Craniosynostosis and maternal smoking

BACKGROUND: Several previous studies suggested increased risk of craniosynostosis among infants born to women who smoked. METHODS: This study used data from the National Birth Defects Prevention Study, a multi‐state, population‐based case‐control study of infants delivered from 1997–2003. Nonmalformed, liveborn controls were selected randomly from birth certificates or birth hospitals. Data from maternal telephone interviews were available for 531 cases and 5008 controls. RESULTS: Smoking during the first month of pregnancy was not associated with craniosynostosis. Smoking later in pregnancy was associated with increased risk, but only among mothers who smoked at least one pack/day. For example, during the second trimester, the odds ratio for smoking <5 cigarettes/day was 1.0 (95% confidence interval [CI] 0.6, 1.8), but the odds ratio (OR) for smoking 15 or more cigarettes/day was 1.6 (95% CI 0.9, 2.8), after adjustment for maternal age, education, race‐ethnicity, sub‐fertility, parity, folic acid supplement intake, body mass index, and study center. Among women who did not smoke, adjusted odds ratios suggested that secondhand smoke exposure at home, but not at work/school, was associated with modestly increased risk; the OR for home exposure was 1.3 (95% CI 0.9, 1.9). Results followed a similar pattern for some, but not all, specific suture types, but numbers for some groupings were small. CONCLUSIONS: The results suggest moderately increased risk of craniosynostosis among mothers who were the heaviest smokers and who continued to smoke after the first trimester. Results are somewhat equivocal, given that most confidence intervals included one. Birth Defects Research (Part A), 2008. © 2007 Wiley‐Liss, Inc.     

Selection against genetic defects in conservation schemes while controlling inbreeding

We studied different genetic models and evaluation systems to select against a genetic disease with additive, recessive or polygenic inheritance in genetic conservation schemes. When using optimum contribution selection with a restriction on the rate of inbreeding (ΔF) to select against a disease allele, selection directly on DNA-genotypes is, as expected, the most efficient strategy. Selection for BLUP or segregation analysis breeding value estimates both need 1–2 generations more to halve the frequency of the disease allele, while these methods do not require knowledge of the disease mutation at the DNA level. BLUP and segregation analysis methods were equally efficient when selecting against a disease with single gene or complex polygene inheritance, i.e. knowledge about the mode of inheritance of the disease was not needed for efficient selection against the disease. Smaller schemes or schemes with a more stringent restriction on ΔF needed more generations to halve the frequency of the disease alleles or the fraction of diseased animals. Optimum contribution selection maintained ΔF at its predefined level, even when selection of females was at random. It is argued that in the investigated small conservation schemes with selection against a genetic defect, control of ΔF is very important.     

The Pattern of Distribution of Defects of Wing Venation in the Banded Agrion (Calopteryx splendens)

The distribution of morphological structures was studied in wings of the banded agrion (Calopteryx splendens Harr.) from different intrapopulation groups. Dragon flies of odd years of emergence are characterized by a more stable pattern of ontogenetic processes according to the mean total number of venation defects. The sharply increased level of radiation in summer 1986, which coincided with the flight of dragon-flies, could have caused hereditary defects expressed in a sequence of generations of even years of emergence. Apparently, most alternative features of wing venation in dragon-flies can be considered as markers of stability of the ontogenetic processes, which reflect, to a great extent, genotypic features of the organisms in a population. A possible mechanism has been described, which explains the proposed topological model of formation of the venation defects of different types. The increase in mean frequencies of defects can suggest an enhanced development over the aberrant epigenetic trajectories, which may lead to the elimination of these organisms under the influence of various agents, i.e., to the stabilizing selection in a population. The results obtained suggest that defects of venation arise on the stochastic basis and their frequency increases upon destabilization of ontogenetic processes not only by the environmental factors, but also by genetic stress. Venation defects can be successfully used in population biomonitoring.     

