The microRNA-29 family in cartilage homeostasis and osteoarthritis

MicroRNAs have been shown to function in cartilage development and homeostasis, as well as in progression of osteoarthritis. The objective of the current study was to identify microRNAs involved in the onset or early progression of osteoarthritis and characterise their function in chondrocytes. MicroRNA expression in mouse knee joints post-DMM surgery was measured over 7 days. Expression of miR-29b-3p was increased at day 1 and regulated in the opposite direction to its potential targets. In a mouse model of cartilage injury and in end-stage human OA cartilage, the miR-29 family were also regulated. SOX9 repressed expression of miR-29a-3p and miR-29b-3p via the 29a/b1 promoter. TGFβ1 decreased expression of miR-29a, b and c (3p) in primary chondrocytes, whilst IL-1β increased (but LPS decreased) their expression. The miR-29 family negatively regulated Smad, NFκB and canonical WNT signalling pathways. Expression profiles revealed regulation of new WNT-related genes. Amongst these, FZD3, FZD5, DVL3, FRAT2, CK2A2 were validated as direct targets of the miR-29 family. These data identify the miR-29 family as microRNAs acting across development and progression of OA. They are regulated by factors which are important in OA and impact on relevant signalling pathways

Adaptation and qualitative evaluation of the BETTER intervention for chronic disease prevention and screening by public health nurses in low income neighbourhoods : views of community residents

The adaptation phase is one component of a study funded as a grant proposal entitled 'Advancing Cancer Prevention Among Deprived Neighbourhoods' by the Canadian Cancer Society Research Institute grant #704042 and by the Canadian Institutes of Health Research Institute of Cancer grant OCP #145450. Aisha Lofters is supported by a CIHR New Investigator Award, as a Clinician Scientist by the Department of Family and Community Medicine, University of Toronto, and as Chair in Implementation Science at the Peter Gilgan Centre for Women’s Cancers at Women’s College Hospital in partnership with the Canadian Cancer Society. Dr. Andrew Pinto holds a Canadian Institutes of Health Research Applied Public Health Chair and is supported as a Clinician-Scientist in the Department of Family and Community Medicine, Temerty Faculty of Medicine, University of Toronto, and supported by the Department of Family and Community Medicine, St. Michael’s Hospital, and the Li Ka Shing Knowledge Institute, St. Michael’s Hospital. He is also the Associate Director for Clinical Research at the University of Toronto Practice-Based Research Network. Lawrence Paszat is supported by a Clinician Scientist award funded by the Ontario Ministry of Health and Long Term Care.Background The BETTER intervention is an effective comprehensive evidence-based program for chronic disease prevention and screening (CDPS) delivered by trained prevention practitioners (PPs), a new role in primary care. An adapted program, BETTER HEALTH, delivered by public health nurses as PPs for community residents in low income neighbourhoods, was recently shown to be effective in improving CDPS actions. To obtain a nuanced understanding about the CDPS needs of community residents and how the BETTER HEALTH intervention was perceived by residents, we studied how the intervention was adapted to a public health setting then conducted a post-visit qualitative evaluation by community residents through focus groups and interviews. Methods We first used the ADAPT-ITT model to adapt BETTER for a public health setting in Ontario, Canada. For the post-PP visit qualitative evaluation, we asked community residents who had received a PP visit, about steps they had taken to improve their physical and mental health and the BETTER HEALTH intervention. For both phases, we conducted focus groups and interviews; transcripts were analyzed using the constant comparative method. Results Thirty-eight community residents participated in either adaptation (n = 14, 64% female; average age 54 y) or evaluation (n = 24, 83% female; average age 60 y) phases. In both adaptation and evaluation, residents described significant challenges including poverty, social isolation, and daily stress, making chronic disease prevention a lower priority. Adaptation results indicated that residents valued learning about CDPS and would attend a confidential visit with a public health nurse who was viewed as trustworthy. Despite challenges, many recipients of BETTER HEALTH perceived they had achieved at least one personal CDPS goal post PP visit. Residents described key relational aspects of the visit including feeling valued, listened to and being understood by the PP. The PPs also provided practical suggestions to overcome barriers to meeting prevention goals. Conclusions Residents living in low income neighbourhoods faced daily stress that reduced their capacity to make preventive lifestyle changes. Key adapted features of BETTER HEALTH such as public health nurses as PPs were highly supported by residents. The intervention was perceived valuable for the community by providing access to disease prevention. Trial registration #NCT03052959, 10/02/2017.Peer reviewe

Effect of oral lactulose on clinical and immunohistochemical parameters in patients with inflammatory bowel disease: a pilot study

