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Cusi K.,University of Florida | Cusi K.,Malcom Randall Veterans Administration Medical Center
Diabetologia | Year: 2016

Non-alcoholic fatty liver disease (NAFLD) is reaching epidemic proportions in patients with type 2 diabetes. Patients with NAFLD are at increased risk of more aggressive liver disease (non-alcoholic steatohepatitis [NASH]) and at a higher risk of death from cirrhosis, hepatocellular carcinoma and cardiovascular disease. Dysfunctional adipose tissue and insulin resistance play an important role in the pathogenesis of NASH, creating the conditions for hepatocyte lipotoxicity. Mitochondrial defects are at the core of the paradigm linking chronic excess substrate supply, insulin resistance and NASH. Recent work indicates that patients with NASH have more severe insulin resistance and lipotoxicity compared with matched obese controls with only isolated steatosis. This review focuses on available agents and future drugs under development for the treatment of NAFLD/NASH in type 2 diabetes. Reversal of lipotoxicity with pioglitazone is associated with significant histological improvement, which occurs within 6 months and persists with continued treatment (or for at least 3 years) in patients with prediabetes or type 2 diabetes, holding potential to modify the natural history of the disease. These results also suggest that pioglitazone may become the standard of care for this population. Benefit has also been reported in non-diabetic patients. Recent promising results with glucagon-like peptide 1 receptor agonists have opened another new treatment avenue for NASH. Many agents in Phase 2-3 of development are being tested, aiming to restore glucose/lipid metabolism, ameliorate adipose tissue and liver inflammation, or to inhibit liver fibrosis. By targeting a diversity of relevant pathways, combination therapy in NASH will likely provide greater success in the future. In summary, increased clinical awareness and improved screening strategies (as currently done for diabetic retinopathy and nephropathy) are needed, to translate recent treatment progress into early treatment and improved quality of life for patients with type 2 diabetes and NASH. This review summarises a presentation given at the symposium ‘The liver in focus’ at the 2015 annual meeting of the EASD. It is accompanied by two other reviews on topics from this symposium (by John Jones, DOI: 10.1007/s00125-016-3940-5, and by Hannele Yki-Järvinen, DOI: 10.1007/s00125-016-3944-1) and a commentary by the Session Chair, Michael Roden (DOI: 10.1007/s00125-016-3911-x). © 2016, The Author(s).


Bearden S.T.,Malcom Randall Veterans Administration Medical Center | Nay L.B.,Malcom Randall Veterans Administration Medical Center
Neurodiagnostic Journal | Year: 2011

EEG is a safe, inexpensive, mobile test that can be integrated with the neurologic clinical examination and other testing to help physicians move more quickly and accurately to the right branch of the differential diagnostic tree even when the EEG result is not specifically diagnostic itself. As technology evolves to allow faster, easier electrode application and remote transmission of EEG data to electroencephalographers; the use of EEG in the emergency room and intensive care units to assist with differential diagnosis is likely to sharply increase. We examine some differential diagnostic scenarios and actual cases where EEG proved useful. Neurologists are trained to think in differential diagnostic terms. As they review EEG tracings, they often ask neurodiagnostic technologists questions pertaining to the patient history or other testing results that help them assimilate the relevant differential diagnostic data. Neurodiagnostic technologists have a unique opportunity to collect useful differential diagnostic information because they spend about 20 minutes talking with the patient as they apply electrodes and they see the EEG results while the patient, family members, or the patient's nurse is still available for questioning. Those technologists who are able to see the bigger picture and think in differential diagnostic terms as they do EEG testing are more likely to include in their patient's history important clinical details that will help the neurologist reach the correct diagnosis of the patient. © ASET, Missouri.


Sunny N.E.,University of Florida | Kalavalapalli S.,University of Florida | Bril F.,University of Florida | Garrett T.J.,University of Florida | And 6 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2015

