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G Howard

Publications and source records attributed to G Howard.

At least 37 records · Page 2Linked to original sources
PubMed2000

Effect of contralateral occlusion on long-term efficacy of endarterectomy in the asymptomatic carotid atherosclerosis study (ACAS). ACAS Investigators.

BACKGROUND AND PURPOSE: The Asymptomatic Carotid Atherosclerosis Study (ACAS) established the effectiveness of prophylactic carotid endarterectomy, for patients in good health who had stenosis >/=60%, if conducted by surgeons with a surgical morbidity and mortality of <3%. This secondary analysis was performed to determine whether the presence of contralateral cervical carotid occlusion alters the efficacy of asymptomatic ipsilateral carotid endarterectomy. METHODS: One hundred sixty-three participants who had a baseline contralateral occlusion documented by Doppler ultrasound (77 medical, 86 surgical) were compared with 1485 participants with a patent contralateral carotid artery (748 medical, 737 surgical) for the risk of a combined end point of perioperative (30-day) death or stroke or long-term (5-year) ipsilateral stroke. RESULTS: For those without contralateral occlusion, surgery was associated with a 6.7% absolute reduction in the 5-year risk (95% CI, 2.1% to 11.4%), while for those with a contralateral occlusion, surgery was associated with a 2.0% absolute increase in risk (95% CI, -9.3% to 5.2%), which was a statistically significant difference in the effect of surgery (P:=0.047). This difference is primarily attributable to low long-term risk for medically managed patients with contralateral occlusion. CONCLUSIONS: While this post hoc analysis should be interpreted with caution, the findings suggest that endarterectomy in asymptomatic subjects with contralateral occlusion provides no long-term benefit (and may be harmful) in preventing stroke and death. These findings were a result of the benign course of medically treated subjects.

Aged↗
PubMed2000

A comparison of the extent and impacts of sewage contamination on urban groundwater in developed and developing countries.

In much of the world urban groundwater is an important resource for domestic and industrial use. In many developing countries, groundwater taken directly (untreated) from individual springs and wells is the only option available to communities where comprehensive, reliable reticulated supply systems are absent. A common feature of urban groundwater in both developing and developed countries is contamination by sewage. Current and recent research is presented that shows sewer leakage impacts groundwater in developed countries whilst on-site sanitation contaminates groundwater in developing countries. In the latter case, the competing demands of sanitation and groundwater protection must be addressed. Limitations on the usefulness of accepted standard sewage indicator species in groundwater are also highlighted. As sewage contamination of groundwater is usually addressed only if an actual health risk is posed, it is vital both to developed and developing countries to understand the movement of actual pathogens in groundwater in the context of groundwater management. Further research is required on microbial survival and health risks posed by sewage contamination.

Cross-Cultural Comparison↗
PubMed1999

Activities of conjugating and antioxidant enzymes following endotoxin exposure.

Endotoxin exposure elicits various responses in mammals including the acute phase response that has been shown to cause changes in the activity of several forms of cytochrome P450s and other enzymes. Therefore, the hepatic conjugating enzyme, glutathione S-transferase (GST), and UDP-glucuronosyltransferase (UDPGT), the antioxidant enzymes, glutathione peroxidase (GSHPx), catalase, and superoxide dismutase (SOD), as well as lipid peroxidation were investigated following the administration of endotoxin to male Sprague-Dawley rats (8 mg/kg body weight). Rats were euthanized at various times following endotoxin administration and the livers removed and processed to assess various enzyme activities. Glutathione S-transferase, UDPGT, and GSHPx activity showed statistically significant decreases after 24 hours and remained lower than controls for the duration of the study. Decreases in total SOD and catalase activities were seen at 24, 48, and 72 hours following endotoxin administration; however, only catalase activity showed statistically significant differences between control and treated samples at those time points, and total SOD activity showed a statistically significant decrease at 24 hours. No statistically significant changes were seen in the level of lipid peroxidation in the liver microsomes from endotoxin-treated animals. Changes in the conjugative enzymes and the free-radical scavenging enzymes following endotoxin exposure may alter the host's metabolism and response to free radicals.

Animals↗
PubMed1999

Characterization of cytochrome P450 and glutathione S-transferase activity and expression in male and female ob/ob mice.

