Biomedical subjects
Publications and source records attributed to S G West.
Fibromyalgia is an enigmatic medical condition whose specific etiology remains undiscovered but currently plagues five million Americans. Research indicates that the origin of the disease is most likely multifactorial. Treatment should therefore be tailored accordingly. Thus, it is often necessary to combine different options in order to achieve the maximum benefit in patients suffering from fibromyalgia.
Neural tube defects (NTDs) are the second most common birth defects (1 in 1000 live births) in the world. Periconceptional maternal folate supplementation reduces NTD risk by 50-70%; however, studies of folate related and other developmental genes in humans have failed to definitively identify a major causal gene for NTD. The aetiology of NTDs remains unknown and both genetic and environmental factors are implicated. We present findings from a microsatellite based screen of 44 multiplex pedigrees ascertained through the NTD Collaborative Group. For the linkage analysis, we defined our phenotype narrowly by considering individuals with a lumbosacral level myelomeningocele as affected, then we expanded the phenotype to include all types of NTDs. Two point parametric analyses were performed using VITESSE and HOMOG. Multipoint parametric and nonparametric analyses were performed using ALLEGRO. Initial results identified chromosomes 7 and 10, both with maximum parametric multipoint lod scores (Mlod) >2.0. Chromosome 7 produced the highest score in the 24 cM interval between D7S3056 and D7S3051 (parametric Mlod 2.45; nonparametric Mlod 1.89). Further investigation demonstrated that results on chromosome 7 were being primarily driven by a single large pedigree (parametric Mlod 2.40). When this family was removed from analysis, chromosome 10 was the most interesting region, with a peak Mlod of 2.25 at D10S1731. Based on mouse human synteny, two candidate genes (Meox2, Twist1) were identified on chromosome 7. A review of public databases revealed three biologically plausible candidates (FGFR2, GFRA1, Pax2) on chromosome 10. The results from this screen provide valuable positional data for prioritisation of candidate gene assessment in future studies of NTDs.
AIMS/HYPOTHESIS: We examined the acute postprandial effects of meals containing unsaturated fatty acids on flow-mediated dilation (FMD) of the brachial artery and triacylglycerols in individuals with type 2 diabetes. We hypothesised that consumption of omega-3 fatty acids would enhance vascular function. Saturated fat reduces FMD for several hours, but there is inconsistent evidence about whether foods containing unsaturated fats impair FMD acutely. Little is known about the acute effects of omega-3 fatty acids on vascular reactivity. METHODS: We measured FMD before and 4 h after 3 test meals (50 g fat, 2,615 kJ) in 18 healthy adults with type 2 diabetes. The monounsaturated fatty acids (MUFA) meal contained 50 g fat from high oleic safflower and canola oils. Two additional meals were prepared by replacing 7% to 8% of MUFA with docosahexaenoic acid and eicosapentaenoic acid from sardine oil or alpha-linolenic acid from canola oil. RESULTS: In the sample as a whole, FMD was increased 17% at 4 h vs. the fasting baseline. After the MUFA meal, subjects with the largest increases in triacylglycerols had the largest FMD decreases. The opposite pattern was observed after meals containing docosahexaenoic acid and eicosapentaenoic acid or alpha-linolenic acid. In subjects with high fasting triacylglycerols, meals containing 3 to 5 g of omega-3 fatty acids increased FMD by 50% to 80% and MUFA alone had no significant effects on FMD. CONCLUSIONS/INTERPRETATION: Endothelium-dependent vasodilation was not impaired 4 h after meals containing predominantly unsaturated fatty acids. The fatty acid composition of the meal and the metabolic status of the individual determine the vascular effects of a high-fat meal.
AIMS/HYPOTHESIS: Dysfunction of the vascular endothelium is commonly observed in Type 2 diabetes, and endothelial function may be an important outcome for clinical trials in diabetic samples. However, the most commonly used non-invasive test of endothelial function (flow-mediated dilation [FMD]) is technically challenging to perform, and no previous studies have carefully examined the reproducibility of FMD measurements in individuals with Type 2 diabetes. In this study, we tested the hypothesis that larger day-to-day changes in insulin and glucose are associated with larger fluctuations in FMD. METHODS: Ultrasound was used to measure the FMD (% change from baseline diameter) of the brachial artery in 18 healthy adults with Type 2 diabetes on three separate occasions, in the absence of changes to diet, activity level or medications. The CV and mean deviations between pairs of FMD scores in the same individual were used as the primary outcome variables. RESULTS: The CV for FMD (29.7%) was higher than the level traditionally accepted for biochemical assays. However, this CV estimate is within the low range of published values for FMD in healthy individuals. FMD scores were not significantly correlated with glucose or insulin levels. However, subjects with the largest variability in FMD also showed the largest fluctuations in glucose ( r=0.52), insulin ( r=0.47) and heart rate ( r=0.48) ( p</=0.05). CONCLUSIONS/INTERPRETATION: FMD can be reliably measured in individuals with Type 2 diabetes, and population-specific data on reliability is critical for the design of adequately powered studies of endothelial function.
