Estrogen-related Receptor Alpha (ERRα) is Required for PGC-1α-dependent Gene Expression in the Mouse Brain.

Deficiency in peroxisome proliferator-activated receptor gamma coactivator 1-alpha. (PGC-1α) expression or function is implicated in numerous neurological and psychiatric disorders. PGC-1α is required for the expression of genes involved in synchronous neurotransmitter release, axonal integrity, and metabolism, especially in parvalbumin-positive interneurons. As a transcriptional coactivator, PGC-1α requires transcription factors to specify cell-type-specific gene programs; while much is known about these factors in peripheral tissues, it is unclear if PGC-1α utilizes these same factors in neurons. Here, we identified putative transcription factors controlling PGC-1α-dependent gene expression in the brain using bioinformatics and then validated the role of the top candidate in a knockout mouse model. We transcriptionally profiled cells overexpressing PGC-1α and searched for over-represented binding motifs in the promoters of upregulated genes. Binding sites of the estrogen-related receptor (ERR) family of transcription factors were enriched, and blockade of ERRα attenuated PGC-1α-mediated induction of mitochondrial and synaptic genes in cell culture. Localization in the mouse brain revealed enrichment of ERRα expression in parvalbumin-expressing neurons with tight correlation of expression with PGC-1α across brain regions. In ERRα null mice, PGC-1α-dependent genes were reduced in multiple regions, including neocortex, hippocampus, and cerebellum, though not to the extent observed in PGC-1α null mice. Behavioral assessment revealed ambulatory hyperactivity in response to amphetamine and impairments in sensorimotor gating without the overt motor impairment characteristic of PGC-1α null mice. These data suggest that ERRα is required for normal levels of expression of PGC-1α-dependent genes in neurons but that additional factors may be involved in their regulation.

A Role for PGC-1α in Transcription and Excitability of Neocortical and Hippocampal Excitatory Neurons.

The transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is a critical regulator of genes involved in neuronal metabolism, neurotransmission, and morphology. Reduced PGC-1α expression has been implicated in several neurological and psychiatric disorders. An understanding of PGC-1α's roles in different cell types will help determine the functional consequences of PGC-1α dysfunction and/or deficiency in disease. Reports from our laboratory and others suggest a critical role for PGC-1α in inhibitory neurons with high metabolic demand such as fast-spiking interneurons. Here, we document a previously unrecognized role for PGC-1α in maintenance of gene expression programs for synchronous neurotransmitter release, structure, and metabolism in neocortical and hippocampal excitatory neurons. Deletion of PGC-1α from these neurons caused ambulatory hyperactivity in response to a novel environment and enhanced glutamatergic transmission in neocortex and hippocampus, along with reductions in mRNA levels from several PGC-1α neuron-specific target genes. Given the potential role for a reduction in PGC-1α expression or activity in Huntington Disease (HD), we compared reductions in transcripts found in the neocortex and hippocampus of these mice to that of an HD knock-in model; few of these transcripts were reduced in this HD model. These data provide novel insight into the function of PGC-1α in glutamatergic neurons and suggest that it is required for the regulation of structural, neurosecretory, and metabolic genes in both glutamatergic neuron and fast-spiking interneuron populations in a region-specific manner. These findings should be considered when inferring the functional relevance of changes in PGC-1α gene expression in the context of disease.

Hyperactivity and cortical disinhibition in mice with restricted expression of mutant huntingtin to parvalbumin-positive cells.

Recent evidence suggests that interneurons are involved in the pathophysiology of Huntington Disease (HD). Abnormalities in the function of interneurons expressing the calcium buffer parvalbumin (PV) have been observed in multiple mouse models of HD, although it is not clear how PV-positive interneuron dysfunction contributes to behavioral and synaptic deficits. Here, we use the cre-lox system to drive expression of mutant huntingtin (mthtt) in parvalbumin (PV)-positive neurons and find that mutant mice exhibit diffuse mthtt immunoreactivity in PV-rich areas at 10months of age and mthtt aggregates in PV-positive processes at 24months of age. At midlife, mutant mice are hyperactive and display impaired GABA release in the motor cortex, characterized by reduced miniature inhibitory events and severely blunted responses to gamma frequency stimulation, without a loss of PV-positive interneurons. In contrast, 24month-old mutant mice show normalized behavior and responses to gamma frequency stimulation, possibly due to compensatory changes in pyramidal neurons or the formation of inclusions with age. These data indicate that mthtt expression in PV-positive neurons is sufficient to drive a hyperactive phenotype and suggest that mthtt-mediated dysfunction in PV-positive neuronal populations could be a key factor in the hyperkinetic behavior observed in HD. Further clarification of the roles for specific PV-positive populations in this phenotype is warranted to definitively identify cellular targets for intervention.

