First consumption ever of multiple substances: applying an expert-based taxonomy to a Swiss national sample of adolescents.

The use of multiple legal and illegal substances by adolescents is a growing concern in all countries, but since no consensus about a taxonomy did emerge yet, it is difficult to understand the different patterns of consumption and to implement tailored prevention and treatment programs directed towards specific subgroups of the adolescent population. Using data from a Swiss survey on adolescent health, we analyzed the age at which ten legal and illegal substances were consumed for the first time ever by applying a method combining the strength of both automatic clustering and use of substance experts. Results were then compared to 30 socio-economic factors to establish the usefulness of and to validate our taxonomy. We also analyzed the succession of substance first use for each group. The final taxonomy consists of eight groups ranging from non-consumers to heavy drug addicts. All but four socio-economic factors were significantly associated with the taxonomy, the strongest associations being observed with health, behavior, and sexuality factors. Numerous factors influence adolescents in their decision to first try substances or to use them on a regular basis, and no factor alone can be considered as an absolute marker of problematic behavior regarding substance use. Different processes of experimentation with substances are associated with different behaviors, therefore focusing on only one substance or only one factor is not efficient. Prevention and treatment programs can then be tailored to address specific issues related to different youth subgroups.

Heterogeneity of t(4;14) in multiple myeloma. Long-term follow-up of 100 cases treated with tandem transplantation in IFM99 trials.

One hundred de novo multiple myeloma patients with t(4;14) treated with double intensive therapy according to IFM99 protocols were retrospectively analyzed. The median overall survival (OS) and event-free survival (EFS) were 41.4 and 21 months, respectively, as compared to 65 and 37 for patients included in the IFM99 trials without t(4;14) (P<10(-7)). We identified a subgroup of patients presenting at diagnosis with both low beta(2)-microglobulin <4 mg/l and high hemoglobin (Hb) >/=10 g/l (46% of the cases) with a median OS of 54.6 months and a median EFS of 26 months, respectively, which benefits from high-dose therapy (HDT); conversely patients with one or both adverse prognostic factor (high beta(2)-microglobulin and/or low Hb) had a poor outcome. The achievement of either complete response or very good partial response after HDT was also a powerful independent prognostic factor for both OS and EFS.

Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia.

We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia. The most significant evidence for linkage to TG levels was found in a subset of Turkish families at 11q22 [logarithm of the odds ratio (LOD)=3.34] and at 17q12 (LOD=3.44). We performed sequential oligogenic linkage analysis to examine whether multiple QTLs jointly influence TG levels in the Turkish families. These analyses revealed loci at 20q13 that showed strong epistatic effects with 11q22 (conditional LOD=3.15) and at 7q36 that showed strong epistatic effects with 17q12 (conditional LOD=3.21). We also found linkage on the 8p21 region for TG in the entire group of families (LOD=3.08). For HDL-C levels, evidence of linkage was identified on chromosome 15 in the Turkish families (LOD=3.05) and on chromosome 5 in the entire group of families (LOD=2.83). Linkage to QTLs for TC was found at 8p23 in the entire group of families (LOD=4.05) and at 5q13 in a subset of Turkish and Mediterranean families (LOD=3.72). These QTLs provide important clues for the further investigation of genes responsible for these complex lipid phenotypes. These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci.

Multiple Kernel Learning of Environmental Data. Case study: Analysis and Mapping of Wind Fields

The paper presents the Multiple Kernel Learning (MKL) approach as a modelling and data exploratory tool and applies it to the problem of wind speed mapping. Support Vector Regression (SVR) is used to predict spatial variations of the mean wind speed from terrain features (slopes, terrain curvature, directional derivatives) generated at different spatial scales. Multiple Kernel Learning is applied to learn kernels for individual features and thematic feature subsets, both in the context of feature selection and optimal parameters determination. An empirical study on real-life data confirms the usefulness of MKL as a tool that enhances the interpretability of data-driven models.

An interaction network of the mammalian COP9 signalosome identifies Dda1 as a core subunit of multiple Cul4-based E3 ligases.

The COP9 signalosome (CSN) is an evolutionarily conserved macromolecular complex that interacts with cullin-RING E3 ligases (CRLs) and regulates their activity by hydrolyzing cullin-Nedd8 conjugates. The CSN sequesters inactive CRL4(Ddb2), which rapidly dissociates from the CSN upon DNA damage. Here we systematically define the protein interaction network of the mammalian CSN through mass spectrometric interrogation of the CSN subunits Csn1, Csn3, Csn4, Csn5, Csn6 and Csn7a. Notably, we identified a subset of CRL complexes that stably interact with the CSN and thus might similarly be activated by dissociation from the CSN in response to specific cues. In addition, we detected several new proteins in the CRL-CSN interactome, including Dda1, which we characterized as a chromatin-associated core subunit of multiple CRL4 proteins. Cells depleted of Dda1 spontaneously accumulated double-stranded DNA breaks in a similar way to Cul4A-, Cul4B- or Wdr23-depleted cells, indicating that Dda1 interacts physically and functionally with CRL4 complexes. This analysis identifies new components of the CRL family of E3 ligases and elaborates new connections between the CRL and CSN complexes.