OBJECTIVE: To characterize the effect(s) of gender, age (glycemic status) and obese state, on hepatic biotransformation activities, expression of cytochrome P450 (CYP450) mRNAs and glutathione transferase activity in the ob/ob mouse. DESIGN: Male and female, ob/ob or ob/+ mice were killed at 3-4 months or 7-8 months of age. Hepatic microsomes, cytosol and RNA were prepared from each animal. ANIMALS: Male and female ob/ob and ob/+ mice, 3-4 or 7-8 months of age. MEASUREMENTS: CYP450 form-specific activities of CYP1A1/1A2, CYP3A and CYP2B were estimated by determining the 0-dealkylation of alkoxyresorufin substrates (ethoxy-EROD, benzoxy-BROD and pentoxy-resorufin, PROD, respectively). CYP2E1-dependent, 4-nitrophenol hydroxylase (PNP-OH) and CYP3A-dependent erythromycin N-demethylase (ERY-DM) were also measured in hepatic microsomes. CYP1A2, CYP2E1 and CYP3A protein in microsomal fractions was determined by ELISA. Glutathione transferase activity (GST) was determined in hepatic cytosol and CYP1A2 and CYP2E1 mRNA was estimated by Northern blot analysis. RESULTS: Female mice, regardless of glycemic status, showed an obesity enhanced level of CYP2E1-dependent PNP-OH activity and CYP2E1 protein as shown by ELISA. These increases were observed to be independent of the diabetic state, since 7-8 month-old mice had blood glucose levels identical to lean mice. The mRNA level of CYP2E1 in female mice also exhibited age-and obesity-influenced decreases in expression. No significant differences in CYP2E1 activity or expression were observed in male mice. CYP3A-dependent ERY-DM activity was significantly higher in young males, regardless of phenotype. CYP3A and CYP2B activities did not differ among any animals; however, CYP1A activity, while depressed in obese animals of both genders, was significantly different in old animals. Glutathione S-transferase activity was lower in obese male mice, whereas no difference was observed between lean and obese females CONCLUSION: This study supports earlier observations in man and rats that the obese state produces alterations in the expression of important oxidation and conjugation pathways. In addition, this report more thoroughly examines the role of gender and glycemic status on biotransformation activities in the ob/ob mouse as demonstrated by increased CYP2E1 protein and CYP2E1-dependent activity in obese females, decreased CYP1A2 protein and CYP1A2-dependent activity in obese animals, and obesity had no effect of glutathione transferase in female mice, in contrast with the previously reported obesity-dependent decrease of this activity in male mice.

Aging↗
PubMed1999

Communication between older adults and their physicians about urinary incontinence.

BACKGROUND: Urinary incontinence (UI) is a common but undertreated condition in older adults. The study objective was to determine older patients' characteristics related to communication patterns with their physicians about UI. METHODS: Telephone surveys of a sample of patients age 60 and older who visited a primary care provider (PCP) for any reason within the past 2 months were conducted. Participating physicians included general internists and family physicians from 41 primary care practices located in the 17 counties of northwest North Carolina whose 435 incontinent and 711 continent patients completed the surveys. The main outcome measures were patients' frequency and amount of urinary leakage, being asked about incontinence, and initiating a discussion of incontinence if not asked by their PCP. RESULTS: Age and gender were significant independent predictors of incontinence. PCPs were significantly more likely to assess incontinent women than incontinent men (21% vs 10%, p = .053). The older cohorts of older adults were significantly more likely to be symptomatic for UI than their younger counterparts. However, the younger cohorts were more likely to be screened for incontinence by their physicians. CONCLUSIONS: Despite the publication of guidelines on improving the screening and management of UI, the problem remains common and underdetected in older adults. Physicians don't ask and patients don't tell. Interventions are needed to remind physicians to screen high risk patients and to encourage patients with UI to communicate with their physicians.

Age Factors↗
PubMed1999

Why do we have a stroke belt in the southeastern United States? A review of unlikely and uninvestigated potential causes.

