Integrated Social- and Neurocognitive Model of Physical Activity Behavior in Older Adults with Metabolic Disease.

BACKGROUND: Despite the proven benefits of physical activity to treat and prevent metabolic diseases, such as diabetes (T2D) and metabolic syndrome (MetS), most individuals with metabolic disease do not meet physical activity (PA) recommendations. PA is a complex behavior requiring substantial motivational and cognitive resources. The purpose of this study was to examine social cognitive and neuropsychological determinants of PA behavior in older adults with T2D and MetS. The hypothesized model theorized that baseline self-regulatory strategy use and cognitive function would indirectly influence PA through self-efficacy. METHODS: Older adults with T2D or MetS (M age = 61.8 ± 6.4) completed either an 8-week physical activity intervention (n = 58) or an online metabolic health education course (n = 58) and a follow-up at 6 months. Measures included cognitive function, self-efficacy, self-regulatory strategy use, and PA. RESULTS: The data partially supported the hypothesized model (χ2 = 158.535(131), p > .05, comparative fit index = .96, root mean square error of approximation = .04, standardized root mean square residual = .06) with self-regulatory strategy use directly predicting self-efficacy (ß = .33, p < .05), which in turn predicted PA (ß = .21, p < .05). Performance on various cognitive function tasks predicted PA directly and indirectly via self-efficacy. Baseline physical activity (ß = .62, p < .01) and intervention group assignment via self-efficacy (ß = -.20, p < .05) predicted follow-up PA. The model accounted for 54.4 % of the variance in PA at month 6. CONCLUSIONS: Findings partially support the hypothesized model and indicate that select cognitive functions (i.e., working memory, inhibition, attention, and task-switching) predicted PA behavior 6 months later. Future research warrants the development of interventions targeting cognitive function, self-regulatory skill development, and self-efficacy enhancement. TRIAL REGISTRATION NUMBER: The trial was registered with the clinical trial number NCT01790724.

Fitness, but not physical activity, is related to functional integrity of brain networks associated with aging.

Greater physical activity and cardiorespiratory fitness are associated with reduced age-related cognitive decline and lower risk for dementia. However, significant gaps remain in the understanding of how physical activity and fitness protect the brain from adverse effects of brain aging. The primary goal of the current study was to empirically evaluate the independent relationships between physical activity and fitness with functional brain health among healthy older adults, as measured by the functional connectivity of cognitively and clinically relevant resting state networks. To build context for fitness and physical activity associations in older adults, we first demonstrate that young adults have greater within-network functional connectivity across a broad range of cortical association networks. Based on these results and previous research, we predicted that individual differences in fitness and physical activity would be most strongly associated with functional integrity of the networks most sensitive to aging. Consistent with this prediction, and extending on previous research, we showed that cardiorespiratory fitness has a positive relationship with functional connectivity of several cortical networks associated with age-related decline, and effects were strongest in the default mode network (DMN). Furthermore, our results suggest that the positive association of fitness with brain function can occur independent of habitual physical activity. Overall, our findings provide further support that cardiorespiratory fitness is an important factor in moderating the adverse effects of aging on cognitively and clinically relevant functional brain networks.

White matter microstructure mediates the relationship between cardiorespiratory fitness and spatial working memory in older adults.

White matter structure declines with advancing age and has been associated with a decline in memory and executive processes in older adulthood. Yet, recent research suggests that higher physical activity and fitness levels may be associated with less white matter degeneration in late life, although the tract-specificity of this relationship is not well understood. In addition, these prior studies infrequently associate measures of white matter microstructure to cognitive outcomes, so the behavioral importance of higher levels of white matter microstructural organization with greater fitness levels remains a matter of speculation. Here we tested whether cardiorespiratory fitness (VO2max) levels were associated with white matter microstructure and whether this relationship constituted an indirect pathway between cardiorespiratory fitness and spatial working memory in two large, cognitively and neurologically healthy older adult samples. Diffusion tensor imaging was used to determine white matter microstructure in two separate groups: Experiment 1, N=113 (mean age=66.61) and Experiment 2, N=154 (mean age=65.66). Using a voxel-based regression approach, we found that higher VO2max was associated with higher fractional anisotropy (FA), a measure of white matter microstructure, in a diverse network of white matter tracts, including the anterior corona radiata, anterior internal capsule, fornix, cingulum, and corpus callosum (PFDR-corrected<.05). This effect was consistent across both samples even after controlling for age, gender, and education. Further, a statistical mediation analysis revealed that white matter microstructure within these regions, among others, constituted a significant indirect path between VO2max and spatial working memory performance. These results suggest that greater aerobic fitness levels are associated with higher levels of white matter microstructural organization, which may, in turn, preserve spatial memory performance in older adulthood.

