Detecting the hidden burden of pre-diabetes and diabetes in Western Sydney.

AIMS: Examining pre-diabetes and diabetes rates using glycated haemoglobin (HbA1c) in emergency department (ED) and in general practice (GP) in western Sydney. METHODS: Epidemiological study of HbA1c measurements in individuals ≥18 years receiving a blood test (1) in the hospital setting of the ED at Blacktown/Mt Druitt hospital (1/06/2016 to 31/05/2018) and (2) in primary care involving Bridgeview Medical Practice (BVMP) (1/03/2017 to 01/02/2018) as well as other general practices (June 2018 only). RESULTS: Totals of 55,568 individuals from ED and 5911 individuals from GP. The prevalence of diabetes in tested individuals was 17.3% (n = 9704) in ED and 17.4% (n = 1027) in GP. The prevalence of pre-diabetes in ED was 30.2% (n = 16,854) and 26.6% (n = 1576) in GP. Regression controlling for age, season, and gender revealed a weekly increase of 1.1% in odds for diabetes and 1.5% for pre-diabetes (p < 0.001), in line with the yearly absolute increase of 1% in rate for both tested and coded hospital patients. In BVMP the rate of diabetes rose by 22% during the testing period from 8.9% to 11%. CONCLUSIONS: There exists a high burden of diabetes both in hospitals and general practice. Testing in ED and general practice revealed similarly high burdens of diabetes across different areas of the healthcare system. In the appropriate hospital and primary care setting, HbA1c can be used to identify individuals with diabetes that may benefit from targeted intervention.

Apoptosis in experimental NASH is associated with p53 activation and TRAIL receptor expression.

BACKGROUND AND AIMS: We examined extrinsic and intrinsic (endogenous) mitochondrial apoptosis pathways in experimental non-alcoholic steatohepatitis (NASH). METHODS: To assess extrinsic pathways, we measured hepatic expression of death-inducing cytokine receptors (tumor necrosis factor-alpha-receptor (TNF-R)1, TNF-R2, Fas, and TNFalpha-related apoptosis-inducing ligand-receptor (TRAIL-R) mRNA, TUNEL, caspase 3 activation, liver injury and liver pathology in mice fed a methionine and choline deficient (MCD) diet. For endogenous stress pathways, we determined serum insulin-like growth factor-1 (IGF-1), hepatic p53, Bcl-XL, tBid and p21 expression. RESULTS: Methionine and choline deficient feeding increased alanine aminotransferase (ALT) and apoptosis from day 10, without increases in TNF-R1, TNF-R2, and Fas. However, murine TRAIL receptors, particularly decoyTRAIL-R1/TNFRSFH23 and Killer/DR5 mRNA increased. MCD feeding enhanced hepatic p53 expression, corresponding to approximately 50% fall in serum IGF-1, decreased Bcl-XL, enhanced Bid cleavage to tBid, and up-regulation of p21. Nutritional restitution experiments showed that correcting either methionine or choline deficiency suppressed liver inflammation (extrinsic pathway), but failed to correct apoptosis, IGF-1 or p53. CONCLUSIONS: Methionine and choline deficiency lower IGF-1 to de-repress p53 during induction of steatohepatitis. The p53 induced by nutritional stress is biologically active in mediating mitochondrial cell death pathways, but may also be responsible for TRAIL receptor expression, thereby linking intrinsic and exogenous apoptosis pathways in NASH.

Constitutive activation of NF-kappaB in human hepatocellular carcinoma: evidence of a cytoprotective role.

Activation of nuclear factor-kappaB (NF-kappaB) can promote or inhibit apoptosis. Oxidative stress is an important mechanism by which certain anticancer drugs kill cancer cells, and is also one of the mechanisms that activate NF-kappaB. We therefore examined hepatic expression of the NF-kappaB monomer p65 in human hepatocellular carcinoma (HCC) tissue samples from eight patients and compared it with their respective samples of surrounding liver tissues. We also studied the effect of NF-kappaB inhibition in human HCC cells exposed to oxidative stress, by infecting HuH7 cells with a recombinant adenovirus carrying mutant IkappaBalpha (mIkappaBalpha). Cultured HuH7 cells were infected with mIkappaBalpha or beta-galactosidase (beta-Gal) for 24 hr followed by treatment with increasing concentrations of H2O2. Cytotoxicity, NF-kappaB translocation, NF-kappaB DNA binding, cell proliferation, and apoptosis were determined. The monomer p65 was overexpressed in six of eight human HCC tissues. In HuH7 cells, introduction of mIkappaBalpha potently inhibited the translocation, activation, and DNA binding of NF- kappaB. In control (beta-Gal-infected) HuH7 cells, exposure to H2O2 produced a dose-dependent increase in apoptosis, regardless of NF-kappaB status. mIkappaBalpha-mediated inhibition of NF-kappaB activation sensitized HuH7 cells to H2O2-induced inhibition of cell growth, and further promoted cell death. Addition of H2O2 (200-500 microM) to control or mIkappaBalpha-infected HuH7 cells enhanced caspase-3 activity and cleavage. Adenovirus-mediated transfer of mIkappaBalpha potently inhibits NF-kappaB activity in HuH7 cells, and this enhances oxidative stress-induced cell killing.