Publications

CONTEXT

The expression of adipogenic genes in sc adipose tissue has been reported to be lower among patients with HIV-associated lipoatrophy than HIV-uninfected controls. It is unclear whether this is a result or cause of lipoatrophy.

OBJECTIVE

The objective of the study was to investigate the temporal relationships among changes in adipogenic gene expression in sc adipose tissue and changes in body fat distribution and metabolic complications in HIV-infected subjects on antiretroviral therapy.

DESIGN

This was a prospective longitudinal study.

SETTING

The study was conducted at HIV clinics in Seattle, Washington.

PARTICIPANTS

The study population included 31 HIV-infected and 12 control subjects.

INTERVENTIONS

Subjects were followed up for 12 months after they initiated or modified their existing antiretroviral regimen.

MAIN OUTCOME MEASURES

Changes in body composition, plasma lipids, insulin sensitivity, and gene expression in sc abdominal and thigh adipose tissue.

RESULTS

Subjects who developed lipoatrophy (n=10) had elevated fasting triglycerides [3.16 (sd 2.79) mmol/liter] and reduced insulin sensitivity as measured by frequently sampled iv glucose tolerance test [1.89 (sd 1.27)x10(-4) min(-1)/microU.ml] after 12 months, whereas those without lipoatrophy (n=21) did not show any metabolic complications [triglycerides 1.32 (sd 0.58) mmol/liter, P=0.01 vs. lipoatrophy; insulin sensitivity 3.52 (sd 1.91)x10(-4) min(-1)/microU.ml, P=0.01 vs. lipoatrophy]. In subjects developing lipoatrophy, the expression of genes involved in adipocyte differentiation, lipid uptake, and local cortisol production in thigh adipose tissue was significantly reduced already at the 2-month visit, several months before any loss of extremity fat mass was evident.

CONCLUSIONS

In HIV-infected subjects, lipoatrophy is associated with elevated fasting triglycerides and insulin resistance and might be caused by a direct or indirect effect of antiretroviral drugs on sc adipocyte differentiation.

Optimizing duration of participation in health promotion programs has important implications for program reach and costs. We examined data from 355 participants in EnhanceWellness (EW) to determine whether improvements in disability risk factors (depression, physical inactivity) occurred early or late in the enrollment period. Participants had a mean age of 74 years; 76% were women, and 16% were non-white. The percent depressed declined from enrollment to six months (35% to 28%, p = .001) and from six to 12 months (28% to 22%, p = .03). The percent physically inactive declined over the first six months, without substantial change thereafter (47%, 29%, and 29%). Those remaining inactive at six months had worse self-rated health and more depressive symptoms initially; a subset of those increased their physical activity by 12 months. These data suggest that enrollment could be reduced from 12 to six months without compromising favorable effects of EW participation, although additional benefits may accrue beyond six months.

Previous studies have shown that COPD adversely affects distant organs and body systems, including the brain. This pilot study aims to model the relationships between respiratory insufficiency and domains related to brain function, including low mood, subtly impaired cognition, systemic inflammation, and brain structural and neurochemical abnormalities. Nine healthy controls were compared with 18 age- and education-matched medically stable-COPD patients, half of whom were oxygen-dependent. Measures included depression, anxiety, cognition, health status, spirometry, oximetry at rest and during 6-minute walk, and resting plasma cytokines and soluble receptors, brain MRI, and MR spectroscopy in regions relevant to mood and cognition. ANOVA was used to compare controls with patients and with COPD subgroups (oxygen users [n = 9] and nonusers [n = 9]), and only variables showing group differences at p < or = 0.05 were included in multiple regressions controlling for age, gender, and education to develop the final model. Controls and COPD patients differed significantly in global cognition and memory, mood, and soluble TNFR1 levels but not brain structural or neurochemical measures. Multiple regressions identified pathways linking disease severity with impaired performance on sensitive cognitive processing measures, mediated through oxygen dependence, and with systemic inflammation (TNFR1), related through poor 6-minute walk performance. Oxygen desaturation with activity was related to indicators of brain tissue damage (increased frontal choline, which in turn was associated with subcortical white matter attenuation). This empirically derived model provides a conceptual framework for future studies of clinical interventions to protect the brain in patients with COPD, such as earlier oxygen supplementation for patients with desaturation during everyday activities.

