Showing papers by "Wake Forest University published in 1999"

Quantitative RT-PCR: pitfalls and potential.

Abstract: Reverse transcription PCR (RT-PCR) represents a sensitive and powerful tool for analyzing RNA. While it has tremendous potential for quantitative applications, a comprehensive knowledge of its technical aspects is required. Successful quantitative RT-PCR involves correction for experimental variations in individual RT and PCR efficiencies. This review addresses the mathematics of RT-PCR, choice of RNA standards (internal vs. external) and quantification strategies (competitive, noncompetitive and kinetic [real-time] amplification). Finally, the discussion turns to practical considerations in experimental design. It is hoped that this review will be appropriate for those undertaking these experiments for the first time or wishing to improve (or validate) a technique in what is frequently a confusing and contradictory field.

Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly.

Abstract: Background Although aortic-valve stenosis is clearly associated with adverse cardiovascular outcomes, it is unclear whether valve sclerosis increases the risk of cardiovascular events. Methods We assessed echocardiograms obtained at base line from 5621 men and women 65 years of age or older who were enrolled in a population-based prospective study. On echocardiography, the aortic valve was normal in 70 percent (3919 subjects), sclerotic without outflow obstruction in 29 percent (1610), and stenotic in 2 percent (92). The subjects were followed for a mean of 5.0 years to assess the risk of death from any cause and of death from cardiovascular causes. Cardiovascular morbidity was defined as new episodes of myocardial infarction, angina pectoris, congestive heart failure, or stroke. Results There was a stepwise increase in deaths from any cause (P for trend, <0.001) and deaths from cardiovascular causes (P for trend, <0.001) with increasing aortic-valve abnormality; the respective rates were 14.9 and 6.1 per...

Stroke Incidence and Survival Among Middle-Aged Adults: 9-Year Follow-Up of the Atherosclerosis Risk in Communities (ARIC) Cohort

Abstract: 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.

Arterial Stiffness and the Development of Hypertension: The ARIC Study

Abstract: Decreased elasticity in large and medium-sized arteries has been postulated to be associated with cardiovascular diseases. We prospectively examined the relation between arterial elasticity and the development of hypertension over 6 years of follow-up in a cohort of 6992 normotensive men and women aged 45 to 64 years at baseline from the biracial, population-based Atherosclerosis Risk in Communities (ARIC) Study. Arterial elasticity was measured from high-resolution B-mode ultrasound examination of the left common carotid artery as adjusted arterial diameter change (in micrometers, simultaneously adjusted for diastolic blood pressure, pulse pressure, pulse pressure squared, diastolic arterial diameter, and height), Peterson's elastic modulus (in kilopascals), Young's elastic modulus (in kilopascals), and beta stiffness index. Incident hypertension (n=551) was defined as systolic blood pressure >/=160 mm Hg, diastolic blood pressure >/=95 mm Hg, or the use of antihypertensive medication at a follow-up examination conducted every 3 years. The age-, ethnicity-, center-, gender-, education-, smoking-, heart rate-, and obesity-adjusted means (SE) of baseline adjusted arterial diameter change, Peterson's elastic modulus, Young's elastic modulus, and beta stiffness index were 397 (5), 148 (2.0), 787 (12.7), and 11.43 (0.16), respectively, in persons who developed hypertension during follow-up, in contrast to 407 (1), 124 (0.6), 681 (3.7), and 10.34 (0.05), respectively, for persons who did not. The similarly adjusted cumulative incident rates of hypertension from the highest to the lowest quartiles of arterial elasticity were 6.7%, 8.0%, 7.3%, and 9.6%, respectively, when measured by adjusted arterial diameter change (P<0.01). One standard deviation decrease in arterial elasticity was associated with 15% greater risk of hypertension, independent of established risk factors for hypertension and the level of baseline blood pressure. These results suggest that lower arterial elasticity is related to the development of hypertension.