Urine proteomics in the diagnosis of stable angina.

BACKGROUND: We have previously described a panel of 238 urinary polypeptides specific for established severe coronary artery disease (CAD). Here we studied this polypeptide panel in patients with a wider range of CAD severity. METHODS: We recruited 60 patients who underwent elective coronary angiography for investigation of stable angina. Patients were selected for either having angiographic evidence of CAD or not (NCA) following coronary angiography (n = 30/30; age, 55 ± 6 vs. 56 ± 7 years, P = 0.539) to cover the extremes of the CAD spectrum. A further 66 patients with severe CAD (age, 64 ± 9 years) prior to surgical coronary revascularization were added for correlation studies. The Gensini score was calculated from coronary angiograms as a measure of CAD severity. Urinary proteomic analyses were performed using capillary electrophoresis coupled online to micro time-of-flight mass spectrometry. The urinary polypeptide pattern was classified using a predefined algorithm and resulting in the CAD238 score, which expresses the pattern quantitatively. RESULTS: In the whole cohort of patients with CAD (Gensini score 60 [40; 98]) we found a close correlation between Gensini scores and CAD238 (ρ = 0.465, P < 0.001). After adjustment for age (ß = 0.144; P = 0.135) the CAD238 score remained a significant predictor of the Gensini score (ß =0.418; P < 0.001). In those with less severe CAD (Gensini score 40 [25; 61]), however, we could not detect a difference in CAD238 compared to patients with NCA (-0.487 ± 0.341 vs. -0.612 ± 0.269, P = 0.119). CONCLUSIONS: In conclusion the urinary polypeptide CAD238 score is associated with CAD burden and has potential as a new cardiovascular biomarker.

Differential exercise effects on quality of life and health-related quality of life in older adults: a randomized controlled trial.

PURPOSE: Maintaining quality of life (QOL) and physical and mental health status are important outcomes throughout the aging process. Although cross-sectional studies suggest a relationship between global QOL and physical activity, it is unclear whether such a relationship exists as a function of exercise training. METHODS: We examined the effects of two exercise intervention arms on health-related quality of life (HRQOL) and global QOL. Low-active, older adults (n = 179) were randomly assigned to either a 12-month aerobic walking group or a strengthening and flexibility group. HRQOL and QOL were measured at baseline, 6, and 12 months. RESULTS: There was a significant group by time effect on QOL [F(2,176) = 3.11, p = 0.047, η (2) = 0.03]. There was also a significant overall group by time effect for HRQOL [F(4,174) = 2.46, p = 0.047, η (2) = 0.05], which was explained by the significant group by time interaction for mental health status (p = 0.041, η (2) = 0.02) favoring the walking condition. Further analyses using latent class analysis revealed three classes of individuals with differential patterns of change in QOL and HRQOL across time. These classes reflected no change, declines, and improvements in these constructs across time. CONCLUSIONS: Walking appears to enhance the mental aspect of HRQOL and global QOL when compared to a non-aerobic intervention. Additionally, the patterns of change in QOL and HRQOL were not linear over time. Our findings are in contrast to previous reports that these outcomes change a little or not at all in randomized trials.

Impact of a brief intervention on self-regulation, self-efficacy and physical activity in older adults with type 2 diabetes.