Unintentional weight loss may occur spontaneously in older humans and animals. Further weight losses after surgery or illness in the older patients result in increased morbidity, mortality, and hospital readmission rate. A growing body of work has shown increased appetite and weight gain in response to administration of ghrelin, the "hunger hormone." We conducted two studies in senescent male Brown Norway rats to assess the ability of peripheral administration of ghrelin to increase body weight and food intake. One study assessed the effect of 2 wk of daily subcutaneous ghrelin administration (1 mg.kg(-1).day(-1)) to senescent rats in a baseline condition; a second study used the same administration protocol in an interventional experiment with aged rats subjected to a surgery with 10-15% blood loss as a model of elective surgery. In both studies, animals receiving ghrelin maintained their body weights, whereas control animals lost weight. Body weight stability was achieved in ghrelin-treated animals despite a lack of increase in daily or cumulative food intake in both experiments. Hormone and proinflammatory cytokine levels were measured before surgery and after 14 days of treatment. Ghrelin treatment appeared to blunt declining ghrelin levels and also to blunt cytokine increases seen in the surgical control group. The ability of peripheral ghrelin treatment to maintain body weights of senescent rats without concomitant increases in food intake may be due to its known ability to decrease sympathetic activity and metabolic rate, perhaps by limiting cytokine-driven inflammation.

In the event of a radiation accident or attack, it will be imperative to quickly assess the amount of radiation exposure to accurately triage victims for appropriate care. RNA-based radiation dosimetry assays offer the potential to rapidly screen thousands of individuals in an efficient and cost-effective manner. However, prior to the development of these assays, it will be critical to identify those genes that will be most useful to delineate different radiation doses. Using global expression profiling, we examined expression changes in nonimmortalized T cells across a wide range of doses (0.15-12 Gy). Because many radiation responses are highly dependent on time, expression changes were examined at three different times (3, 8, and 24 h). Analyses identified 61, 512 and 1310 genes with significant linear dose-dependent expression changes at 3, 8 and 24 h, respectively. Using a stepwise regression procedure, a model was developed to estimate in vitro radiation exposures using the expression of three genes (CDKN1A, PSRC1 and TNFSF4) and validated in an independent test set with 86% accuracy. These findings suggest that RNA-based expression assays for a small subset of genes can be employed to develop clinical biodosimetry assays to be used in assessments of radiation exposure and toxicity.

This prospective cohort study sought to identify predictors of functional decline in patients aged 65 years or older who underwent major, nonemergent abdominal or thoracic surgery in our tertiary hospital from 2006 to 2008. We used the Stanford Health Assessment Questionnaire-Disability Index (HAQ-DI) to evaluate functional decline; a 0.1 or greater increase was used to indicate a clinically significant decline. The preoperative Duke Activity Status Index (DASI) and a physical function score (PFS), assessing gait speed, grip strength, balance, and standing speed, were evaluated as predictors of decline. We enrolled 215 patients (71.2 ± 5.2 years; 56.7% female); 204 completed follow-up HAQ assessments (71.1 ± 5.3 years; 57.8% female). A significant number of patients had functional decline out to 1 year. Postoperative HAQ-DI increases of 0.1 or greater occurred in 45.3 per cent at 1 month, 30.1 per cent at 3 months, and 28.3 per cent at 1 year. Preoperative DASI and PFS scores were not predictors of functional decline. Male sex at 1 month (odds ratio [OR], 3.05; 95% confidence interval [CI], 1.41 to 6.85); American Society of Anesthesiologists class (OR, 3.41; 95% CI, 1.31 to 8.86), smoking (OR, 3.15; 95% CI, 1.27 to 7.85), and length of stay (OR, 1.09; 95% CI, 1.01 to 1.16) at 3 months; and cancer diagnosis at 1 year (OR, 2.6; 95% CI, 1.14 to 5.96) were associated with functional decline.

The entire healthcare workforce needs to be educated to better care for older adults. The purpose of this study was to determine whether fellows are being trained to teach, to assess the attitudes of fellowship directors toward training fellows to be teachers, and to understand how to facilitate this type of training for fellows. A nine-question survey adapted from a 2001 survey issued to residency program directors inquiring about residents-as-teachers curricula was developed and administered. The survey was issued electronically and sent out three times over a 6-week period. Of 144 ACGME-accredited geriatric fellowship directors from geriatric, internal medicine, and family medicine departments who were e-mailed the survey, 101 (70%) responded; 75% had an academic affiliation, 15% had a community affiliation, and 10% did not report. Academic and community programs required their fellows to teach, but just 55% of academic and 29% of community programs offered teaching skills instruction as part of their fellowship curriculum; 67% of academic programs and 79% of community programs felt that their fellows would benefit from more teaching skill instruction. Program directors listed fellow (39%) and faculty (46%) time constraints as obstacles to creation and implementation of a teaching curriculum. The majority of fellowship directors believe that it is important for geriatric fellows to become competent educators, but only approximately half of programs currently provide formal instruction in teaching skills. A reproducible, accessible curriculum on teaching to teach that includes a rigorous evaluation component should be created for geriatrics fellowship programs.

Antihypertensives are among the most commonly prescribed drugs for the elderly. Several studies have discussed the benefits of stepped-care drug therapy for hypertension in the elderly, and propranolol, methyldopa, and more recently, clonidine and prazosin have been recommended as step-two antihypertensive drugs. Recent articles omit reserpine as an alternative. A case is made for the use of reserpine by comparing factors of special importance to most elderly: cost, side-effects, frequency of dosage, number of tablets, and the effect of omitted doses.