Although there is widespread recognition of a region with high stroke mortality in the southeastern United States that has persisted over the past 50 years (ie, the "stroke belt"), there is little agreement as to its underlying cause(s). Herein, we review data supporting 10 potential causes for the stroke belt, and assess: (1) the likelihood that each is the contributing factor to the excess mortality, and (2) areas of investigation where data are lacking and that require additional research efforts.

Black or African American↗
PubMed1999

Stroke incidence and survival among middle-aged adults: 9-year follow-up of the Atherosclerosis Risk in Communities (ARIC) cohort.

BACKGROUND AND PURPOSE: Although stroke mortality rates in the United States are well documented, assessment of incidence rates and case fatality are less well studied. METHODS: A cohort of 15 792 men and women aged 45 to 64 years from a population sample of households in 4 US communities was followed from 1987 to 1995, an average of 7. 2 years. Incident strokes were identified through annual phone contacts and hospital record searching and were then validated. RESULTS: Of the 267 incident definite or probable strokes, 83% (n=221) were categorized as ischemic strokes, 10% (n=27) were intracerebral hemorrhages, and 7% (n=19) were subarachnoid hemorrhages. The age-adjusted incidence rate (per 1000 person-years) of total strokes was highest among black men (4.44), followed by black women (3.10), white men (1.78), and white women (1.24). The black versus white age-adjusted rate ratio (RR) for ischemic stroke was 2.41 (95% CI, 1.85 to 3.15), which was attenuated to 1.38 (95% CI, 1.01 to 1.89) after adjustment for baseline hypertension, diabetes, education level, smoking status, and prevalent coronary heart disease. There was a tendency for the adjusted case fatality rates to be higher among blacks and men, although none of the case fatality comparisons across sex or race was statistically significant. CONCLUSIONS: After accounting for established baseline risk factors, blacks still had a 38% greater risk of incident ischemic stroke compared with whites. Identification of new individual and community-level risk factors accounting for the elevated incidence of stroke requires further investigation and incorporation into intervention planning.

Age Distribution↗
PubMed1999

Environmental tobacco smoke and measures of subclinical vascular disease.

Assessing the relationship of exposure to environmental tobacco smoke (ETS) with subclinical measures of atherosclerotic disease supplements the epidemiologic data on fatal and nonfatal cardiovascular events. In addition, such assessment offers the opportunity to study smaller populations (including subgroups within larger studies) through improved statistical precision relative to the analysis of the relationship of ETS and clinical events and provides insights into the mechanisms of the harmful effects of ETS. In this article we review the published literature on the relationship of ETS with several indices of subclinical atherosclerosis including carotid artery intimal-medial thickness, brachial artery endothelial functioning, and silent cerebral infarctions. In each of these domains, exposure to ETS is associated with evidence of increased subclinical vascular disease.

Arteriosclerosis↗
PubMed1999

Why is environmental tobacco smoke more strongly associated with coronary heart disease than expected? A review of potential biases and experimental data.

Despite exposure levels estimated to be equivalent to smoking only 0. 1-1.0 cigarettes per day, exposure to environmental tobacco smoke (ETS) is estimated to increase the risk of death from coronary heart disease (CHD) between 25 and 35% above the risk of nonexposed persons. This surprisingly large risk associated with a seemingly small exposure has raised doubts about the validity of attributing the increased CHD risk to ETS exposure. This paper reviews various biases that have been hypothesized to account for the increased CHD risk associated with ETS in the epidemiologic studies and characterizes the adverse effects of ETS on thrombosis, vascular endothelium, and exercise tolerance observed in experimental studies of humans and laboratory animals. None of the identified factors that has been proposed to introduce a spurious association between ETS and heart disease seem to invalidate the epidemiologic findings, either separately or in combination. In addition, experimental studies of ETS and heart disease demonstrate that acute exposure of humans and other species to ETS affects platelet function, vascular endothelium, and myocardial exercise tolerance at exposure concentrations widely prevalent in the workplace. Because exposure to ETS affects multiple physiologic pathways, it appears biologically plausible that ETS could cause the substantial increase in CHD risk that has been observed in epidemiologic studies.

Animals↗
PubMed1999

Prospective associations of fasting insulin, body fat distribution, and diabetes with risk of ischemic stroke. The Atherosclerosis Risk in Communities (ARIC) Study Investigators.

