Integrated genomics and proteomics define huntingtin CAG length-dependent networks in mice.

To gain insight into how mutant huntingtin (mHtt) CAG repeat length modifies Huntington's disease (HD) pathogenesis, we profiled mRNA in over 600 brain and peripheral tissue samples from HD knock-in mice with increasing CAG repeat lengths. We found repeat length-dependent transcriptional signatures to be prominent in the striatum, less so in cortex, and minimal in the liver. Coexpression network analyses revealed 13 striatal and 5 cortical modules that correlated highly with CAG length and age, and that were preserved in HD models and sometimes in patients. Top striatal modules implicated mHtt CAG length and age in graded impairment in the expression of identity genes for striatal medium spiny neurons and in dysregulation of cyclic AMP signaling, cell death and protocadherin genes. We used proteomics to confirm 790 genes and 5 striatal modules with CAG length-dependent dysregulation at the protein level, and validated 22 striatal module genes as modifiers of mHtt toxicities in vivo

Colorectal cancer health services research study protocol: the CCR-CARESS observational prospective cohort project

BACKGROUND: Colorectal cancers are one of the most common forms of malignancy worldwide. But two significant areas of research less studied deserve attention: health services use and development of patient stratification risk tools for these patients. METHODS:DESIGN: a prospective multicenter cohort study with a follow up period of up to 5 years after surgical intervention. Participant centers: 22 hospitals representing six autonomous communities of Spain. Participants/Study population: Patients diagnosed with colorectal cancer that have undergone surgical intervention and have consented to participate in the study between June 2010 and December 2012. Variables collected include pre-intervention background, sociodemographic parameters, hospital admission records, biological and clinical parameters, treatment information, and outcomes up to 5 years after surgical intervention. Patients completed the following questionnaires prior to surgery and in the follow up period: EuroQol-5D, EORTC QLQ-C30 (The European Organization for Research and Treatment of Cancer quality of life questionnaire) and QLQ-CR29 (module for colorectal cancer), the Duke Functional Social Support Questionnaire, the Hospital Anxiety and Depression Scale, and the Barthel Index. The main endpoints of the study are mortality, tumor recurrence, major complications, readmissions, and changes in health-related quality of life at 30 days and at 1, 2, 3 and 5 years after surgical intervention. STATISTICAL ANALYSIS: In relation to the different endpoints, predictive models will be used by means of multivariate logistic models, Cox or linear mixed-effects regression models. Simulation models for the prediction of discrete events in the long term will also be used, and an economic evaluation of different treatment strategies will be performed through the use of generalized linear models. DISCUSSION: The identification of potential risk factors for adverse events may help clinicians in the clinical decision making process. Also, the follow up by 5 years of this large cohort of patients may provide useful information to answer different health services research questions

Echium oil is not protective against weight loss in head and neck cancer patients undergoing curative radio(chemo)therapy: a randomised-controlled trial

Background: Therapy-induced mucositis and dysphagia puts head and neck (H&N) cancer patients at increased risk for developing cachexia. Omega-3 fatty acids (n-3 FA) have been suggested to protect against cachexia. We aimed to examine if echium oil, a plant source of n-3 FA, could reduce weight loss in H&N cancer patients undergoing radio(chemo)therapy with curative intent. Methods: In a double-blind trial, patients were randomly assigned to echium oil (intervention (I) group; 7.5 ml bis in die (b.i.d.), 235 mg/ml α-linolenic acid (ALA) + 95 mg/ml stearidonic acid (SDA) + 79 mg/ml γ-linolenic acid (GLA)) or n-3 FA deficient sunflower oil high oleic (control (C) group; 7.5 ml b.i.d.) additional to standard nutritional support during treatment. Differences in percentage weight loss between both groups were analysed according to the intention-to-treat principle. Erythrocyte FA profile, body composition, nutritional status and quality of life were collected. Results: Ninety-one eligible patients were randomised, of whom 83 were evaluable. Dietary supplement adherence was comparable in both groups (median, I: 87%, C: 81%). At week 4, the I group showed significantly increased values of erythrocyte n-3 eicosapentanoic acid (EPA, 14% vs −5%) and n-6 GLA (42% vs −20%) compared to the C group, without a significant change in n-6 arachidonic acid (AA, 2% vs −1%). Intention-to-treat analysis could not reveal a significant reduction in weight loss related to echium oil consumption (median weight loss, I: 8.9%, C: 7.6%). Also, no significant improvement was observed in the other evaluated anthropometric parameters. Conclusions: Echium oil effectively increased erythrocyte EPA and GLA FAs in H&N cancer patients. It failed however to protect against weight loss, or improve nutritional parameters. Trial registration: ClinicalTrials.gov Identifier NCT01596933

Health-related quality of life in young adults with symptoms of constipation continuing from childhood into adulthood

