Adaptive resynthesis of O6-methylguanine-accepting protein can explain the differences between mammalian cells proficient and deficient in methyl excision repair

Mammalian cells have been classified as proficient (Mer(+)) or deficient (Mer(-)) in methyl excision repair in terms of their cytotoxic reactions to agents that form O(6)-alkylguanine and their abilities to reactivate alkylated adenoviruses. O(6)-Methylguanine (O(6)MeGua) is considered to be a lethal, mutagenic, and carcinogenic lesion. We measured the abilities of cell extracts to transfer the methyl group from an exogenous DNA containing O(6)MeGua to acceptor protein. The constitutive level of acceptor activity was independent of the Mer phenotype and was approximately 100,000 acceptor sites per cell. Treatment of cells with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) results in a dose-dependent decrease in the acceptor activity in extracts because the rapid reaction between endogenous O(6)MeGua and acceptor protein makes the latter unavailable for further reaction. Treatment of cells with 1 muM MNNG for 15 min or 2 muM for approximately 2 min uses up >95% of the constitutive activity. However, Mer(+) cells, which are resistant to MNNG, rapidly resynthesize new acceptor protein, and the activity returns to the basal level in approximately 90 min. In Mer(-) tumor cells and Chinese hamster cells, which are sensitive to MNNG, resynthesis is not detectable in 90 min. Mer(-) simian virus 40-transformed fibroblasts, known to have an intermediate sensitivity to MNNG, have an intermediate resynthesis rate. Treatment of cells with multiple low doses of MNNG results in the enhanced production of O(6)MeGua-accepting protein in levels 2.5-fold above the constitutive values for Mer(+) tumor cells and to approximately 1.5-fold for Mer(+) fibroblasts or Mer(-) simian virus 40-transformed cells. Such treatments reduce the activities in Mer(-) tumor cells and Chinese hamster cells. We conclude: (i) estimates of O(6)MeGua in cellular DNA shortly after treatment may be seriously in error because of the rapid repair of this lesion, and (ii) the adaptive resynthesis of acceptor protein, not its constitutive level, is the important correlate of cell resistance to methylating agents.     

Introduction to the Special Section on Health and Cognitive Function.

Numerous factors related to health and diseases have been studied in relation to cognitive function. It has been shown that across the life span, systemic medical diseases can negatively impact cognitive function. Factors that influence the development of medical diseases, such as poor health habits, biological risk factors, hormones, genetic factors, exposure to environmental toxins, and certain treatments for disease, can also have an adverse effect on cognitive function. Conversely, factors such as high levels of education, good health habits, and some treatments for disease can be protective. Included in this special section are 6 empirical articles that examine the relation of health or disease to cognitive function. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Blood pressure reactivity and cognitive function in the Baltimore Longitudinal Study of Aging.

Objective: Several blood pressure indexes of autonomic dysregulation, including stress-induced blood pressure responses (i.e., reactivity), have been associated previously with stroke, silent cerebrovascular disease, and decreased cognitive function. Design: The authors examined the cross-sectional relations among systolic blood pressure (SBP) and diastolic blood pressure (DBP) reactivity and cognitive function in a sample of stroke- and dementia-free older adults (n = 73, 53% male, 72% Caucasian, mean age = 70.14 years) from the Baltimore Longitudinal Study of Aging. Main Outcome Measures: Age, education, baseline, and reactive blood pressure levels were regressed on cognitive test scores measuring the domains of attention, learning and memory, verbal functions/language skills, and perceptuo-motor speed. A Bonferroni correction was employed and results significant at the standard p     

Cardiovascular reactivity and central adiposity in older African Americans.

This study examined central adiposity, as measured by waist circumference (WC), in relation to mental-stress induced systolic (SBP) and diastolic blood pressure (DBP) and heart rate (HR) responses, body composition, the metabolic syndrome, and health practices in 22 older, African American men and women (ages 52–79 years). The high WC (>100 cm) group showed significantly greater SBP, DBP, and HR reactivity, greater fasting insulin levels, lower high density lipoprotein cholesterol levels, greater fat mass in both truncal and peripheral regions, and greater body mass index as compared to the low WC (     

Hostility and Distraction Have Differential Influences on Cardiovascular Recovery From Anger Recall in Women.

This study investigated the relation of dispositional hostility to cardiovascular reactivity during an anger-recall task and of hostility and distraction to posttask recovery in 80 healthy women (ages 18-30). Half were randomly assigned to distraction during recovery. Hostility predicted slower systolic blood pressure and preejection period during recovery. Distraction was related to faster cardiac recovery, higher high-frequency (HF) power, lower low-frequency (LF) power and LF:HF ratios, and lower state anger and rumination during recovery. These results indicate deleterious influences of hostility on cardiovascular recovery but not during anger recall. The findings also show beneficial effects of distraction in expediting cardiovascular recovery, possibly through reducing rumination and anger. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Hypertension and neuropsychological function: a lifespan perspective

This article explores the relationship of hypertension to neuropsychological performance from a lifespan perspective. First, I examine cross-sectional and longitudinal studies of neuropsychological performance in cohorts of young to middle-aged hypertensive patients (ages 20-60); older hypertensive patients (ages 60-80+); and the young, normotensive offspring of hypertensive parents (ages 18-25). The pattern of performance deficits associated with hypertension is generally found to differ from that related to hypertension risk. Next, I discuss potential mechanisms underlying hypertension-performance relationships in the aforementioned cohorts. I suggest that lowered levels of performance in the offspring of hypertensives reflect genetic risk for hypertension. Compromised neuropsychological function in young and middle-aged hypertensives may occur secondary to alterations in neurophysiological function that result from elevated blood pressure. Such neurophysiological changes may predispose to neuroanatomical changes in older hypertensive patients.     

Hypertension and neuropsychological performance in men: Interactive effects of age.

Potentially interactive effects of hypertension and age on the performance of neuropsychological and information processing tests were examined in 123 untreated hypertensive and 50 normotensive men. After covarying education, average alcohol consumption, trait anxiety, and depression scores, results indicated an interaction of age and hypertension. Young hypertensive men (23–40 years) scored significantly worse than young normotensive men on tests of attention/executive function and working memory; middle-aged hypertensive (41–56 years) and normotensive participants were not distinguished by any measures. Hypertensive men performed significantly more poorly than normotensive men on tests of manual dexterity. Results suggest that neuropsychological sequelae of hypertension are more pronounced in young than in middle-aged hypertensive individuals and are independent of various demographic, psychosocial, and alcohol-related factors. (PsycINFO Database Record (c) 2010 APA, all rights reserved)