Activation of the selenopritein SEPS1 gene expression by pro-inflammatory cytokines in Hep G2 cells

SEPS1 (also called selenoprotein S, SelS) plays an important role in the production of inflammatory cytokines and its expression is activated by endoplasmic reticulum (ER) stress. In this report, we have identified two binding sites for the nuclear factor kappa B in the human SEPS1 promoter. SEPS1 gene expression, protein levels and promoter activity were all increased 2–3-fold by TNF-α and IL-1β in HepG2 cells. We have also confirmed that the previously proposed ER stress response element GGATTTCTCCCCCGCCACG in the SEPS1 proximate promoter is fully functional and responsive to ER stress. However, concurrent treatment of HepG2 cells with IL-1β and ER stress produced no additive effect on SEPS1 gene expression. We conclude that SEPS1 is a new target gene of NF-κB. Together with our previous findings that SEPS1 may regulate cytokine production in macrophage cells, we propose a regulatory loop between cytokines and SEPS1 that plays a key role in control of the inflammatory response.

Enhancing the health of medical students : outcomes of an integrated mindfulness and lifestyle program

Medical students experience various stresses and many poor health behaviours. Previous studies consistently show that student wellbeing is at its lowest pre-exam. Little core-curriculum is traditionally dedicated to providing self-care skills for medical students. This paper describes the development, implementation and outcomes of the Health Enhancement Program (HEP) at Monash University. It comprises mindfulness and ESSENCE lifestyle programs, is experientially-based, and integrates with biomedical sciences, clinical skills and assessment. This study measured the program’s impact on medical student psychological distress and quality of life. A cohort study performed on the 2006 first-year intake measured effects of the HEP on various markers of wellbeing. Instruments used were the depression, anxiety and hostility subscales of the Symptom Checklist-90-R incorporating the Global Severity Index (GSI) and the WHO Quality of Life (WHOQOL) questionnaire. Pre-course data (T1) was gathered mid-semester and post-course data (T2) corresponded with pre-exam week. To examine differences between T1 and T2 repeated measures ANOVA was used for the GSI and two separate repeated measures MANOVAs were used to examine changes in the subscales of the SCL-90-R and the WHOQOL-BREF. Follow-up t-tests were conducted to examine differences between individual subscales. A total of 148 of an eligible 270 students returned data at T1 and T2 giving a response rate of 55%. 90.5% of students reported personally applying the mindfulness practices. Improved student wellbeing was noted on all measures and reached statistical significance for the depression (mean T1 = 0.91, T2 = 0.78; p = 0.01) and hostility (0.62, 0.49; 0.03) subscales and the GSI (0.73, 0.64; 0.02) of the SCL-90, but not the anxiety subscale (0.62, 0.54; 0.11). Statistically significant results were also found for the psychological domain (62.42, 65.62; p < 0.001) but not the physical domain (69.11, 70.90; p = 0.07) of the WHOQOL. This study is the first to demonstrate an overall improvement in medical student wellbeing during the pre-exam period suggesting that the common decline in wellbeing is avoidable. Although the findings of this study indicate the potential for improving student wellbeing at the same time as meeting important learning objectives, the limitations in study design due to the current duration of follow-up and lack of a control group means that the data should be interpreted with caution. Future research should be directed at determining the contribution of individual program components, long-term outcomes, and impacts on future attitudes and clinical practice.

Computer-assisted image analysis of liver collagen: relationship to Ishak scoring and hepatic venous pressure gradient

