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Fung M.M.,San Diego Veterans Affairs Healthcare System | Peters K.,California Pacific Medical Center Research Institute | Redline S.,Harvard University | Barrett-Connor E.,University of California at San Diego | Stone K.L.,California Pacific Medical Center Research Institute
Hypertension | Year: 2011

The importance of sleep to health and cardiovascular disease has become increasingly apparent. Sleep-disordered breathing, sleep duration, and sleep architecture may all influence metabolism and neurohormonal systems, yet no previous study has evaluated these sleep characteristics concurrently in relation to incident hypertension. Our objective was to determine whether incident hypertension is associated with polysomnography measures of sleep-disordered breathing, sleep duration, and sleep architecture in older men. Participants were 784 community-dwelling, ambulatory men 65 years of age (mean age: 75.1±4.9 years) from the Outcomes of Sleep Disorders in Older Men Study who did not have hypertension at the time of their in-home polysomnography sleep studies (2003-2005) and who returned for follow-up (2007-2009). Of 784 older men included in this report, 243 met criteria for incident hypertension after a mean follow-up of 3.4 years. In unadjusted analyses, incident hypertension was associated with increased hypoxemia, increased sleep stages N1 and N2, and decreased stage N3 (slow wave sleep [SWS]). After adjustment for age, nonwhite race, study site, and body mass index, the only sleep index to remain significantly associated with incident hypertension was SWS percentage (odds ratio for lowest to highest quartile of SWS: 1.83 [95% CI: 1.18 to 2.85]). No attenuation of this association was seen after accounting for sleep duration, sleep fragmentation, and indices of sleep-disordered breathing. Percentage time in SWS was inversely associated with incident hypertension, independent of sleep duration and fragmentation, and sleep-disordered breathing. Selective deprivation of SWS may contribute to adverse blood pressure in older men. © 2011 American Heart Association, Inc. Source


Fung M.M.,San Diego Veterans Affairs Healthcare System | Fung M.M.,University of California at San Diego | Peters K.,California Pacific Medical Center Research Institute | Ancoli-Israel S.,University of California at San Diego | And 3 more authors.
Journal of Clinical Sleep Medicine | Year: 2013

Study Objective: To evaluate whether actigraphy-measured total sleep time and other sleep characteristics predict incident hypertension in older men. Methods: Study subjects were community-dwelling participants in the ancillary sleep study of the Osteoporotic Fractures in Men Study (MrOS) who were normotensive at the time of actigraphy (based on self-report, lack of antihypertensive medication use, and with systolic blood pressure < 140 mm Hg and diastolic blood pressure < 90 mm Hg). In 853 community-dwelling men 67 years and older (mean 75.1 years), sleep measures (total sleep time [TST]), percent sleep [%-sleep], latency, and wake after sleep onset [WASO]) were obtained using validated wrist actigraphy with data collected over a mean duration of 5.2 consecutive 24-h periods. We evaluated incident hypertension (based on self-report, use of antihypertensive medication, or measured systolic blood pressure ≥ 140 mm Hg or diastolic blood pressure ≥ 90 mm Hg) at a follow-up visit an average of 3.4 years later. Baseline prehypertension was defined as a systolic blood pressure 120 to < 140 mm Hg or diastolic blood pressure 80 to < 90 mm Hg. Results: At follow-up, 31% of initially normotensive men were hypertensive (264 of 853). Those with incident hypertension had higher baseline body mass index (BMI; kg/m2) and were more likely to have had prehypertension at the sleep visit than those men who remained normotensive. However, neither TST (reference 6 to < 8 h; < 6 h OR 0.96 [95% CI 0.7, 1.3] and ≥ 8 h OR 0.93 [0.5, 1.7]) nor the other actigraphic-measured sleep variables, including % -sleep (reference > 85%; < 70% OR 1.17 [0.66, 2.08]) and 70% to ≤ 85% OR 1.23 (0.9, 1.68), sleep latency (reference < 30 min; ≥ 30 min OR 1.29 [0.94, 1.76]), or WASO (reference < 30 min; 30 to < 60 min OR 0.7 [0.43, 1.14] and ≥ 60 min OR 0.92 [0.58, 1.47]) differed in those community-dwelling men who developed incident hypertension compared to those who remained normotensive. Conclusion: TST and other sleep parameters determined by wrist actigraphy were not associated with incident hypertension in community-dwelling older men. Source


Liu H.,University of California at San Diego | Kim Y.,University of California at San Diego | Chattopadhyay S.,University of California at San Diego | Shubayev I.,San Diego Veterans Affairs Healthcare System | And 2 more authors.
Journal of Neuropathology and Experimental Neurology | Year: 2010

