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ATM mediates repression of DNA end-degradation in an ATP-dependent manner
(Elsevier, 2008) Rahal, Elias A.; Henricksen, Leigh A.; Li, Yuling; Turchi, John J.; Pawelczak, Katherine S.; Dixon, Kathleen; Medicine, School of Medicine
Ataxia telangiectasia mutated (ATM) is a PI3-kinase-like kinase (PIKK) associated with DNA double-strand break (DSB) repair and cell cycle control. We have previously reported comparable efficiencies of DSB repair in nuclear extracts from both ATM deficient (A-T) and control (ATM+) cells; however, the repair products from the A-T nuclear extracts contained deletions encompassing longer stretches of DNA compared to controls. These deletions appeared to result from end-joining at sites of microhomology. These data suggest that ATM hinders error-prone repair pathways that depend on degradation of DNA ends at a break. Such degradation may account for the longer deletions we formerly observed in A-T cell extracts. To address this possibility we assessed the degradation of DNA duplex substrates in A-T and control nuclear extracts under DSB repair conditions. We observed a marked shift in signal intensity from full-length products to shorter products in A-T nuclear extracts, and addition of purified ATM to A-T nuclear extracts restored full-length product detection. This repression of degradation by ATM was both ATP-dependent and inhibited by the PIKK inhibitors wortmannin and caffeine. Addition of pre-phosphorylated ATM to an A-T nuclear extract in the presence of PIKK inhibitors was insufficient in repressing degradation, indicating that kinase activities are required. These results demonstrate a role for ATM in preventing the degradation of DNA ends possibly through repressing nucleases implicated in microhomology-mediated end-joining.
Rating neighborhoods for older adult health: results from the African American Health study
(BioMed Central, 2008-01-25) Andresen, Elena M.; Malmstrom, Theodore K.; Wolinsky, Fredric D.; Schootman, Mario; Miller, J. Philip; Miller, Douglas K.; Medicine, School of Medicine
Background: Social theories suggest that neighborhood quality affects health. Observer ratings of neighborhoods should be subjected to psychometric tests.
Methods: African American Health (AAH) study subjects were selected from two diverse St. Louis metropolitan catchment areas. Interviewers rated streets and block faces for 816 households. Items and a summary scale were compared across catchment areas and to the resident respondents' global neighborhood assessments.
Results: Individual items and the scale were strongly associated with both the catchment area and respondent assessments. Ratings based on both block faces did not improve those based on a single block face. Substantial interviewer effects were observed despite strong discriminant and concurrent validity.
Conclusion: Observer ratings show promise in understanding the effect of neighborhood on health outcomes. The AAH Neighborhood Assessment Scale and other rating systems should be tested further in diverse settings.
“Acting” on GLUT4: Membrane & Cytoskeletal Components of Insulin Action
(Bentham Science, 2007) Brozinick, Joseph T., Jr.; Berkemeier, Bradley A.; Elmendorf, Jeffrey S.; Cellular and Integrative Physiology, School of Medicine
The dissection of mechanisms that regulate glucose transport by insulin has revealed an intricate network of signaling molecules scattered from the insulin receptor to the intracellular glucose transporter GLUT4. It is also appreciated that some insulin receptor signals jaunt in different directions to regulate events essential for the efficient redistribution of GLUT4 to the plasma membrane. Moreover key assists in the process appear to be arranged by membrane lipids and cytoskeletal proteins. Following current considerations of insulin signals regulating GLUT4, this review will focus on in vitro and in vivo evidence that supports an essential role for phosphoinositides and actin filaments in the control of glucose transport. The discussion will visit recent cell culture, whole animal, and human data highlighting membrane and cytoskeletal aspects of insulin resistance.
Predictors of serum testosterone and DHEAS in African-American men
(Wiley, 2008) Haren, Matthew T.; Banks, William A.; Perry, H. M., III; Patrick, Ping; Malmstrom, Theodore K.; Miller, Douglas K.; Morley, John E.; Medicine, School of Medicine
There are few reported data on biochemical and functional correlates of androgen levels in African-American men. This study aimed at reporting physical and biochemical correlates of serum total testosterone (total T), bioavailable testosterone (BT) and dehydroepiandrosterone-sulphate (DHEAS) levels in community-dwelling, African-American men aged 50-65 years. Home-based physical examinations and health status questionnaires were administered to randomly sampled men. Body composition (dual-energy X-ray absorptiometry), lower limb and hand-grip muscle strength, and neuropsychological functions were assessed. Levels of serum total T, BT, DHEAS, oestradiol (E2), adiponectin, leptin, triglycerides and glucose were measured. Multiple linear regression models were constructed to identify factors independently associated with androgen levels. DHEAS levels declined from age 50 to 65 years (p < 0.0001), but total T and BT levels remained constant. Independent of other associated factors, higher total T levels were associated with lower serum triglyceride levels (beta = -0.142, p = 0.049); higher BT was associated with better performance on the trail-making tests (TMT-B:TMT-A ratio: beta = -0.118, p = 0.024) and higher DHEAS levels were associated with lower adiponectin (beta = -0.293, p = 0.047) and higher mini-mental state examination (MMSE) score (beta = 0.098, p = 0.008). Multiple regression models predicted 21, 18 and 29% of variance in total T, BT and DHEAS, respectively. Higher total T levels were associated with serum metabolic markers, particularly lower triglycerides, whereas higher BT was associated with better cognitive and muscle function and DHEAS with lower adiponectin and higher MMSE scores.
Can teaching agenda-setting skills to physicians improve clinical interaction quality? A controlled intervention
(BioMed Central, 2008-01-14) Rodriguez, Hector P.; Anastario, Michael P.; Frankel, Richard M.; Odigie, Esosa G.; Rogers, William H.; von Glahn, Ted; Safran, Dana G.; Medicine, School of Medicine
Background: Physicians and medical educators have repeatedly acknowledged the inadequacy of communication skills training in the medical school curriculum and opportunities to improve these skills in practice. This study of a controlled intervention evaluates the effect of teaching practicing physicians the skill of "agenda-setting" on patients' experiences with care. The agenda-setting intervention aimed to engage clinicians in the practice of initiating patient encounters by eliciting the full set of concerns from the patient's perspective and using that information to prioritize and negotiate which clinical issues should most appropriately be dealt with and which (if any) should be deferred to a subsequent visit.
Methods: Ten physicians from a large physician organization in California with baseline patient survey scores below the statewide 25th percentile participated in the agenda-setting intervention. Eleven physicians matched on baseline scores, geography, specialty, and practice size were selected as controls. Changes in survey summary scores from pre- and post-intervention surveys were compared between the two groups. Multilevel regression models that accounted for the clustering of patients within physicians and controlled for respondent characteristics were used to examine the effect of the intervention on survey scale scores.
Results: There was statistically significant improvement in intervention physicians' ability to "explain things in a way that was easy to understand" (p = 0.02) and marginally significant improvement in the overall quality of physician-patient interactions (p = 0.08) compared to control group physicians. Changes in patients' experiences with organizational access, care coordination, and office staff interactions did not differ by experimental group.
Conclusion: A simple and modest behavioral training for practicing physicians has potential to positively affect physician-patient relationship interaction quality. It will be important to evaluate the effect of more extensive trainings, including those that work with physicians on a broader set of communication techniques.