CONTEXT: The relative contribution of genes vs environment in idiopathic Parkinson disease (PD) is controversial. Although genetic studies have identified 2 genes in which mutations cause rare single-gene variants of PD and observational studies have suggested a genetic component, twin studies have suggested that little genetic contribution exists in the common forms of PD. OBJECTIVE: To identify genetic risk factors for idiopathic PD. DESIGN, SETTING, AND PARTICIPANTS: Genetic linkage study conducted 1995-2000 in which a complete genomic screen (n = 344 markers) was performed in 174 families with multiple individuals diagnosed as having idiopathic PD, identified through probands in 13 clinic populations in the continental United States and Australia. A total of 870 family members were studied: 378 diagnosed as having PD, 379 unaffected by PD, and 113 with unclear status. MAIN OUTCOME MEASURES: Logarithm of odds (lod) scores generated from parametric and nonparametric genetic linkage analysis. RESULTS: Two-point parametric maximum parametric lod score (MLOD) and multipoint nonparametric lod score (LOD) linkage analysis detected significant evidence for linkage to 5 distinct chromosomal regions: chromosome 6 in the parkin gene (MLOD = 5.07; LOD = 5.47) in families with at least 1 individual with PD onset at younger than 40 years, chromosomes 17q (MLOD = 2.28; LOD = 2.62), 8p (MLOD = 2.01; LOD = 2.22), and 5q (MLOD = 2.39; LOD = 1.50) overall and in families with late-onset PD, and chromosome 9q (MLOD = 1.52; LOD = 2.59) in families with both levodopa-responsive and levodopa-nonresponsive patients. CONCLUSIONS: Our data suggest that the parkin gene is important in early-onset PD and that multiple genetic factors may be important in the development of idiopathic late-onset PD.
We evaluated seven families segregating pure, autosomal dominant familial spastic paraplegia (SPG) for linkage to four recently identified SPG loci on chromosomes 2q (1), 8q (2), 12q (3), and 19q (4). These families were previously shown to be unlinked to SPG loci on chromosomes 2p, 14q, and 15q. Two families demonstrated linkage to the new loci. One family (family 3) showed significant evidence for linkage to chromosome 12q, peaking at D12S1691 (maximum lod = 3.22). Haplotype analysis of family 3 did not identify any recombinants among affected individuals in the 12q candidate region. Family 5 yielded a peak lod score of 2.02 at marker D19S868 and excluded linkage to other known SPG loci. Haplotype analysis of family 5 revealed several cross-overs in affected individuals, thereby potentially narrowing the SPG12 candidate region to a 5-cM region between markers D19S868 and D19S220. Three of the families definitively excluded all four loci examined, providing evidence for further genetic heterogeneity of pure, autosomal dominant SPG. In conclusion, these data confirm the presence of SPG10 (chromosome 12), potentially reduce the minimum candidate region for SPG12 (chromosome 19q), and suggest there is at least one additional autosomal dominant SPG locus.
New technology for studying vascular activity in vivo has shown that the endothelium plays a critical role in the development of atherosclerosis. The healthy endothelium is a metabolically active tissue that exquisitely regulates vascular tone via release of the powerful vasodilator, nitric oxide. Endothelial integrity reduces cell adhesion, lipid deposition, and other early steps in atherogenesis. There is compelling evidence that endothelial function can be altered within hours of eating certain foods, further affirming the role of dietary factors in the prevention and progression of cardiovascular disease. This article reviews recent work on dietary factors (fatty acids, L-arginine, antioxidants, polyphenols, and folic acid) that alter vascular tone, and critically evaluates two noninvasive measures (flow-mediated dilation and total peripheral resistance) for use in dietary intervention trials.
