Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.

Genetic association of CD247 (CD3ζ) with SLE in a large-scale multiethnic study.

A classic T-cell phenotype in systemic lupus erythematosus (SLE) is the downregulation and replacement of the CD3ζ chain that alters T-cell receptor signaling. However, genetic associations with SLE in the human CD247 locus that encodes CD3ζ are not well established and require replication in independent cohorts. Our aim was therefore to examine, localize and validate CD247-SLE association in a large multiethnic population. We typed 44 contiguous CD247 single-nucleotide polymorphisms (SNPs) in 8922 SLE patients and 8077 controls from four ethnically distinct populations. The strongest associations were found in the Asian population (11 SNPs in intron 1, 4.99 × 10(-4) < P < 4.15 × 10(-2)), where we further identified a five-marker haplotype (rs12141731-rs2949655-rs16859085-rs12144621-rs858554; G-G-A-G-A; P(hap) = 2.12 × 10(-5)) that exceeded the most associated single SNP rs858554 (minor allele frequency in controls = 13%; P = 4.99 × 10(-4), odds ratio = 1.32) in significance. Imputation and subsequent association analysis showed evidence of association (P < 0.05) at 27 additional SNPs within intron 1. Cross-ethnic meta-analysis, assuming an additive genetic model adjusted for population proportions, showed five SNPs with significant P-values (1.40 × 10(-3) < P< 3.97 × 10(-2)), with one (rs704848) remaining significant after Bonferroni correction (P(meta) = 2.66 × 10(-2)). Our study independently confirms and extends the association of SLE with CD247, which is shared by various autoimmune disorders and supports a common T-cell-mediated mechanism.

A functional haplotype of UBE2L3 confers risk for systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse clinical manifestations characterized by the development of pathogenic autoantibodies manifesting in inflammation of target organs such as the kidneys, skin and joints. Genome-wide association studies have identified genetic variants in the UBE2L3 region that are associated with SLE in subjects of European and Asian ancestry. UBE2L3 encodes an ubiquitin-conjugating enzyme, UBCH7, involved in cell proliferation and immune function. In this study, we sought to further characterize the genetic association in the region of UBE2L3 and use molecular methods to determine the functional effect of the risk haplotype. We identified significant associations between variants in the region of UBE2L3 and SLE in individuals of European and Asian ancestry that exceeded a Bonferroni-corrected threshold (P<1 × 10(-4)). A single risk haplotype was observed in all associated populations. Individuals harboring the risk haplotype display a significant increase in both UBE2L3 mRNA expression (P=0.0004) and UBCH7 protein expression (P=0.0068). The results suggest that variants carried on the SLE-associated UBE2L3 risk haplotype influence autoimmunity by modulating UBCH7 expression.

Thymic stromal lymphopoietin (TSLP)-mediated dermal inflammation aggravates experimental asthma.

Individuals with one atopic disease are far more likely to develop a second. Approximately half of all atopic dermatitis (AD) patients subsequently develop asthma, particularly those with severe AD. This association, suggesting a role for AD as an entry point for subsequent allergic disease, is a phenomenon known as the "atopic march." Although the underlying cause of the atopic march remains unknown, recent evidence suggests a role for the cytokine thymic stromal lymphopoietin (TSLP). We have established a mouse model to determine whether TSLP plays a role in this phenomenon, and in this study show that mice exposed to the antigen ovalbumin (OVA) in the skin in the presence of TSLP develop severe airway inflammation when later challenged with the same antigen in the lung. Interestingly, neither TSLP production in the lung nor circulating TSLP is required to aggravate the asthma that was induced upon subsequent antigen challenge. However, CD4 T cells are required in the challenge phase of the response, as was challenge with the sensitizing antigen, demonstrating that the response was antigen specific. This study, which provides a clean mouse model to study human atopic march, indicates that skin-derived TSLP may represent an important factor that triggers progression from AD to asthma.

Hopelessness and Excessive Drinking among Aboriginal Adolescents: The Mediating Roles of Depressive Symptoms and Drinking to Cope.

Canadian Aboriginal youth show high rates of excessive drinking, hopelessness, and depressive symptoms. We propose that Aboriginal adolescents with higher levels of hopelessness are more susceptible to depressive symptoms, which in turn predispose them to drinking to cope-which ultimately puts them at risk for excessive drinking. Adolescent drinkers (n = 551; 52% boys; mean age = 15.9 years) from 10 Canadian schools completed a survey consisting of the substance use risk profile scale (hopelessness), the brief symptom inventory (depressive symptoms), the drinking motives questionnaire-revised (drinking to cope), and quantity, frequency, and binge measures of excessive drinking. Structural equation modeling demonstrated the excellent fit of a model linking hopelessness to excessive drinking indirectly via depressive symptoms and drinking to cope. Bootstrapping indicated that this indirect effect was significant. Both depressive symptoms and drinking to cope should be intervention targets to prevent/decrease excessive drinking among Aboriginal youth high in hopelessness.

