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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.


Bril F.,University of Florida | Bril F.,Malcom Randall Veterans Administration Medical Center | Ortiz-Lopez C.,University of Texas Health Science Center at San Antonio | Lomonaco R.,University of Florida | And 12 more authors.
Liver International | Year: 2015

Background & Aims: Liver ultrasound (US) is usually used in the clinical setting for the diagnosis and follow-up of patients with nonalcoholic fatty liver disease (NAFLD). However, no large study has carefully assessed its performance using a semiquantitative ultrasonographic scoring system in overweight/obese patients, in comparison to magnetic resonance spectroscopy (1H-MRS) and histology. Methods: We recruited 146 patients and performed: a liver US using a 5-parameter scoring system, a liver 1H-MRS to quantify liver fat content, and a liver biopsy to assess histology. All measurements were repeated in a subgroup of patients (n = 62) after 18 months of follow-up. Results: The performance of liver US (parenchymal echo alone) was rather modest, and significantly worse than 1H-MRS (AUROC: 0.82 [0.69-0.94] vs. 0.96 [0.90-1.00]; P = 0.04). However, the AUROC improved when different echographic parameters were taken into account (AUROC: 0.89 [0.83-0.96], P = 0.15 against 1H-MRS). Optimum sensitivity for liver US was achieved at a liver fat content ≥12.5%, suggesting that below this threshold, liver US is less sensitive. Liver 1H-MRS showed a high accuracy for the diagnosis of NAFLD, and correlated strongly with histological steatosis (r = 0.73, P < 0.0001). None of the imaging tests was adequate enough to predict changes over time in histology. Conclusions: Despite its widespread use, liver US has several important limitations that healthcare providers should recognize, particularly because of its low sensitivity. Using a combination of echographic parameters, liver US showed a significant improvement in its diagnostic performance, but still was of limited value for monitoring treatment over time. © 2015 John Wiley & Sons A/S.


Bril F.,University of Florida | Bril F.,Malcom Randall Veterans Administration Medical Center | Maximos M.,Malcom Randall Veterans Administration Medical Center | Maximos M.,University of Florida | And 16 more authors.
Journal of Hepatology | Year: 2015

Background & Aims: The role of plasma vitamin D deficiency in the development of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) remains poorly understood. Previous studies have suggested a role for vitamin D deficiency in the pathogenesis of NAFLD/NASH, but they have been rather small, and/or NAFLD was diagnosed using only aminotransferases or liver ultrasound. This study aimed to assess the role of vitamin D deficiency in relationship to liver fat accumulation and severity of NASH. Methods: A total of 239 patients were recruited and state-of-theart techniques were used to measure insulin resistance (euglycemic insulin clamp with 3-3H-glucose), liver fat accumulation (magnetic resonance spectroscopy or 1H-MRS), total body fat (dual energy X-ray absorptiometry), and severity of liver disease (liver biopsy). Results: Patients were divided into 3 groups according to plasma 25-hydroxyvitamin D levels (normal: >30 ng/ml; insufficiency: 20-30 ng/ml; deficiency: <20 ng/ml). When well-matched for clinical parameters (BMI, total adiposity, or prevalence of prediabetes/ type 2 diabetes), no significant differences were observed among groups in terms of skeletal muscle, hepatic, or adipose tissue insulin sensitivity, the amount of liver fat by 1H-MRS, or the severity of histological inflammation, ballooning, or fibrosis. Patients were then divided according to liver histology into those with definite NASH and those without NASH. Although patients with NASH had higher insulin resistance, plasma vitamin D concentrations were similar between both groups. Conclusions: Our results suggest that plasma vitamin D levels are not associated with insulin resistance, the amount of liver fat accumulation, or the severity of NASH. © 2014 European Association for the Study of the Liver.


Portillo-Sanchez P.,University of Florida | Portillo-Sanchez P.,Malcom Randall Veterans Administration Medical Center | Bril F.,University of Florida | Bril F.,Malcom Randall Veterans Administration Medical Center | And 12 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2015

Context and Objective: Nonalcoholic fatty liver disease (NAFLD) and its more severe form with steatohepatitis (NASH) are common in patients with type 2 diabetes mellitus (T2DM). However, they are usually believed to largely affect those with elevated aminotransferases. The aim of this study was to determine the prevalence of NAFLD by the gold standard, liver magnetic resonance spectroscopy (1H-MRS) in patients with T2DM and normal aminotransferases, and to characterize their metabolic profile. Participants and Methods: We recruited 103 patients with T2DM and normal plasma aminotransferases (age, 60 ± 8 y; body mass index [BMI], 33 ± 5 kg/m2; glycated hemoglobin [A1c], 7.6 ô 1.3%). We measured the following: 1) liver triglyceride content by1 H-MRS; 2) systemic insulin sensitivity (homeostasis model assessment-insulin resistance); and 3) adipose tissue insulin resistance, both fasting (as the adipose tissue insulin resistance index: fasting plasma free fatty acids [FFA] × insulin) and during an oral glucose tolerance test (as the suppression of FFA). Results: The prevalence of NAFLD and NASH were much higher than expected (50% and 56% of NAFLD patients, respectively). The prevalence of NAFLD was higher in obese compared with nono-bese patients as well as with increasing BMI (P = .001 for trend). Higher plasma A1c was associated with a greater prevalence of NAFLD and worse liver triglyceride accumulation (P = .01). Compared with nonobese patients without NAFLD, patients with NAFLD had severe systemic (liver/muscle) and, particularly, adipose tissue (fasting/postprandial) insulin resistance (all P < .01). Conclusions: The prevalence of NAFLD is much higher than previously believed in overweight/ obese patients with T2DM and normal aminotransferases. Moreover, many are at increased risk of NASH. Physicians should have a lower threshold for screening patients with T2DM for NAFLD/NASH. Copyright © 2015 by the Endocrine Society.