Abnormalities of inflammatory and hormonal measures are common in SLE patients. Although cognitive dysfunction has been documented in SLE patients, the biological mechanism of these deficits has not been clarified. The goal of this study was to explore the relationship between inflammatory and hormonal activity and measures of learning, fluency, and attention in systemic lupus erythematosus patients without neuropsychiatric symptoms (non-CNS-SLE), patients with rheumatoid arthritis (RA), and healthy controls (HC). Fifteen non-CNS-SLE patients, 15 RA patients and 15 HC participants similar in age, education, and gender (female) were compared on tests of cognition, depression, and plasma levels of interleukin-6 (IL-6), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEA-S) and cortisol. Non-CNS-SLE patients demonstrated lower learning and poorer attention. Furthermore, non-CNS-SLE and RA patients had significantly lower levels of DHEA and DHEA-S than HC participants. Hierarchical regression analysis demonstrates that DHEA-S and IL-6 accounts for a unique portion of the variance in subject performance on measures of learning and attention after controlling for depression and corticosteroid treatment. This data highlights the value of hierarchical analyses with covariates, and provides evidence in humans of a relationship between peripheral cytokine levels and cognitive function.
Traditional approaches to missing data (e.g., listwise deletion) can lead to less than optimal results in terms of bias, statistical power, or both. This article introduces the 3 articles in the special section of Psychological Methods, which consider multiple imputation and maximum-likelihood methods, new approaches to missing data that can often yield improved results. Computer software is now available to implement these new methods.
OBJECTIVE: Our aim was to compare the effects of transdermal versus oral estrogens on vascular resistance index, mean arterial pressure, serum lipid concentrations, norepinephrine, and left ventricular structure. STUDY DESIGN: Ten postmenopausal women received transdermal estradiol (0.05 mg/d) plus cyclic oral progesterone for 6 months. Responses were compared with those of 23 women receiving oral conjugated estrogens (0.625 mg/d) plus cyclic progesterone and with those of 9 subjects receiving placebo in a concurrent randomized trial. We assessed the vascular resistance index and the mean arterial pressure at rest and during behavioral stressors. RESULTS: Oral and transdermal estrogen significantly decreased the vascular resistance index, mean arterial pressure, norepinephrine, and total and low-density lipoprotein cholesterol to a similar extent. Changes in the vascular resistance index and mean arterial pressure were equally evident at rest and during stress. Although both treatments reduced left ventricular mass (-4% to -6%) and relative wall thickness (-3% to -5%), these changes were not statistically significant. CONCLUSIONS: Equivalent reductions in vascular resistance index, norepinephrine, mean arterial pressure, and cholesterol were observed with transdermal and oral estrogens. Future studies comparing novel hormone regimens with oral hormone replacement therapy should include multiple risk markers to allow better assessment of their potential impact on coronary artery health.
BACKGROUND: Postmenopausal estrogen replacement, with or without progestins, has been related to lower cardiovascular risks. OBJECTIVE: We investigated whether the actions of estrogen on vascular resistance contribute to this cardioprotective effect. DESIGN AND METHODS: In a 6-month double-blind study, pre- and post-treatment blood pressure, cardiac index, total vascular resistance index and plasma catecholamine responses during baseline and mental stressors were compared in 69 women (including 19 with mild hypertension but no history of heart disease). Women were randomized to receive either conjugated estrogens alone, estrogens plus medroxyprogesterone, or placebo. RESULTS: Both groups on active hormone replacement showed similar decreases in vascular resistance and modest blood pressure reductions, which differed from the unchanged responses of those on placebo (P< 0.05) after 3 and 6 months of treatment. Hypertensive women showed greater reductions in vascular resistance than normotensives (P< 0.05) and their blood pressure reductions tended to be larger. Women receiving hormone replacement showed increased stroke volume and cardiac index at 6 months, particularly among hypertensives and those receiving medroxyprogesterone (P < 0.05). Hormone replacement was also related to decreases in plasma norepinephrine. Finally, in 33 women receiving hormone replacement, significant 5 and 3% decreases in echocardiographic measures of left ventricular mass index and relative wall thickness were evident at 6 months (P < 0.05), while 20 placebo-treated women showed no reliable echocardiographic improvements (P= NS). CONCLUSIONS: These findings suggest that estrogen-mediated reductions in hemodynamic load on the heart may contribute to the reduced risk of cardiovascular events in relatively healthy postmenopausal women who use hormone replacement.
Women who smoke and take oral contraceptives (OCs) have significantly increased risk of cardiovascular disease, but the exact mechanismsfor the increased risk are not known. Cardiovascular reactivity to psychological stress may be one mechanism for the enhanced risk, but the small number of studies examining whether OC users who smoke have greater reactivity have produced mixed results. The purpose of this study was to examine the effect of chronic cigarette smoking, acute nicotine administration, and OC use on cardiovascular and lipid reactivity. Sixty healthy women, half of whom had been using OCs for at least the previous 6 months, participated in the study. Approximately two thirds were smokers and were randomized to be tested after either a 12-hr nicotine deprivation or administration of nicotine gum. One third were nonsmokers. Heart rate, blood pressure, and lipid measures were taken at rest, during a videotaped speech task, and during recovery from the task. Results indicated that, among OC nonusers, there was no effect of smoking status or nicotine administration on cardiovascular reactivity. However, among OC users, nonsmokers had significantly greater heart rate and diastolic blood pressure reactivity to stress. These data show that acute nicotine administration, in the form of nicotine gum, has no effect on cardiovascular or lipid stress reactivity in women. However OC use among nonsmoking women is associated with greater cardiovascular reactivity to stress.