The impact of angiotensin II receptor blockade and the DASH diet on markers of endogenous fibrinolysis.

Hypertension is associated with impaired fibrinolysis. Both angiotensin receptor blockers (ARB) and the DASH (Dietary Approaches to Stop Hypertension) diet effectively lower blood pressure in hypertensive patients. Some evidence suggests that treatment with ARBs could increase fibrinolysis, however, data is conflicting. The impact of the DASH diet on fibrinolytic parameters is not known. Fifty-five hypertensive participants (35 African-American, 20 white) were randomly assigned to receive 8 weeks of either a control diet or the DASH diet. The diets did not differ in sodium content (approximately 3 g/day). Within each diet, individuals were randomly assigned to receive losartan or placebo for 4 weeks in double-blind, cross-over fashion. Tissue plasminogen activator (t-PA) antigen, t-PA activity, plasminogen activator inhibitor-1 (PAI-1) activity and plasma renin activity (PRA) were measured at the end of a 2-week run-in period on the control diet and after each treatment period. The DASH diet did not affect markers of fibrinolysis. Losartan significantly lowered t-PA antigen levels (-1.8 ng/mL, P = 0.045), but had no effect on t-PA or PAI-1 activities. This effect was more pronounced in whites (-4.1 ng/mL (P = 0.003)) compared with African-Americans (-0.3 ng/mL (P = 0.7), P-interaction = 0.03). Results were not materially affected by adjustment for basline values or changes in blood pressure. This study demonstrates that losartan reduces t-PA antigen levels in white, but not African-American hypertensive individuals. In contrast, the DASH diet had no significant effect on markers of fibrinolysis in whites or African-Americans.

Epidemiology of over-the-counter drug use in community dwelling elderly: United States perspective.

Among US community dwelling individuals aged > or = 65 years, about as many persons take nonprescription drugs as take prescription drugs. A review of US data from the last 2 decades indicates that the average number of over-the-counter (OTC) drugs taken daily is around 1.8, but varies with geographical area (highest in the Midwest) and race/ethnicity (lowest use among Hispanics, followed by African Americans. and highest use among Whites). Use has consistently been found to be higher in women than in men. While OTC use appears to be increasing over time, it also decreases with increase in age. The most common OTC classes used are analgesics, laxatives and nutritional supplements. Our ability to explain or to predict OTC use and change in use is poor, and further studies, particularly on use by elderly individuals of minority races, are needed.

A descriptive study of hypertension in Vietnamese Americans.

This study focused on the extent of hypertension (HTN) and risk factors in 201 Vietnamese in a Gulf Coast community. Blood pressure and pulse were measured by a Welch-Allyn Vital Signs Monitor (Model AD-9000, Armstrong Medical, Lincolnshire, IL). The survey tool consisted of demographic information, health status, medications, dietary habits, smoking and alcohol use, education, family configuration, family health history, and 12 true or false items on HTN knowledge. Participants believed that HTN was inherited, presented symptoms, was caused by stress and lack of daily exercise, and had no cure. Of the factors correlated with high blood pressure, the most significant item was the total knowledge score. Nearly 44% of the participants in this sample were hypertensive. Other significant correlation findings included smoking r = .45, p < .05) and exercise r = .15, p < .05) were related to high blood pressure. Cultural sensitivity was found to be critical in the data collection process. This study demonstrates a profound need for health education related to cardiovascular disease, smoking, and alcohol use in Vietnamese Americans.

Exposure to 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDT) in relation to bone mineral density and rate of bone loss in menopausal women.