OBJECTIVE: We tested the hypothesis that diabetes, body fat distribution, and (in nondiabetic subjects) fasting insulin levels are positively associated with ischemic stroke incidence in the general population. RESEARCH DESIGN AND METHODS: As part of the Atherosclerosis Risk in Communities (ARIC) Study, we measured diabetes by using fasting glucose criteria, waist and hip circumferences, and fasting insulin levels with a radioimmunoassay in > 12,000 adults aged 45-64 years who had no cardiovascular disease at baseline. We followed them for 6-8 years for ischemic stroke occurrence (n = 191). RESULTS: After adjustment for age, sex, race, ARIC community, smoking, and education level, the relative risk of ischemic stroke was 3.70 (95% CI 2.7-5.1) for diabetes, 1.74 (1.4-2.2) for a 0.11 increment of waist-to-hip ratio, and 1.19 (1.1-1.3) for a 50-pmol/l increment of fasting insulin among nondiabetic subjects. Ischemic stroke incidence was not statistically significantly associated with BMI (comparably adjusted relative risk = 1.15, 95% CI 0.97-1.36). With adjustment for other stroke risk factors (some of which may mediate the effects of diabetes, fat distribution, and hyperinsulinemia), the relative risks for diabetes, waist-to-hip ratio, and fasting insulin level were 2.22 (95% CI 1.5-3.2), 1.08 (0.8-1.4), and 1.14 (1.01-1.3), respectively. CONCLUSIONS: Diabetes is a strong risk factor for ischemic stroke. Aspects of insulin resistance, as reflected by elevated waist-to-hip ratios and elevated fasting insulin levels, may also contribute to a greater risk of ischemic stroke.

Adipose Tissue↗
PubMed1999

Effect of leptin on cytochrome P-450, conjugation, and antioxidant enzymes in the ob/ob mouse.

Leptin is a hormone that is secreted by adipocytes and regulates body weight through its effect on satiety and energy metabolism. The ob/ob mouse is deficient in this protein and is characterized by obesity and other metabolic disorders. This study investigated the alterations of several hepatic cytochrome P-450 (CYP), conjugation, and antioxidant enzymes in lean and ob/ob mice and the role leptin plays in the modulation of these enzymes. Lean and ob/ob male mice were injected with leptin (100 microg) or PBS for 15 days. Liver microsomes from ob/ob mice, when compared with lean controls, displayed significantly reduced chlorzoxazone 6-hydroxylation activity (27%); however, 7alpha- and 16alpha- testosterone hydroxylation and pentoxyresorufin O-dealkylation activities were significantly higher (47%, 22%, and 39%, respectively). Leptin administration corrected alterations seen with all P-450 activities. Dealkylation of ethoxyresorufin and omega-hydroxylation of lauric acid activities from ob/ob and lean mice were not statistically different; however, leptin exposure significantly increased ethoxyresorufin activity in lean mice (14%) and decreased the activity in ob/ob mice (36%). UDP-glucuronosyl-transferase and glutathione S-transferase activities were not altered. The antioxidant enzymes, catalase (11%) and glutathione peroxidase (26%), as well as glutathione reductase (17%), were lower in the ob/ob mice and leptin treatment corrected these alterations. The results of this study demonstrate alterations in constitutive expression of CYP2B, CYP2E, CYP2A, catalase, glutathione peroxidase, and glutathione reductase in ob/ob mice that were restored to lean control values following leptin treatment. Additionally, CYP3A activity was increased following leptin treatment in ob/ob mice. The mechanism for the observed alterations may be due to direct leptin effects or via indirect alterations in insulin, corticosterone, and/or growth hormone.

Animals↗
PubMed1998

Cigarette smoking and progression of atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study.

