was to determine the composition, distribution and diversity of Lutzomyia species that serve as vectors of ACL. Sandfly sampling was conducted in forests, fragmented forests and rural environments, in locations with records of ACL. Lutzomyia gomezi, Lutzomyia panamensis and Lutzomyia trapidoi were the most widely distributed and prevalent species. Analysis of each sampling point showed that the species abundance and diversity were greatest at points located in the fragmented forest landscape. However, when the samples were grouped according to the landscape characteristics of the locations, there was a greater diversity of species in the rural environment locations. The Kruskal Wallis analysis of species abundance found that Lu. gomezi and Lu. trapidoi were associated with fragmented environments, while Lu. panamensis, Lutzomyia olmeca bicolor and Lutzomyia ylephiletor were associated with forested environments. Therefore, we suggest that human activity influences the distribution, composition and diversity of the vector species responsible for leishmaniasis in Panama.

Common variants of the liver fatty acid binding protein gene influence the risk of type 2 diabetes and insulin resistance in Spanish population

SUMMARY The main objective was to evaluate the association between SNPs and haplotypes of the FABP1-4 genes and type 2 diabetes, as well as its interaction with fat intake, in one general Spanish population. The association was replicated in a second population in which HOMA index was also evaluated. METHODS 1217 unrelated individuals were selected from a population-based study [Hortega study: 605 women; mean age 54 y; 7.8% with type 2 diabetes]. The replication population included 805 subjects from Segovia, a neighboring region of Spain (446 females; mean age 52 y; 10.3% with type 2 diabetes). DM2 mellitus was defined in a similar way in both studies. Fifteen SNPs previously associated with metabolic traits or with potential influence in the gene expression within the FABP1-4 genes were genotyped with SNPlex and tested. Age, sex and BMI were used as covariates in the logistic regression model. RESULTS One polymorphism (rs2197076) and two haplotypes of the FABP-1 showed a strong association with the risk of DM2 in the original population. This association was further confirmed in the second population as well as in the pooled sample. None of the other analyzed variants in FABP2, FABP3 and FABP4 genes were associated. There was not a formal interaction between rs2197076 and fat intake. A significant association between the rs2197076 and the haplotypes of the FABP1 and HOMA-IR was also present in the replication population. CONCLUSIONS The study supports the role of common variants of the FABP-1 gene in the development of type 2 diabetes in Caucasians.

Validation interne de la version française du NEO-PI-R et influence de l'âge, du sexe et de la profession

We have examined the internal validity of the French translation of the NEO PI-R personality test which measures the « big five » (Rolland, 1993). The impact of age, gender and professional categories on the NEO PI-R scales was assessed. A large sample (n=731) of subjects of different age, gender and profession and a sample of Swiss students (n=261) responding anonymously were used. Factor analyses confirmed the structure of the instrument (5 domains) and the structures of the domains in terms of facets (six facets within each domain). On the other hand, the age has a significant impact on all the domains of the NEO PI-R; the gender has an impact on the scores on N (neuroticism), O (openness) and A (agreeableness), and the profession has an impact on the domains E (extraversion), O (openness) and A (agreeableness). The scores on several facets are also affected by those three variables. Our study gives the researchers and the practitioner a reference score table according to the studied variables.

Validation de la version française de l'échelle de contrôle de Levenson (IPC), influence de variables démographiques et de la personnalité

We have examined the internal validity of the Levenson's locus of control scales (IPC, Internal, Powerful others and Chances), translated by Loas et al. (1994). The impact of different demographic variables on the Levenson's locus of control scales was assessed. After, we studied the relation between the IPC scales and the NEO PI R, personality inventory that measures the big five. A large sample (n=200) of subjects of different age, gender and profession and a sample of Swiss students (n=161) responding anonymously were used. The reliability of the IPC scale is acceptable. The analyses of the impact of the demographic variables show that gender and level of education have an influence on the I (intern) scale. Age, gender, level of education and profession have an impact on the P (powerful others) scale. The analyses of the relationship between locus of control and personality showed that there was a negative correlation between I (intern) and Neuroticism and a positive correlation between I and Extraversion and Consciousness. The P (powerful others) scale correlate positively with Neuroticism and negatively with Openness and Agreability. The C scale (chance) correlate positively with Neuroticism. Our study also gives the researchers and the practitioner a reference score table according to the gender, the age, the level of education and the profession.

Telemedicine influence on the follow-up of type 2 diabetes patients.