Reexcitation mechanisms in epicardial tissue: Role of Ito density heterogeneities and INa inactivation kinetics

Dispersion of action potential repolarization is known to be an important arrhythmogenic factor in cardiopathies such as Brugada syndrome. In this work, we analyze the effect of a variation in sodium current (I_Na) inactivation and a heterogeneous rise of transient outward current (I_to) in the probability of reentry in epicardial tissue. We use the Luo-Rudy model of epicardial ventricular action potential to study wave propagation in a one-dimensional fiber. Spatial dispersion in repolarization is introduced by splitting the fiber into zones with different strength of I_to. We then analyze the pro-arrhythmic effect of a variation in the relaxation time and steady-state of the sodium channel fast inactivating gate h. We quantify the probability of reentry measuring the percentage of reexcitations that occurs in 200 beats. We find that, for high stimulation rates, this percentage is negligible, but increases notably for pacing periods above 700 ms. Surprisingly, with decreasing I_Na inactivation time, the percentage of reexcitations does not grow monotonically, but presents vulnerable windows, separated by values of the I_Na inactivation speed-up where reexcitation does not occur. By increasing the strength of L-type calcium current I_CaL above a certain threshold, reexcitation disappears. Finally, we show the formation of reentry in stimulated two-dimensional epicardial tissue with modified I_Na kinetics and I_to heterogeneity. Thus, we confirm that while I_to dispersion is necessary for phase-2 reentry, altered sodium inactivation kinetics influences the probability of reexcitation in a highly nonlinear fashion.     

Peripartum Cardiomyopathy Presenting With Ventricular Tachycardia: A Rare Presentation

A 25-year-old previously asymptomatic pregnant woman at 36 weeks'' gestation was noticed to have repetitive monomorphic ventricular tachycardia. A dilated left ventricle with moderately reduced systolic function was found on echocardiographic examination. This is a very rare presentation of peripartum cardiomyopathy (PPCMP) presenting with repetitive monomorphic ventricular tachycardia.     

Mitochondria in cardiomyocyte Ca signaling

Ca²⁺ signaling is of vital importance to cardiac cell function and plays an important role in heart failure. It is based on sarcolemmal, sarcoplasmic reticulum and mitochondrial Ca²⁺ cycling. While the first two are well characterized, the latter remains unclear, controversial and technically challenging.In mammalian cardiac myocytes, Ca²⁺ influx through L-type calcium channels in the sarcolemmal membrane triggers Ca²⁺ release from the nearby junctional sarcoplasmic reticulum to produce Ca²⁺ sparks. When this triggering is synchronized by the cardiac action potential, a global [Ca²⁺]_i transient arises from coordinated Ca²⁺ release events. The ends of intermyofibrillar mitochondria are located within 20 nm of the junctional sarcoplasmic reticulum and thereby experience a high local [Ca²⁺] during the Ca²⁺ release process. Both local and global Ca²⁺ signals may thus influence calcium signaling in mitochondria and, reciprocally, mitochondria may contribute to the local control of calcium signaling. In addition to the intermyofibrillar mitochondria, morphologically distinct mitochondria are also located in the perinuclear and subsarcolemmal regions of the cardiomyocyte and thus experience a different local [Ca²⁺].Here we review the literature in regard to several issues of broad interest: (1) the ultrastructural basis for mitochondrion – sarcoplasmic reticulum cross-signaling; (2) mechanisms of sarcoplasmic reticulum signaling; (3) mitochondrial calcium signaling; and (4) the possible interplay of calcium signaling between the sarcoplasmic reticulum and adjacent mitochondria.Finally, this review discusses experimental findings and mathematical models of cardiac calcium signaling between the sarcoplasmic reticulum and mitochondria, identifies weaknesses in these models, and suggests strategies and approaches for future investigations.     