After peripheral nerve injury, Schwann cells (SCs) vigorously divide to survive and produce a sufficient number of cells to accompany regenerating axons. Matrix metalloproteinases (MMPs) have emerged as modulators of SC signaling and mitosis. Using a 5-bromo-2-deoxyuridine (BrdU) incorporation assay, we previously found that a broad-spectrum MMP inhibitor (MMPi), GM6001 (or ilomastat), enhanced division of cultured primary SCs. Here, we tested the hypothesis that the ability of MMPi to stimulate SC mitosis may advance nerve regeneration in vivo. GM6001 administration immediately after rat sciatic nerve crush and daily thereafter produced increased nerve regeneration as determined by nerve pinch test and growth-associated protein 43 expression. The MMPi promoted endoneurial BrdU incorporation relative to vehicle control. The dividing cells were mainly SCs and were associated with growth-associated protein 43-positive regenerating axons. After MMP inhibition, myelin basic protein mRNA expression (determined by Taqman real-time quantitative polymerase chain reaction) and active mitosis of myelin-forming SCs were reduced, indicating that MMPs may suppress their dedifferentiation preceding mitosis. Intrasciatic injection of mitomycin,the inhibitor of SC mitosis, suppressed nerve regrowth, which wasreversed by MMPi, suggesting that its effect on axonal growth promotion depends on its promitogenic action in SCs. These studies establish novel roles for MMPs in peripheral nerve repair via control ofSC mitosis, differentiation, and myelin protein mRNA expression. © 2010 by the American Association of Neuropathologists, Inc. Source


Greenwood T.A.,University of California at San Diego | Joo E.-J.,Eulji University | Shekhtman T.,San Diego Veterans Affairs Healthcare System | Sadovnick A.D.,University of British Columbia | And 4 more authors.
American Journal of Medical Genetics, Part B: Neuropsychiatric Genetics | Year: 2013

Bipolar disorder (BD) and attention deficit hyperactivity disorder (ADHD) exhibit remarkably high rates of comorbidity, as well as patterns of familial co-segregation. Epidemiological data suggests that these disorders either share a common genetic architecture or that ADHD features in BD may represent an etiologically distinct subtype. We previously used the Wender Utah Rating Scale (WURS) to assess ADHD features in BD families and identified three heritable factors relating to impulsivity, mood instability, and inattention. Linkage analysis revealed a LOD score of 1.33 for the inattention factor on 5p15.3 near the dopamine transporter gene (DAT1), which has been associated with both BD and ADHD. Pharmacological evidence also suggests a role for DAT in both disorders. We have now evaluated the association of ten DAT1 variants for the WURS total score and factors in an overlapping sample of 87 BD families. Significant associations for three SNPs were observed across the WURS measures, notably for a SNP in intron 8 with the WURS total score (P=0.007) and for variants in introns 9 and 13 with mood instability (P=0.009 and 0.004, respectively). Analysis of an independent sample of 52 BD cases and 46 healthy controls further supported association of the intron 8 variant with mood instability (P=0.005), and a combined analysis confirmed the associations of this SNP with WURS total score. Impulsivity and mood instability (P=0.002, 0.007, and 8×10-4, respectively). These data suggest that variants within DAT1 may predispose to a subtype of BD characterized by early prodromal features that include attentional deficits. © 2012 Wiley Periodicals, Inc. Source


Worley M.J.,San Diego State University | Tate S.R.,San Diego Veterans Affairs Healthcare System | Mcquaid J.R.,San Francisco Veterans Affairs Medical Center | Granholm E.L.,San Diego Veterans Affairs Healthcare System | And 2 more authors.
Substance Abuse | Year: 2013

Among substance-dependent individuals, comorbid major depressive disorder (MDD) is associated with greater severity and poorer treatment outcomes, but little research has examined mediators of posttreatment substance use outcomes within this population. Using latent growth curve models, the authors tested relationships between individual rates of change in 12-step involvement and substance use, utilizing posttreatment follow-up data from a trial of group Twelve-Step Facilitation (TSF) and integrated cognitive-behavioral therapy (ICBT) for veterans with substance dependence and MDD. Although TSF patients were higher on 12-step affiliation and meeting attendance at end-of-treatment as compared with ICBT, they also experienced significantly greater reductions in these variables during the year following treatment, ending at similar levels as ICBT. Veterans in TSF also had significantly greater increases in drinking frequency during follow-up, and this group difference was mediated by their greater reductions in 12-step affiliation and meeting attendance. Patients with comorbid depression appear to have difficulty sustaining high levels of 12-step involvement after the conclusion of formal 12-step interventions, which predicts poorer drinking outcomes over time. Modifications to TSF and other formal 12-step protocols or continued therapeutic contact may be necessary to sustain 12-step involvement and reduced drinking for patients with substance dependence and MDD. © 2013 Copyright Taylor and Francis Group, LLC. Source

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