Longitudinal Metabolomic Profiling of Amino Acids and Lipids across Healthy Pregnancy

Pregnancy is characterized by a complexity of metabolic processes that may impact fetal development and ultimately, infant health outcomes. However, our understanding of whole body maternal and fetal metabolism during this critical life stage remains incomplete. The objective of this study is to utilize metabolomics to profile longitudinal patterns of fasting maternal metabolites among a cohort of non-diabetic, healthy pregnant women in order to advance our understanding of changes in protein and lipid concentrations across gestation, the biochemical pathways by which they are metabolized and to describe variation in maternal metabolites between ethnic groups. Among 160 pregnant women, amino acids, tricarboxylic acid (TCA) cycle intermediates, keto-bodies and non-esterified fatty acids were detected by liquid chromatography coupled with mass spectrometry, while polar lipids were detected through flow-injected mass spectrometry. The maternal plasma concentration of several essential and non-essential amino acids, long-chain polyunsaturated fatty acids, free carnitine, acetylcarnitine, phosphatidylcholines and sphingomyelins significantly decreased across pregnancy. Concentrations of several TCA intermediates increase as pregnancy progresses, as well as the keto-body β-hydroxybutyrate. Ratios of specific acylcarnitines used as indicators of metabolic pathways suggest a decreased beta-oxidation rate and increased carnitine palmitoyltransferase-1 enzyme activity with advancing gestation. Decreasing amino acid concentrations likely reflects placental uptake and tissue biosynthesis. The absence of any increase in plasma non-esterified fatty acids is unexpected in the catabolic phase of later pregnancy and may reflect enhanced placental fatty acid uptake and utilization for fetal tissue growth. While it appears that energy production through the TCA cycle increases as pregnancy progresses, decreasing patterns of free carnitine and acetylcarnitine as well as increased carnitine palmitoyltransferase-1 rate and β-hydroxybutyrate levels suggest a concomitant upregulation of ketogenesis to ensure sufficient energy supply in the fasting state. Several differences in metabolomic profiles between Hispanic and non-Hispanic women demonstrate phenotypic variations in prenatal metabolism which should be considered in future studies.     

Elevated maternal cortisol early in pregnancy predicts third trimester levels of placental corticotropin releasing hormone (CRH): priming the placental clock

The purposes of this study were to determine the intervals when placental corticotrophic-releasing hormone (CRH) was most responsive to maternal cortisol. A sample of 203 women each were evaluated at 15, 19, 25 and 31 weeks gestation and followed to term. Placental CRH and maternal adrenocorticotropin hormone (ACTH), B-endorphin and cortisol were determined from plasma. CRH levels increased faster and were higher in women who delivered preterm compared with women who delivered at term (F3,603 = 5.73, p < .001). Simple effects indicated that CRH levels only at 31 weeks predicted preterm birth (F1,201 = 5.53, p = .02). Levels of cortisol were higher in women who delivered preterm at 15 weeks gestation (F1,201 = 4.45, p = .03) with a similar trend at 19 weeks gestation. Hierarchical regression suggested that the influence on birth outcome of maternal cortisol early in pregnancy was mediated by its influence on placental CRH at 31 weeks. Elevated cortisol at 15 weeks predicted the surge in placental CRH at 31 weeks (R = .49, d.f. = 1,199, Fchange = 61.78, p < .0001). Every unit of change in cortisol (microg/dl) at 15 weeks was associated with a 34 unit change of CRH (pg/ml) at 31 weeks. These findings suggested that early detection of stress signals by the placenta stimulated the subsequent release of CRH and resulted in increased risk for preterm delivery.     

