Huntington's disease and its therapeutic target genes: a global functional profile based on the HD Research Crossroads database.

BACKGROUND: Huntington's disease (HD) is a fatal progressive neurodegenerative disorder caused by the expansion of the polyglutamine repeat region in the huntingtin gene. Although the disease is triggered by the mutation of a single gene, intensive research has linked numerous other genes to its pathogenesis. To obtain a systematic overview of these genes, which may serve as therapeutic targets, CHDI Foundation has recently established the HD Research Crossroads database. With currently over 800 cataloged genes, this web-based resource constitutes the most extensive curation of genes relevant to HD. It provides us with an unprecedented opportunity to survey molecular mechanisms involved in HD in a holistic manner. METHODS: To gain a synoptic view of therapeutic targets for HD, we have carried out a variety of bioinformatical and statistical analyses to scrutinize the functional association of genes curated in the HD Research Crossroads database. In particular, enrichment analyses were performed with respect to Gene Ontology categories, KEGG signaling pathways, and Pfam protein families. For selected processes, we also analyzed differential expression, using published microarray data. Additionally, we generated a candidate set of novel genetic modifiers of HD by combining information from the HD Research Crossroads database with previous genome-wide linkage studies. RESULTS: Our analyses led to a comprehensive identification of molecular mechanisms associated with HD. Remarkably, we not only recovered processes and pathways, which have frequently been linked to HD (such as cytotoxicity, apoptosis, and calcium signaling), but also found strong indications for other potentially disease-relevant mechanisms that have been less intensively studied in the context of HD (such as the cell cycle and RNA splicing, as well as Wnt and ErbB signaling). For follow-up studies, we provide a regularly updated compendium of molecular mechanism, that are associated with HD, at http://hdtt.sysbiolab.eu Additionally, we derived a candidate set of 24 novel genetic modifiers, including histone deacetylase 3 (HDAC3), metabotropic glutamate receptor 1 (GRM1), CDK5 regulatory subunit 2 (CDK5R2), and coactivator 1ß of the peroxisome proliferator-activated receptor gamma (PPARGC1B). CONCLUSIONS: The results of our study give us an intriguing picture of the molecular complexity of HD. Our analyses can be seen as a first step towards a comprehensive list of biological processes, molecular functions, and pathways involved in HD, and may provide a basis for the development of more holistic disease models and new therapeutics

Characteristics of chronic non-specific musculoskeletal pain in children and adolescents attending a rheumatology outpatients clinic: a cross-sectional study

Background: Chronic non-specific musculoskeletal pain (CNSMSP) may develop in childhood and adolescence, leading to disability and reduced quality of life that continues into adulthood. The purpose of the study was to build a biopsychosocial profile of children and adolescents with CNSMSP. Methods: CNSMSP subjects (n = 30, 18 females, age 7-18) were compared with age matched pain free controls across a number of biopsychosocial domains. Results: In the psychosocial domain CNSMSP subjects had increased levels of anxiety and depression, and had more somatic pain complaints. In the lifestyle domain CNSMSP subjects had lower physical activity levels, but no difference in television or computer use compared to pain free subjects. Physically, CNSMSP subjects tended to sit with a more slumped spinal posture, had reduced back muscle endurance, increased presence of joint hypermobility and poorer gross motor skills. Conclusion: These findings support the notion that CNSMSP is a multidimensional biopsychosocial disorder. Further research is needed to increase understanding of how the psychosocial, lifestyle and physical factors develop and interact in CNSMSP

Prediction of chronic disability in work-related musculoskeletal disorders: a prospective, population-based study

BACKGROUND: Disability associated with work-related musculoskeletal disorders is an increasingly serious societal problem. Although most injured workers return quickly to work, a substantial number do not. The costs of chronic disability to the injured worker, his or her family, employers, and society are enormous. A means of accurate early identification of injured workers at risk for chronic disability could enable these individuals to be targeted for early intervention to promote return to work and normal functioning. The purpose of this study is to develop statistical models that accurately predict chronic work disability from data obtained from administrative databases and worker interviews soon after a work injury. Based on these models, we will develop a brief instrument that could be administered in medical or workers' compensation settings to screen injured workers for chronic disability risk. METHODS: This is a population-based, prospective study. The study population consists of workers who file claims for work-related back injuries or carpal tunnel syndrome (CTS) in Washington State. The Washington State Department of Labor and Industries claims database is reviewed weekly to identify workers with new claims for work-related back injuries and CTS, and these workers are telephoned and invited to participate. Workers who enroll complete a computer-assisted telephone interview at baseline and one year later. The baseline interview assesses sociodemographic, employment-related, biomedical/health care, legal, and psychosocial risk factors. The follow-up interview assesses pain, disability, and work status. The primary outcome is duration of work disability over the year after claim submission, as assessed by administrative data. Secondary outcomes include work disability status at one year, as assessed by both self-report and work disability compensation status (administrative records). A sample size of 1,800 workers with back injuries and 1,200 with CTS will provide adequate statistical power (0.96 for low back and 0.85 for CTS) to predict disability with an alpha of .05 (two-sided) and a hazard ratio of 1.2. Proportional hazards regression models will be constructed to determine the best combination of predictors of work disability duration at one year. Regression models will also be developed for the secondary outcomes