Confirmatory factor analysis of the childhood anxiety sensitivity index: a gender comparison.

The Childhood Anxiety Sensitivity Index (CASI) is an 18-item self-report tool designed to measure the construct of anxiety sensitivity (i.e. the belief that anxiety may have harmful consequences such as sickness, embarrassment, or loss of control) in children and adolescents. Previous factor analytic examinations of the CASI have produced varied results. Gender may play a role in this observed variability. In an effort to confirm the factor structure of the measure across gender, CASI items for 671 children and adolescents were subjected to confirmatory factor analysis. Results indicated that for boys two-, three-, and four-factor structures provided a relatively good fit to the data, with the three-factor structure emerging as having the best fit overall. In contrast, for girls only the three-factor structure fitted the data well. Direct comparison of fit of the three-factor model across gender provided evidence to support the notion that childhood anxiety sensitivity is similar in structure across gender.

The influence of TSLP on the allergic response.

Exposure to allergens first occurs at body surfaces in direct contact with the environment such as the skin, airways, and gastrointestinal tract, and compelling evidence suggests that allergic inflammatory responses are profoundly influenced by the products of epithelial cells located at these sites. One such product is thymic stromal lymphopoietin (TSLP), which is capable of affecting multiple cell lineages involved in allergic reactions. In this review we discuss recent work that has provided insight into the role TSLP plays in both aberrant and protective allergic inflammatory responses, as well as regulation, associations with disease, sources, and functions of this important cytokine.

The structure of drinking motives in First Nations adolescents in Nova Scotia.

OBJECTIVE: The factor structure of the Drinking Motives Questionnaire - Revised (DMQ-R; Cooper, 1994) was examined in a sample of First Nations (i.e., Mi'kmaq) adolescents. RESULTS: Exploratory principal components analysis indicated a three-factor structure (conformity, coping, and positive reinforcement motives), with the positive reinforcement motives of enhancement and social motives not separating into the expected two distinct factors. Moreover, community informants (e.g., school personnel) anecdotally indicated possible wording problems with some of the social motive items for the cultural group. A qualitative methodology - focus group interviews with Mi'kmaq adolescents - was used to explore potential reasons for these observed differences in the structure of drinking motives from previous findings in the majority culture (i.e., a measurement problem vs. a real difference in the structure of drinking motives in the Mi'kmaq culture). CONCLUSIONS: Qualitative findings support the interpretation that a true social motive for alcohol use does not exist in this cultural/age group and that drinking in social contexts for this group seems less motivated by social affiliation than by enhancement motives (e.g., drinking to party).

Anxiety sensitivity taxonicity across gender among youth.

The present investigation comparatively evaluated the latent class structure and parameters of anxiety sensitivity (AS) among female and male youth using the Childhood Anxiety Sensitivity Index. Participants were 4462 adolescents (2189 females) in grades 7-12 (M(age)=15.6 years). Consistent with prediction, taxometric analyses indicated the latent structure of AS was taxonic in both males and females, demonstrating the taxonic latent structure of AS is similarly observed across gender. Also consistent with prediction, the base rate of the AS taxon differed between genders -- higher for females (12%) compared to males (7%). These findings are discussed in terms of their implications for the study of AS and panic vulnerability among youth.

New developments in prevention and early intervention for alcohol abuse in youths.

This article summarizes a symposium held at the 2004 Annual Meeting of the Research Society on Alcoholism in Vancouver, British Columbia, Canada. It was prepared by the conference co-organizers/co-chairs with substantial input from each of the symposium participants. Increasingly, alcohol abuse interventions focus on preventing alcohol problems or intervening early before risky drinking behavior becomes ingrained. Universal prevention programs have produced no or only modest effects on the drinking behavior of youths. Although some existing targeted prevention programs have proved effective, they have not tapped the full range of potential intervention targets, such as the underlying motivations for alcohol misuse in youths who are at greatest risk. The set of papers presented in this symposium outline exciting new developments in the field of targeted prevention and early intervention programs for adolescent drinking problems, presented by an international panel of researchers. These developments include attention to making interventions relevant to adolescents' lives, focus on personality and motivational factors underlying alcohol misuse, and combining existing cognitive behavioral programs with expectancy challenge and motivational interviewing techniques.

The effects of supplemental carbohydrate ingestion on intermittent isokinetic leg exercise.