Despite evidence of the benefits of physical activity, most individuals with type 2 diabetes do not meet physical activity recommendations. The purpose of this study was to test the efficacy of a brief intervention targeting self-efficacy and self-regulation to increase physical activity in older adults with type 2 diabetes. Older adults (Mage = 61.8 ± 6.4) with type 2 diabetes or metabolic syndrome were randomized into a titrated physical activity intervention (n = 58) or an online health education course (n = 58). The intervention included walking exercise and theory-based group workshops. Self-efficacy, self-regulation and physical activity were assessed at baseline, post-intervention, and a follow-up. Results indicated a group by time effect for self-regulation [F(2,88) = 14.021, p < .001, η (2) = .24] and self-efficacy [F(12,77) = 2.322, p < .05, η (2) = .266] with increases in the intervention group. The intervention resulted in short-term increases in physical activity (d = .76, p < .01), which were partially maintained at the 6-month follow-up (d = .35, p < .01). The intervention increased short-term physical activity but was not successful at maintaining increases in physical activity. Similar intervention effects were observed in self-efficacy and self-regulation. Future research warrants adjusting intervention strategies to increase long-term change.

Physical activity levels and patterns in older adults: the influence of a DVD-based exercise program.

The use of multimedia to influence health behaviors offers unique advantages over more traditional center-based programs, however, little is known about the effectiveness of such approaches in improving physical activity levels over time. The purpose of this study was to examine the efficacy of a progressive and age-appropriate, DVD-delivered exercise program in promoting physical activity levels among older adult cohorts. Community dwelling older adults (N = 307, Mean age = 71 years) were randomized to one of two groups: a 6-month home-based DVD-delivered exercise (i.e., FlexToBa™) intervention group or a healthy aging DVD control group. Physical activity was assessed objectively using a standard 7-day accelerometer wear period and subjectively using the Godin Leisure Time Exercise Questionnaire, at baseline and follow-up. Analysis of covariances indicated a statistically significant treatment effect for subjectively [F(1,250) = 8.42, P = .004, η(2) = .03] and objectively [F(1,240) = 3.77, P = .05, η(2) = .02] measured physical activity. The older cohort (>70) in the FlexToBa condition further had significantly larger improvements in physical activity levels compared to their younger counterparts. From a public health perspective, media-delivered interventions such as the FlexToBa program might prove to be cost-effective, have a broader reach and at the same time be effective in improving physical activity levels in older adults.

Influence of allowable interruption period on estimates of accelerometer wear time and sedentary time in older adults.

The criteria one uses to reduce accelerometer data can profoundly influence the interpretation of research outcomes. The purpose of this study was to examine the influence of 3 different interruption periods (i.e., 20, 30, and 60 min) on the amount of data retained for analyses and estimates of sedentary time among older adults. Older adults (N = 311, M age = 71.1) wore an accelerometer for 7 d and reported wear time on an accelerometer log. Accelerometer data were downloaded and scored using 20-, 30-, and 60-min interruption periods. Estimates of wear time, derived using each interruption period, were compared with self-reported wear time, and descriptive statistics were used to compare estimates of sedentary time. Results showed a longer interruption period (i.e., 60 min) yields the largest sample size and the closest approximation of self-reported wear time. A short interruption period (i.e., 20 min) is likely to underestimate sedentary time among older adults.

Neurobiological markers of exercise-related brain plasticity in older adults.

The current study examined how a randomized one-year aerobic exercise program for healthy older adults would affect serum levels of brain-derived neurotrophic factor (BDNF), insulin-like growth factor type 1 (IGF-1), and vascular endothelial growth factor (VEGF) - putative markers of exercise-induced benefits on brain function. The study also examined whether (a) change in the concentration of these growth factors was associated with alterations in functional connectivity following exercise, and (b) the extent to which pre-intervention growth factor levels were associated with training-related changes in functional connectivity. In 65 participants (mean age=66.4), we found that although there were no group-level changes in growth factors as a function of the intervention, increased temporal lobe connectivity between the bilateral parahippocampus and the bilateral middle temporal gyrus was associated with increased BDNF, IGF-1, and VEGF for an aerobic walking group but not for a non-aerobic control group, and greater pre-intervention VEGF was associated with greater training-related increases in this functional connection. Results are consistent with animal models of exercise and the brain, but are the first to show in humans that exercise-induced increases in temporal lobe functional connectivity are associated with changes in growth factors and may be augmented by greater baseline VEGF.