Increased Blood Glucose and Insulin, Body Size, and Incident Colorectal Cancer

Abstract: Background: Abdominal obesity-an elevated level of visceral adipose tissue-has been linked to colorectal cancer. Furthermore, elevated levels of visceral adipose tissue have been associated with hyperinsulinemia, and insulin is a growth factor in the colon. We assessed whether waist circumference, a surrogate measure of visceral adipose tissue, and metabolic parameters associated with visceral adipose tissue were related to colorectal cancer. Methods: In the Cardiovascular Health Study cohort, we examined the relationship of baseline measurements of body size, glucose, insulin, and lipoproteins to incident colorectal cancer. All P values are two-sided. Results: Among 5849 participants, 102 incident cases of colorectal cancer were identified. Individuals in the highest quartile of fasting glucose had a nearly twofold increased risk of colorectal cancer (relative risk [RR] = 1.8; 95% confidence interval [CI] = 1.0-3.1), and the linear trend RR (LT RR = 1.2; 95% CI = 1.0-1.5) for fasting glucose level was statistically significant (P = .02). Glucose and insulin levels 2 hours after oral glucose challenge also exhibited statistically significant associations with colorectal cancer (2-hour glucose levels: RR = 2.4 [95% CI = 1.2-4.7]/LT RR = 1.3 [95% CI = 1.0-1.6; P = .02]; 2-hour insulin levels: RR = 2.0 [95% CI = 1.0-3.8]/LT RR = 1.2 [95% CI = 1.0-1.5; P = .04]). Analysis of fasting insulin levels suggested a threshold effect, with values above the median associated with colorectal cancer (RR = 1.6; 95% CI = 1.1-2.4 ; P = .02). Higher levels of waist circumference were also statistically significantly associated with colorectal cancer (RR = 1.9; 95% CI = 1.1-3.3; P = .02). Conclusions: These data provide, to our knowledge, the first direct evidence of an association between elevated visceral adipose tissue level, its associated metabolic effects, and colorectal cancer.

Protein-sulfenic acids: diverse roles for an unlikely player in enzyme catalysis and redox regulation.

Abstract: While it has been known for more than 20 years that unusually stable cysteine-sulfenic acid (Cys-SOH) derivatives can be introduced in selected proteins by mild oxidation, only recently have chemical and crystallographic evidence for functional Cys-SOH been presented with native proteins such as NADH peroxidase and NADH oxidase, nitrile hydratase, and the hORF6 and AhpC peroxiredoxins. In addition, Cys-SOH forms of protein tyrosine phosphatases and glutathione reductase have been suggested to play key roles in the reversible inhibition of these enzymes during tyrosine phosphorylation-dependent signal transduction events and nitrosative stress, respectively. Substantial chemical data have also been presented which implicate Cys-SOH in redox regulation of transcription factors such as Fos and Jun (activator protein-1) and bovine papillomavirus-1 E2 protein. Functionally, the Cys-SOHs in NADH peroxidase, NADH oxidase, and the peroxiredoxins serve as either catalytically essential redox centers or transient intermediates during peroxide reduction. In nitrile hydratase, the active-site Cys-SOH functions in both iron coordination and NO binding but does not play any catalytic redox role. In Fos and Jun and the E2 protein, on the other hand, a key Cys-SH serves as a sensor for intracellular redox status; reversible oxidation to Cys-SOH as proposed inhibits the corresponding DNA binding activity. These functional Cys-SOHs have roles in diverse cellular processes, including signal transduction, oxygen metabolism and the oxidative stress response, and transcriptional regulation, as well as in the industrial production of acrylamide, and their detailed analyses are beginning to provide the chemical foundation necessary for understanding protein-SOH stabilization and function.

Prevention of a first stroke: a review of guidelines and a multidisciplinary consensus statement from the National Stroke Association.