Histopathological scoring of disease stage uses descriptive categories without measuring the amount of fibrosis. Collagen, the major component of fibrous tissue, can be quantified by computer-assisted digital image analysis (DIA) using histological sections. We determined relationships between DIA, Ishak stage, and hepatic venous pressure gradient (HVPG) reflecting severity of fibrosis. One hundred fifteen patients with hepatitis C virus (HCV) who had undergone transplantation had 250 consecutive transjugular liver biopsies combined with HVPG (median length, 22 mm; median total portal tracts, 12), evaluated using the Ishak system and stained with Sirus red for DIA. Liver collagen was expressed as collagen proportionate area (CPA). Median CPA was 6% (0.2-45), correlating with Ishak stage (stage 6 range, 13%-45%), and with HVPG (r = 0.62; P < 0.001). Median CPA was 4.1% when HVPG was less than 6 mm Hg and 13.8% when HVPG was 6 mm Hg or more (P < 0.0001) and 6% when HVPG was less than 10 mm Hg and 17.3% when HVPG was 10 mm Hg or higher (P < 0.0001). Only CPA, not Ishak stage/grade, was independently associated by logistic regression, with HVPG of 6 mm Hg or more [odds ratio, 1.206; 95% confidence interval (CI), 1.094-1.331; P < 0.001], or HVPG of 10 mm Hg or more (odds ratio, 1.105; 95% CI, 1.026-1.191; P = 0.009). CPA increased by 50% (3.6%) compared with 20% in HVPG (1 mm Hg) in 38 patients with repeated biopsies. Conclusion: CPA assessed by DIA correlated with Ishak stage scores and HVPG measured contemporaneously. CPA was a better histological correlate with HVPG than Ishak stage, had a greater numerical change when HVPG was low, and resulted in further quantitation of fibrosis in cirrhosis.

Fuzzy ARTMAP and hybrid evolutionary programming for pattern classification

In this paper, an Evolutionary Artificial Neural Network (EANN) that combines the Fuzzy ARTMAP (FAM) network and a Hybrid Evolutionary Programming (HEP) model is introduced. The proposed FAM-HEP model, which combines the strengths of FAM and HEP, is able to construct its network structure autonomously as well as to perform learning and evolutionary search and adaptation concurrently. The effectiveness of the proposed FAM-HEP network is assessed empirically using several benchmark data sets and a real medical diagnosis problem. The performance of FAM-HEP is analyzed, and the results are compared with those of FAM-EP, FAM, and other classification models. In general, the results of FAM-HEP are better than those of FAM-EP and FAM, and are comparable with those from other classification models. The study also reveals the potential of FAM-HEP as an innovative EANN model for undertaking pattern classification problems in general, and a promising computerized decision support tool for tackling medical diagnosis tasks in particular.

Caveolin-1 orchestrates the balance between glucose and lipid-dependent energy metabolism : implications for liver regeneration

Caveolin-1 (CAV1) is a structural protein of caveolae involved in lipid homeostasis and endocytosis. Using newly generated pure Balb/C CAV1 null (Balb/CCAV1−/−) mice, CAV1−/− mice from Jackson Laboratories (JAXCAV1−/−), and CAV1−/− mice developed in the Kurzchalia Laboratory (KCAV1−/−), we show that under physiological conditions CAV1 expression in mouse tissues is necessary to guarantee an efficient progression of liver regeneration and mouse survival after partial hepatectomy. Absence of CAV1 in mouse tissues is compensated by the development of a carbohydrate-dependent anabolic adaptation. These results were supported by extracellular flux analysis of cellular glycolytic metabolism in CAV1-knockdown AML12 hepatocytes, suggesting cell autonomous effects of CAV1 loss in hepatic glycolysis. Unlike in KCAV1−/− livers, in JAXCAV1−/− livers CAV1 deficiency is compensated by activation of anabolic metabolism (pentose phosphate pathway and lipogenesis) allowing liver regeneration. Administration of 2-deoxy-glucose in JAXCAV1−/− mice indicated that liver regeneration in JAXCAV1−/− mice is strictly dependent on hepatic carbohydrate metabolism. Moreover, with the exception of regenerating JAXCAV1−/− livers, expression of CAV1 in mice is required for efficient hepatic lipid storage during fasting, liver regeneration, and diet-induced steatosis in the three CAV1−/− mouse strains. Furthermore, under these conditions CAV1 accumulates in the lipid droplet fraction in wildtype mouse hepatocytes. Conclusion: Our data demonstrate that lack of CAV1 alters hepatocyte energy metabolism homeostasis under physiological and pathological conditions.