Sex-dependent associations of maternal androgen levels with offspring BMI and weight trajectory from birth to early childhood.

CONTEXT: In preclinical studies, high androgen levels during pregnancy are associated with low birth weight and rapid postnatal weight gain in the offspring. However, human data linking prenatal androgens with birth weight and early life weight gain in the offspring are scarce. DESIGN: We evaluated 516 mother-child pairs enrolled in the New England birth cohorts of the Collaborative Perinatal Project (1959-1966). We assayed androgen bioactivity in maternal sera during third-trimester using a receptor-mediated luciferase expression bioassay. Age and sex-specific BMI Z-scores (BMIz), defined using established standards, were assessed at birth, 4 months, 1 year, 4 years, and 7 years. We used linear mixed models to evaluate the relation of maternal androgens with childhood BMIz overall and by sex. We examined the association of maternal androgens with fetal growth restriction. The association of weight trajectories with maternal androgens was examined using multinomial logistic regression. RESULTS: Higher maternal androgen levels associated with lower BMIz at birth (ß = - 0.39, 95% CI: - 0.73, - 0.06); this relation was sex-dependent, such that maternal androgens significantly associated with BMIz at birth in girls alone (ß = - 0.72, 95% CI: - 1.40, - 0.04). The relation of maternal androgens with fetal growth restriction revealed dose threshold effects that differed by sex. There was no significant association between maternal androgens and weight trajectory overall. However, we found a significant sex interaction (p = 0.01); higher maternal androgen levels associated with accelerated catch-up growth in boys (aOR = 2.14, 95% CI: 1.14, 4.03). CONCLUSION: Our findings provide evidence that maternal androgens may have differential effects on the programming of intrauterine growth and postnatal weight gain depending on fetal sex.

Fatty Acid desaturase gene variants, cardiovascular risk factors, and myocardial infarction in the costa rica study.

Genetic variation in fatty acid desaturases (FADS) has previously been linked to long-chain polyunsaturated fatty acids (PUFAs) in adipose tissue and cardiovascular risk. The goal of our study was to test associations between six common FADS polymorphisms (rs174556, rs3834458, rs174570, rs2524299, rs174589, rs174627), intermediate cardiovascular risk factors, and non-fatal myocardial infarction (MI) in a matched population based case-control study of Costa Rican adults (n = 1756). Generalized linear models and multiple conditional logistic regression models were used to assess the associations of interest. Analyses involving intermediate cardiovascular risk factors and MI were also conducted in two replication cohorts, The Nurses' Health Study (n = 1200) and The Health Professionals Follow-Up Study (n = 1295). In the Costa Rica Study, genetic variation in the FADS cluster was associated with a robust linear decrease in adipose gamma-linolenic, arachidonic, and eicosapentaenoic fatty acids, and significant or borderline significant increases in the eicosadienoic, eicosatrienoic, and dihomo-gamma-linolenic fatty acids. However, the associations with adipose tissue fatty acids did not translate into changes in inflammatory biomarkers, blood lipids, or the risk of MI in the discovery or the replication cohorts. In conclusion, fatty acid desaturase polymorphisms impact long-chain PUFA biosynthesis, but their overall effect on cardiovascular health likely involves multiple pathways and merits further investigation.

Genetic variation in fatty acid elongases is not associated with intermediate cardiovascular phenotypes or myocardial infarction.