Abstract: ObjectiveTo establish, in a single resource, up-to-date recommendations for primary care physicians regarding prevention strategies for a first strokeParticipantsMembers of the National Stroke Association's (NSA's) Stroke Prevention Advisory Board and Cedars-Sinai Health System Department of Health Services Research convened on April 9, 1998, in an open meeting The conference attendees, selected to participate by the NSA, were recognized experts in neurology (9), cardiology (2), family practice (1), nursing (1), physician assistant practices (1), and health services research (2)EvidenceA literature review was carried out by the Department of Health Services Research, Cedars-Sinai Health System, Los Angeles, Calif, using the MEDLINE database search for 1990 through April 1998 and updated in November 1998 English-language guidelines, statements, meta-analyses, and overviews on prevention of a first stroke were reviewedConsensus ProcessAt the meeting, members of the advisory board identified 6 important stroke risk factors (hypertension, myocardial infarction [MI], atrial fibrillation, diabetes mellitus, blood lipids, asymptomatic carotid artery stenosis), and 4 lifestyle factors (cigarette smoking, alcohol use, physical activity, diet)ConclusionsSeveral interventions that modify well-documented and treatable cardiovascular and cerebrovascular risk factors can reduce the risk of a first stroke Good evidence for direct stroke reduction exists for hypertension treatment; using warfarin for patients after MI who have atrial fibrillation, decreased left ventricular ejection fraction, or left ventricular thrombus; using 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors for patients after MI; using warfarin for patients with atrial fibrillation and specific risk factors; and performing carotid endarterectomy for patients with stenosis of at least 60% Observational studies support the role of modifying lifestyle-related risk factors (eg, smoking, alcohol use, physical activity, diet) in stroke prevention Measures to help patients improve adherence are an important component of a stroke prevention plan

Bright Light Therapy: Improved Sensitivity to Its Effects on Rest-Activity Rhythms in Alzheimer Patients by Application of Nonparametric Methods

Abstract: Sleep-wake rhythm disturbances in patients with Alzheimer's disease (AD) make a strong demand on caregivers and are among the most important reasons for institutionalization. Several previous studies reported that the disturbances improve with increased environmental light, which, through the retinohypothalamic tract, activates the suprachiasmatic nucleus (SCN), the biological clock of the brain. The data of recently published positive and negative reports on the effect of bright light on actigraphically assessed rest-activity rhythms in demented elderly were reanalyzed using several statistical procedures. It was demonstrated that the light-induced improvement in coupling of the rest-activity rhythm to the environmental zeitgeber of bright light is better detected using nonparametric procedures. Cosinor, complex demodulation, and Lomb-Scargle periodogram-derived variables are much less sensitive to this effect because of the highly nonsinusoidal waveform of the rest-activity rhythm. Guidelines for analyses of actigraphic data are given to improve the sensitivity to treatment effects in future studies.

Cytotoxic and genotoxic potential of dopamine

Abstract: A variety of in vitro and in vivo studies demonstrate that dopamine is a toxic molecule that may contribute to neurodegenerative disorders such as Parkinson's disease and ischemia-induced striatal damage. While much attention has focused on the fact that the metabolism of dopamine produces reactive oxygen species (peroxide, superoxide, and hydroxyl radical), growing evidence suggests that the neurotransmitter itself may play a direct role in the neurodegenerative process. Oxidation of the dopamine molecule produces a reactive quinone moiety that is capable of covalently modifying and damaging cellular macromolecules. This quinone formation occurs spontaneously, can be accelerated by metal ions (manganese or iron), and also arises from selected enzyme-catalyzed reactions. Macromolecular damage, combined with increased oxidant stress, may trigger cellular responses that eventually lead to cell death. Reactive quinones have long been known to represent environmental toxicants and, within the context of dopamine metabolism, may also play a role in pathological processes associated with neurodegeneration. The present discussion will review the oxidative metabolism of dopamine and describe experimental evidence suggesting that dopamine quinone may contribute to the cytotoxic and genotoxic potential of this essential neurotransmitter.

A randomized trial comparing the effect of casein with that of soy protein containing varying amounts of isoflavones on plasma concentrations of lipids and lipoproteins

