Validation study of the French version of the observer-rater scales measuring coping and cognitive errors (CE-CAP) on a non-clinical population

This study examined the validity and reliability of the French version of two observer-rated measures developed to assess cognitive errors (cognitive errors rating system [CERS]) [6] and coping action patterns (coping action patterns rating system [CAPRS]) [22,24]. The CE measures 14 cognitive errors, broken down according to their valence positive or negative (see the definitions by A.T. Beck), and the CAP measures 12 coping categories, based on an comprehensive review literature, each broken down into three levels of action (affective, behavioural, cognitive). Thirty (N = 30) subjects recruited in a community sample participated in the study. They were interviewed according to a standardized clinical protocol: these interviews were transcribed and analysed with both observer-rated systems. Results showed that the inter-rater reliability of the two measures is good and that their internal validity is satisfactory, due to a non-significant canonical correlation between CAP and CE. With regard to discriminant validity, we found a non-significant canonical correlation between CAPRS and CISS, one of most widely used self-report questionnaire measuring coping. The same can be said for the correlation with a self-report questionnaire measuring symptoms (SCL-90-R). These results confirm the absence of confounds in the assessment of cognitive errors and of coping as assessed by these observer-rated scales and add an argument in favour of the French validation of the CE-CAP rating scales. (C) 2010 Elsevier Masson SAS. All rights reserved.

Species-Specific Recognition of Aspergillus fumigatus by Toll-like Receptor 1 and Toll-like Receptor 6.

Background. Aspergillus fumigatus causes invasive aspergillosis, a potentially fatal infection in oncohematological patients. Innate immune detection of A. fumigatus involves Toll-like receptor (TLR) 4 and TLR2, which forms a heterodimer with either TLR1 or TLR6. The role of those coreceptors in Aspergillus sensing is unknown. Methods. Cytokine production was measured in bone marrow-derived macrophages (BMDMs) from wild-type (WT) and TLR-deficient mice after incubation with a WT and an immunogenic RodA-deficient (ΔrodA-47) strain of A. fumigatus and in lungs from these mice after intranasal mold inoculation. Aspergillus fumigatus-mediated NF-κB activation was measured in HEK293T cells transfected with plasmids expressing mouse or human TLRs. Results. Bone marrow-derived macrophages from TLR1- and TLR6-deficient mice produced lower amounts of interleukin 12p40, CXCL2, interleukin 6, and tumor necrosis factor α than BMDMs from WT mice after stimulation with A. fumigatus. Lungs from TLR1- and TLR6-deficient mice had diminished CXCL1 and CXCL2 production and increased fungal burden after intranasal inoculation of ΔrodA A. fumigatus compared with lungs from WT mice. ΔrodA strain-mediated NF-κB activation was observed in HEK293T cells expressing mouse TLR2/1, mouse TLR2/6, and human TLR2/1 but not human TLR2/6. Conclusions. Innate immune detection of A. fumigatus is mediated by TLR4 and TLR2 together with TLR1 or TLR6 in mice and TLR1 but not TLR6 in humans.

Mutations in the heparan-sulfate proteoglycan glypican 6 (GPC6) impair endochondral ossification and cause recessive omodysplasia.

Glypicans are a family of glycosylphosphatidylinositol (GPI)-anchored, membrane-bound heparan sulfate (HS) proteoglycans. Their biological roles are only partly understood, although it is assumed that they modulate the activity of HS-binding growth factors. The involvement of glypicans in developmental morphogenesis and growth regulation has been highlighted by Drosophila mutants and by a human overgrowth syndrome with multiple malformations caused by glypican 3 mutations (Simpson-Golabi-Behmel syndrome). We now report that autosomal-recessive omodysplasia, a genetic condition characterized by short-limbed short stature, craniofacial dysmorphism, and variable developmental delay, maps to chromosome 13 (13q31.1-q32.2) and is caused by point mutations or by larger genomic rearrangements in glypican 6 (GPC6). All mutations cause truncation of the GPC6 protein and abolish both the HS-binding site and the GPI-bearing membrane-associated domain, and thus loss of function is predicted. Expression studies in microdissected mouse growth plate revealed expression of Gpc6 in proliferative chondrocytes. Thus, GPC6 seems to have a previously unsuspected role in endochondral ossification and skeletal growth, and its functional abrogation results in a short-limb phenotype.