BACKGROUND/OBJECTIVES: Elongases 2, 4 and 5, encoded by genes ELOVL2, ELOVL4 and ELOVL5, have a key role in the biosynthesis of very long chain polyunsaturated fatty acids (PUFAs). To date, few studies have investigated the associations between elongase polymorphisms and cardiovascular health. We investigated whether ELOVL polymorphisms are associated with adipose tissue fatty acids, serum lipids, inflammation and ultimately with nonfatal myocardial infarction (MI) in a Costa Rican population. SUBJECTS/METHODS: MI cases (n=1650) were matched to population-based controls (n=1650) on age, sex and area of residence. Generalized linear and multiple conditional logistic regression models were used to assess the associations between seven common ELOVL polymorphisms and cardiometabolic outcomes. Analyses were replicated in The Nurses' Health Study (n=1200) and The Health Professionals Follow-Up Study (n=1295). RESULTS: Variation in ELOVL2, ELOVL4 and ELOVL5 was not associated with adipose tissue fatty acids, intermediate cardiovascular risk factors or MI. In the Costa Rica study, the number of the minor allele copies at rs2294867, located in the ELOVL5 gene, was associated with an increase in total and LDL cholesterol (adjusted P-values=0.001 and <0.0001 respectively). Additionally, the number of the minor allele copies at rs761179, also located in the ELOVL5 gene, was significantly associated with an increase in total cholesterol (adjusted P-value=0.04). However, the observed associations were not replicated in independent populations. CONCLUSION: Common genetic variants in elongases are not associated with adipose tissue fatty acids, serum lipids, biomarkers of systemic inflammation, or the risk of MI.

Therapeutic potential of platelet-activating factor antagonism in the management of myocardial infarction.

BACKGROUND: Antagonists of platelet-activating factor (PAF) reduce myocardial postischemia reperfusion injury when given before the onset of ischemia. However, the effects of PAF antagonists when administered at a clinically modelled time (during ischemia but before reperfusion) are controversial. Moreover, the extended survival (eight day) and the characteristics of scar formation after treatment with PAF antagonists have not been investigated. OBJECTIVES: To determine the therapeutic potential of PAF antagonist TCV-309 for the treatment of regional myocardial ischemia-reperfusion injury; and to determine the effects of TCV-309 on cardiovascular recovery, evolution of scar formation and survival eight days after a myocardial infarction treated with reperfusion. ANIMALS AND METHODS: Swine underwent regional myocardial ischemia for 60 mins by ligation of the left anterior descending coronary artery, followed by reperfusion for eight days. The treated group (n=7) received PAF antagonist TCV-309 (0.1 mg/kg) 45 mins after ligation; the untreated group (n=7) received vehicle only. RESULTS: Untreated animals experienced significantly (P<0.001) lower systemic arterial blood pressure during the reperfusion period than animals treated with TCV-309. Furthermore, untreated animals required significantly more (P<0.01) antiarrhythmic and inotropic support. Only two of seven animals in the untreated group survived, which was significantly different (P<0.05) from the six of seven treated animals that survived for eight days. Morphometric analyses did not show differences between groups in the characteristics of scar formation following reperfusion for eight days. CONCLUSIONS: PAF antagonist TCV-309 improves survival and reduces cardiovascular dysfunctions associated with regional myocardial ischemia reperfusion injury when administered at a clinically modelled time.

The role of platelet-activating factor in regional myocardial ischemia-reperfusion injury.

BACKGROUND: This swine model was designed to elucidate the role of platelet-activating factor in regional myocardial ischemia-reperfusion injury. METHODS: In groups 1 and 2 (n = 12 each), the left anterior descending coronary artery was ligated for 60 minutes to induce regional myocardial ischemia followed by 6 hours of reperfusion. Group 1 received the platelet-activating factor antagonist TCV-309 before ischemia, whereas group 2 did not. Group 3 (n = 3) had a sham operation. RESULTS: Animals in group 2 exhibited significant (p < 0.05) hemodynamic instability and myocardial depression during the reperfusion period. Despite preventive measures, 7 of the 12 animals experienced severe dysrhythmias in the form of atrial and ventricular fibrillation leading to cardiac arrest. In contrast, animals in group 1 in whom the effects of platelet-activating factor were blocked by the specific platelet-activating factor receptor antagonist TCV-309 were hemodynamically stable and had significantly (p < 0.05) better myocardial function. This significant difference in global myocardial function between the groups was observed in the presence of similar morphologic findings and regional myocardial function. CONCLUSIONS: These results suggest that platelet-activating factor has a definite influence on global myocardial dysfunction associated with regional myocardial ischemia-reperfusion injury.