Altered decision-making in multiple sclerosis: a sign of impaired emotional reactivity?

We assessed decision-making capacity and emotional reactivity in 20 patients with multiple sclerosis (MS) and in 16 healthy subjects using the Gambling Task (GT), a model of real-life decision making, and the skin conductance response (SCR). Demographic, neurological, affective, and cognitive parameters were analyzed in MS patients for their effect on decision-making performance. MS patients persisted longer (slope, -3.6%) than the comparison group (slope, -6.4%) in making disadvantageous choices as the GT progressed (p < 0.001), suggesting significant slower learning in MS. Patients with higher Expanded Disability Status Scale scores (EDSS >2.0) showed a different pattern of impairment in the learning process compared with patients with lower functional impairment (EDSS </=2.0). This slower learning was associated with impaired emotional reactivity (anticipatory SCR 3.9 vs 6.1 microSiemens [microS] for patients vs the comparison group, p < 0.0001; post-choice SCR 3.9 vs 6.2 microS, p < 0.0001), but not with executive dysfunction. Impaired emotional dimensions of behavior (assessed using the Dysexecutive Questionnaire, p < 0.002) also correlated with slower learning. Given the considerable consequences that impaired decision making can have on daily life, we suggest that this factor may contribute to handicap and altered quality of life secondary to MS and is dependent on emotional experience. Ann Neurol 2004.

One naive T cell, multiple fates in CD8+ T cell differentiation.

The mechanism by which the immune system produces effector and memory T cells is largely unclear. To allow a large-scale assessment of the development of single naive T cells into different subsets, we have developed a technology that introduces unique genetic tags (barcodes) into naive T cells. By comparing the barcodes present in antigen-specific effector and memory T cell populations in systemic and local infection models, at different anatomical sites, and for TCR-pMHC interactions of different avidities, we demonstrate that under all conditions tested, individual naive T cells yield both effector and memory CD8+ T cell progeny. This indicates that effector and memory fate decisions are not determined by the nature of the priming antigen-presenting cell or the time of T cell priming. Instead, for both low and high avidity T cells, individual naive T cells have multiple fates and can differentiate into effector and memory T cell subsets.

Effect of modafinil on subjective fatigue in multiple sclerosis and stroke patients.

BACKGROUND: Modafinil has anecdotal response to neurological fatigue, but such an effect may depend on the type and location of cerebral impairment. OBJECTIVES: It was the aim of this study to compare fatigue observed in different neurological pathologies, to evaluate the tolerability to modafinil, and to describe changes in subjective fatigue. METHODS: We enrolled 14 brainstem or diencephalic stroke (BDS) patients, 9 cortical stroke (CS) patients and 17 multiple sclerosis (MS) patients. The Fatigue Assessment Instrument severity scale was performed at baseline, after 3 months of modafinil and after 1 month of washout. Cognition, mood and somnolence were assessed. A subgroup of 14 patients underwent activity measures before and during treatment. RESULTS: Thirty-one patients completed the study (10 BDS, 9 CS, 12 MS). The responder profile is more frequent in MS than in CS (p = 0.04), and in BDS than in CS patients (p = 0.04). Actiwatch measures showed no changes in activity during, before and after therapy. CONCLUSION: Modafinil was tolerated in 75% of patients at small doses and seemed to improve the severity of fatigue in the MS and BDS groups but not in the CS group. There was no modification in measured physical activity.

Induction of CD8 T-cell responses restricted to multiple HLA class I alleles in a cancer patient by immunization with a 20-mer NY-ESO-1f (NY-ESO-1 91-110) peptide.

Immunogenicity of a long 20-mer NY-ESO-1f peptide vaccine was evaluated in a lung cancer patient TK-f01, immunized with the peptide with Picibanil OK-432 and Montanide ISA-51. We showed that internalization of the peptide was necessary to present CD8 T-cell epitopes on APC, contrasting with the direct presentation of the short epitope. CD8 T-cell responses restricted to all five HLA class I alleles were induced in the patient after the peptide vaccination. Clonal analysis showed that B*35:01 and B*52:01-restricted CD8 T-cell responses were the two dominant responses. The minimal epitopes recognized by A*24:02, B*35:01, B*52:01 and C*12:02-restricted CD8 T-cell clones were defined and peptide/HLA tetramers were produced. NY-ESO-1 91-101 on A*24:02, NY-ESO-1 92-102 on B*35:01, NY-ESO-1 96-104 on B*52:01 and NY-ESO-1 96-104 on C*12:02 were new epitopes first defined in this study. Identification of the A*24:02 epitope is highly relevant for studying the Japanese population because of its high expression frequency (60%). High affinity CD8 T-cells recognizing tumor cells naturally expressing the epitopes and matched HLA were induced at a significant level. The findings suggest the usefulness of a long 20-mer NY-ESO-1f peptide harboring multiple CD8 T-cell epitopes as an NY-ESO-1 vaccine. Characterization of CD8 T-cell responses in immunomonitoring using peptide/HLA tetramers revealed that multiple CD8 T-cell responses comprised the dominant response.