Nicotine gum treatment before smoking cessation: a randomized trial.

BACKGROUND: New ways of improving the efficacy of nicotine therapy need to be explored. We tested whether starting nicotine polacrilex gum treatment 4 weeks before the quit date improved smoking abstinence rates compared with starting treatment on the quit date. METHODS: An open randomized trial of 314 daily smokers (mean, 23.7 cigarettes/d) enrolled through the Internet and by physicians in Switzerland from November 2005 to January 2007. In the precessation treatment group, participants received nicotine polacrilex gum (4 mg, unflavored) by mail for 4 weeks before and 8 weeks after their target quit date, and they were instructed to decrease their cigarette consumption by half before quitting. In the usual care group, participants received the same nicotine gum for 8 weeks after their quit date and were instructed to quit abruptly. Instructions were limited to a booklet sent by mail and access to a smoking cessation Web site. Results are expressed as self-reported abstinence rates at the end of treatment and as biochemically verified smoking abstinence (cotinine plus carbon monoxide) after 12 months. RESULTS: Eight weeks after the target quit date, self-reported 4-week abstinence rates were 41.6% in the precessation treatment group and 44.4% in the usual care group (P = .61). One year after the target quit date, biochemically verified 4-week smoking abstinence rates were 20.8% in the precessation treatment group and 19.4% in the usual care group (P = .76). CONCLUSION: Starting nicotine gum treatment 4 weeks before the target quit date was no more effective than starting treatment on the quit date.

Dual role of the antioxidant enzyme peroxiredoxin 6 in skin carcinogenesis.

The antioxidant enzyme peroxiredoxin 6 (Prdx6) is a key regulator of the cellular redox balance, particularly under stress conditions. We identified Prdx6 as an important player in different phases of skin carcinogenesis. Loss of Prdx6 in mice enhanced the susceptibility to skin tumorigenesis, whereas overexpression of Prdx6 in keratinocytes of transgenic mice had the opposite effect. The tumor-preventive effect of Prdx6, which was observed in a human papilloma virus 8-induced and a chemically induced tumor model, was not due to alterations in keratinocyte proliferation, apoptosis, or in the inflammatory response. Rather, endogenous and overexpressed Prdx6 reduced oxidative stress as reflected by the lower levels of oxidized phospholipids in the protumorigenic skin of Prdx6 transgenic mice and the higher levels in Prdx6-knockout mice than in control animals. In contrast to its beneficial effect in tumor prevention, overexpression of Prdx6 led to an acceleration of malignant progression of existing tumors, revealing a dual function of this enzyme in the pathogenesis of skin cancer. Finally, we found strong expression of PRDX6 in keratinocytes of normal human skin and in the tumor cells of squamous cell carcinomas, indicating a role of Prdx6 in human skin carcinogenesis. Taken together, our data point to the potential usefulness of Prdx6 activators or inhibitors for controlling different stages of skin carcinogenesis.

Simultaneous detection of aneuploidies for chromosomes 4, 6, 10 and 17 by automated four colour I-FISH in high hyperdiploid acute lymphoblastic leukemia : diagnostic assessment, clonal heterogeneity and chromosomal instability in adults

