Adjuvant therapy with antidepressants for the management of inflammatory bowel disease

BACKGROUND: Symptoms of anxiety and depression are common in inflammatory bowel disease (IBD). Antidepressants are taken by approximately 30% of people with IBD. However, there are no current guidelines on treating co-morbid anxiety and depression in people with IBD with antidepressants, nor are there clear data on the role of antidepressants in managing physical symptoms of IBD. OBJECTIVES: The objectives were to assess the efficacy and safety of antidepressants for treating anxiety and depression in IBD, and to assess the effects of antidepressants on quality of life (QoL) and managing disease activity in IBD. SEARCH METHODS: We searched MEDLINE; Embase, CINAHL, PsycINFO, CENTRAL, and the Cochrane IBD Group Specialized Register from inception to 23 August 2018. Reference lists, trials registers, conference proceedings and grey literature were also searched. SELECTION CRITERIA: Randomised controlled trials (RCTs) and observational studies comparing any type of antidepressant to placebo, no treatment or an active therapy for IBD were included. DATA COLLECTION AND ANALYSIS: Two authors independently screened search results, extracted data and assessed bias using the Cochrane risk of bias tool. We used the Newcastle-Ottawa Scale to assess quality of observational studies. GRADE was used to evaluate the certainty of the evidence supporting the outcomes. Primary outcomes included anxiety and depression. Anxiety was assessed using the Hospital Anxiety and Depression Scale (HADS) or the Hamilton Anxiety Rating Scale (HARS). Depression was assessed using HADS or the Beck Depression Inventory. Secondary outcomes included adverse events (AEs), serious AEs, withdrawal due to AEs, quality of life (QoL), clinical remission, relapse, pain, hospital admissions, surgery, and need for steroid treatment. QoL was assessed using the WHO-QOL-BREF questionnaire. We calculated the risk ratio (RR) and corresponding 95% confidence intervals (CI) for dichotomous outcomes. For continuous outcomes, we calculated the mean difference (MD) with 95% CI. A fixed-effect model was used for analysis. MAIN RESULTS: We included four studies (188 participants). Two studies were double-blind RCTs, one was a non-randomised controlled trial, and one was an observational retrospective case-matched study. The age of participants ranged from 27 to 37.8 years. In three studies participants had quiescent IBD and in one study participants had active or quiescent IBD. Participants in one study had co-morbid anxiety or depression. One study used duloxetine (60 mg daily), one study used fluoxetine (20 mg daily), one study used tianeptine (36 mg daily), and one study used various antidepressants in clinical ranges. Three studies had placebo controls and one study had a no treatment control group. One RCT was rated as low risk of bias and the other was rated as high risk of bias (incomplete outcome data). The non-randomised controlled trial was rated as high risk of bias (random sequence generation, allocation concealment, blinding). The observational study was rated as high methodological quality, but is still considered to be at high risk of bias given its observational design.The effect of antidepressants on anxiety and depression is uncertain. At 12 weeks, the mean anxiety score in antidepressant participants was 6.11 + 3 compared to 8.5 + 3.45 in placebo participants (MD -2.39, 95% -4.30 to -0.48, 44 participants, low certainty evidence). At 12 months, the mean anxiety score in antidepressant participants was 3.8 + 2.5 compared to 4.2 + 4.9 in placebo participants (MD -0.40, 95% -3.47 to 2.67, 26 participants; low certainty evidence). At 12 weeks, the mean depression score in antidepressant participants was 7.47 + 2.42 compared to 10.5 + 3.57 in placebo participants (MD -3.03, 95% CI -4.83 to -1.23, 44 participants; low certainty evidence). At 12 months, the mean depression score in antidepressant participants was 2.9 + 2.8 compared to 3.1 + 3.4 in placebo participants (MD -0.20, 95% -2.62 to 2.22, 26 participants; low certainty evidence).The effect of antidepressants on AEs is uncertain. Fifty-seven per cent (8/14) of antidepressant participants group reported AEs versus 25% (3/12) of placebo participants (RR 2.29, 95% CI 0.78 to 6.73, low certainty evidence). Commonly reported AEs include nausea, headache, dizziness, drowsiness, sexual problems, insomnia, fatigue, low mood/anxiety, dry mouth, muscle spasms and hot flushes. None of the included studies reported any serious AEs. None of the included studies reported on pain.One study (44 participants) reported on QoL at 12 weeks and another study (26 participants) reported on QoL at 12 months. Physical, Psychological, Social and Environmental QoL were improved at 12 weeks compared to placebo (all low certainty evidence). There were no group differences in QoL at 12 months (all low certainty evidence). The effect of antidepressants on maintenance of clinical remission and endoscopic relapse is uncertain. At 12 months, 64% (9/14) of participants in the antidepressant group maintained clinical remission compared to 67% (8/12) of placebo participants (RR 0.96, 95% CI 0.55 to 1.69; low certainty evidence). At 12 months, none (0/30) of participants in the antidepressant group had endoscopic relapse compared to 10% (3/30) of placebo participants (RR 0.14, 95% CI 0.01 to 2.65; very low certainty evidence). AUTHORS' CONCLUSIONS: The results for the outcomes assessed in this review are uncertain and no firm conclusions regarding the efficacy and safety of antidepressants in IBD can be drawn. Future studies should employ RCT designs, with a longer follow-up and develop solutions to address attrition. Inclusion of objective markers of disease activity is strongly recommended as is testing antidepressants from different classes, as at present it is unclear if any antidepressant (or class thereof) has differential efficacy