Preventive effect of piperonyl butoxide on cyclophosphamide-induced teratogenesis in rats

BACKGROUND: Cyclophosphamide induces fetal defects through metabolic activation by cytochrome P-450 monooxygenases (CYP). The effects of piperonyl butoxide (PBO), a CYP inhibitor, on the fetal development and external, visceral, and skeletal abnormalities induced by cyclophosphamide were investigated in rats. METHODS: Pregnant rats were daily administered PBO (400 mg/kg) by gavage for 7 days (the 6th to 12th day of gestation), and intraperitoneally administered with cyclophosphamide (12 mg/kg) 4 h after the final treatment. On the 20th day of gestation, maternal and fetal abnormalities were determined by Cesarean section. RESULTS: Cyclophosphamide reduced fetal body weights by 30–40% without increasing resorption or death. In addition, it induced malformations in live fetuses: 100, 98, and 98.2% of the external (head and limb defects), visceral (cerebroventricular dilatation, cleft palate, and renal pelvic/ureteric dilatation), and skeletal (acrania, vertebral/costal malformations, and delayed ossification) abnormalities, respectively. The pre-treatment of PBO greatly decreased mRNA expression and activity of hepatic CYP2B, which metabolizes cyclophosphamide into teratogenic acrolein and cytotoxic phosphoramide mustard. Moreover, PBO remarkably attenuated cyclophosphamide-induced body weight loss and abnormalities of fetuses; score 3.57 versus 1.87 for exencephaly, 75.5% versus 42.5% for limb defects, 65.3% versus 22% for cerebroventricular dilatation, 59.2% versus 5.1% for cleft palate, score 1.28 versus 0.93 for renal pelvic/ureteric dilatation, 71.9–82.5% versus 23–45.9% for vertebral/costal malformations, and 84.2% versus 57.4% for delayed ossification in cyclophosphamide alone and PBO co-administration groups. CONCLUSIONS: These results suggest that repeated treatment with PBO may improve cyclophosphamide-induced body weight loss and malformations of fetuses by down-regulating CYP2B. Birth Defects Res (Part B) 86:402–408, 2009. © 2009 Wiley-Liss, Inc.     

Gene and microRNA expression in p53‐deficient day 8.5 mouse embryos

BACKGROUND: Neural tube defects (NTDs) are one of the most common human birth defects, with a prevalence of approximately 1 in 1000 live births in the United States. In animal studies, deletion of p53 leads to a significant increase in embryos that exhibit exencephaly. Whereas several studies have closely investigated the morphologic changes of p53‐deficient embryos, no study has reported the molecular‐level alteration in p53‐deficient embryos. Here we attempt to identify genes and microRNAs (miRNAs) modified by deletion of p53 in day 8.5 mouse embryos. METHODS: Mouse embryos from p53 heterozygous crosses were collected, genotyped, and embryos of similar genotype (+/+; +/?; ?/?) were pooled. RNA from the pooled samples was isolated to determine mRNA and miRNA expression levels using Whole Genome Bioarrays and Low Density Arrays, respectively. RESULTS: In p53 ?/? embryos, 388 genes showed statistically significant alteration in gene expression of more than twofold compared to p53 +/+ embryos. Expression of p53 and well known p53 target genes, such as p21 and cyclin G1, were significantly down‐regulated in p53 ?/? embryos. In contrast, expression of other p53 target genes, such as Mdm2, Noxa, and Puma, were unchanged. We also identified six genes (Csk, Itga3, Jarid2, Prkaca, Rarg, and Sall4), known to cause NTDs when deleted, that are also down‐regulated in p53 ?/? embryos. Finally, five miRNAs (mir‐1, mir‐30e‐3p, mir‐142‐3p, mir‐301, and mir‐331) also showed statistically significant alterations in expression levels in p53 ?/? embryos compared to p53 +/+ embryos. Combined analysis of the experimental data using stepwise regression model and two publicly available algorithms identified putative target genes of these miRNAs. CONCLUSIONS: Our data have identified genes and miRNAs that may be involved in the mechanisms underlining NTDs and begin to define the developmental role of p53 in the etiology of NTDs. Birth Defects Research (Part A), 2009. © 2009 Wiley‐Liss, Inc.