SummarySimultaneous detection of aneuploidies for chromosomes 4, 6,10 and 17 by automated four color l-FISH in high hyperdiploid acute lymphoblastic leukemia: diagnostic assessment, clonal heterogeneity and chromosomal instability in adultsAnna Talamo BlandinService de Génétique Médicale, Unité de Cytogénétique du Cancer, CHUVAcute lymphoblastic leukemia (ALL) is a malignant hemopathy characterized by the accumulation of the immature lymphoid cells in the bone marrow and, most often, in the peripheral blood. ALL is a heterogeneous disease with distinct biological and prognostic entities. At diagnosis, cytogenetic and molecular findings constitute important and independent prognostic factors. High hyperdiploidy with 51-67 chromosomes (HeH), one of the largest cytogenetic subsets of ALL, in childhood particularly, is generally associated with a relatively favorable outcome. Chromosome gain is nonrandom, extracopies of some chromosome occurring more frequently than those of others. Concurrent presence of trisomy for chromosomes 4, 10 and 17 confers an especially good prognosis. The first aim of our work was to develop an automated four color interphase fluorescence in situ hybridization (l-FISH) methodology and to assess its ability to detect concurrent aneuploidies 4, 6, 10 and 17 in 10 ALL patients. Various combinations of aneuploidies were identified. All clones detected by conventional cytogenetics were also observed by l-FISH. However, in all patients, l-FISH revealed numerous additional abnormal clones, leading to a high level of clonal heterogeneity. Our second aim has been to investigate the nature and origin of this clonal heterogeneity and to test for the presence of chromosome instability (CIN) in HeH ALL at initial presentation. Ten HeH ALL and 10 non-HeH ALL patients were analysed by four colour l-FISH and numerical CIN values were determined for all four chromosomes together and for each chromosome and patient group, an original approach in ALL. CIN values in HeH ALL proved to be much higher than#iose in non-HeH ALL, suggesting that numerical CIN may be at the origin of the high level of clonal heterogeneity revealed by l-FISH. Our third aim has been to study the evolution of these cytogenetic features during the course of the disease in 10 HeH ALL patients. Clonal heterogeneity was also observed again during disease progression, particularly at relapse. Clones detected at initial presentation generally reappeared in relapse, in most cases with newly generated ones. A significant correlation between the number of abnormal clones and CIN suggested that the higher the instability, the larger the number of abnormal clones. Whereas clonal heterogeneity and its evolution most probably result from underlying chromosome instability, operating processes remain conjectural.RésuméLa leucémie lymphoblastique aiguë (LLA) est une hémopathie maligne qui résulte de l'accumulationde cellules lymphoïdes immatures dans la moelle osseuse, et, le plus souvent, dans le sangpériphérique également. La LLA est une affection hétérogène au sein de laquelle se distinguentplusieurs entités biologiques et pronostiques. Les données cytogénétiques et moléculaires font partieintégrante du diagnostic et jouent un rôle essentiel dans l'évaluation du pronostic. L'hyperdiploïdieélevée à 51-­67 chromosomes (HeH), relativement fréquente, en particulier chez l'enfant, s'associe àun pronostic favorable. Le gain de chromosomes ne relève pas du hasard, certains chromosomesétant plus fréquemment impliqués que d'autres. La présence simultanée des trisomies 4, 6, et 17s'associe à un pronostic particulièrement bon. Le premier but du travail a été de développer uneméthode d'analyse automatique par hybridation in situ fluorescente interphasique (I-­FISH) à 4couleurs et de tester sa capacité à identifier la présence simultanée d'aneuploïdies 4, 6, 10 et 17 dans10 cas de LLA. Différentes combinaisons d'aneuploïdies ont été identifiées. Tous les clones détectéspar cytogénétique conventionnelle l'ont été par I-­FISH. Or, chez tous les patients, l'I-­FISH a révélé denombreux clones anormaux additionnels générant un degré élevé d'hétérogénéité clonale. Notredeuxième but a été d'investiguer la nature et l'origine de cette hétérogénéité et de tester la présenced'instabilité chromosomique (CIN) chez les patients avec une LLA HeH en presentation initiale. DixLLA HeH et 10 LLA non-­HeH ont été analysées par I-­FISH et les valeurs de CIN numérique ont étédéterminées pour les 4 chromosomes ensemble et pour chaque chromosome et groupe de patients,approche originale dans la LLA. Ces valeurs étant beaucoup plus élevées dans la LLA HeH que dansla LLA non-­HeH, elles favorisent l'hypothèse selon laquelle la CIN serait à l'origine de l'hétérogénéitéclonale révélée par I-­FISH. Le troisième but de notre travail a été d'étudier l'évolution de cescaractéristiques cytogénétiques au cours de la maladie dans 10 cas de LLA HeH. L'hétérogénéitéclonale a été retrouvée lors de la progression de la maladie, en particulier en rechute, où les clonesanormaux détectés en présentation initiale réapparaissent, généralement accompagnés de clonesnouveaux. La corrélation existant entre nombre de clones anormaux et valeurs de CIN suggère queplus l'instabilité est élevée, plus le nombre de clones anormaux est grand. Bien que l'hétérogénéitéclonale et son évolution résultent très probablement de l'instabilité chromosomique, les processus àl'oeuvre ne sont pas entièrement élucidés.