Chronic pain and sex differences:Women accept and move, while men feel blue

Purpose The aim of this study is to explore differences between male and female patients entering a rehabilitation program at a pain clinic in order to gain a greater understanding of different approaches to be used in rehabilitation. Method 1371 patients referred to a specialty pain rehabilitation clinic, completed sociodemographic and pain related questionnaires. They rated their pain acceptance (CPAQ-8), their kinesiophobia (TSK), the impact of pain in their life (MPI), anxiety and depression levels (HAD) and quality of life scales: the SF-36, LiSat-11, and the EQ-5D. Because of the large sample size of the study, the significance level was set at the p amp;lt;= .01. Results Analysis by t-test showed that when both sexes experience the same pain severity, women report significantly higher activity level, pain acceptance and social support while men report higher kinesiophobia, mood disturbances and lower activity level. Conclusion Pain acceptance (CPAQ-8) and kinesiophobia (TSK) showed the clearest differences between men and women. Pain acceptance and kinesiophobia are behaviorally defined and have the potential to be changed.Funding Agencies|Swedish Association of Local Authorities and Regions (SALAR); Vardal Foundation; RehSAM; AFA insurance, Sweden; Swedish Association for Survivors of Accident and Injury (RTP); Renee Eanders Foundation</p

Ansiedade ao tratamento odontológico em atendimento de urgência Dental anxiety in an emergency dental service

OBJETIVO: Avaliar a freqüência de pacientes com ansiedade ou medo do tratamento odontológico em um setor de urgência. MÉTODOS: Participaram do estudo 252 pacientes, com 18 anos ou mais, que compareceram ao setor de urgência de uma faculdade de odontologia, de São Paulo, SP, entre agosto e novembro de 2001. Para avaliar a ansiedade, foram utilizadas a Modified Dental Anxiety Scale (MDAS), e a Escala de Medo de Gatchel. O grupo estudado respondeu a questões sobre: tempo decorrido desde a última visita ao dentista e desde o início dos sintomas, escolaridade, renda familiar e história prévia de trauma. Os resultados foram analisados pelos testes estatísticos (chi2 e Teste Exato de Fisher). RESULTADOS: Foram identificados 28,2% de indivíduos com algum grau de ansiedade, segundo a MDAS, na qual as mulheres foram consideradas mais ansiosas que os homens (chi2=0,01); e 14,3% de pacientes com alto grau de medo segundo a Escala de Medo de Gatchel. Em 44,4% da amostra a demora para procura de alívio dos sintomas foi > sete dias. Mulheres ansiosas procuraram atendimento mais rapidamente e em maior número. Experiência traumática anterior ocorreu em 46,5% dos pacientes ansiosos. Não foi possível relacionar escolaridade e renda familiar com ansiedade e/ou medo. CONCLUSÕES: Pacientes ansiosos, com destaque para as mulheres, são freqüentes no atendimento odontológico de urgência. Experiência prévia traumática mostrou-se importante para o desenvolvimento da ansiedade em relação ao atendimento odontológico.<br>OBJECTIVE: The purpose of the study was to assess the frequency of dental anxiety and/or fear among patients in an emergency dental service. METHODS: Research was based on interviews with 252 patients, aged 18 years old and over, attended at an emergency dentistry service of São Paulo, Brazil, from August to November, 2001. Two methods were used to measure dental anxiety: the Modified Dental Anxiety Scale (MDAS) and the Gatchel Fear Scale. The study group answered questions concerning major complaint, how much time had elapsed since their last visit to the dentist and since the initial symptoms leading to the current visit to the emergency service, level of education, family income and previous traumas. Statistical analysis (chi2 and Fisher exact test) was performed to evaluate these characteristics. RESULTS: It was found that 28.17% of this sample was dentally anxious, according to the MDAS, and 14.29%, felt fear related to dental treatment according to the Gatchel Fear Scale. Women were more anxious than men at a statistically significant rate (MDAS). The time elapsed since the onset of initial symptoms was more than 7 days for 44.44% of the participants. A large proportion of anxious women returned to treatment during the last year. A previous traumatic experience with dental was identified in 46.48% of the dentally anxious patients. No significant relation between level of education or income and dental anxiety was found. CONCLUSIONS: Dentally anxious patients frequent attend emergency care. Females are more likely to report high dental anxiety than males. Previous experience seems to be an important factor contributing to avoidance of dental care