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Fortier C.B.,The Geriatric Research Education and Clinical Center | Fortier C.B.,Harvard University | Fortier C.B.,Boston Healthcare System Neuroimaging Research Center for Veterans | Leritz E.C.,The Geriatric Research Education and Clinical Center | And 17 more authors.
Alcoholism: Clinical and Experimental Research | Year: 2011

Background: Chronic misuse of alcohol results in widespread damage to the brain. Prior morphometric studies have examined cortical atrophy in individuals with alcoholism; however, no previous studies have examined alcohol-associated atrophy using cortical thickness measurements to obtain regional mapping of tissue loss across the full cortical surface. Methods: We compared cortical thickness measures from 31 abstinent individuals with a history of prior alcohol abuse to 34 healthy nonalcoholic control participants (total sample size=65). Cortical surface models were created from high-resolution T1-weighted images, and cortical thickness was then estimated as the distance between the gray matter/white matter boundary and the outer cortical surface. Results: Abstinent alcoholics showed reduced whole-brain thickness as compared to nonalcoholic participants. Decreases in thickness were found bilaterally in (i) superior frontal, (ii) precentral, (iii) postcentral, (iv) middle frontal, (v) middle/superior temporal, (vi) middle temporal, and (vii) lateral occipital cortical regions. Decreased cortical thickness in the alcoholic group was associated with severity of alcohol abuse. Conclusions: These findings demonstrate widespread reduction in cortical thickness as a consequence of chronic alcoholism, with most severe reductions in frontal and temporal brain regions. Copyright © 2011 by the Research Society on Alcoholism.


Liu Y.,University of Texas Health Science Center at San Antonio | Diaz V.,University of Texas Health Science Center at San Antonio | Fernandez E.,University of Texas Health Science Center at San Antonio | Fernandez E.,The Geriatric Research Education and Clinical Center | And 8 more authors.
Aging | Year: 2014

The inhibition of mTOR (mechanistic target of rapamycin) by the macrolide rapamycin has many beneficial effects in mice, including extension of lifespan and reduction or prevention of several age-related diseases. At the same time, chronic rapamycin treatment causes impairments in glucose metabolism including hyperglycemia, glucose intolerance and insulin resistance. It is unknown whether these metabolic effects of rapamycin are permanent or whether they can be alleviated. Here, we confirmed that rapamycin causes glucose intolerance and insulin resistance in both inbred and genetically heterogeneous mice fed either low fat or high fat diets, suggesting that these effects of rapamycin are independent of genetic background. Importantly, we also found that these effects were almost completely lost within a few weeks of cessation of treatment, showing that chronic rapamycin treatment does not induce permanent impairment of glucose metabolism. Somewhat surprisingly, chronic rapamycin also promoted increased accumulation of adipose tissue in high fat fed mice. However, this effect too was lost when rapamycin treatment was ended suggesting that this effect of rapamycin is also not permanent. The reversible nature of rapamycin's alterations of metabolic function suggests that these potentially detrimental side-effects might be managed through alternative dosing strategies or concurrent treatment. © Liu et al.


Salmon A.B.,University of Texas Health Science Center at San Antonio | Richardson A.,University of Texas Health Science Center at San Antonio | Richardson A.,The Geriatric Research Education and Clinical Center | Perez V.I.,University of Texas Health Science Center at San Antonio
Free Radical Biology and Medicine | Year: 2010

The oxidative stress theory of aging predicts that manipulations that alter oxidative stress/damage will alter aging. The gold standard for determining whether aging is altered is life span, i.e., does altering oxidative stress/damage change life span? Mice with genetic manipulations in their antioxidant defense system designed to directly address this prediction have, with few exceptions, shown no change in life span. However, when these transgenic/knockout mice are tested using models that develop various types of age-related pathology, they show alterations in progression and/or severity of pathology as predicted by the oxidative stress theory: increased oxidative stress accelerates pathology and reduced oxidative stress retards pathology. These contradictory observations might mean that (a) oxidative stress plays a very limited, if any, role in aging but a major role in health span and/or (b) the role that oxidative stress plays in aging depends on environment. In environments with minimal stress, as expected under optimal husbandry, oxidative damage plays little role in aging. However, under chronic stress, including pathological phenotypes that diminish optimal health, oxidative stress/damage plays a major role in aging. Under these conditions, enhanced antioxidant defenses exert an "antiaging" action, leading to changes in life span, age-related pathology, and physiological function as predicted by the oxidative stress theory of aging. © 2009 Elsevier Inc. All rights reserved.


Liu Y.,University of Texas Health Science Center at San Antonio | Qi W.,University of Texas Health Science Center at San Antonio | Richardson A.,The Geriatric Research Education and Clinical Center | Richardson A.,University of Texas Health Science Center at San Antonio | And 6 more authors.
Biochemical and Biophysical Research Communications | Year: 2013

The development of insulin resistance is the primary step in the etiology of type 2 diabetes mellitus. There are several risk factors associated with insulin resistance, yet the basic biological mechanisms that promote its development are still unclear. There is growing literature that suggests mitochondrial dysfunction and/or oxidative stress play prominent roles in defects in glucose metabolism. Here, we tested whether increased expression of CuZn-superoxide dismutase (Sod1) or Mn-superoxide dismutase (Sod2) prevented obesity-induced changes in oxidative stress and metabolism. Both Sod1 and Sod2 overexpressing mice were protected from high fat diet-induced glucose intolerance. Lipid oxidation (F2-isoprostanes) was significantly increased in muscle and adipose with high fat feeding. Mice with increased expression of either Sod1 or Sod2 showed a significant reduction in this oxidative damage. Surprisingly, mitochondria from the muscle of high fat diet-fed mice showed no significant alteration in function. Together, our data suggest that targeting reduced oxidative damage in general may be a more applicable therapeutic target to prevent insulin resistance than is improving mitochondrial function. © 2013.


Kochar J.,Beth Israel Deaconess Medical Center | Kochar J.,Harvard University | Kochar J.,Brigham and Women's Hospital | Gaziano J.M.,Harvard University | And 7 more authors.
Clinical Nutrition | Year: 2012

Background & aims: Hypertension is a major public health problem. While many dietary factors affect the risk of developing hypertension, limited data are available on the association between consumption of breakfast cereal and incident hypertension. We examined the association between breakfast cereal consumption and the risk of hypertension. Methods: We prospectively analyzed data from 13,368 male participants of the Physicians' Health Study I. Consumption of breakfast cereals was estimated using an abbreviated food frequency questionnaire and incident hypertension was ascertained through yearly follow-up questionnaires. Results: The average age of study participants was 52.4±8.9 years (range 39.7-85.9) during the initial assessment of cereal intake (1981-1983). During a mean follow up of 16.3 years, 7267 cases of hypertension occurred. The crude incidence rates of hypertension were 36.7, 34.0, 31.7, and 29.6 cases/1000 person-years for people reporting breakfast cereal intake of 0, ≤1, 2-6, and ≥7 servings/week, respectively. In a Cox regression model adjusting for age, smoking, body mass index, alcohol consumption, fruit and vegetable consumption, physical activity, and history of diabetes mellitus, hazard ratios (95% CI) for hypertension were 1.0 (reference), 0.93 (0.88-0.99), 0.88 (0.83-0.94), and 0.81 (0.75-0.86) from the lowest to the highest category of cereal consumption, respectively (p for trend <0.0001). This association was strongest for whole grain cereals and was observed in lean as well as overweight or obese participants. Conclusions: The results of this longitudinal cohort study suggest that whole grain breakfast cereal consumption confers a lower risk of hypertension in middle-aged adult males. © 2011 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism.

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