<p>Abstract</p> <p>Background</p> <p>Children with functional constipation report impaired Health-related Quality of Life (HRQoL) in relation to physical complaints and long duration of symptoms. In about one third of children with constipation, symptoms continue into adulthood. Knowledge on HRQoL in adults with constipation persisting from childhood is lacking.</p> <p>Objectives</p> <p>To assess HRQoL in adults with constipation from early childhood in comparison to that of their peers. Furthermore to gain insight into the specific social consequences related to continuing symptoms of constipation and/or fecal incontinence at adult age.</p> <p>Methods</p> <p>One HRQoL questionnaire and one self-developed questionnaire focusing on specific consequences of symptoms of constipation continuing into adulthood were administrated to 182 adults with a history of childhood constipation. Successful clinical outcome was defined as a defecation frequency three or more times per week with less than two episodes of fecal incontinence per month, irrespective of laxative use. HRQoL of both adults with unsuccessful and successful clinical outcome were compared to a control group of 361 peers from the general Dutch population.</p> <p>Results</p> <p>No differences in HRQoL were found between the whole study population and healthy peers, nor between adults with successful clinical outcome (n = 139) and the control group. Adults with an unsuccessful clinical outcome (n = 43) reported significantly lower HRQoL compared to the control group with respect to scores on bodily pain (mean ± SD 77.4 ± 19.6 versus 85.7 ± 19.5, p = 0.01) and general health (67.6 ± 18.8 versus 74.0 ± 18.1, p = 0.04). Adults with an unsuccessful clinical outcome reported difficulties with social contact and intimacy (20% and 12.5%, respectively), related to their current symptoms. Current therapy in these adults was more often self-administered treatment (e.g. diet modifications) (60.4%) than laxatives (20.9%).</p> <p>Conclusion</p> <p>Overall, young adults with constipation in childhood report a good quality of life, as HRQoL of adults with successful clinical outcome was comparable to that of their peers. However, when childhood constipation continues into adulthood, it influences HRQoL negatively with social consequences in 20% of these adults.</p

Stay@Work: Participatory Ergonomics to prevent low back and neck pain among workers: design of a randomised controlled trial to evaluate the (cost-)effectiveness

<p>Abstract</p> <p>Background</p> <p>Low back pain (LBP) and neck pain (NP) are a major public health problem with considerable costs for individuals, companies and society. Therefore, prevention is imperative. The Stay@Work study investigates the (cost-)effectiveness of Participatory Ergonomics (PE) to prevent LBP and NP among workers.</p> <p>Methods</p> <p>In a randomised controlled trial (RCT), a total of 5,759 workers working at 36 departments of four companies is expected to participate in the study at baseline. The departments consisting of about 150 workers are pre-stratified and randomised. The control departments receive usual practice and the intervention departments receive PE. Within each intervention department a working group is formed including eight workers, a representative of the management, and an occupational health and safety coordinator. During a one day meeting, the working group follows the steps of PE in which the most important risk factors for LBP and NP, and the most adequate ergonomic measures are identified on the basis of group consensus. The implementation of ergonomic measures at the department is performed by the working group. To improve the implementation process, so-called 'ergocoaches' are trained.</p> <p>The primary outcome measure is an episode of LBP and NP. Secondary outcome measures are actual use of ergonomic measures, physical workload, psychosocial workload, intensity of pain, general health status, sick leave, and work productivity. The cost-effectiveness analysis is performed from the societal and company perspective. Outcome measures are assessed using questionnaires at baseline and after 6 and 12 months. Data on the primary outcome as well as on intensity of pain, sick leave, work productivity, and health care costs are collected every 3 months.</p> <p>Discussion</p> <p>Prevention of LBP and NP is beneficial for workers, employers, and society. If the intervention is proven (cost-)effective, the intervention can have a major impact on LBP and NP prevention and, thereby, on work disability prevention. Results are expected in 2010.</p> <p>Trial registration</p> <p>ISRCTN27472278</p

Quality of Life After Sentinel Lymph Node Biopsy or Axillary Lymph Node Dissection in Stage I/II Breast Cancer Patients: A Prospective Longitudinal Study

Background:\ud Breast cancer patients’ quality of life (QoL) after surgery has been reported to improve significantly over time. Little is known about QoL recovery after sentinel lymph node biopsy (SLNB) in comparison to axillary lymph node dissection (ALND).\ud \ud Methods:\ud 175 of 195 stage I/II breast cancer patients completed the EORTC QLQ-C30: one day before surgery (T0) and after 6 (T1), 26 (T2), 52 (T3) and 104 (T4) weeks. Of these, 54 patients underwent SLNB, 56 SLNB+ALND and 65 ALND. General linear models and paired T-tests between T0–T4 and T1–T4 were computed. Complications, radiotherapy and systemic therapy were added to the model.\ud \ud Results:\ud Significant time effects were found on physical, role and emotional functioning. Physical and role functioning decreased between T0 and T1. At T4, SLNB patients’ functioning had increased to their T0 level; ALND (+/– SLNB) patients’ functioning had increased, but had not improved to T0 level. Emotional functioning increased linearly between T0 and T4. At T4, emotional functioning was significantly higher in all groups as compared with T0. No significant group or interaction (time × group) effects were found. Complications and chemotherapy had a significant negative effect on role, emotional and cognitive functioning. Complications had a significant effect on social functioning also. Effect sizes varied between 0.00 and 0.06.\ud \ud Conclusion:\ud Two years post surgery, breast cancer patients’ QoL is comparable to that shortly before surgery. Women rated their emotional functioning as even better. SLNB is not associated with a better QoL than ALND. However, undergoing systemic therapy and/or experiencing complications affects QoL negatively