Recent developments in the treatment of atherosclerosis

Atherosclerosis is one of the most frequent causes of cardiac arrest. The major cause of this disease is high concentrations of lipid in the blood. Medicinal agents so far have been quite successful in the management of hyperlipidemia. Among the several widely used drugs, (fibrates, statins and niacin) statins are the most frequently prescribed in many forms of hyperlipidemia. Recently, statins have been found to produce serious toxicities, which are rare but can be potentially harmful and are noise concern for the immediate need to develop some new chemical entities in this category. This review is primarily concerned with recent developments in atherosclerotic drug discovery including novel inhibitors of cholesterol biosynthesis, cholesterol absorption inhibitors and antioxidants. The review also focuses on possible future targets including gene therapy.     

Behavioral perinatology: biobehavioral processes in human fetal development

Behavioral perinatology is as an interdisciplinary area of research that involves conceptualization of theoretical models and conduct of empirical studies of the dynamic time-, place-, and context-dependent interplay between biological and behavioral processes in fetal, neonatal, and infant life using an epigenetic framework of development. The biobehavioral processes of particular interest to our research group relate to the effects of maternal pre- and perinatal stress and maternal-placental-fetal stress physiology. We propose that behavioral perinatology research may have important implications for a better understanding of the processes that underlie or contribute to the risk of three sets of outcomes: prematurity, adverse neurodevelopment, and chronic degenerative diseases in adulthood. Based on our understanding of the ontogeny of human fetal development and the physiology of pregnancy and fetal development, we have articulated a neurobiological model of pre- and perinatal stress. Our model proposes that chronic maternal stress may exert a significant influence on fetal developmental outcomes. Maternal stress may act via one or more of three major physiological pathways: neuroendocrine, immune/inflammatory, and vascular. We further suggest that placental corticotropin-releasing hormone (CRH) may play a central role in coordinating the effects of endocrine, immune/inflammatory, and vascular processes on fetal developmental outcomes. Finally, we hypothesize that the effects of maternal stress are modulated by the nature, duration, and timing of occurrence of stress during gestation. In this paper, we elaborate on the conceptual and empirical basis for this model, highlight some relevant issues and questions, and make recommendations for future research in this area.     

Nanosecond Laser–Assisted Tuning of the Plasmon Band of Triangular-Shaped Ag Nanostructures and Development of a Broadband Visible-Near Infrared Light Absorber

Plasmonics - Most of the outstanding applications of silver nanoparticles (Ag NPs) have arisen from their tunable localized surface plasmon resonance (LSPR). In this report, we have systematically...     

Improved prognosis since 1969 of myocardial infarction treated in a coronary care unit: lack of relation with changes in severity.

OBJECTIVE--To study changes from 1969 to 1983 in the prognosis of patients with acute myocardial infarction treated in a coronary care unit. DESIGN--Mortality follow up of all patients with definite acute myocardial infarction. SETTING--The coronary care unit of the Royal Melbourne Hospital, a tertiary referral centre. SUBJECTS--4253 Patients (3366 men, 887 women) admitted from 1969 to 1983. MAIN OUTCOME MEASURE--Mortality recorded at discharge from hospital and 12 months after admission. RESULTS--Details of clinical findings, history, electrocardiograms, arrhythmias, and radiological findings were recorded on admission. Mean ages were 63 for women and 57 for men, and women had haemodynamically more severe infarcts than men. In the later years patients were older and had less severe infarcts. Overall, hospital mortality in men was 16.7% in 1969-73 and 8.5% in 1979-83 and declined in all grades of the Norris and Killip infarct severity indices compared with a constant 19.2% in women. Even after adjustment for age and severity by logistic regression, hospital mortality fell in men by an average of 8% (95% confidence interval 4% to 11%) a year but remained constant in women. By 1983 male mortality was 60% that of women of similar age and comparable severity of infarction. Mortality of hospital survivors at 12 months declined by 7% (4% to 9%) a year in both sexes, even after adjustment for age and severity, with a male to female mortality ratio of about 0.8. New indices were derived to predict mortality in hospital and at 12 months. CONCLUSION--The observed declines in mortality cannot be explained by changes in severity of infarction or in prognostic characteristics of patients.     

