From chronic overfeeding to hepatic injury: role of endoplasmic reticulum stress and inflammation.

We analyse how chronic overfeeding, by increasing circulating fatty acids, might lead to inflammation, insulin resistance (IR) and injury in the liver. Chronic overfeeding causes an increase in adipose tissue depots and is characterised by an increased presence of hypertrophic adipocytes when adipose tissue expandability is inadequate. Adipocyte hypertrophy is a possible stress condition for the endoplasmic reticulum (ER), which will activate inflammatory and apoptotic pathways and cause IR in adipose tissue. Insulin-resistant adipocytes, being more lipolytic and less liposynthetic, induce an increase in circulating free fatty acids. Moreover, the strongly compromised secretion/function of the adipocyte hormones, adiponectin and leptin, decreases lipid oxidation, particularly in the liver, causing lipid accumulation, ER stress and IR in hepatocytes. ER stress may lead to reduced very-low-density lipoprotein (VLDL) secretion and increased lipogenic gene expression despite the presence of IR. These events and reduced lipid oxidation may lead to further hepatic lipid accumulation. When the triglyceride storage capacity of hepatocytes is exceeded, hepatic injury may occur. ER-stressed steatotic hepatocytes activate apoptotic and inflammatory pathways, which trigger IR and the release of chemokines and cytokines, and these, in turn, elicit an increased influx of Kupffer cells (KCs) and hepatic stellate cells (HSCs) around dying hepatocytes. Soluble mediators, secreted mainly by ER-stressed steatotic hepatocytes and activated KCs, induce the transdifferentiation of HSCs to myofibroblasts, which secrete fibrogenic cytokines and matrix components that trigger fibrosis. In conclusion, chronic lipid overloading due to inadequate fat-storing capacity of adipose tissue can induce hepatic injury when triglyceride storage capacity of hepatocytes is exceeded.

Assessing apathy in multiple sclerosis: Validation of the dimensional apathy scale and comparison with apathy evaluation scale.

BACKGROUND: Apathy is a predictor of cognitive decline in the course of multiple sclerosis (MS). Early identification of apathetic patients is relevant in clinical settings. OBJECTIVE: To assess applicability and psychometric properties of the self-rated version of the Dimensional Apathy Scale (DAS) in a large cohort of patients with MS and to compare its diagnosing accuracy with that of the Apathy Evaluation Scale (AES). METHODS: One hundred and twenty-four patients underwent clinical interview based on diagnostic criteria for apathy, DAS, AES, and assessment of depression, global cognitive functioning, and non-verbal intelligence. RESULTS: According to diagnostic criteria, apathy occurred in 33.4% of the patients. The DAS showed high consistency, and good convergent, discriminant and criterion validity. Factor analysis indicated a three-factor structure: executive, behavioural and emotional apathy. Unlike AES, no significant association between DAS score and severity of neurological disability (expressed by EDSS total score) was found, suggesting that the DAS might be less related to levels of disability. Receiver operating characteristics analyses, with clinical diagnostic criteria for apathy as the gold standard, revealed that a DAS score of 28/29 and an AES score of 35/36 were optimal cut-off values for identifying clinically relevant apathy. The two scales had similar diagnostic accuracy in the present sample. CONCLUSIONS: The DAS is a valid and reliable multidimensional tool to assess apathy in MS, with diagnostic accuracy similar to that of the AES. However, the DAS score appears to be less strongly related to neurological disability.