Abstract: Context Isolated soy protein reduces plasma concentrations of total and low-density lipoprotein (LDL) cholesterol. Objective To identify the agent(s) responsible for the cholesterol-lowering effect of soy in mildly hypercholesterolemic volunteers: isoflavones isolated together with soy protein or soy protein itself. Design Double-blind randomized parallel trial. Setting Single-center study. Participants A total of 156 healthy men and women with LDL cholesterol levels between 3.62 mmol/L (140 mg/dL) and 5.17 mmol/L (200 mg/dL) after instruction in a National Cholesterol Education Program Step I diet and recruited by advertisement from the community. Intervention One of 5 daily diets (25 g of casein [for isoflavone-free comparison] or 25 g of isolated soy protein containing 3, 27, 37, or 62 mg of isoflavones). Main Outcome Measures Change and percent change from baseline in plasma concentrations of triglycerides and total, LDL, and high-density lipoprotein cholesterol after 9 weeks. Results Compared with casein, isolated soy protein with 62 mg of isoflavones lowered total and LDL cholesterol levels by 4% (P=.04) and 6% (P=.01), respectively. In patients with LDL cholesterol levels in the top half of the population studied (>4.24 mmol/L [>164 mg/dL]), comparable reductions were 9% (P Conclusions Naturally occurring isoflavones isolated with soy protein reduce the plasma concentrations of total and LDL cholesterol without affecting concentrations of triglycerides or high-density lipoprotein cholesterol in mildly hypercholesterolemic volunteers consuming a National Cholesterol Education Program Step I diet. Ethanol-extracted isolated soy protein did not significantly reduce plasma concentrations of total or LDL cholesterol.

The relationship between early age of onset of initial substance use and engaging in multiple health risk behaviors among young adolescents

Abstract: BACKGROUND: Previous research based on problem-behavior theory has found that early age of onset of substance use is associated with engaging in multiple health risk behaviors among high school students It is unknown whether these relationships begin during early adolescence OBJECTIVE: To examine the relationships between early age of onset of cigarette, alcohol, marijuana, and cocaine use and engaging in multiple risk behaviors among middle school students METHODS: A modified version of the Centers for Disease Control and Prevention Youth Risk Behavior Survey was administered to 2227 sixth through eighth grade students attending 53 randomly selected middle schools in North Carolina A Health Risk Behavior Scale was constructed from 16 behaviors, including indicators of violence and weapon carrying; current substance use; nonuse of helmets when biking, in-line skating or skateboarding; not wearing a seat belt; riding with a driver who had been drinking; and suicide plans Among this sample of middle school students, the scale had a mean (SD) of 41 (27) (range=O-15), and had a high internal reliability coefficient (alpha(=074) The independent variables included first time use of cigarettes, alcohol, marijuana, and cocaine at age 11 years or earlier; actual age of onset of each substance; race and ethnicity; family composition; sex; school grade; academic ranking; and older age for school grade These data were analyzed with analysis of variance, Spearman r, and multiple linear regression RESULTS: All the independent variables were found to be associated (P Language: en

The Ownership Effect in Consumer Responses to Brand Line Stretches

Abstract: In this article, the authors examine how ownership status moderates the effects of stretch direction (up or down), brand image (prestige or nonprestige), and branding strategy (subbrand name or dir...

Making Sense of Self-Esteem

Abstract: Sociometer theory proposes that the self-esteem system evolved as a monitor of social acceptance, and that the so-called self-esteem motive functions not to maintain self-esteem per se but rather to avoid social devaluation and rejection. Cues indicating that the individual is not adequately valued and accepted by other people lower self-esteem and motivate behaviors that enhance relational evaluation. Empirical evidence regarding the self-esteem motive, the antecedents of self-esteem, the relation between low self-esteem and psychological problems, and the consequences of enhancing self-esteem is consistent with the theory.

A Fetal Fatty-Acid Oxidation Disorder as a Cause of Liver Disease in Pregnant Women

Abstract: Background Acute fatty liver of pregnancy and the HELLP syndrome (hemolysis, elevated liver-enzyme levels, and a low platelet count) are serious hepatic disorders that may occur during pregnancy in...

Control of mRNA Decay by Heat Shock-Ubiquitin-Proteasome Pathway

Abstract: Cytokine and proto-oncogene messenger RNAs (mRNAs) are rapidly degraded through AU-rich elements in the 3′ untranslated region. Rapid decay involves AU-rich binding protein AUF1, which complexes with heat shock proteins hsc70-hsp70, translation initiation factor eIF4G, and poly(A) binding protein. AU-rich mRNA decay is associated with displacement of eIF4G from AUF1, ubiquitination of AUF1, and degradation of AUF1 by proteasomes. Induction of hsp70 by heat shock, down-regulation of the ubiquitin-proteasome network, or inactivation of ubiquitinating enzyme E1 all result in hsp70 sequestration of AUF1 in the perinucleus-nucleus, and all three processes block decay of AU-rich mRNAs and AUF1 protein. These results link the rapid degradation of cytokine mRNAs to the ubiquitin-proteasome pathway.