Suppression of protein aggregation by chaperone modification of high molecular weight complexes

Protein misfolding and aggregation are associated with many neurodegenerative diseases, including Huntington's disease. The cellular machinery for maintaining proteostasis includes molecular chaperones that facilitate protein folding and reduce proteotoxicity. Increasing the protein folding capacity of cells through manipulation of DNAJ chaperones has been shown to suppress aggregation and ameliorate polyglutamine toxicity in cells and flies. However, to date these promising findings have not been translated to mammalian models of disease. To address this issue, we developed transgenic mice that over-express the neuronal chaperone HSJ1a (DNAJB2a) and crossed them with the R6/2 mouse model of Huntington's disease. Over-expression of HSJ1a significantly reduced mutant huntingtin aggregation and enhanced solubility. Surprisingly, this was mediated through specific association with K63 ubiquitylated, detergent insoluble, higher order mutant huntingtin assemblies that decreased their ability to nucleate further aggregation. This was dependent on HSJ1a client binding ability, ubiquitin interaction and functional co-operation with HSP70. Importantly, these changes in mutant huntingtin solubility and aggregation led to improved neurological performance in R6/2 mice. These data reveal that prevention of further aggregation of detergent insoluble mutant huntingtin is an additional level of quality control for late stage chaperone-mediated neuroprotection. Furthermore, our findings represent an important proof of principle that DNAJ manipulation is a valid therapeutic approach for intervention in Huntington's disease

Social change and the family: Comparative perspectives from the west, China, and South Asia

This paper examines the influence of social and economic change on family structure and relationships: How do such economic and social transformations as industrialization, urbanization, demographic change, the expansion of education, and the long-term growth of income influence the family? We take a comparative and historical approach, reviewing the experiences of three major sociocultural regions: the West, China, and South Asia. Many of the changes that have occurred in family life have been remarkably similar in the three settings—the separation of the workplace from the home, increased training of children in nonfamilial institutions, the development of living arrangements outside the family household, increased access of children to financial and other productive resources, and increased participation by children in the selection of a mate. While the similarities of family change in diverse cultural settings are striking, specific aspects of change have varied across settings because of significant pre-existing differences in family structure, residential patterns of marriage, autonomy of children, and the role of marriage within kinship systems.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/45661/1/11206_2005_Article_BF01124383.pd

The Shorter Oxford English Dictionary On Historical Principles

27 cm; 2515 ha

A renewed focus on primary health care: revitalize or reframe?

The year 2008 celebrated 30 years of Primary Health Care (PHC) policy emerging from the Alma Ata Declaration with publication of two key reports, the World Health Report 2008 and the Report of the Commission on the Social Determinants of Health. Both reports reaffirmed the relevance of PHC in terms of its vision and values in today's world. However, important challenges in terms of defining PHC, equity and empowerment need to be addressed. This article takes the form of a commentary reviewing developments in the last 30 years and discusses the future of this policy. Three challenges are put forward for discussion (i) the challenge of moving away from a narrow technical bio-medical paradigm of health to a broader social determinants approach and the need to differentiate primary care from primary health care; (ii) The challenge of tackling the equity implications of the market oriented reforms and ensuring that the role of the State in the provision of welfare services is not further weakened; and (iii) the challenge of finding ways to develop local community commitments especially in terms of empowerment. These challenges need to be addressed if PHC is to remain relevant in today's context. The paper concludes that it is not sufficient to revitalize PHC of the Alma Ata Declaration but it must be reframed in light of the above discussion