Growth arrest-specific gene 6 (GAS6) as an intra-hospital mortality predictor for patients in septic shock

Aim: Gas6 is known to be elevated in sepsis, correlating with the severity of infection and organ failure. We aimed to investigate the performance of Gas6 plasma levels at admission to predict the risk of mortality in a cohort of septic patients.Methods: We used prospectively collected data and plasma samples from the 'Sepsis Cohorte Romande'. Gas6 level was measured by ELISA at admission and expressed in percentage relative to its level in a pool of normal plasma.Results: Non-survivors (n = 19) presented higher Gas6 levels than survivors (n = 78; median 287% vs. 158%, IQR 182 and 119 respectively; P = 0.0003). Gas6 correlated positively with different cytokine and was the best mortality predictor, as shown by the ROC curves area (Fig. 1). In patients with septic shock (n = 67), using 249% as a cut-off value, Gas6 measurement had a specificity of 81% and a sensitivity of 68% for predicting mortality. ROC curve area was 0.76. Positive and negative predictive values were 59% and 87%, respectively.Conclusion: Thus, Gas6 plasma level at admission might be a useful tool to predict mortality in patients with septic shock. Nevertheless, independent association of Gas6 level with mortality still needs to be assessed. Although Gas6 hold promise as an early sepsis marker, its precise implication in sepsis remains to be elucidated.

Epidemiology of incident heart failure in a contemporary elderly cohort: the health, aging, and body composition study.

BACKGROUND: The race- and sex-specific epidemiology of incident heart failure (HF) among a contemporary elderly cohort are not well described. METHODS: We studied 2934 participants without HF enrolled in the Health, Aging, and Body Composition Study (mean [SD] age, 73.6 [2.9] years; 47.9% men; 58.6% white; and 41.4% black) and assessed the incidence of HF, population-attributable risk (PAR) of independent risk factors for HF, and outcomes of incident HF. RESULTS: During a median follow-up of 7.1 years, 258 participants (8.8%) developed HF (13.6 cases per 1000 person-years; 95% confidence interval, 12.1-15.4). Men and black participants were more likely to develop HF. No significant sex-based differences were observed in risk factors. Coronary heart disease (PAR, 23.9% for white participants and 29.5% for black participants) and uncontrolled blood pressure (PAR, 21.3% for white participants and 30.1% for black participants) carried the highest PAR in both races. Among black participants, 6 of 8 risk factors assessed (smoking, increased heart rate, coronary heart disease, left ventricular hypertrophy, uncontrolled blood pressure, and reduced glomerular filtration rate) had more than 5% higher PAR compared with that among white participants, leading to a higher overall proportion of HF attributable to modifiable risk factors in black participants vs white participants (67.8% vs 48.9%). Participants who developed HF had higher annual mortality (18.0% vs 2.7%). No racial difference in survival after HF was noted; however, rehospitalization rates were higher among black participants (62.1 vs 30.3 hospitalizations per 100 person-years, P < .001). CONCLUSIONS: Incident HF is common in older persons; a large proportion of HF risk is attributed to modifiable risk factors. Racial differences in risk factors for HF and in hospitalization rates after HF need to be considered in prevention and treatment efforts.