Docetaxel-induced skin toxicities in breast cancer patients subsequent to paclitaxel shortage: a case series and literature review.

PURPOSE: As the result of a recent national shortage in paclitaxel, some patients who were receiving or scheduled to receive weekly paclitaxel were converted to every 3-week (q3w) docetaxel with granulocyte colony-stimulating factor support. Our institution noted higher than expected incidence of severe skin toxicity events attributable to docetaxel during the shortage period among our breast cancer patients. In this report, we summarize the clinical course of the first five cases, review the literature surrounding docetaxel-induced skin toxicity, and offer possible prevention and treatment strategies to improve docetaxel tolerability. METHODS: The observation period for this case series was August 1 through October 21, 2011. All patients treated with docetaxel were identified from our electronic medical record. Operable stage I-III breast cancer patients who received ≥ 1 dose of docetaxel monotherapy at 75-100 mg/m(2) q3w were included in this study. The cases of grade 3-4 docetaxel-induced skin toxicities identified by the treating oncologists were then contacted and signed an informed consent through an Institutional Review Board-approved protocol. RESULTS: Thirty-four patients met the inclusion criteria. Five patients (14.7 %) experienced grade 3 skin toxicity events attributable to docetaxel, a significantly higher rate than previously reported for docetaxel dosed at 75-100 mg/m(2). CONCLUSIONS: Docetaxel-induced dermatologic toxicity is well characterized; nonetheless, its etiology is largely unknown and evidence-based prevention and management strategies are lacking. This report shows that the use of docetaxel 75-100 mg/m(2) q3w subsequent to dose-dense doxorubicin and cyclophosphamide regimen can lead to unacceptable rate of severe skin toxicity.

A profile for predicting attrition from exercise in older adults.

The purpose of this study was to determine a profile for predicting attrition among older adults involved in a 12-month exercise program. The parent study was a single-blinded randomized controlled trial. The study took place between 2006 and 2009 within a university setting. Older adults (N = 179) completed baseline assessments of functional performance and psychosocial measures. Participants who were randomized, elected to receive treatment, and did not complete the exercise program were considered "dropouts" (n = 35). Those who completed the program (n = 144) were classified as "completers." A latent profile analysis revealed two distinct patterns of memory complaints, self-efficacy to overcome barriers to exercise, balance performance, and stair performance. Dropouts were nearly twice as likely to be members of the profile that exhibited a higher degree of memory complaints, lower self-efficacy for overcoming exercise barriers, poorer single leg balance, and longer times to walk down stairs. The results provide an initial validation of a profile for discriminating between "dropouts" and "completers," one that may have considerable utility for screening older adults prior to study entry.

Kinetic evaluation of cell membrane hydrolysis during apoptosis by human isoforms of secretory phospholipase A2.

Some isoforms of secretory phospholipase A(2) (sPLA(2)) distinguish between healthy and damaged or apoptotic cells. This distinction reflects differences in membrane physical properties. Because various sPLA(2) isoforms respond differently to properties of artificial membranes such as surface charge, they should also behave differently as these properties evolve during a dynamic physiological process such as apoptosis. To test this idea, S49 lymphoma cell death was induced by glucocorticoid (6-48 h) or calcium ionophore. Rates of membrane hydrolysis catalyzed by various concentrations of snake venom and human groups IIa, V, and X sPLA(2) were compared after each treatment condition. The data were analyzed using a model that evaluates the adsorption of enzyme to the membrane surface and subsequent binding of substrate to the active site. Results were compared temporally to changes in membrane biophysics and composition. Under control conditions, membrane hydrolysis was confined to the few unhealthy cells present in each sample. Increased hydrolysis during apoptosis and necrosis appeared to reflect substrate access to adsorbed enzyme for the snake venom and group X isoforms corresponding to weakened lipid-lipid interactions in the membrane. In contrast, apoptosis promoted initial adsorption of human groups V and IIa concurrent with phosphatidylserine exposure on the membrane surface. However, this observation was inadequate to explain the behavior of the groups V and IIa enzymes toward necrotic cells where hydrolysis was reduced or absent. Thus, a combination of changes in cell membrane properties during apoptosis and necrosis capacitates the cell for hydrolysis differently by each isoform.