The organochlorine pesticide 2,2-bis(p-chlorophenyl)-1,1,1,-trichloroethane (DDT) and its metabolite 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) are examples of an environmental contaminant that may have hormonal properties. Bone metabolism is both estrogen- and androgen-dependent. Exposures to various environmental endocrine disrupters can affect bone metabolism in animals, but there are no published data concerning the effect of DDE exposure on bone metabolism in humans. We hypothesized that high levels of DDE would be associated with lower bone density in peri- and postmenopausal women than in premenopausal women. Study subjects were drawn from the cohort of women who had participated in the Mount Sinai Medical Center Longitudinal Normative Bone Density Study (1984-1987). We used serum samples obtained at study entry to measure DDE levels in 103 (50 black, 53 white) women (mean age = 54.5 y [standard deviation = 5 y]). Measurements of bone mineral density at the lumbar spine and radius were made at 6-mo intervals during a 2-y period. DDE concentrations were significantly (p < .001) higher in blacks (13.9 ng/ml) than in whites (8.4 ng/ml), but there was no correlation between DDE concentration and bone density at the spine (mean levels = 1.065 g/cm2 and 1.043 g/cm2 in the lowest and highest quartiles, respectively, of DDE [trend p value = .85]) or at the radius (mean levels = 0.658 g/cm and 0.664 g/cm in the lowest and highest quartiles, respectively, of DDE [trend p value = .34]). Longitudinal analyses revealed no correlation between DDE and the rate of bone loss at either bone site. Similar results were seen in race-stratified analyses, as well as in analyses in which we controlled for lactation history and other potential confounders. We found little evidence that chronic low-level DDT exposure is associated with bone density in peri- and postmenopausal women.

When choosing injectable penicillin for the treatment of group A beta-hemolytic streptococcal pharyngitis, there is a less painful choice.

OBJECTIVE: To determine whether injection of patients with Bicillin CR is less painful than injection with Bicillin LA. To discover if Bicillin CR with the addition of procaine, which doubles the volume, causes the injection to be less painful. DESIGN: An experimental, double-blinded crossover design was used for this study. SETTING: University children's and women's tertiary care emergency Department (ED) with an annual pediatric census of 22,000. PARTICIPANTS: A convenience sample was enrolled from the student body of a large university and house staff, and employees of a 152 bed children's and women's hospital in southern Alabama. The sample size was limited to 50 participants, all of whom completed the study. METHODS: Each participant received two penicillin injections, one Bicillin CR and one Bicillin LA, and rated the pain of the injection immediately after the injection, 1 hour after the injection and 12 hours after the injection. A visual analogue scale was the tool used for measuring the pain. The penicillin injections were randomized using a random number generator. RESULTS: For each of the three periods, comparisons of pain were made between the Bicillin CR versus Bicillin LA injections. Bicillin LA pain score values were consistently higher for all but the 12-hour comparison. These differences were statistically significant (P < 0.008-0.002). CONCLUSIONS: Injection of Bicillin CR with the addition of procaine to the benzathine penicillin G is statistically significantly less painful than the injection of Bicillin LA without the addition of procaine to the benzathine penicillin G, even though the Bicillin LA is one-half the volume of the Bicillin CR due to the addition of procaine to the Bicillin CR.

Association of race and other potential risk factors with nonvertebral fractures in community-dwelling elderly women.

This study determined potential associations of sociodemographic, lifestyle, health, and drug use factors known to affect bone metabolism with incident nonvertebral fractures. The baseline sample consisted of 2,590 female, nonproxy subjects from the Duke Established Populations for Epidemiologic Studies of the Elderly, which focuses on five adjacent counties in the Piedmont area of North Carolina. Information about potential risk factors was collected during a baseline in-home interview during 1986-1987. Subsequent nonvertebral fractures were reported at follow-up interviews during the annual follow-up periods (1988-1993). The authors used multivariate analyses in which weighted data were adjusted for sampling design. After controlling for other potential confounding sociodemographic, lifestyle, health, and drug use factors, they found that African American race (adjusted odds ratio (OR) = 0.43, 95% confidence interval (CI) 0.31-0.58), age (adjusted OR = 1.04, 95% CI 1.01-1.06), alcohol consumption (adjusted OR = 1.61, 95% CI 1.01-2.57), being underweight (adjusted OR = 1.63, 95% CI 1.13-2.34), cognitive impairment (adjusted OR = 1.67, 95% CI 1.12-2.48), impaired mobility (adjusted OR = 1.15, 95% CI 1.03-1.29), and phenytoin use (adjusted OR = 2.93, 95% CI 1.04-8.30) were associated with first fracture occurrence. Similar findings were observed for nonhip, nonvertebral fractures. African Americans were less likely than Whites to have nonvertebral fractures, and these differences were not related to lifestyle or health factors examined in this study.

Osteoporosis and African American women.