Platelet-activating factor antagonism: a new concept in the management of regional myocardial ischemia-reperfusion injury.

Reperfusion therapies for treatment of myocardial infarction successfully reduce patient mortality; however, regional myocardial ischemia-reperfusion (RMIR) causes its own expression of cardiovascular dysfunction, including myocardial depression, hemodynamic instability, and dysrhythmias, which have increased patient mortality within the first 24 h after starting reperfusion therapy. Current evidence suggests that the release of oxygen-derived reactive substances and subsequent inflammatory mediators during ischemia-reperfusion contribute toward this injury. Platelet-activating factor (PAF), a mediator released during RMIR, has been emphasized by many investigators as playing a central role in causing RMIR injury. Similar cardiovascular dysfunctions that occur during RMIR, including myocardial depression, hemodynamic instability, and dysrhythmias, occur after administration of PAF and are ameliorated with PAF antagonists. Further, PAF antagonists have been shown to be cardioprotective and improve survival when administered before onset of reperfusion. A variety of phospholipid analogues, naturally derived compounds, and synthetic compounds have been developed that form the different classes of PAF antagonists, each with unique antagonizing properties. Several of these compounds have successfully passed safety and efficacy testing in humans; however, to date, no clinical trials have investigated the protective effects of PAF antagonists against RMIR injury. A current theory in the pathogenesis of RMIR injury considers the ischemic and necrotic portion of the myocardium and regional dysfunction due to tissue necrosis to be solely responsible for global cardiac dysfunction leading to hemodynamic instability and death. Evidence now suggests, however, that the global dysfunction is also due to the effect of inflammatory mediators such as PAF, thromboxanes, leukotrienes, and endothelins that are released during RMIR and are distributed throughout the heart on reperfusion. Antagonizing a central inflammatory mediator such as PAF, as adjunct treatment with currently used reperfusion therapies, improves cardiovascular function and survival in animals and should be introduced into clinical trials to investigate if similar protective effects can be provided in humans.

Mapping materials properties with Raman spectroscopy utilizing a 2-D detector.

An imaging Raman system based on a 2-D detector and capable of collecting simultaneously 1024 spatially resolved spectra has been constructed. Hardware and software are described which allow real time analysis of the spectral data, leading to a large reduction in the data storage requirements. The analysis yields a 1-D profile (1024 points) across the sample of chemical or physical properties that are distinguishable by their Raman spectral features. Sample translations, along with repeated collection and analysis cycles, allow 2-D maps of chemical or physical properties to be generated rapidly. The spatial resolution and spectral precision are 5microm and 0.16 cm(-1) respectively. Applications to the analysis of phase transformed zones in microengineered zirconias and to measurement of an in situ temperature profile of a single carbon fiber are presented. In a typical application, 66,560 Raman spectra from an 8- x 6-mm area on a partially stabilized zirconia sample were collected and analyzed in 5.4 h to produce a 2-D map of the fraction of tetragonal phase transformed to monoclinic phase during crack propagation.

Antibiotic induced electrophoretic mobility shifts of DNA restriction fragments.

Several antibiotics, netropsin, distamycin A, actinomycin D, Hoechst 33258 and olivomycin, which demonstrate base specificity in their DNA binding properties have been found to alter the electrophoretic mobility of DNA restriction fragments in native polyacrylamide gels. The antibiotics mostly reduced the migration of larger DNA fragments, but netropsin and Hoechst 33258 were observed to increase the migration rate of several DNA fragments of intermediate size. DNA fragments of similar molecular weight which comigrate as a single gel band can at times be separated as the result of differential mobility shifts promoted by antibiotic DNA complex formations.