Measuring enjoyment of physical activity in older adults: invariance of the physical activity enjoyment scale (paces) across groups and time.

The purpose of this study was to validate the Physical Activity Enjoyment Scale (PACES) in a sample of older adults. Participants within two different exercise groups were assessed at two time points, 6 months apart. Group and longitudinal invariance was established for a novel, 8-item version of the PACES. The shortened, psychometrically sound measure provides researchers and practitioners an expedited and reliable instrument for assessing the enjoyment of physical activity.

Longitudinal invariance and construct validity of the abbreviated late-life function and disability instrument in healthy older adults.

OBJECTIVE: To cross-validate the psychometric properties of the abbreviated Late-Life Function and Disability Instrument (LL-FDI), a measure of perceived functional limitations and disability. DESIGN: Baseline and 12-month follow-up assessments conducted across the course of a 12-month exercise program. SETTING: University research community. PARTICIPANTS: Older healthy adults (N=179; mean ± SD age, 66.43±5.67y) at baseline; 145 were retained at follow-up. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: LL-FDI and functional performance measures. RESULTS: Factor analyses confirmed the factor structure of the abbreviated LL-FDI, and all subscales met minimal criteria for temporal invariance. Significant correlations also were found between functional limitations subscales and an array of physical function performance measures, supporting the scale's construct validity. CONCLUSIONS: The abbreviated LL-FDI with some modifications appears to be temporally invariant in community-dwelling older adults. Additionally, moderate relationships between functional limitations and functional performance provide further support for these being conceptually distinct constructs.

Trajectories of change in self-esteem in older adults: exercise intervention effects.

This 12-month, 2 arm, single blind randomized controlled exercise trial examined relationships among changes in multidimensional self-esteem as a function of intervention mode (i.e., walking vs. flexibility-toning-balance). Data were collected on three equidistant occasions (baseline, 6 and 12 months). One-hundred seventy-nine older adults (M(age) = 66.38) began the study and 145 completed assessments at all time points. Participants completed measures of physical and global self-esteem as well as demographic information. There were no significant group differences at baseline on these demographic indicators or esteem variables. Data were analyzed using linear and parallel process growth modeling procedures. Results supported the position that across both groups, domain-level (i.e., physical self-worth) was dependent upon sub-domain-level (i.e., perceived attractiveness, strength, and condition) esteem change. Furthermore, greater improvements were observed in the flexibility-toning-balance group, in terms of perceived strength and attractiveness esteem, compared to the walking group. Our findings support theoretically-based predictions and extend the literature showing unique psychological responses conditional on specific types of physical activities.

The Mre11 complex mediates the S-phase checkpoint through an interaction with replication protein A.

The Mre11/Rad50/Nbs1 complex (MRN) plays an essential role in the S-phase checkpoint. Cells derived from patients with Nijmegen breakage syndrome and ataxia telangiectasia-like disorder undergo radioresistant DNA synthesis (RDS), failing to suppress DNA replication in response to ionizing radiation (IR). How MRN affects DNA replication to control the S-phase checkpoint, however, remains unclear. We demonstrate that MRN directly interacts with replication protein A (RPA) in unperturbed cells and that the interaction is regulated by cyclin-dependent kinases. We also show that this interaction is needed for MRN to correctly localize to replication centers. Abolishing the interaction of Mre11 with RPA leads to pronounced RDS without affecting phosphorylation of Nbs1 or SMC1 following IR. Moreover, MRN is recruited to sites at or adjacent to replication origins by RPA and acts there to inhibit new origin firing upon IR. These studies suggest a direct role of MRN at origin-proximal sites to control DNA replication initiation in response to DNA damage, thereby providing an important mechanism underlying the intra-S-phase checkpoint in mammalian cells.

What proportion of the brain structural and functional abnormalities observed among children with fetal alcohol spectrum disorder is explained by their prenatal alcohol exposure and their other prenatal and postnatal risks?

