ER stress transcription factor Xbp1 suppresses intestinal tumorigenesis and directs intestinal stem cells

Unresolved endoplasmic reticulum (ER) stress in the epithelium can provoke intestinal inflammation. Hypomorphic variants of ER stress response mediators, such as X-box–binding protein 1 (XBP1), confer genetic risk for inflammatory bowel disease. We report here that hypomorphic Xbp1 function instructs a multilayered regenerative response in the intestinal epithelium. This is characterized by intestinal stem cell (ISC) expansion as shown by an inositol-requiring enzyme 1α (Ire1α)–mediated increase in Lgr5+ and Olfm4+ ISCs and a Stat3-dependent increase in the proliferative output of transit-amplifying cells. These consequences of hypomorphic Xbp1 function are associated with an increased propensity to develop colitis-associated and spontaneous adenomatous polyposis coli (APC)–related tumors of the intestinal epithelium, which in the latter case is shown to be dependent on Ire1α. This study reveals an unexpected role for Xbp1 in suppressing tumor formation through restraint of a pathway that involves an Ire1α- and Stat3-mediated regenerative response of the epithelium as a consequence of ER stress. As such, Xbp1 in the intestinal epithelium not only regulates local inflammation but at the same time also determines the propensity of the epithelium to develop tumors

Study protocol of effectiveness of a biopsychosocial multidisciplinary intervention in the evolution of non-speficic sub-acute low back pain in the working population : cluster randomised trial

Background: Non-specific low back pain is a common cause for consultation with the general practitioner, generating increased health and social costs. This study will analyse the effectiveness of a multidisciplinary intervention to reduce disability, severity of pain, anxiety and depression, to improve quality of life and to reduce the incidence of chronic low back pain in the working population with non-specific low back pain, compared to usual clinical care. Methods/Design: A Cluster randomised clinical trial will be conducted in 38 Primary Health Care Centres located in Barcelona, Spain and its surrounding areas. The centres are randomly allocated to the multidisciplinary intervention or to usual clinical care. Patients between 18 and 65 years old (n = 932; 466 per arm) and with a diagnostic of a non-specific sub-acute low back pain are included. Patients in the intervention group are receiving the recommendations of clinical practice guidelines, in addition to a biopsychosocial multidisciplinary intervention consisting of group educational sessions lasting a total of 10 hours. The main outcome is change in the score in the Roland Morris disability questionnaire at three months after onset of pain. Other outcomes are severity of pain, quality of life, duration of current non-specific low back pain episode, work sick leave and duration, Fear Avoidance Beliefs and Goldberg Questionnaires. Outcomes will be assessed at baseline, 3, 6 and 12 months. Analysis will be by intention to treat. The intervention effect will be assessed through the standard error of measurement and the effect-size. Responsiveness of each scale will be evaluated by standardised response mean and receiver-operating characteristic method. Recovery according to the patient will be used as an external criterion. A multilevel regression will be performed on repeated measures. The time until the current episode of low back pain takes to subside will be analysed by Cox regression. Discussion: We hope to provide evidence of the effectiveness of the proposed biopsychosocial multidisciplinary intervention in avoiding the chronification of low back pain, and to reduce the duration of non-specific low back pain episodes. If the intervention is effective, it could be applied to Primary Health Care Centres

The Unified Multiple System Atrophy Rating Scale: Status, Critique, and Recommendations

: The Unified Multiple System Atrophy (MSA) Rating Scale was developed to provide a surrogate marker of disease severity and clinical progression in patients with MSA. It is comprised of four subscales: UMSARS-I (12 items) rates patient-reported functional disability; UMSARS-II (14 items) assesses motor impairment based on a clinical examination; UMSARS-III records blood pressure and heart rate in the supine and standing positions; and UMSARS-IV (1 item) rates chore-based disability. Strengths of the UMSARS include its wide acceptance in the field, the comprehensive coverage of motor symptoms and its clinimetric properties (including reliability and validity). However, with its increasing use, potential areas of improvement in the UMSARS have become apparent. To address these limitations, a task force, involving clinicians, researchers, patient groups, and industry representatives, has recently been endorsed by the International Parkinson’s Disease and Movement Disorders Society. The present viewpoint summarizes strengths and weaknesses of the UMSARS and suggests a roadmap to develop an improved MSA clinical outcome assessment