OBJECTIVE This study was designed to evaluate the impact of a teleassistance system on the metabolic control of type 2 diabetes patients. RESEARCH DESIGN AND METHODS We conducted a 1-year controlled parallel-group trial comparing patients randomized (1) to an intervention group, assigned to a teleassistance system using real-time transmission of blood glucose results, with immediate reply when necessary, and telephone consultations, or (2) to a control group, being regularly followed-up at their healthcare center. Study subjects were type 2 diabetes patients >30 years of age followed in the primary care setting. RESULTS A total of 328 type 2 diabetes patients were recruited from 35 family practices in the province of Málaga, Spain. There was a reduction in hemoglobin A1c after 12 months from 7.62 +/- 1.60% to 7.40 +/- 1.43% (P = 0.027) in the intervention group and from 7.44 +/- 1.31% to 7.35 +/- 1.38% (P = 0.303) in the control group. The difference in the change between groups was not statistically significant. There was also a significant decrease in systolic and diastolic blood pressure, total cholesterol, low-density lipoprotein cholesterol, and body mass index in the intervention group. In the control group, the only significant decline was in low-density lipoprotein cholesterol. CONCLUSIONS A teleassistance system using real-time transmission of blood glucose results with an option to make telephone consultations is feasible in the primary care setting as a support tool for family physicians in their follow-up of type 2 diabetes patients.

Genotype-phenotype correlation of age-related macular degeneration : influence of complement factor H polymorphism

RAPPORT DE SYNTHESE La dégénérescence maculaire liée à l'âge (DMLA) est une maladie très fréquente qui représente la cause principale de cécité légale chez les sujets de plus de 50 ans en Occident. Bien que l'étiologie exacte de cette affection ne soit pas complètement connue, des facteurs environnementaux et génétiques influencent sa survenue et son évolution. A ce sujet, de récentes recherches ont notamment montré une association marquée à une variante du gène CFH, Y402H. Nous ignorons toutefois si le polymorphisme Y402H est associé à un phénotype particulier de la maladie. Cette étude a pour but d'établir si cette variante du gène CFH est associée à certaines caractéristiques phénotypiques précoces. L'étude porte sur quatre cent vingt patients atteints de DMLA qui ont été phénotypés sur la base de photographie du fond d'oeil (International Classification and Grading system for age- related macular degeneration) et génotypés à partir d'ADN leucocytaire à la recherche de la variante Y402H du gène CFH. Ces données ont ensuite fait l'objet d'une analyse statistique de l'association génotype-phénotype (le génotype de 50 sujets-contrôle a été utilisé pour confirmer l'association du polymorphisme avec la DMLA). Les résultats obtenus, corrigés pour l'âge et le sexe, montrent un odds ratio (OR) de développer une DMLA de 2.95 en présence d'au moins un allèle à risque C et de 9.05 pour les homozygotes CC. Par contre, aucune influence n'est observée sur les stades de la maladie (précoce-tardif)? Une association significative entre le génotype CC et la présence de druses périphériques (p=0.028), ainsi que la localisation centrale des druses (p=0,049) a été mise en évidence. Aucune autre tendance n'a été dégagée concernant les critères restants (taille, surface totale recouverte, localisation nasale des druses) ou les changements pigmentaires. Cette étude a permis de confirmer l'association entre la variante Y4G2H et la DMLA dans la population suisse et de conclure que la variante Y402H du gène CFH présente une association géno-phénotypique pour certaines caractéristiques des druses. Il est probable que d'autres facteurs génétiques encore influencent le phénotype de la DMLA. De nouvelles recherches seront nécessaires pour préciser l'influence de ces autres facteurs génétiques ou environnementaux, en vue d'une meilleure compréhension de la pathogenèse de cette affection, et pour développer des mesures thérapeutiques et prophylactiques adaptées.

Étude de l'influence de l'activité inflammatoire liée au TNFα sur les altérations cognitives et comportementales et le dépôt de plaques β amyloïdes chez la souris