BACKGROUND: Individuals with prenatal alcohol exposure (PAE) often present with a myriad of other prenatal (e.g. exposure to tobacco and other illicit drugs, poor prenatal care) and postnatal risk factors (e.g. multiple home placements, physical/sexual abuse, low socio-economic status)-all of which are likely contributing to their adverse outcomes. METHODS: A comprehensive neuropsychological battery, coupled with magnetic resonance imaging, was administered to children with fetal alcohol spectrum disorders (FASD) in 2009. Study participants diagnosed with FASD by the University of Washington using the FASD 4-Digit Code were compared to typically-developing peers with no PAE. Data from this MRI study were used to explore the proportion of variance in brain structural and functional abnormalities explained by PAE and 14 other prenatal and postnatal risk factors. RESULTS: PAE was the dominant risk factor explaining the largest proportion of variance in regional brain size (total brain, frontal lobe, caudate, hippocampus and corpus callosum) and brain function (intellect, achievement, memory, language, executive-function, motor, adaptation, behavior-attention and mental health symptoms). Other prenatal and postnatal risk factors were 3 to 7-fold more prevalent than in the general population. Individually, each risk factor explained a statistically significant, but smaller proportion of variance in brain outcome compared to PAE. In combination, the proportion of variance explained by the presence of multiple prenatal and postnatal risks rivaled that of PAE. CONCLUSION: A better understanding of the impact other prenatal and postnatal risk factors have on the neurodevelopmental outcomes of individuals with FASD can inform more effective prevention and intervention strategies.

Effects of metronidazole on the fecal microbiome and metabolome in healthy dogs.

BACKGROUND: Metronidazole has a substantial impact on the gut microbiome. However, the recovery of the microbiome after discontinuation of administration, and the metabolic consequences of such alterations have not been investigated to date. OBJECTIVES: To describe the impact of 14-day metronidazole administration, alone or in combination with a hydrolyzed protein diet, on fecal microbiome, metabolome, bile acids (BAs), and lactate production, and on serum metabolome in healthy dogs. ANIMALS: Twenty-four healthy pet dogs. METHODS: Prospective, nonrandomized controlled study. Dogs fed various commercial diets were divided in 3 groups: control group (no intervention, G1); group receiving hydrolyzed protein diet, followed by metronidazole administration (G2); and group receiving metronidazole only (G3). Microbiome composition was evaluated with sequencing of 16S rRNA genes and quantitative polymerase chain reaction (qPCR)-based dysbiosis index. Untargeted metabolomics analysis of fecal and serum samples was performed, followed by targeted assays for fecal BAs and lactate. RESULTS: No changes were observed in G1, or G2 during diet change. Metronidazole significantly changed microbiome composition in G2 and G3, including decreases in richness (P < .001) and in key bacteria such as Fusobacteria (q < 0.001) that did not fully resolve 4 weeks after metronidazole discontinuation. Fecal dysbiosis index was significantly increased (P < .001). Those changes were accompanied by increased fecal total lactate (P < .001), and decreased secondary BAs deoxycholic acid and lithocholic acid (P < .001). CONCLUSION AND CLINICAL IMPORTANCE: Our results indicate a minimum 4-week effect of metronidazole on fecal microbiome and metabolome, supporting a cautious approach to prescription of metronidazole in dogs.

Comparison of the 4-Digit Code, Canadian 2015, Australian 2016 and Hoyme 2016 fetal alcohol spectrum disorder diagnostic guidelines.