Repeated reading to enhance fluency: Old approaches and new directions

Abstract: As phoneme awareness deficits and resulting decoding weaknesses are increasingly addressed, there is heightened awareness of the role of fluency in reading. This paper reviews the history of fluency training, discusses the theoretical bases of such training, and summarizes the current knowledge about the efficacy of training procedures. We focus on Repeated Reading (RR), the most familiar and researched approach to fluency training. Outcome data on Repeated Reading, presented in the form of questions, is meant to answer practitioners’ questions about implementation and efficacy and to provide a starting point for researchers interested in the topic. Although some answers are straightforward, others indicate the subtleties involved in answering the broad question, “Does Repeated Reading work?” In addition to a list of practical suggestions based on Repeated Readings findings, three new approaches to fluency training are introduced.

Effect of soy protein supplementation on serum lipoproteins, blood pressure, and menopausal symptoms in perimenopausal women.

Abstract: ObjectiveTo investigate the effect of soy protein supplementation with known levels of phyto-estrogens on cardiovascular disease risk factors and menopausal symptoms in perimenopausal women.MethodsA randomized, double-blind crossover trial was conducted in 51 women consuming isocaloric suppl

Surfactant-Mediated Cloud Point Extractions: An Environmentally Benign Alternative Separation Approach

Abstract: Aqueous solutions of certain surfactant micelles exhibit phase separation behavior upon temperature alteration. This phenomenon can be exploited in separation science for the development of extraction, purification, and preconcentration schemes for desired analytes. Since the addition of just a small amount of an appropriate nonionic or zwitterionic surfactant to the aqueous sample solution is required, this approach is convenient and fairly benign, eliminating the need for the use of organic solvents as in conventional liquid−liquid or solid−liquid extraction. The basic features, experimental protocols, and selected recent applications of this alternative extraction approach, termed cloud point extraction (CPE) or micelle-mediated extraction (ME), are briefly reviewed. In addition, the advantages, limitations, and anticipated future directions of this methodology are discussed.

Effects of estrogen and estrogen-progestin on mammographic parenchymal density

Abstract: age of women with density grade increases was 0% (95% CI, 0.0% to 4.6%) in the placebo group, 3.5% (CI, 1.0% to 12.0%) in the CEE group, 23.5% (CI, 11.9% to 35.1%) in the CEE plus cyclic MPA group, 19.4% (CI, 9.9% to 28.9%) in the CEE plus daily MPA group, and 16.4% (CI, 6.6% to 26.2%) in the CEE plus cyclic MP group. At 12 months, the odds of an increase in mammographic density were 13.1 (95% CI, 2.4 to 73.3) with CEE plus cyclic MPA, 9.0 (CI, 1.6 to 50.1) with CEE plus daily MPA, and 7.2 (CI, 1.3 to 40.0) with CEE plus cyclic micronized progesterone compared with CEE alone. Conclusions: Further study of the magnitude and meaning of increased mammographic density due to use of estrogen and estrogen‐progestins is warranted because mammographic density may be a marker for risk for breast cancer.

Pilocarpine Tablets for the Treatment of Dry Mouth and Dry Eye Symptoms in Patients With Sjögren Syndrome: A Randomized, Placebo-Controlled, Fixed-Dose, Multicenter Trial