CONTEXT: Cigarette smoking is a powerful risk factor for incident heart disease and stroke, but the relationship of active and passive smoking with the progression of atherosclerosis has not been described. OBJECTIVE: To examine the impact of active smoking and exposure to environmental tobacco smoke (ETS) on the progression of atherosclerosis. DESIGN: A longitudinal assessment of the relationship between smoking exposure evaluated at the initial visit and the 3-year change in atherosclerosis. SETTING: A population-based cohort of middle-aged adults from 4 communities in the United States. PARTICIPANTS: A total of 10914 participants from the Atherosclerosis Risk in Communities (ARIC) study enrolled between 1987 and 1989. MAIN OUTCOME MEASURE: Change in atherosclerosis from baseline to the 3-year follow-up as indexed by intimal-medial thickness of the carotid artery assessed by ultrasound and adjusted for demographic characteristics, cardiovascular risk factors, and lifestyle variables. RESULTS: Exposure to cigarette smoke was associated with progression of atherosclerosis. Relative to never smokers and after adjustment for demographic characteristics, cardiovascular risk factors, and lifestyle variables, current cigarette smoking was associated with a 50% increase in the progression of atherosclerosis (mean progression rate over 3 years, 43.0 microm for current and 28.7 microm for never smokers, regardless of ETS exposure), and past smoking was associated with a 25% increase (mean progression rate over 3 years, 35.8 microm for past smokers and 28.7 microm for never smokers). Relative to those not exposed to ETS, exposure to ETS was associated with a 20% increase (35.2 microm for those exposed to ETS vs 29.3 microm for those not exposed). The impact of smoking on atherosclerosis progression was greater for subjects with diabetes and hypertension. Although more pack-years of exposure was independently associated with faster progression (P<.001), after controlling for the number of pack-years, the progression rates of current and past smokers did not differ (P=.11). CONCLUSIONS: Both active smoking and ETS exposure are associated with the progression of an index of atherosclerosis. Smoking is of particular concern for patients with diabetes and hypertension. The fact that pack-years of smoking but not current vs past smoking was associated with progression of atherosclerosis suggests that some adverse effects of smoking may be cumulative and irreversible.

Arteriosclerosis↗
PubMed1998

Characterization of nuclear protein binding (AP-1, GR, and STAT) in the genetically obese (fa/fa) Zucker rat.

There is evidence to suggest that obese populations have an increased susceptibility to various pathologic disorders. Both AP-1 and STAT nuclear binding proteins have been suggested to play a role in certain obesity-related diseases. The objective of our studies reported herein was to compare constitutive binding activity of nuclear proteins (AP-1, GR, and STAT), that may be relevant to obesity-related diseases in the obese (fa/fa) Zucker rat to lean (Fa/?) littermates. AP-1, GR, and STAT liver nuclear protein binding activity was analyzed using the electrophoretic mobility shift assay (EMSA). EMSA analysis of liver nuclear protein from obese and lean Zucker rats revealed high constitutive AP-1 binding activity in the obese animals. AP-1 binding activity in the obese rats was not further elevated by treatment with phenobarbital, a known inducer of AP-1 binding activity. No differences were observed in GR binding to a consensus GRE between obese and lean animals; however, STAT binding activity to a consensus GAS element was lower in liver tissue from obese Zucker rats. Our findings presented herein suggest that the fa/fa Zucker rat may be a suitable obese rodent model for studying the roles AP-1 and STAT may play in the pathologies of these diseases.

Animals↗
PubMed1998

Alfentanil decreases the excitatory phenomena of sodium methohexital.

STUDY OBJECTIVE: To evaluate the effects of alfentanil or lidocaine on the excitatory phenomena (myoclonus, cough, hiccough) caused by methohexital anesthesia and on the hemodynamic changes induced by retrobulbar block. DESIGN: Prospective, randomized, placebo-controlled, double-blind study. SETTING: University-affiliated, tertiary-care hospital. PATIENTS: 60 ASA physical status II and III patients who were admitted for elective cataract extractions and intraocular lens implantations. INTERVENTIONS: Patients were randomly assigned to one of three groups. After adequate preoxygenation in the holding area, Group 1 received alfentanil 5 micrograms/kg intravenously (i.v.), Group 2 received lidocaine 1 mg/kg i.v. and Group 3 received the placebo (saline) i.v. Immediately after the bolus injection of the study solution, sodium methohexital 1.5 mg/kg was injected i.v. over 30 seconds. As soon as the eyelid reflex was lost, the retrobulbar block was placed over 5 seconds. MEASUREMENTS AND MAIN RESULTS: Occurrences of excitatory phenomena were recorded by an independent observer who was blinded as to treatment allocation. Other side effects such as oculocardiac reflex, nausea, vomiting, itching, or chest wall rigidity were recorded. Vital signs were recorded at baseline and 1, 3, and 5 minutes after placement of the block. In the alfentanil group, the incidence of myoclonus or cough was significantly less than in the lidocaine or placebo groups. Alfentanil also decreased systolic and diastolic blood pressure significantly at 1, 3, and 5 minutes after retrobulbar block. Changes in heart rate were not significantly different from baseline. CONCLUSION: A small dose of alfentanil (5 micrograms/kg i.v.) decreases myoclonus and cough induced by sodium methohexital anesthesia i.v., resulting in improved quality of induction of anesthesia. Alfentanil also attenuates the cardiovascular responses caused by placement of a retrobulbar block.