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.


PubMed | University of Texas Health Science Center at San Antonio, University of Florida and Malcom Randall Veterans Administration Medical Center
Type: Journal Article | Journal: Journal of hepatology | Year: 2015

The role of plasma vitamin D deficiency in the development of non-alcoholic fatty liver disease (NAFLD) and steatohepatitis (NASH) remains poorly understood. Previous studies have suggested a role for vitamin D deficiency in the pathogenesis of NAFLD/NASH, but they have been rather small, and/or NAFLD was diagnosed using only aminotransferases or liver ultrasound. This study aimed to assess the role of vitamin D deficiency in relationship to liver fat accumulation and severity of NASH.A total of 239 patients were recruited and state-of-the-art techniques were used to measure insulin resistance (euglycemic insulin clamp with 3-(3)H-glucose), liver fat accumulation (magnetic resonance spectroscopy or (1)H-MRS), total body fat (dual energy X-ray absorptiometry), and severity of liver disease (liver biopsy).Patients were divided into 3 groups according to plasma 25-hydroxyvitamin D levels (normal: >30 ng/ml; insufficiency: 20-30 ng/ml; deficiency: <20 ng/ml). When well-matched for clinical parameters (BMI, total adiposity, or prevalence of prediabetes/type 2 diabetes), no significant differences were observed among groups in terms of skeletal muscle, hepatic, or adipose tissue insulin sensitivity, the amount of liver fat by (1)H-MRS, or the severity of histological inflammation, ballooning, or fibrosis. Patients were then divided according to liver histology into those with definite NASH and those without NASH. Although patients with NASH had higher insulin resistance, plasma vitamin D concentrations were similar between both groups.Our results suggest that plasma vitamin D levels are not associated with insulin resistance, the amount of liver fat accumulation, or the severity of NASH.


Mahmoud A.,University of Florida | Mahmoud A.,Malcom Randall Veterans Administration Medical Center | Elgendy I.Y.,University of Florida | Bavry A.A.,University of Florida
American Journal of Medicine | Year: 2016

Background Individual randomized trials have yielded variable results regarding the benefits of targeted temperature management in patients encountering out-of-hospital cardiac arrest. This study aimed to systemically determine if targeted temperature management initiated after an out-of-hospital cardiac arrest was associated with improved outcomes. Methods Electronic databases were searched for published randomized trials that compared targeted temperature management (core body temperature 32-34°C) vs control (core body temperature ≥36°C) after an out-of-hospital cardiac arrest. The main outcomes assessed were all-cause mortality and poor neurological outcome. Results Six trials with 1391 patients were included in the analysis. Compared with the control group, targeted temperature management was associated with a nonsignificant reduction in all-cause mortality (relative risk [RR] 0.90; 95% confidence interval [CI], 0.77-1.04; P =.15, I2 = 34%), which was similar among those with a shockable rhythm (RR 0.89; 95% CI, 0.74-1.08, P =.25, I2 = 46%). All-cause mortality was significantly reduced with targeted temperature management after exclusion of one trial that allowed for mild hypothermia in the control arm (RR 0.83; 95% CI, 0.71-0.96; P =.01, I2 = 0%). There was a nonsignificant reduction in poor neurological outcome with targeted temperature management compared with control (RR 0.87; 95% CI, 0.74-1.03, P =.10, I2 = 54%), which was similar among those with a shockable rhythm (RR 0.87; 95% CI, 0.70-1.07, P =.19, I2 = 63%). Poor neurological outcome was significantly reduced with targeted temperature management after exclusion of one trial that allowed for mild hypothermia in the control arm (RR 0.82; 95% CI, 0.70-0.95; P =.01, I2 = 19%). Conclusion Targeted temperature management initiated after successful resuscitation in patients who encountered an out-of-hospital cardiac arrest was associated with a nonsignificant reduction in mortality and poor neurological outcome. Lack of benefit was strongly influenced by inclusion of one study that used mild hypothermia in the control arm. These results indicate that only mild hypothermia may be needed to improve outcomes among patients presenting with an out-of-hospital cardiac arrest. © 2016 Elsevier Inc.


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).


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.


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.

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