With use of a randomized, placebo-controlled trial, 62 healthy, postmenopausal smokers and nonsmokers were tested for resting and stress-induced hemodynamic variables before and after 6 months of treatment with either oral hormone replacement therapy or placebo. Smokers had significantly less reduction in both resting and stress-induced vascular resistance and blood pressure after treatment with oral hormone replacement therapy than nonsmokers.
Traditional research on moderator variables in personality has focused on measures of relative consistency. In contrast, using Goldberg's (1992) adjectives representing the Big Five personality traits, the authors examined the applicability of moderator variables to measures of personality coherence. The authors considered 3 traditional moderator variables (interitem variability, construct similarity, and scalability) and one new moderator variable: the temporal stability of response patterns. Across 2 studies, individuals with temporally stable response patterns had higher levels of personality coherence, as measured by self-other profile agreement and informant profile consensus, than did individuals with less temporally stable patterns. By comparison, the normatively based moderator variables did not moderate self-other profile agreement and informant profile consensus. The implications for personality structure and coherence are discussed.
Scaling of time (age) in latent growth curve (LGC) models has important implications for studies of development. When participants begin a study at different ages, sample means and covariance-based structural equation modeling (SEM) approaches produce biased estimates of the variance of the intercept and the covariance between the Intercept and Slope factors. However, individual data vector-based SEM approaches produce proper estimates of these parameters that are identical to those produced by multilevel modeling (MLM). Scaling of the time variable also raises issues regarding the interpretation of within- and between-persons effects of time that parallel those associated with centering of predictor variables in MLM. A numerical example is used to illustrate these issues, and an Mx script for fitting individual data vector-based LGC models is provided.
We investigated the relationship of pessimistic attributional style (specifically, stable attributions for negative events) and socioeconomic status (SES) to cardiovascular and catecholamine profiles in a biracial sample of 37 postmenopausal women (aged 39-64 years) not taking hormone replacement therapy (HRT). Blood pressure (BP) variation in response to the demands of daily life was assessed by 24-hour ambulatory monitoring on a typical workday. Subjects were classified into groups by stable pessimistic attributions (high vs. low pessimism) and by SES (high vs. low). Significant SES x pessimism interactions were found. Low SES/high pessimism women demonstrated higher systolic BP (SBP) during the day, evening, and sleep periods of 24-hour ambulatory monitoring compared with the other three groups. A greater proportion of this group was in the hypertensive range (> or = 140/90 mm Hg) compared with the other groups (57% vs. 8%-29%). Low SES/high pessimism women also reported reduced available social support compared with the other three groups.
Investigated the interaction between parenting and temperament in predicting adjustment problems in children of divorce. The study utilized a sample of 231 mothers and children, 9 to 12 years old, who had experienced divorce within the previous 2 years. Both mothers' and children's reports on parenting, temperament, and adjustment variables were obtained and combined to create cross-reporter measures of the variables. Parenting and temperament were directly and independently related to outcomes consistent with an additive model of their effects. Significant interactions indicated that parental rejection was more strongly related to adjustment problems for children low in positive emotionality, and inconsistent discipline was more strongly related to adjustment problems for children high in impulsivity. These findings suggest that children who are high in impulsivity may be at greater risk for developing problems, whereas positive emotionality may operate as a protective factor, decreasing the risk of adjustment problems in response to negative parenting.
This study evaluated the efficacy of 2 theory-based preventive interventions for divorced families: a program for mothers and a dual component mother-child program. The mother program targeted mother-child relationship quality, discipline, interparental conflict, and the father-child relationship. The child program targeted active coping, avoidant coping, appraisals of divorce stressors, and mother-child relationship quality. Families with a 9- to 12-year-old child (N = 240) were randomly assigned to the mother, dual-component, or self-study program. Postintervention comparisons showed significant positive program effects of the mother program versus self-study condition on relationship quality, discipline, attitude toward father-child contact, and adjustment problems. For several outcomes, more positive effects occurred in families with poorer initial functioning. Program effects on externalizing problems were maintained at 6-month follow-up. A few additive effects of the dual-component program occurred for the putative mediators; none occurred for adjustment problems.