Abstract: Background: Patients with Sjogren syndrome (SS) ex- perience slowly progressive infiltration of lacrimal and salivary glands by mononuclear cells. This leads to di- minished secretions, with resultant symptoms of xero- stomia and xerophthalmia. Although pilocarpine hydro- chloride tablets are currently indicated for the treatment of radiation-induced xerostomia, their effects on dry mouth or dry eyes in patients with SS are unclear. Objective: To assess the safety and efficacy of pilocar- pine (Salagen) tablets as symptomatic treatment for dry mouth and dry eyes caused by SS in a multicenter, double- blind, placebo-controlled trial. Methods: After providing written informed consent, 373 patients with primary or secondary SS and clinically sig- nificant dry mouth and dry eyes were randomized to re- ceive 2.5-mg pilocarpine, 5-mg pilocarpine, or placebo tablets 4 times daily for 12 weeks. Symptoms were as- sessed by questionnaires with visual analog scales or cat- egorical checkboxes. Whole-mouth salivary flow rates were measured. Results: A significantly greater proportion of patients in the 5-mg pilocarpine group showed improvement com- pared with the placebo group (P#.01) in global assess- ments of dry mouth, dry eyes, and other symptoms of dryness (P#.05). Salivary flow was significantly in- creased 2- to 3-fold (P,.001) after administration of the first dose and was maintained throughout the 12-week study. The most common adverse effect was sweating, and no serious drug-related adverse experiences were re- ported.

A Region of Human Chromosome 9p Required for Testis Development Contains Two Genes Related to Known Sexual Regulators

Abstract: Deletion of the distal short arm of chromosome 9 (9p) has been reported in a number of cases to be associated with gonadal dysgenesis and XY sex reversal, suggesting that this region contains one or more genes required in two copies for normal testis development. Recent studies have greatly narrowed the interval containing this putative autosomal testis-determining gene(s) to the distal portion of 9p24.3. We previously identified DMRT1, a human gene with sequence similarity to genes that regulate the sexual development of nematodes and insects. These genes contain a novel DNA-binding domain, which we named the DM domain. DMRT1 maps to 9p24. 3 and in adults is expressed specifically in the testis. We have investigated the possible role of DM domain genes in 9p sex reversal. We identified a second DM domain gene, DMRT2, which also maps to 9p24.3. We found that point mutations in the coding region of DMRT1 and the DM domain of DMRT2 are not frequent in XY females. We showed by fluorescence in situ hybridization analysis that both genes are deleted in the smallest reported sex-reversing 9p deletion, suggesting that gonadal dysgenesis in 9p-deleted individuals might be due to combined hemizygosity of DMRT1 and DMRT2.

Mutations in the Gene Encoding KRIT1, a Krev-1/rap1a Binding Protein, Cause Cerebral Cavernous Malformations (CCM1)

Abstract: Cerebral cavernous malformations (CCM) are congenital vascular anomalies of the brain that can cause significant neurological disabilities, including intractable seizures and hemorrhagic stroke. One locus for autosomal dominant CCM ( CCM1 ) maps to chromosome 7q21-q22. Recombination events in linked family members define a critical region of approximately 2 Mb and a shared disease haplotype associated with a presumed founder effect in families of Mexican-American descent points to a potentially smaller region of interest. Using a genomic sequence-based positional cloning strategy, we have identified KRIT1, encoding a protein that interacts with the Krev-1/rap1a tumor suppressor, as the CCM1 gene. Seven different KRIT1 mutations have been identified in 23 distinct CCM1 families. The identical mutation is present in 16 of 21 Mexican-American families analyzed, substantiating a founder effect in this population. Other Mexican-American and non-Hispanic Caucasian CCM1 kindreds harbor other KRIT1 mutations. Identification of a common Mexican-American mutation has potential clinical significance for presymptomatic diagnosis of CCM in this population. In addition, these data point to a key role for the Krev-1/rap1a signaling pathway in angiogenesis and cerebrovascular disease.

Utility of Fast Cine Magnetic Resonance Imaging and Display for the Detection of Myocardial Ischemia in Patients Not Well Suited for Second Harmonic Stress Echocardiography

Abstract: Background—Some patients referred for pharmacological stress testing with transthoracic echocardiography (TTE) are unable to undergo testing owing to poor acoustic windows. Fast cine MRI can be used to assess left ventricular contraction, but its utility for detection of myocardial ischemia in patients poorly suited for echocardiography is unknown. Methods and Results—One hundred fifty-three patients (86 men and 67 women aged 30 to 88 years) with poor acoustic windows that prevented adequate second harmonic TTE imaging were consecutively referred for MRI to diagnose inducible myocardial ischemia during intravenous dobutamine and atropine. Diagnostic studies were completed in an average of 53 minutes. No patients experienced myocardial infarction, ventricular fibrillation, exacerbation of congestive heart failure, or death. In patients who underwent computer-assisted quantitative coronary angiography, the sensitivity and specificity for detecting a >50% luminal diameter narrowing were 83% and 83%, respecti...

