Obese diet-induced mouse models of nonalcoholic steatohepatitis-tracking disease by liver biopsy

AIM: To characterize development of diet-induced nonalcoholic steatohepatitis (NASH) by performing liver biopsy in wild-type and genetically obese mice. METHODS: Male wild-type C57BL/6J (C57) mice (DIO-NASH) and male Lep(ob)/Lep(ob) (ob/ob) mice (ob/ob-NASH) were maintained on a diet high in trans-fat (40%), fructose (22%) and cholesterol (2%) for 26 and 12 wk, respectively. A normal chow diet served as control in C57 mice (lean chow) and ob/ob mice (ob/ob chow). After the diet-induction period, mice were liver biopsied and a blinded histological assessment of steatosis and fibrosis was conducted. Mice were then stratified into groups counterbalanced for steatosis score and fibrosis stage and continued on diet and to receive daily PO dosing of vehicle for 8 wk. Global gene expression in liver tissue was assessed by RNA sequencing and bioinformatics. Metabolic parameters, plasma liver enzymes and lipids (total cholesterol, triglycerides) as well as hepatic lipids and collagen content were measured by biochemical analysis. Non-alcoholic fatty liver disease activity score (NAS) (steatosis/inflammation/ballooning degeneration) and fibrosis were scored. Steatosis and fibrosis were also quantified using percent fractional area. RESULTS: Diet-induction for 26 and 12 wk in DIO-NASH and ob/ob-NASH mice, respectively, elicited progressive metabolic perturbations characterized by increased adiposity, total cholesterol and elevated plasma liver enzymes. The diet also induced clear histological features of NASH including hepatosteatosis and fibrosis. Overall, the metabolic NASH phenotype was more pronounced in ob/ob-NASH vs DIO-NASH mice. During the eight week repeated vehicle dosing period, the metabolic phenotype was sustained in DIO-NASH and ob/ob-NASH mice in conjunction with hepatomegaly and increased hepatic lipids and collagen accumulation. Histopathological scoring demonstrated significantly increased NAS of DIO-NASH mice (0 vs 4.7 ± 0.4, P < 0.001 compared to lean chow) and ob/ob-NASH mice (2.4 ± 0.3 vs 6.3 ± 0.2, P < 0.001 compared to ob/ob chow), respectively. Furthermore, fibrosis stage was significantly elevated for DIO-NASH mice (0 vs 1.2 ± 0.2, P < 0.05 compared to lean chow) and ob/ob NASH (0.1 ± 0.1 vs 3.0 ± 0.2, P < 0.001 compared to ob/ob chow). Notably, fibrosis stage was significantly (P < 0.001) increased in ob/ob-NASH mice, when compared to DIO-NASH mice. CONCLUSION: These data introduce the obese diet-induced DIO-NASH and ob/ob-NASH mouse models with biopsy-confirmed individual disease staging as a preclinical platform for evaluation of novel NASH therapeutics

Managing employees’ depression from the employees’, co-workers’ and employers’ perspectives. An integrative review

Purpose: To synthesize evidence on factors promoting or hindering work participation (WP) of employees with depression from the employees’, co-workers’ and employers’ perspectives, as well as an additional focus on the influence of the employee’s occupation. Methods: An integrative review was conducted. Pre-defined eligibility criteria guided study selection. Articles were critically appraised using tools developed by Joanna Briggs and Mixed Methods Appraisal Tool. Findings were analysed and synthesised using qualitative inductive content analysis. Results: Seventeen studies were included: 12 quantitative studies, three qualitative studies and two mixed methods studies. From these, 144 findings were extracted and combined into six categories from which two syntheses were developed. One synthesis demonstrated that employees, co-workers and employers hold different perspectives on rehabilitation stakeholders’ responsibilities hindering WP. The other synthesis revealed that WP is influenced by interactions between individual and occupational factors. Conclusions: Sufficient treatment from health professionals promotes WP. Employees’ fear of stigmatization hinders WP. Co-workers and employers find that open communication is important, however, employers are concerned about entering employees’ private sphere. When managing employees with depression, employers intervene at the individual level. There is a need for structural interventions to promote WP among employees with depression.Implications for RehabilitationThe responsibilities of rehabilitation stakeholders should be clarified to promote collaboration.Structural workplace interventions should be initiated to supplement individual level interventions.Workplace interventions may focus on more open communication and awareness towards mental illness.Interactions between the occupational factors and individual factors should be carefully considered. The responsibilities of rehabilitation stakeholders should be clarified to promote collaboration. Structural workplace interventions should be initiated to supplement individual level interventions. Workplace interventions may focus on more open communication and awareness towards mental illness. Interactions between the occupational factors and individual factors should be carefully considered