Adult↗
PubMed1998

Ability of alternative indices of insulin sensitivity to predict cardiovascular risk: comparison with the "minimal model". Insulin Resistance Atherosclerosis Study (IRAS) Investigators.

INTRODUCTION: Although recognition of insulin sensitivity as a risk factor for cardiovascular disease is growing, a deeper understanding of its role is impeded by the cost and complexity of currently available measures. This report evaluates previously described alternative indices of insulin sensitivity with the goal of identifying a reliable, but logistically simpler, alternative. METHODS: Data from 1460 participants in the Insulin Resistance Atherosclerosis Study (IRAS) were used to assess the proportion of the relationship between a recognized measure of insulin sensitivity (Bergman's SI) and cardiovascular risk factors that is contained in each of nine alternative measures. RESULTS: A number of the alternative indices contained a substantial proportion of the information available in Bergman's SI. The Galvin's index and the homeostasis model were most promising. However, there remained a significant amount of the information in Bergman's SI that was not contained in any of the alternative indices. DISCUSSION: There are simpler alternative indices of insulin sensitivity for use in epidemiological studies, but each alternative is associated with some loss of information. It may be possible that this loss can be overcome with an increased sample size; however, using the alternative indices may also confound the assessment of insulin sensitivity with other underlying factors (i.e., hyperinsulinemia). The alternative indices are not recommended for the clinical assessment of insulin sensitivity for an individual patient or subject.

Cardiovascular Diseases↗
PubMed1998

The effect of high dose endotoxin on CYP3A2 expression in the rat.

PURPOSE: The purpose of our research was two-fold: 1) to further characterize the downregulation of CYP3A2 mRNA, protein, and activity during an acute phase response (APR); 2) most importantly, to relate the time-dependent activation of nuclear proteins to putative DNA binding sequences within the CYP3A2 5'-flanking region, with the loss in CYP3A2 expression. METHODS: Rats were injected (2.0 mg/animal, i.p.) with LPS and sacrificed at 1, 2, 4, 6, 8, 24, 48, and 72 hours. Hepatic nuclear protein was isolated and analyzed for binding activity to AP-1, NFkappaB, and NF-IL6 consensus sequences. Hepatic CYP3A2 mRNA levels were determined by solution hybridization and CYP3A2 protein, CYP3A2 activity, and total P450 were measured in hepatic microsomes. RESULTS: Computer analysis of the 5'-flanking region of CYP3A2 revealed the presence of 5 NF-IL6 and 4 AP-1 putative DNA binding sites. The strongest increase in AP-1 binding activity occurred between 6 and 24 hr, and the alteration in binding complexes to an NF-IL6 oligonucleotide occurred between 4 and 24 hr. Maximum loss in CYP3A2 mRNA occurred at 8 hr post-LPS injection and remained lowered at the 24 hr timepoint. CYP3A2 protein was significantly decreased at 24, 48, and 72 hours post-LPS treatment with corresponding decreases in CYP3A2 activity and total P450. CONCLUSIONS: The changes in NF-IL6 and AP-1 binding after LPS treatment, which appears to correlate with the changes in CYP3A2 mRNA, combined with the presence of putative NF-IL6 and AP-1 sites located in the CYP3A25'-flanking region, may indicate a potential role for NF-IL6 and AP-1 in CYP3A2 downregulation during an APR.

Acute-Phase Reaction↗