<p>Abstract</p> <p>Background</p> <p>The prebiotic potential of lactulose is well established and preclinical studies demonstrated a protective effect of lactulose in murine models of colitis. The aim of the present study was to investigate the clinical and histological efficacy of lactulose in patients with inflammatory bowel disease (IBD), for which probiotic therapy yielded promising results.</p> <p>Methods</p> <p>Patients were treated with standard medication alone or combined with 10 g lactulose daily as adjuvant therapy for 4 months. Clinical efficacy of treatment was assessed using clinical activity indices, a quality of life index (IBDQ), endoscopic scores, defecation frequency and monitoring corticosteroid medication. Orsomucoid, alpha1-antitrypsin and other laboratory parameters were determined. In addition, in some participants colonic biopsies were analyzed with haematoxylin-eosin staining or with antibodies against HLA-DR, CD68, IgA and CD3, and evaluated systematically. All measurements were performed both at enrolment and at the end of the trial.</p> <p>Results</p> <p>14 patients presenting ulcerative colitis (UC) and 17 patients presenting Crohn's disease (CD), most of them in a clinically active state, were enrolled in this pilot study. After 4 month no significant improvement of clinical activity index, endoscopic score or immunohistochemical parameters was observed in CD or UC patients receiving lactulose in comparison to the control group. However, significant improvement of quality of life was observed in UC patients receiving lactulose compared to the control group (p = 0.04).</p> <p>Conclusion</p> <p>The findings of the present pilot study indicate that oral lactulose has no beneficial effects in IBD patients in particular with regard to clinical activity, endoscopic score or immunohistochemical parameters. The importance of the beneficial effect of lactulose in UC patients regarding the quality of life needs further evaluation in larger controlled clinical trials.</p> <p>Trial registration</p> <p>Current Controlled Trials ISRCTN92101486</p

HCV Induces Oxidative and ER Stress, and Sensitizes Infected Cells to Apoptosis in SCID/Alb-uPA Mice

Hepatitis C virus (HCV) is a blood-borne pathogen and a major cause of liver disease worldwide. Gene expression profiling was used to characterize the transcriptional response to HCV H77c infection. Evidence is presented for activation of innate antiviral signaling pathways as well as induction of lipid metabolism genes, which may contribute to oxidative stress. We also found that infection of chimeric SCID/Alb-uPA mice by HCV led to signs of hepatocyte damage and apoptosis, which in patients plays a role in activation of stellate cells, recruitment of macrophages, and the subsequent development of fibrosis. Infection of chimeric mice with HCV H77c also led an inflammatory response characterized by infiltration of monocytes and macrophages. There was increased apoptosis in HCV-infected human hepatocytes in H77c-infected mice but not in mice inoculated with a replication incompetent H77c mutant. Moreover, TUNEL reactivity was restricted to HCV-infected hepatocytes, but an increase in FAS expression was not. To gain insight into the factors contributing specific apoptosis of HCV infected cells, immunohistological and confocal microscopy using antibodies for key apoptotic mediators was done. We found that the ER chaperone BiP/GRP78 was increased in HCV-infected cells as was activated BAX, but the activator of ER stress–mediated apoptosis CHOP was not. We found that overall levels of NF-κB and BCL-xL were increased by infection; however, within an infected liver, comparison of infected cells to uninfected cells indicated both NF-κB and BCL-xL were decreased in HCV-infected cells. We conclude that HCV contributes to hepatocyte damage and apoptosis by inducing stress and pro-apoptotic BAX while preventing the induction of anti-apoptotic NF-κB and BCL-xL, thus sensitizing hepatocytes to apoptosis

Health, education, and social care provision after diagnosis of childhood visual disability

Aim: To investigate the health, education, and social care provision for children newly diagnosed with visual disability.Method: This was a national prospective study, the British Childhood Visual Impairment and Blindness Study 2 (BCVIS2), ascertaining new diagnoses of visual impairment or severe visual impairment and blindness (SVIBL), or equivalent vi-sion. Data collection was performed by managing clinicians up to 1-year follow-up, and included health and developmental needs, and health, education, and social care provision.Results: BCVIS2 identified 784 children newly diagnosed with visual impairment/SVIBL (313 with visual impairment, 471 with SVIBL). Most children had associated systemic disorders (559 [71%], 167 [54%] with visual impairment, and 392 [84%] with SVIBL). Care from multidisciplinary teams was provided for 549 children (70%). Two-thirds (515) had not received an Education, Health, and Care Plan (EHCP). Fewer children with visual impairment had seen a specialist teacher (SVIBL 35%, visual impairment 28%, χ2p < 0.001), or had an EHCP (11% vs 7%, χ2p < 0 . 01).Interpretation: Families need additional support from managing clinicians to access recommended complex interventions such as the use of multidisciplinary teams and educational support. This need is pressing, as the population of children with visual impairment/SVIBL is expected to grow in size and complexity.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited

Non-Standard Errors

In statistics, samples are drawn from a population in a data-generating process (DGP). Standard errors measure the uncertainty in estimates of population parameters. In science, evidence is generated to test hypotheses in an evidence-generating process (EGP). We claim that EGP variation across researchers adds uncertainty: Non-standard errors (NSEs). We study NSEs by letting 164 teams test the same hypotheses on the same data. NSEs turn out to be sizable, but smaller for better reproducible or higher rated research. Adding peer-review stages reduces NSEs. We further find that this type of uncertainty is underestimated by participants