BACKGROUND: As clinicians strive to achieve consensus worldwide on how best to diagnose fetal alcohol spectrum disorders (FASD), the most recent FASD diagnostic systems show convergence and divergence. Applying these systems to a single clinical population illustrates the contrasts between them, but validation studies are ultimately required to identify the best system. METHODS: The 4-Digit-Code, Hoyme 2016, Canadian 2015 and Australian 2016 FASD diagnostic systems were applied to 1,392 patient records evaluated for FASD at the University of Washington. The diagnostic criteria and tools, the prevalence and concordance of diagnostic outcomes, and validity measures were compared between the systems. RESULTS: The proportion diagnosed with fetal alcohol syndrome (FAS) and FASD varied significantly (4-Digit-Code 2.1%, ≤79%; Hoyme 6.4%, 44%, Australian 1.8%, 29%; Canadian 1.8%, 16%). Eighty-two percent were diagnosed FASD by at least one system; only 11% by all four systems. Key factors contributing to discordance include: requiring high alcohol exposure; excluding growth deficiency; relaxing the facial criteria; requiring brain criteria that prevent diagnosis of infants/toddlers; and excluding moderate dysfunction from the spectrum. Primate research confirms moderate dysfunction (1-2 domains ≤-2 standard deviations) is the most prevalent outcome caused by PAE (FAS 5%, severe dysfunction 31%, moderate dysfunction 59%). Only the 4-Digit-Code replicated this diagnostic pattern. CONCLUSION: The needs of individuals with FASD are best met when diagnostic systems provide accurate, validated diagnoses across the lifespan, the full spectrum of outcome, the full continuum of alcohol exposure; and utilize diagnostic nomenclature that accurately reflects the association between outcome and alcohol exposure.

Transgenic overexpression of glutathione S-transferase µ-type 1 reduces hypertension and oxidative stress in the stroke-prone spontaneously hypertensive rat.

BACKGROUND: Combined congenic breeding and microarray gene expression profiling previously identified glutathione S-transferase µ-type 1 (Gstm1) as a positional and functional candidate gene for blood pressure (BP) regulation in the stroke-prone spontaneously hypertensive (SHRSP) rat. Renal Gstm1 expression in SHRSP rats is significantly reduced when compared with normotensive Wistar Kyoto (WKY) rats. As Gstm1 plays an important role in the secondary defence against oxidative stress, significantly lower expression levels may be functionally relevant in the development of hypertension. The aim of this study was to investigate the role of Gstm1 in BP regulation and oxidative stress by transgenic overexpression of the Gstm1 gene. METHOD: Two independent Gstm1 transgenic SHRSP lines were generated by microinjecting SHRSP embryos with a linear construct controlled by the EF-1α promoter encoding WKY Gstm1 cDNA [SHRSP-Tg(Gstm1)1 and SHRSP-Tg(Gstm1)2]. RESULTS: Transgenic rats exhibit significantly reduced BP and pulse pressure when compared with SHRSP [systolic: SHRSP 205.2 ±â€Š3.7 mmHg vs. SHRSP-Tg(Gstm1)1 175.5 ±â€Š1.6 mmHg and SHRSP-Tg(Gstm1)2 172 ±â€Š3.2 mmHg, P < 0.001; pulse pressure: SHRSP 58.4 ±â€Š0.73 mmHg vs. SHRSP-Tg(Gstm1)1 52.7 ±â€Š0.19 mmHg and SHRSP-Tg(Gstm1)2 40.7 ±â€Š0.53 mmHg, P < 0.001]. Total renal and aortic Gstm1 expression in transgenic animals was significantly increased compared with SHRSP [renal relative quantification (RQ): SHRSP-Tg(Gstm1)1 1.95 vs. SHRSP 1.0, P < 0.01; aorta RQ: SHRSP-Tg(Gstm1)1 2.8 vs. SHRSP 1.0, P < 0.05]. Renal lipid peroxidation (malondialdehyde: protein) and oxidized : reduced glutathione ratio levels were significantly reduced in both transgenic lines when compared with SHRSP [malondialdehyde: SHRSP 0.04 ±â€Š0.009 µmol/l vs. SHRSP-Tg(Gstm1)1 0.024 ±â€Š0.002 µmol/l and SHRSP-Tg(Gstm1)2 0.021 ±â€Š0.002 µmol/l; (oxidized : reduced glutathione ratio): SHRSP 5.19 ±â€Š2.26 µmol/l vs. SHRSP-Tg(Gstm1)1 0.17 ±â€Š0.11 µmol/l and SHRSP-Tg(Gstm1)2 0.47 ±â€Š0.22 µmol/l]. Transgenic SHRSP rats containing the WKY Gstm1 gene demonstrate significantly lower BP, reduced oxidative stress and improved levels of renal Gstm1 expression. CONCLUSION: These data support the hypothesis that reduced renal Gstm1 plays a role in the development of hypertension.