Randomized placebo-controlled trial of a 42-day tapering course of dexamethasone to reduce the duration of ventilator dependency in very low birth weight infants: outcome of study participants at 1-year adjusted age.

Abstract: Objective. Ventilator-dependent preterm infants are often treated with a prolonged tapering course of dexamethasone to decrease the risk and severity of chronic lung disease. The objective of this study was to assess the effect of this therapy on developmental outcome at 1 year of age. Methods. Study participants were 118 very low birth weight infants who, at 15 to 25 days of life, were not weaning from assisted ventilation and were then enrolled in a randomized, placebo-controlled, double-blind trial of a 42-day tapering course of dexamethasone. Infants were examined at 1 year of age, adjusted for prematurity, by a pediatrician and a child psychologist. A physical and neurologic examination was performed, and the Bayley Scales of Infant Development were administered. All examiners were blind to treatment group. Results. Groups were similar in terms of birth weight, gestational age, gender, and race. A higher percentage of dexamethasone recipients had major intracranial abnormalities diagnosed by ultrasonography (21% vs 11%). Group differences were not found for Bayley Mental Development Index (median [range] for dexamethasone-treated group, 94 [50-123]; for placebo group, 90 [28-117]) or Psychomotor Development Index Index (median [range]) for dexamethasone-treated group, 78 (50-109); for placebo-treated group, 81 [28-117]). More dexamethasone-treated infants had cerebral palsy (25% vs 7%) and abnormal neurologic examination findings (45% vs 16%). In stratified analyses, adjusted for major cranial ultrasound abnormalities, these associations persisted (OR values for cerebral palsy, 5.3; 95% Cl: 1.3-21.4; OR values for neurologic abnormality 3.6; 95% Cl: 1.2-11.0). Conclusions. A 42-day tapering course of dexamethasone was associated with an increased risk of cerebral palsy. Possible explanations include an adverse effect of this therapy on brain development and/or improved survival of infants who either already have neurologic injury or who are at increased risk for such injury. Pediatrics 1999;104:15-21; bronchopulmonary dysplasia, dexamethasone, chronic lung disease, very low birth weight, randomized controlled trials, developmental outcome, cerebral palsy.

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

Abstract: 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.

Assessment and control for confounding by indication in observational studies.

Abstract: In the evaluation of pharmacologic therapies, the controlled clinical trial is the preferred design. When clinical trial results are not available, the alternative designs are observational epidemiologic studies. A traditional concern about the validity of findings from epidemiologic studies is the possibility of bias from uncontrolled confounding. In studies of pharmacologic therapies, confounding by indication may arise when a drug treatment serves as a marker for a clinical characteristic or medical condition that triggers the use of the treatment and that, at the same time, increases the risk of the outcome under study. Confounding by indication is not conceptually different from confounding by other factors, and the approaches to detect and control for confounding--matching, stratification, restriction, and multivariate adjustment--are the same. Even after adjustment for known risk factors, residual confounding may occur because of measurement error or unmeasured or unknown risk factors. Although residual confounding is difficult to exclude in observational studies, there are limits to what this "unknown" confounding can explain. The degree of confounding depends on the prevalence of the putative confounding factor, the level of its association with the disease, and the level of its association with the exposure. For example, a confounding factor with a prevalence of 20% would have to increase the relative odds of both outcome and exposure by factors of 4 to 5 before the relative risk of 1.57 would be reduced to 1.00. Observational studies have provided important scientific evidence about the risks associated with several risk factors, including drug therapies, and they are often the only option for assessing safety. Understanding the methods to detect and control for confounding makes it possible to assess the plausibility of claims that confounding is an alternative explanation for the findings of particular studies.