BACKGROUND: The purpose of this investigation was to examine the effects of carbohydrate (CHO) supplementation on isokinetic leg extension/flexion exercise performance, blood glucose responses, blood free fatty acid (FFA) responses, and blood lactate (La) responses. METHODS: Eight resistance trained males (mean+/-SEM, age: 23.7+/-1.3 yrs, height: 180.0+/-3.5 cm, bodymass: 94.9+/-4.9 kg) participated in a randomized, double blind protocol with testing sessions separated by 7-d. Subjects were given CHO or placebo (P) while performing 16 sets of 10 repetitions at 120 degrees x s(-1) on a Cybex isokinetic dynamometer. Performance variables measured were; total work (TW), average work (AW), peak torque (PT) and average torque (AT). Plasma glucose (PG), FFA, and La were measured prior to testing (PRE), after set 8 (MID), and 16 (POST). RESULTS: Results indicated that the CHO treatment elicited significantly (p<0.05) more TW (CHO: 41.1+/-3.9 kJ; P: 38.1+/-3.9 kJ) and AW (CHO: 2.6+/-0.2 kJ; P: 2.4+/-0.2 kJ). There were no differences (p<0.05) between treatments for PT of the hamstrings (CHO: 91.6+/-6.5 Nm; P: 87.4+/-8.5 Nm) and quadriceps (CHO: 129.7+/-9.5 Nm; P: 123.0+/-10.6 Nm). The AT of the hamstrings (CHO: 77.8+/-5.2 Nm; P: 75.7+/-8.7 Nm) and quadriceps (CHO: 116.9+/-8.9 Nm; P: 110.0+/-8.5 Nm) were not statistically different (p>0.05) between the treatments. PG was significantly higher at the POST blood draw in the CHO treatment. No significant differences (p>0.05) were observed between the treatments for FFA and La concentrations. CONCLUSIONS: The data from this investigation indicate that the use of CHO supplementation during isokinetic leg exercise allows for the performance of more work.

Hyperacusis in Williams syndrome.

OBJECTIVE: To define hyperacusis in audiologic parameters and to further elucidate central and peripheral auditory pathways. DESIGN AND SETTING: Theories surrounding hyperacusis have always been highly debated. A group of children with Williams syndrome universally complain of hyperacusis. They have highly reproducible behavioural responses to noise and are thus hampered in their social interactions. Loss of inhibitory modulation to efferent sensory input to the cochlea is thought to be a possible mechanism. METHODS: Nine patients with Williams syndrome received a complete audiologic work-up, including audiogram, speech reception thresholds, acoustic reflexes, impedance, and transient evoked otoacoustic emissions (TEOAEs). MAIN OUTCOME MEASURES: Assessment of the efferent system is done by measuring changes in TEOAEs following stimulation of the contralateral ear. RESULTS: Three patients had high-frequency sensorineural hearing loss (SNHL) and thus, as expected, absent TEOAEs, indicating cochlear damage. Two had normal hearing and normal TEOAEs. However, four patients had normal hearing with absent TEOAEs. CONCLUSIONS: These findings are suggestive of cochlear disease and may, in fact, support the hypothesis of outer hair cell modulation by the ipsilateral medial olivocochlear system. Behavioural aspects of the syndrome make audiologic testing difficult. Thus, the diagnosis of SNHL may be hampered if it truly exists. The data show a preponderance of SNHL in the older age groups of our study population. This either reflects previously missed diagnoses or underlying cochlear disease, which may manifest later in life. Thus, this finding blurs the boundary between loudness recruitment and hyperacusis.

Job strain and evolution of mental health among nurses.

The objective of this 2nd phase of a 2-year study among female nurses was to provide further empirical validation of the demands-control and social support model. The association of job strain with psychological problems and the potential modifying role of social support at work were examined. A questionnaire was sent at the workplace to 1,741 nurses. The same associations were found between psychological demands, decision latitude, and a combination of the 2 with psychological distress and emotional exhaustion for current exposure and for cumulative exposure. Social support had a direct effect on these psychological symptoms but did not modify their association with job strain. Longitudinal and prospective data are needed to study the occurrence and persistence of health problems when exposure is maintained or retrieved.

Glycogen replenishment and repeated maximal effort exercise: effect of liquid carbohydrate.

We investigated the effects of carbohydrate ingestion on glycogen replenishment and subsequent short duration, high intensity exercise performance. During Session 1, aerobic power was determined and each subject (N = 6) was familiarized with the 100-kJ cycling test (100KJ-Test). During the treatment sessions, the subjects performed a 100KJ-Test (Ride-1), then consumed 0.7 g.kg body mass-1 of maltodextrin (CHO) or placebo (PLC), rested 60 min, and then performed a second 100KJ-Test (Ride-2). Muscle tissue was collected before (Pre-1) and after Ride-1 (Post-1), and before (Pre-2) and after Ride-2 (Post-2), and analyzed for glycogen concentration. Both treatments yielded a significant increase in glycogen levels following the 60-min recovery, but there was no difference between treatments. Time to complete the 100KJ-Test increased significantly for PLC, but not for CHO. These data indicate that the decrease in performance during Ride-2 in PLC was not the result of a difference in glycogen concentration.