Résumé Les mutations du gène APP (amyloïde de la protéine de précurseur) sur le chromosome 21 mènent à une surproduction de protéines β amyloïdes dans la maladie d'Alzheimer (MA). Il existe donc un consensus impliquant la cascade amyloïde dans la genèse et le développement de la MA. C'est pourquoi, afin d'évaluer l'hypothèse de la cascade inflammatoire de la MA, on combine des manipulations génétiques chez des modèles de souris transgéniques avec des traitements anti-inflammatoires. Les animaux porteurs d'une mutation génétique induite permettent d'évaluer le rôle de certains gènes dans le développement de la maladie. Pour ce faire j'ai étudié les performances de différentes cohortes de souris soumises à un ensemble de trois épreuves comportementales complémentaires ; la première étudiant les conduites exploratoires, la deuxième évaluant la capacité de l'animal à effectuer un apprentissage de lieu et la troisième explorant l'efficacité des animaux dans une tâche dite d'élimination. Enfin, une évaluation complémentaire a été fondée sur le répertoire des troubles du comportement des animaux. Chez les animaux APP homozygotes, l'organisation de la mémoire se dégrade et se modifie avec l'âge. Chez ces animaux, le déficit des mémoires de références et de travail se manifeste déjà chez les souris jeunes (dès l'âge de 50 jours).De plus, il est apparu un certain nombre de troubles comportementaux. Enfin les APP homozygotes sont ceux qui ont le plus de dépôt de plaques amyloïdes localisé dans l'hippocampe. Chez les animaux APP hétérozygotes, tant la mémoire de référence, utilisée au cours d'un apprentissage de lieu, que la mémoire de travail permettant d'éviter des bras déjà visités, ne sont affectées que chez les sujets de 15 mois. De plus, tous les troubles du comportement sont présents à 15 mois, mais de manière moins intense que chez les animaux APP homozygotes. Un traitement anti-TNF administré aux APP hétérozygotes n'a pas permis d'améliorer leur performance mais a un effet bénéfique sur les troubles du comportement. Enfin, le pourcentage des dépôts de plaques a été estimé à trois fois moins élevé chez ces animaux hétérozygotes de 16 mois que chez les APP homozygotes de 8 mois. Chez les animaux APP hétérozygotes dont le gène TNFα est bloqué, les mémoires de travail et de référence sont altérées déjà à l'âge de 6 mois, en dépit du blocage de l'expression de TNF. Ces jeunes animaux ont même une capacité cognitive inférieure à celle des animaux hétérozygotes APP, en gardant toutefois leur activité et performance exploratoires intactes. Ainsi, il semble que le blocage de l'expression du gène TNFα chez des souris APP n'influence pas leurs capacités cognitives mais permet, d'une part, d'éviter l'apparition des troubles du comportement et d'autre part, ralentit le processus du déclin cognitif. Enfin, le pourcentage de plaques amyloïdes a été évalué à deux fois plus élevés pour les KO TNF-α APP hétérozygotes de 15 mois par rapport à des APP hétérozygotes sans traitement du même âge. Chez les animaux APP hétérozygotes surexprimant le TNFα, cette association génétique péjore la performance cognitive comparée à celle des APP homozygotes. Ces animaux ont une altération des mémoires de travail et de référence équivalente à celle retrouvée chez des APP homozygotes. Un traitement anti-inflammatoire administré à ces souris n'améliore pas la capacité cognitive mais permet d'une part, d'éviter l'apparition des troubles comportementaux, et d'autre part, d'entraîner la presque disparition des plaques amyloïdes. Abstract Mutations on the amyloid precursor protein (APP) gene on chromosome 21 lead to an overproduction of β amyloid in both human early onset familial Alzheimer's Disease (AD) and transgenic (TG) mice. On the other hand, inflammatory responses in the brain seem to contribute to the genesis and evolution of neurodegenerative damage. To study the influence of inflammatory factors - especially TNFα - on brain amyloid and behavioural components, TG mice expressing mutant amyloid precursor protein were treated with anti-TNFα antibody and compared with controls injected with PBS buffer or human globulins, as well as with APP mice knockout for the TNFα gene. The APP/V717 mutation leads to a brain deposit of amyloid and to significant behavioural deficits in both homozygous at different ages and heterozygous only at 15 months. The percentage of amyloid is almost triple in APP+/+ than in APP+/- animals, indicating a gene dosage effect. There is no significant effect of an anti-TNF treatment on the deposit of brain amyloid nor spatial learning capabilities. Transgenic mice show also stereotyped behaviour but the anti-TNF treatment decreases the production of stereotypies. The blockade of gene TNFα seems several cognitive alterations and increases the production of amyloid in APP mice at 15 months; but this combination allows to avoid the appearance of stereotyped behavior and in addition, the process of the cognitive decline slows down. Tg6074 mice (overexpressing TNF) increase deleterious effects on behavioural adaptive resources. Treatment with anti-TNF doesn't show changes in cognitive performances but seems to increase the production of amyloid and the stereotyped behaviour.

HLA Alleles Influence the Clinical Signature of Amoxicillin-Clavulanate Hepatotoxicity.