Prolonged conservative treatment or 'early' surgery in sciatica caused by a lumbar disc herniation: rationale and design of a randomized trial [ISRCT 26872154]

BACKGROUND: The design of a randomized multicenter trial is presented on the effectiveness of a prolonged conservative treatment strategy compared with surgery in patients with persisting intense sciatica (lumbosacral radicular syndrome). METHODS/DESIGN: Patients presenting themselves to their general practitioner with disabling sciatica lasting less than twelve weeks are referred to the neurology outpatient department of one of the participating hospitals. After confirmation of the diagnosis and surgical indication MRI scanning is performed. If a distinct disc herniation is discerned which in addition covers the clinically expected site the patient is eligible for randomization. Depending on the outcome of the randomization scheme the patient will either be submitted to prolonged conservative care or surgery. Surgery will be carried out according to the guidelines and between six and twelve weeks after onset of complaints. The experimental therapy consists of a prolonged conservative treatment under supervision of the general practitioner, which may be followed by surgical intervention in case of persisting or progressive disability. The main primary outcome measure is the disease specific disability of daily functioning. Other primary outcome measures are perceived recovery and intensity of legpain. Secondary outcome measures encompass severity of complaints, quality of life, medical consumption, absenteeism, costs and preference. The main research question will be answered at 12 months after randomization. The total follow-up period covers two years. DISCUSSION: Evidence is lacking concerning the optimal treatment of lumbar disc induced sciatica. This pragmatic randomized trial, focusses on the 'timing' of intervention, and will contribute to the decision of the general practictioner and neurologist, regarding referral of patients for surgery

The Four-Dimensional Symptom Questionnaire (4DSQ): a validation study of a multidimensional self-report questionnaire to assess distress, depression, anxiety and somatization

BACKGROUND: The Four-Dimensional Symptom Questionnaire (4DSQ) is a self-report questionnaire that has been developed in primary care to distinguish non-specific general distress from depression, anxiety and somatization. The purpose of this paper is to evaluate its criterion and construct validity. METHODS: Data from 10 different primary care studies have been used. Criterion validity was assessed by comparing the 4DSQ scores with clinical diagnoses, the GPs' diagnosis of any psychosocial problem for Distress, standardised psychiatric diagnoses for Depression and Anxiety, and GPs' suspicion of somatization for Somatization. ROC analyses and logistic regression analyses were used to examine the associations. Construct validity was evaluated by investigating the inter-correlations between the scales, the factorial structure, the associations with other symptom questionnaires, and the associations with stress, personality and social functioning. The factorial structure of the 4DSQ was assessed through confirmatory factor analysis (CFA). The associations with other questionnaires were assessed with Pearson correlations and regression analyses. RESULTS: Regarding criterion validity, the Distress scale was associated with any psychosocial diagnosis (area under the ROC curve [AUC] 0.79), the Depression scale was associated with major depression (AUC = 0.83), the Anxiety scale was associated with anxiety disorder (AUC = 0.66), and the Somatization scale was associated with the GPs' suspicion of somatization (AUC = 0.65). Regarding the construct validity, the 4DSQ scales appeared to have considerable inter-correlations (r = 0.35-0.71). However, 30–40% of the variance of each scale was unique for that scale. CFA confirmed the 4-factor structure with a comparative fit index (CFI) of 0.92. The 4DSQ scales correlated with most other questionnaires measuring corresponding constructs. However, the 4DSQ Distress scale appeared to correlate with some other depression scales more than the 4DSQ Depression scale. Measures of stress (i.e. life events, psychosocial problems, and work stress) were mainly associated with Distress, while Distress, in turn, was mainly associated with psychosocial dysfunctioning, including sick leave. CONCLUSION: The 4DSQ seems to be a valid self-report questionnaire to measure distress, depression, anxiety and somatization in primary care patients. The 4DSQ Distress scale appears to measure the most general, most common, expression of psychological problems

Dark Matter in the Milky Way's Dwarf Spheroidal Satellites

The Milky Way's dwarf spheroidal satellites include the nearest, smallest and least luminous galaxies known. They also exhibit the largest discrepancies between dynamical and luminous masses. This article reviews the development of empirical constraints on the structure and kinematics of dSph stellar populations and discusses how this phenomenology translates into constraints on the amount and distribution of dark matter within dSphs. Some implications for cosmology and the particle nature of dark matter are discussed, and some topics/questions for future study are identified.Comment: A version with full-resolution figures is available at http://www.cfa.harvard.edu/~mwalker/mwdsph_review.pdf; 70 pages, 22 figures; invited review article to be published in Vol. 5 of the book "Planets, Stars, and Stellar Systems", published by Springe