Multiple Epiphyseal Dysplasia, Recessive.

Disease characteristics. Recessive multiple epiphyseal dysplasia (EDM4/rMED) is characterized by joint pain (usually in the hips or knees); malformations of hands, feet, and knees; and scoliosis. Approximately 50% of affected individuals have some abnormal finding at birth, e.g., clubfoot, clinodactyly, or (rarely) cystic ear swelling. Onset of articular pain is variable but usually occurs in late childhood. Stature is usually within the normal range prior to puberty; in adulthood, stature is only slightly diminished and ranges from 150 to 180 cm. Functional disability is mild. Diagnosis/testing. Diagnosis of EDM4/rMED is based on clinical and radiographic findings. SLC26A2 is the only gene known to be associated with EDM4/rMED. Molecular genetic testing is available on a clinical basis. Management. Treatment of manifestations: physiotherapy for muscular strengthening; cautious use of analgesic medications such as nonsteroidal anti-inflammatory drugs (NSAIDs); orthopedic surgery as indicated. Surveillance: radiographs as indicated. Agents/circumstances to avoid: sports involving joint overload. Genetic counseling. EDM4/rMED is inherited in an autosomal recessive manner. At conception, each sib of a proband with EDM4/rMED has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3. Carrier testing for at-risk relatives and prenatal testing for pregnancies at increased risk is possible if both disease-causing alleles in the family are known and the carrier status of the parents has been confirmed. Requests for prenatal testing for mild conditions such as EDM4/rMED are not common.

Improved multiple-locus variable-number tandem-repeat assay for Staphylococcus aureus genotyping, providing a highly informative technique together with strong phylogenetic value.

We describe an improved multiple-locus variable-number tandem-repeat (VNTR) analysis (MLVA) scheme for genotyping Staphylococcus aureus. We compare its performance to those of multilocus sequence typing (MLST) and spa typing in a survey of 309 strains. This collection includes 87 epidemic methicillin-resistant S. aureus (MRSA) strains of the Harmony collection, 75 clinical strains representing the major MLST clonal complexes (CCs) (50 methicillin-sensitive S. aureus [MSSA] and 25 MRSA), 135 nasal carriage strains (133 MSSA and 2 MRSA), and 13 published S. aureus genome sequences. The results show excellent concordance between the techniques' results and demonstrate that the discriminatory power of MLVA is higher than those of both MLST and spa typing. Two hundred forty-two genotypes are discriminated with 14 VNTR loci (diversity index, 0.9965; 95% confidence interval, 0.9947 to 0.9984). Using a cutoff value of 45%, 21 clusters are observed, corresponding to the CCs previously defined by MLST. The variability of the different tandem repeats allows epidemiological studies, as well as follow-up of the evolution of CCs and the identification of potential ancestors. The 14 loci can conveniently be analyzed in two steps, based upon a first-line simplified assay comprising a subset of 10 loci (panel 1) and a second subset of 4 loci (panel 2) that provides higher resolution when needed. In conclusion, the MLVA scheme proposed here, in combination with available on-line genotyping databases (including http://mlva.u-psud.fr/), multiplexing, and automatic sizing, can provide a basis for almost-real-time large-scale population monitoring of S. aureus.

The Interplay of Mastery and Performance Goals in Social Comparison: A Multiple-Goal Perspective.

Régner, Escribe, and Dupeyrat (2007) recently demonstrated that not only performance-approach and performance-avoidance goals (respectively, the desire to outperform others and not to be outperformed by others) but also mastery goals (the desire to acquire knowledge) were related to social comparison orientation (SCO, the tendency to search for social comparison information). In the present article, the possibility of a link between mastery goals and social comparison that depends on the level of performance-approach goals-a possibility supported by a multiple-goal perspective-was tested by examining the interaction effect between mastery and performance-approach goals. This is an important endeavor, as educational settings are rarely free from performance-approach goals, even when mastery goals are promoted. In Study 1, we tested self-set achievement goals (mastery, performance-approach, and performance-avoidance goals) as predictors of SCO; the interaction between mastery goals and performance-approach goals indicated that the higher the performance-approach goal endorsement, the stronger the link between mastery goals and SCO. In Study 2, we manipulated goal conditions; mastery goals predicted interest in social comparison in the performance-approach goal condition only. Results are discussed in terms of the importance of multiple-goal pursuit in academic settings. (PsycINFO Database Record (c) 2009 APA, all rights reserved)