BACKGROUND AND AIM The genotype-phenotype interaction in drug-induced liver injury (DILI) is a subject of growing interest. Previous studies have linked amoxicillin-clavulanate (AC) hepatotoxicity susceptibility to specific HLA alleles. In this study we aimed to examine potential associations between HLA class I and II alleles and AC DILI with regards to phenotypic characteristics, severity and time to onset in Spanish AC hepatotoxicity cases. METHODS High resolution genotyping of HLA loci A, B, C, DRB1 and DQB1 was performed in 75 AC DILI cases and 885 controls. RESULTS The distributions of class I alleles A*3002 (P/Pc = 2.6E-6/5E-5, OR 6.7) and B*1801 (P/Pc = 0.008/0.22, OR 2.9) were more frequently found in hepatocellular injury cases compared to controls. In addition, the presence of the class II allele combination DRB1*1501-DQB1*0602 (P/Pc = 5.1E-4/0.014, OR 3.0) was significantly increased in cholestatic/mixed cases. The A*3002 and/or B*1801 carriers were found to be younger (54 vs 65 years, P = 0.019) and were more frequently hospitalized than the DRB1*1501-DQB1*0602 carriers. No additional alleles outside those associated with liver injury patterns were found to affect potential severity as measured by Hy's Law criteria. The phenotype frequencies of B*1801 (P/Pc = 0.015/0.42, OR 5.2) and DRB1*0301-DQB1*0201 (P/Pc = 0.0026/0.07, OR 15) were increased in AC DILI cases with delayed onset compared to those corresponding to patients without delayed onset, while the opposite applied to DRB1*1302-DQB1*0604 (P/Pc = 0.005/0.13, OR 0.07). CONCLUSIONS HLA class I and II alleles influence the AC DILI signature with regards to phenotypic expression, latency presentation and severity in Spanish patients.

R-ESHAP as salvage therapy for patients with relapsed or refractory diffuse large B-cell lymphoma: the influence of prior exposure to rituximab on outcome. A GEL/TAMO study.

BACKGROUND The role of re-treatment with rituximab in aggressive B-cell lymphomas still needs to be defined. This study evaluated the influence of prior exposure to rituximab on response rates and survival in patients with diffuse large B-cell lymphoma treated with rituximab plus etoposide, cytarabine, cisplatinum and methylprednisolone (R-ESHAP). DESIGN AND METHODS We retrospectively analyzed 163 patients with relapsed or refractory diffuse large B-cell lymphoma who received R-ESHAP as salvage therapy with a curative purpose. Patients were divided into two groups according to whether rituximab had been administered (n=94, "R+" group) or not (n=69, "R-" group) prior to R-ESHAP. RESULTS Response rates were significantly higher in the R- group in the univariate but not in the multivariate analysis. In the analysis restricted to the R+ group, we observed very low complete remission and overall response rates in patients with primary refractory disease (8% and 33%, respectively), as compared to those in patients who were in first partial remission (41% and 86%) or who had relapsed disease (50% and 75%) (p<0.01 in both cases). Overall, 60% and 65% of patients in the R+ and R- groups, respectively, underwent stem-cell transplantation after the salvage therapy. With a median follow-up of 29 months (range, 6-84), patients in the R+ group had significantly worse progression-free survival (17% vs. 57% at 3 years, p<0.0001) and overall survival (38% v 67% at 3 years, p=0.0005) than patients in the R- group. Prior exposure to rituximab was also an independent adverse prognostic factor for both progression-free survival (RR: 2.0; 95% CI: 1.2-3.3, p=0.008) and overall survival (RR: 2.2; 95% CI: 1.3-3.9, p=0.004). CONCLUSIONS R-ESHAP was associated with a high response rate in patients who were not refractory to upfront rituximab-based chemotherapy. However, the survival outcome was poor for patients previously exposed to rituximab, as compared to in those who had not previously been treated with rituximab.

Influence of deep sternal wound infection on long-term survival after cardiac surgery.

BACKGROUND: This study aimed to investigate the influence of deep sternal wound infection on long-term survival following cardiac surgery. MATERIAL AND METHODS: In our institutional database we retrospectively evaluated medical records of 4732 adult patients who received open-heart surgery from January 1995 through December 2005. The predictive factors for DSWI were determined using logistic regression analysis. Then, each patient with deep sternal wound infection (DSWI) was matched with 2 controls without DSWI, according to the risk factors identified previously. After checking balance resulting from matching, short-term mortality was compared between groups using a paired test, and long-term survival was compared using Kaplan-Meier analysis and a Cox proportional hazard model. RESULTS: Overall, 4732 records were analyzed. The mean age of the investigated population was 69.3±12.8 years. DSWI occurred in 74 (1.56%) patients. Significant independent predictive factors for deep sternal infections were active smoking (OR 2.19, CI95 1.35-3.53, p=0.001), obesity (OR 1.96, CI95 1.20-3.21, p=0.007), and insulin-dependent diabetes mellitus (OR 2.09, CI95 1.05-10.06, p=0.016). Mean follow-up in the matched set was 125 months, IQR 99-162. After matching, in-hospital mortality was higher in the DSWI group (8.1% vs. 2.7% p=0.03), but DSWI was not an independent predictor of long-term survival (adjusted HR 1.5, CI95 0.7-3.2, p=0.33). CONCLUSIONS: The results presented in this report clearly show that post-sternotomy deep wound infection does not influence long-term survival in an adult general cardio-surgical patient population.