A Pathogenic Mechanism in Huntington's Disease Involves Small CAG-Repeated RNAs with Neurotoxic Activity

Huntington's disease (HD) is an autosomal dominantly inherited disorder caused by the expansion of CAG repeats in the Huntingtin (HTT) gene. The abnormally extended polyglutamine in the HTT protein encoded by the CAG repeats has toxic effects. Here, we provide evidence to support that the mutant HTT CAG repeats interfere with cell viability at the RNA level. In human neuronal cells, expanded HTT exon-1 mRNA with CAG repeat lengths above the threshold for complete penetrance (40 or greater) induced cell death and increased levels of small CAG-repeated RNAs (sCAGs), of ≈21 nucleotides in a Dicer-dependent manner. The severity of the toxic effect of HTT mRNA and sCAG generation correlated with CAG expansion length. Small RNAs obtained from cells expressing mutant HTT and from HD human brains significantly decreased neuronal viability, in an Ago2-dependent mechanism. In both cases, the use of anti-miRs specific for sCAGs efficiently blocked the toxic effect, supporting a key role of sCAGs in HTT-mediated toxicity. Luciferase-reporter assays showed that expanded HTT silences the expression of CTG-containing genes that are down-regulated in HD. These results suggest a possible link between HD and sCAG expression with an aberrant activation of the siRNA/miRNA gene silencing machinery, which may trigger a detrimental response. The identification of the specific cellular processes affected by sCAGs may provide insights into the pathogenic mechanisms underlying HD, offering opportunities to develop new therapeutic approaches

miR-16 Targets Transcriptional Corepressor SMRT and Modulates NF-kappaB-Regulated Transactivation of Interleukin-8 Gene

The signaling pathways associated with the Toll-like receptors (TLRs) and nuclear factor-kappaB (NF-κB) are essential to pro-inflammatory cytokine and chemokine expression, as well as initiating innate epithelial immune responses. The TLR/NF-κB signaling pathways must be stringently controlled through an intricate network of positive and negative regulatory elements. MicroRNAs (miRNAs) are non-coding small RNAs that regulate the stability and/or translation of protein-coding mRNAs. Herein we report that miR-16 promotes NF-κB-regulated transactivation of the IL-8 gene by suppression of the silencing mediator for retinoid and thyroid hormone receptor (SMRT). LPS stimulation activated miR-16 gene transcription in human monocytes (U937) and biliary epithelial cells (H69) through MAPK-dependent mechanisms. Transfection of cells with the miR-16 precursor promoted LPS-induced production of IL-8, IL-6, and IL-1α, without a significant effect on their RNA stability. Instead, an increase in NF-κB-regulated transactivation of the IL-8 gene was confirmed in cells following transfection of miR-16 precursor. Importantly, miR-16 targeted the 3′-untranslated region of SMRT and caused translational suppression of SMRT. LPS decreased SMRT expression via upregulation of miR-16. Moreover, functional manipulation of SMRT altered NF-κB-regulated transactivation of LPS-induced IL-8 expression. These data suggest that miR-16 targets SMRT and modulates NF-κB-regulated transactivation of the IL-8 gene

The Contribution of High Levels of Somatic Symptom Severity to Sickness Absence Duration, Disability and Discharge

Introduction: The primary objectives were to compare the duration of sickness absence in employees with high levels of somatic symptom severity (HLSSS) with employees with lower levels of somatic symptom severity, and to establish the long-term outcomes concerning return to work (RTW), disability and discharge. Secondary objective was to evaluate determinants of the duration of sickness absence in employees with HLSSS. Methods: 489 sick-listed employees registered with five Occupational Health Physician (OHP) group practices were included in this study. We measured their baseline scores for somatic symptoms severity, depressive disorders, anxiety disorders, health anxiety, distress and functional impairment. The OHPs filled in a questionnaire on their diagnosis. A prospective 2-year follow-up was carried out to assess the long-term outcomes concerning sickness absence, and retrospective information was gathered with regard to sickness absence during the 12 months before the employees were sick-listed. Results: The median duration of sickness absence was 78 days longer for employees with HLSSS. They more often remained disabled and were discharged more often, especially due to problems in the relationship between the employer and the employee. HLSSS, health anxiety and older age contributed to a longer duration of sickness absence of employees. Conclusion: High levels of somatic symptom severity are a determinant of prolonged sickness absence, enduring disabilities and health-related job loss. Occupational health physicians should identify employees who are at risk and adhere to guidelines for medically unexplained somatic symptoms

Clinical outcomes and prognostic factors in patients with breast diffuse large B cell lymphoma; Consortium for Improving Survival of Lymphoma (CISL) study