[The professional life and the health of nurses since the transformation of the Québec health system.]. / La vie professionnelle et la santé des infirmières depuis la transformation du réseau de la santé

Over the last years, the Quebec health system has gone through a period of transformation aimed at cost reduction and better efficiency. The present study describes the effects of the transformation on the professional life and on the health of nurses in the Quebec City urban area. Despite a cross-sectional study not allowing links from cause to effect and despite the fact that the study only includes nurses who were still employed by institutions, the research shows an increase of the prevalence of a higher level of psychological distress in nurses since the beginning of the transformation. Interventions in the work place should be geared to professional factors that nurses identify as problematical.

Job strain, psychological distress, and burnout in nurses.

The first phase of this longitudinal study consisted of a questionnaire completed by a cohort of 1,891 nurses (aged 23-65 years) from six acute care hospitals from the province of Québec. This study was set up to investigate the association between the psychosocial environment of work and mental health. After adjusting for confounding factors, a combination of high psychological demands and low decision latitude was associated with psychological distress and emotional exhaustion, one of the three dimensions of burnout. Social support at work, although associated with each of the mental health indicators, did not modify their association with job strain. The present study identified conditions of the work environment that are modifiable and provide the basis for interventions that focus beyond the modification of individual coping strategies.

A poxvirus-encoded semaphorin induces cytokine production from monocytes and binds to a novel cellular semaphorin receptor, VESPR.

The vaccinia virus A39R protein is a member of the semaphorin family. A39R.Fc protein was used to affinity purify an A39R receptor from a human B cell line. Tandem mass spectrometry of receptor peptides yielded partial amino acid sequences that allowed the identification of corresponding cDNA clones. Sequence analysis of this receptor indicated that it is a novel member of the plexin family and identified a semaphorin-like domain within this family, thus suggesting an evolutionary relationship between receptor and ligand. A39R up-regulated ICAM-1 on, and induced cytokine production from, human monocytes. These data, then, describe a receptor for an immunologically active semaphorin and suggest that it may serve as a prototype for other plexin-semaphorin binding pairs.

Epstein-Barr virus uses HLA class II as a cofactor for infection of B lymphocytes.

Infection of B lymphocytes by Epstein-Barr virus (EBV) requires attachment of virus via binding of viral glycoprotein gp350 to CD21 on the cell surface. Penetration of the cell membrane additionally involves a complex of three glycoproteins, gH, gL, and gp42. Glycoprotein gp42 binds to HLA-DR. Interference with this interaction with a soluble form of gp42, with a monoclonal antibody (MAb) to gp42, or with a MAb to HLA-DR inhibited virus infection. It was not possible to superinfect cells that failed to express HLA-DR unless expression was restored by transfection or creation of hybrid cell lines with complementing deficiencies in expression of HLA class II. HLA class II molecules thus serve as cofactors for infection of human B cells.

The extracellular domain of the Epstein-Barr virus BZLF2 protein binds the HLA-DR beta chain and inhibits antigen presentation.

The Epstein-Barr virus BZLF2 gene encodes a glycoprotein that associates with gH and gL and facilitates the infection of B lymphocytes. In order to determine whether the BZLF2 protein recognizes a B-cell-specific surface antigen, a soluble protein containing the extracellular portion of the BZLF2 protein linked to the Fc portion of human immunoglobulin G1 (BZLF2.Fc) was expressed from mammalian cells. BZLF2.Fc was used in an expression cloning system and found to bind to a beta-chain allele of the HLA-DR locus of the class II major histocompatibility complex (MHC). Analysis of amino- and carboxy-terminal deletion mutants of the BZLF2.Fc protein indicated that the first 90 amino acids of BZLF2.Fc are not required for HLA-DR beta-chain recognition. Site-directed mutagenesis of an HLA-DR beta-chain cDNA and subsequent immunoprecipitation of expressed mutant beta-chain proteins using BZLF2.Fc indicated that the beta1 domain, which participates in the formation of peptide binding pockets, is required for BZLF2.Fc recognition. The addition of BZLF2.Fc to sensitized peripheral blood mononuclear cells in vitro abolished their proliferative response to antigen and inhibited cytokine-dependent cytotoxic T-cell generation in mixed lymphocyte cultures. Flow-cytometric analysis of Akata cells induced to express late Epstein-Barr virus antigens indicated that expression of BZLF2 did not result in reduced surface expression levels of MHC class II. The ability of BZLF2.Fc to bind to the HLA-DR beta chain suggests that the BZLF2 protein may interact with MHC class II on the surfaces of B cells.