Synthesis of new chemical entities from paracetamol and NSAIDs with improved pharmacodynamic profile

It was envisaged to combine high antipyretic activity of paracetamol into commonly used NSAIDs. To achieve this goal new chemical entities were synthesized by chemically combining paracetamol and NSAIDs, and biologically evaluated for their antipyretic, analgesic, anti-inflammatory and ulcerogenic potential. The acid chloride of parent NSAIDs was reacted with excess of p-aminophenol to yield the desired p-amidophenol derivatives (1B–7B). Acetate derivatives (1C–7C) of these phenols (1B–7B) were also prepared by their treatment with acetic anhydride, in order to see the impact of blocking the free phenolic group on the biological activity of the derivatives. All the synthesized p-amidophenol derivatives showed improved antipyretic activity than paracetamol with retention of anti-inflammatory activity of their parent NSAIDs. These compounds elicited no ulcerogenicity unlike their parent drugs.     

Corticotropin releasing hormone (CRH) gene variation: comprehensive resequencing for variant and molecular haplotype discovery in monosomic hybrid cell lines.

Candidate gene association studies have met with mixed success due to many reasons including incomplete surveys of genetic variation and differences in patterns of genetic variation among study populations. We present the results of comprehensive variant discovery for the corticotropin releasing hormone gene (CRH on chromosome 8) encoding a neuropeptide that is central to many physiologic pathways. Mouse-human hybrid cell lines were constructed that are monosomic for human chromosome 8 for resequencing of separated CRH alleles to identify variants and directly determine their chromosomal phase for three major ethnic groups including African Americans (AA), Mexican Americans (MA) and European Americans (EA). We also resequenced diploid individuals to evaluate single nucleotide polymorphism (SNP) discovery in the limited numbers of monosomic hybrid cell lines. Our results show that CRH variation is very different in AA, yielding larger numbers of variants and haplotypes compared to MA and EA. Analysis of LD structure found three haplotype blocks in AA and two blocks in EA. Comparisons between AA and EA groups yielded extremely high measures of genetic differentiation (Wright's F(ST)>0.6), likely reflecting disruptive selection in CRH evolution. Network analysis showed that AA have retained an ancestral CRH haplotype, while the most common EA haplotype is derived from a single recombination event.     

Variation in the Maternal Corticotrophin Releasing Hormone-Binding Protein (CRH-BP) Gene and Birth Weight in Blacks, Hispanics and Whites

Background

Given the unique role of the corticotrophin-releasing hormone (CRH) system in human fetal development, the aim of our study was to estimate the association of birth weight with DNA sequence variation in three maternal genes involved in regulating CRH production, bioavailability and action: CRH, CRH-Binding Protein (CRH-BP), and CRH type 1 receptor (CRH-R1), respectively, in three racial groups (African-Americans, Hispanics, and non-Hispanic Whites).

Methods

Our study was carried out on a population-based sample of 575 mother–child dyads. We resequenced the three genes in mouse–human hybrid somatic cell lines and selected SNPs for genotyping.

Results

A significant association was observed in each race between birth weight and maternal CRH-BP SNP genotypes. Estimates of linkage disequilibrium and haplotypes established three common haplotypes marked by the rs1053989 SNP in all three races. This SNP predicted significant birth weight variation after adjustment for gestational age, maternal BMI, parity, and smoking. African American and Hispanic mothers carrying the A allele had infants whose birth weight was on average 254 and 302 grams, respectively, less than infants having C/C mothers. Non-Hispanic White mothers homozygous for the A allele had infants who were on average 148 grams less than those infants having A/C and C/C mothers.

Conclusions

The magnitudes of the estimates of the birth weight effects are comparable to the combined effects of multiple SNPs reported in a recent meta-analysis of 6 GWAS studies and is quantitatively larger than that associated with maternal cigarette smoking. This effect was persistent across subpopulations that vary with respect to ancestry and environment.