<p>Abstract</p> <p>Background</p> <p>The breast is a rare extranodal site of non-Hodgkin lymphoma, and primary breast lymphoma (PBL) has been arbitrarily defined as disease localized to one or both breasts with or without regional lymph nodes involvement. The aim of this study was to evaluate the clinical outcomes in patients with diffuse large B cell lymphoma (DLBCL) and breast involvement, and to find the criteria of PBL reflecting the outcome and prognosis.</p> <p>Methods</p> <p>We retrospectively analyzed data from 68 patients, newly diagnosed with DLBCL and breast involvement at 16 Korean institutions between January 1994 and June 2009.</p> <p>Results</p> <p>Median age at diagnosis was 48 years (range, 20-83 years). Forty-three (63.2%) patients were PBL according to previous arbitrary criteria, sixteen (23.5%) patients were high-intermediate to high risk of international prognostic index. The patients with one extranodal disease in the breast (OED) with or without nodal disease were 49 (72.1%), and those with multiple extranodal disease (MED) were 19 (27.9%). During median follow-up of 41.5 months (range, 2.4-186.0 months), estimated 5-year progression-free survival (PFS) was 53.7 ± 7.6%, and overall survival (OS) was 60.3 ± 7.2%. The 5-year PFS and OS was significantly higher for patients with the OED group than those with the MED group (5-year PFS, 64.9 ± 8.9% vs. 27.5 ± 11.4%, p = 0.001; 5-year OS, 74.3 ± 7.6% vs. 24.5 ± 13.0%, p < 0.001). In multivariate analysis, MED (hazard ratio [HR], 3.61; 95% confidence interval [CI], 1.07-12.2) and fewer than four cycles of systemic chemotherapy with or without local treatments (HR, 4.47; 95% CI, 1.54-12.96) were independent prognostic factors for worse OS. Twenty-five (36.8%) patients experienced progression, and the cumulative incidence of progression in multiple extranodal sites or other than breasts and central nervous system was significantly different between the OED group and the MED group (5-year cumulative incidence, 9.7 ± 5.4% vs. 49.0 ± 15.1%, p = 0.001).</p> <p>Conclusions</p> <p>Our results show that the patients included in OED group, reflecting different treatment outcome, prognosis and pattern of progression, should be considered as PBL in the future trial. Further studies are warranted to validate our suggested criteria.</p

Combinatorial discovery of polymers resistant to bacterial attachment

Bacterial attachment and subsequent biofilm formation are key challenges to the long term performance of many medical devices. Here, a high throughput approach coupled with the analysis of surface structure-property relationships using a chemometics approach has been developed to simultaneously investigate the interaction of bacteria with hundreds of polymeric materials on a microarray format. Using this system, a new group of materials comprising ester and hydrophobic moieties are identified that dramatically reduce the attachment of clinically relevant, pathogenic bacteria (Pseudomonas aeruginosa, Staphylococcus aureus and uropathogenic Escherichia coli). Hit materials coated on silicone catheters resulted in up to a 30 fold reduction in coverage compared to a commercial silver embedded catheter, which has been proven to half the incidence of clinically acquired infection. These polymers represent a new class of materials resistant to bacterial attachment that could not have been predicted from the current understanding of bacteria-surface interactions

Severe MUPS in a sick-listed population: a cross-sectional study on prevalence, recognition, psychiatric co-morbidity and impairment

Background: Medically unexplained physical symptoms (MUPS) have a high prevalence in the general population and are associated with psychiatric morbidity. There are indications that MUPS are an important determinant of frequent and long-term disability. The primary objective was to assess the prevalence of MUPS in sick-listed-employees and its associations with depressive disorders, anxiety disorders, health anxiety, distress and functional impairment. Secondary objectives were to investigate the classification of the occupational health physicians (OHPs), their opinions about the causes as well as the attributions of the employee. Methods: In a cross- sectional study of 489 sick-listed employees from 5 OHP group practices, MUPS, depressive disorders, anxiety disorders, health anxiety, distress and functional impairment were assessed with the Patient Health Questionnaire (PHQ), the Whitely Index (WI), the Four-Dimensional Symptom Questionnaire (4DSQ) and the Short-Form 36 Health Survey (SF-36). We used a cut off score of 15 on the PHQ for the categorisation of severe MUPS. The opinions of the OHPs were evaluated by means of a separate questionnaire with regard to the presence of employees physical symptoms, and the symptoms attributions, and the diagnoses of the OHPs. Results: Severe MUPS had a prevalence of 15.1% in this population of sick-listed employees. These employees had 4-6 times more depressive and anxiety disorders, and were more impaired. Female gender and PHQ-9 scores were determinants of severe MUPS. Most of the time the OHPs diagnosed employees with severe MUPS as having a mental disorder. The employees attributed their physical symptoms in 66% to mental or to both mental and physical causes. Conclusion: The prevalence of severe MUPS is higher in long-term sick-listed employees than in the non-sick-listed working population and at least equals the prevalence in the general practice population. Severe MUPS are associated with psychiatric morbidity and functional impairment and must therefore be specifically recognised as such. Validated questionnaires, such as the PHQ-15, are useful instruments in order to help OHPs to recognise severe MUPS