Elevated plasma branched-chain amino acids (BCAA) in the setting of insulin resistance have been relevant in predicting type 2 diabetes mellitus (T2DM) onset, but their role in the etiology of hepatic insulin resistance remains uncertain. We determined the link between BCAA and dysfunctional hepatic tricarboxylic acid (TCA) cycle, which is a central feature of hepatic insulin resistance and nonalcoholic fatty liver disease (NAFLD). Plasma metabolites under basal fasting and euglycemic hyperinsulinemic clamps (insulin stimulation) were measured in 94 human subjects with varying degrees of insulin sensitivity to identify their relationships with insulin resistance. Furthermore, the impact of elevated BCAA on hepatic TCA cycle was determined in a diet-induced mouse model of NAFLD, utilizing targeted metabolomics and nuclear magnetic resonance (NMR)-based metabolic flux analysis. Insulin stimulation revealed robust relationships between human plasma BCAA and indices of insulin resistance, indicating chronic metabolic overload from BCAA. Human plasma BCAA and long-chain acylcarnitines also showed a positive correlation, suggesting modulation of mitochondrial metabolism by BCAA. Concurrently, mice with NAFLD failed to optimally induce hepatic mTORC1, plasma ketones, and hepatic long-chain acylcarnitines, following acute elevation of plasma BCAA. Furthermore, elevated BCAA failed to induce multiple fluxes through hepatic TCA cycle in mice with NAFLD. Our data suggest that BCAA are essential to mediate efficient channeling of carbon substrates for oxidation through mitochondrial TCA cycle. Impairment of BCAA-mediated upregulation of the TCA cycle could be a significant contributor to mitochondrial dysfunction in NAFLD. © 2015 the American Physiological Society.


Elgendy I.Y.,University of Florida | Kumbhani D.J.,University of Texas Southwestern Medical Center | Mahmoud A.,University of Florida | Bhatt D.L.,Harvard University | And 2 more authors.
Journal of the American College of Cardiology | Year: 2015

Background Acute ischemic stroke is a leading cause of serious disability and death worldwide. Individual randomized trials have shown possible benefits of mechanical thrombectomy after usual care compared with usual care alone (i.e., intravenous thrombolysis) in the management of acute ischemic stroke patients. Objectives This study systematically determined if mechanical thrombectomy after usual care would be associated with better outcomes in patients with acute ischemic stroke caused by large artery occlusion. Methods The authors included randomized trials that compared mechanical thrombectomy after usual care versus usual care alone for acute ischemic stroke. Random effects summary risk ratios (RR) were constructed using a DerSimonian and Laird model. Results Nine trials with 2,410 patients were available for analysis. Compared with usual care alone, mechanical thrombectomy was associated with a higher incidence of achieving good functional outcome, defined as a modified Rankin scale (MRS) of 0 to 2 (RR: 1.45; 95% confidence interval [CI]: 1.22 to 1.72; p < 0.0001) and excellent functional outcome defined as MRS 0 to 1 (RR: 1.67; 95% CI: 1.27 to 2.19; p < 0.0001) at 90 days. There was a trend toward reduced all-cause mortality with mechanical thrombectomy (RR: 0.86; 95% CI: 0.72 to 1.02; p = 0.09). The risk of symptomatic intracranial hemorrhage was similar with either treatment modality (RR 1.06: 95% CI: 0.73 to 1.55; p = 0.76). Conclusions In acute ischemic stroke due to large artery occlusion, mechanical thrombectomy after usual care was associated with improved functional outcomes compared with usual care alone, and was found to be relatively safe, with no excess in intracranial hemorrhage. There was a trend for reduction in all-cause mortality with mechanical thrombectomy. © 2015 American College of Cardiology Foundation.


Kaufman D.A.S.,Saint Louis University | Sozda C.N.,University of Florida | Sozda C.N.,Malcom Randall Veterans Administration Medical Center | Dotson V.M.,University of Florida | And 3 more authors.
Frontiers in Aging Neuroscience | Year: 2016

The present study compared young and older adults on behavioral and neural correlates of three attentional networks (alerting, orienting, and executive control). Nineteen young and 16 older neurologically-healthy adults completed the Attention Network Test (ANT) while behavioral data (reaction time and error rates) and 64-channel event-related potentials (ERPs) were acquired. Significant age-related RT differences were observed across all three networks; however, after controlling for generalized slowing, only the alerting network remained significantly reduced in older compared with young adults. ERP data revealed that alerting cues led to enhanced posterior N1 responses for subsequent attentional targets in young adults, but this effect was weakened in older adults. As a result, it appears that older adults did not benefit fully from alerting cues, and their lack of subsequent attentional enhancements may compromise their ability to be as responsive and flexible as their younger counterparts. N1 alerting deficits were associated with several key neuropsychological tests of attention that were difficult for older adults. Orienting and executive attention networks were largely similar between groups. Taken together, older adults demonstrated behavioral and neural alterations in alerting, however, they appeared to compensate for this reduction, as they did not significantly differ in their abilities to use spatially informative cues to aid performance (e.g., orienting), or successfully resolve response conflict (e.g., executive control). These results have important implications for understanding the mechanisms of age-related changes in attentional networks. © 2016 Kaufman, Sozda, Dotson and Perlstein.

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