The incidence of osteoporosis and related fractures in African American women is half that of Caucasian women. African American women who sustain osteoporosis-related fractures have increased disability and decreased survival. Given the exponential increase in hip fracture rate among African American women over the age of 70 years, the risk of osteoporosis among this population may be underestimated. This review focuses on racial differences in women's bone mineral density (BMD) and bone metabolism and on various explanations for these observed differences. Environmental risk factors for osteoporosis and related fractures among African American women and modalities for prevention and treatment of osteoporosis are discussed. African American women begin menopause with higher BMD and have lower rates of women's bone loss after menopause, which account for their decreased incidence of osteoporosis and related fractures. The risk factors for osteoporosis among African American women are similar to those found in Caucasian women. Lifestyle interventions, such as calcium and vitamin D supplementation, smoking cessation, and increased physical activity, should be encouraged to enhance peak bone mass and to decrease bone loss. These interventions and other treatment modalities, such as hormone replacement therapy, bisphosphonates, and selective estrogen receptor modulators, should be studied further in African American women.

The clinical nurse researcher in a military setting: bringing practice into research.

The clinical nurse researcher (CNR) is emerging as an integral part of every major medical center. The CNR has six basic roles: facilitate the conduct of research projects; stimulate staff to conduct research: upgrade the research skills of the staff; participate on committees related to research; conduct and disseminate research; and obtain funding for research studies. Readiness issues for military missions, health promotion, and disease management and prevention are consistently of interest. The CNR should be an active participant on the institutional review board and should conduct primary studies that further the reputation of the facility. The viability of any military research program today is contingent on procurement of funding; therefore, the CNR must refine skills in grantsmanship. The demands of the medical facility and the needs of the staff must be a prime consideration in the development of the role of the CNR.

The effects of a short-term exercise program on movement, pain, and mood in the elderly. Results of a pilot study.

Therapeutic effects of a short-term Tai Chi exercise program for the elderly were evaluated in a pretest-posttest quasi-experimental design. This pilot study evaluated changes in flexibility, balance, sway, pain, and mood after a short slow-motion exercise. The program consisted of a series of movements involving turning, shifting weight, bending, and arm movements in combination with diaphragmatic breathing with slow movements. The measured effects included improved balance, sway, range of motion, decreased perceived pain, and lessened trait anxiety. Participants included 11 elderly females. Instruments consisted of standard goniometry, the Multiple Affect Adjective Check List, stopwatch measures of single-leg stance and a tandem walk (sway), and visual analog measurement of pain. Findings included significant improvement (p = .05) in trait anxiety and pain perception. Improvements in mood, flexibility, and balance may have a profound effect on the incidence of falls, injuries, resulting disability, and overall quality of life.

The prevalence and 3-year incidence of dementia in older Black and White community residents.

OBJECTIVE: To determine the prevalence and 3-year incidence of dementia in Blacks and Whites age 65 and older in a five-county Piedmont area of North Carolina. DESIGN: Stratified random sample of members of the Duke Established Populations for Epidemiologic Studies of the Elderly (EPESE) (baseline n = 4,136; 55% Black; weighted n = 28,000). Prevalence study members were differentially selected on the basis of score on the Short Portable Mental Status Questionnaire at the second in-person Duke EPESE wave. Incidence study members included all persons with obvious cognitive decline over a 3-year period, and a 10% sample of the remainder. MEASUREMENTS: Self- and informant report on health history, functional status, and memory. Consortium to Establish a Registry for Alzheimer's Disease (CERAD) Neuropsychology Battery administered to all subjects, and CERAD Clinical Battery to those with impaired memory. Clinical consensus to determine presence and type of dementia. RESULTS: Prevalence of dementia for persons > or =68 years old was 0.070 (95% confidence interval = 0.021-0.119) for Blacks and 0.072 (0.022-0.122) for Whites. Rates for Black men (0.078, 0.001-0.155) exceeded those for Black women (0.066, 0.003-0.129), but gender rates for Whites were reversed (men: 0.044, 0.000-0.103), (women: 0.087, 0.015-0.160). Neither race nor gender differences were significant. Prevalence of dementia increased through age 84 and tapered off thereafter. Three-year incidence of dementia was 0.058 (0.026-0.090) for Blacks and 0.062 (0.027-0.097) for Whites. Neither race nor gender differences were significant. Incidence increased through age 84, but moderated thereafter for all but Black men. The proportional representation of different types of dementia varied little by race. CONCLUSION: Prevalence, 3-year incidence, and types of dementia are comparable in Black and White elderly in the Piedmont area of North Carolina.

Drug-induced bone disease.

Drugs can cause accelerated bone loss as well as disturbances in serum calcium levels. This article focuses on chemically induced bone diseases that commonly affect the elderly and result in either osteoporosis, osteomalacia, hypercalcemia or hypocalcemia. Also discussed are drugs that increase the risk of falls, putting those patients with osteoporosis at a greater risk for future.