The incidence of fetal alcohol syndrome has not been declining even though alcohol has been established as a teratogen and significant efforts have been made to educate women not to abuse alcohol ...during pregnancy. In addition to further educational efforts, strategies to prevent or mitigate the damages of prenatal alcohol exposure are now under development. Animal models will play a significant role in the effort to develop these strategies. Because prenatal alcohol exposure causes damage by multiple mechanisms, depending on dose, pattern, and timing of exposure, and because no species of animal is the same as the human, the choice of which animal model to use is complicated. To choose the best animal model, it is necessary to consider the specific scientific question that is being addressed and which model system is best able to address the question. Animal models that are currently in use include nonhuman primates, rodents (rats, mice, guinea pigs), large animal models (pig and sheep), the chick, and simple animals, including fish, insects, and round worms. Each model system has strengths and weaknesses, depending on the question being addressed. Simple animal models are useful in exploring basic science questions that relate to molecular biology and genetics that cannot be explored in higher-order animals, whereas higher-order animal models are useful in studying complex behaviors and validating basic science findings in an animal that is more like the human. Substantial progress in this field will require the judicious use of multiple scientific approaches that use different animal model systems.
Maternal Nutrition and Fetal Development Bazer, Fuller W.; Spencer, Thomas E.; Wu, Guoyao ...
The Journal of nutrition,
09/2004, Letnik:
134, Številka:
9
Journal Article
Recenzirano
Odprti dostop
Nutrition is the major intrauterine environmental factor that alters expression of the fetal genome and may have lifelong consequences. This phenomenon, termed “fetal programming,” has led to the ...recent theory of “fetal origins of adult disease.” Namely, alterations in fetal nutrition and endocrine status may result in developmental adaptations that permanently change the structure, physiology, and metabolism of the offspring, thereby predisposing individuals to metabolic, endocrine, and cardiovascular diseases in adult life. Animal studies show that both maternal undernutrition and overnutrition reduce placental-fetal blood flows and stunt fetal growth. Impaired placental syntheses of nitric oxide (a major vasodilator and angiogenesis factor) and polyamines (key regulators of DNA and protein synthesis) may provide a unified explanation for intrauterine growth retardation in response to the 2 extremes of nutritional problems with the same pregnancy outcome. There is growing evidence that maternal nutritional status can alter the epigenetic state (stable alterations of gene expression through DNA methylation and histone modifications) of the fetal genome. This may provide a molecular mechanism for the impact of maternal nutrition on both fetal programming and genomic imprinting. Promoting optimal nutrition will not only ensure optimal fetal development, but will also reduce the risk of chronic diseases in adults. J. Nutr. 134: 2169–2172, 2004.
Over the last decade, there has been enormous effort to measure neutrino interaction cross sections important to oscillation experiments. However, a number of results from modern experiments appear ...to be in tension with each other, despite purporting to measure the same processes. The TENSIONS2016 workshop was held at University of Pittsburgh July 24–31, 2016 and was sponsored by the Pittsburgh Particle Physics, Astronomy, and Cosmology Center (PITT PACC). The focus was on bringing experts from three experimental collaborations together to compare results in detail and try to find the source of tension by clarifying and comparing signal definitions and the analysis strategies used for each measurement. A set of comparisons between the measurements using a consistent set of models was also made. This paper summarizes the main conclusions of that work.
Anticipating the future use of arginine to enhance fetal and neonatal growth as well as to treat diabetes and obesity, we performed studies in pigs, rats, and sheep to determine the pharmacokinetics ...of orally or i.v. administered arginine and the safety of its chronic supplementation. Our results indicate that all 3 species rapidly catabolized the supplemental arginine. The elevated circulating concentrations of arginine generally returned to baseline levels within 4-5 h after administration, with the rates varying with the age and physiological status of the animals. The clearance of arginine was greater in pregnant than in nonpregnant animals, in young than in adult animals, in lean than in obese animals, and in type-1 diabetic than in nondiabetic animals. I.v. administration of arginine-HCl to pregnant ewes (at least 0.081 g arginine·kg body weight⁻¹·d⁻¹) did not result in any undesirable treatment-related effect. Neonatal pigs, growing-finishing pigs, pregnant pigs, and adult rats tolerated large amounts of chronic supplemental arginine (e.g. 0.62, 0.32, 0.21, and 2.14 g·kg body weight⁻¹·d⁻¹, respectively) administered via enteral diets without the appearance of any adverse effect. On the basis of the comparative studies and a consideration of species differences in food intake per kilogram body weight, we estimate that a 70-kg human subject should be able to tolerate long-term parenteral and enteral supplemental doses of 6 and 15 g/d arginine, respectively, in addition to a basal amount of arginine (4-6 g/d) from regular diets.
Guiding of low intensity 1keV singly charged nitrogen ions through a macroscopic tapered insulating capillary is studied experimentally. The transmitted beam intensities are measured as a function of ...time and different injection positions with respect to the capillary axis. Data are presented for a capillary aligned with the beam axis and when rotated by 1.5°. We found that pA beam intensities are sufficient to produce guiding and that improvements in the beam brightness by using tapered capillaries are minimal.
Individuals with fetal alcohol spectrum disorders (FASD) incur enduring brain damage and neurodevelopmental impairments from prenatal alcohol exposure (PAE). Preclinical rodent models have ...demonstrated that choline supplementation during development can reduce the severity of adverse neurodevelopmental consequences of PAE. This study used the sheep model to evaluate dietary choline supplementation during pregnancy as a therapeutic intervention, testing the hypothesis that choline can ameliorate alcohol-induced cerebellar Purkinje cell loss. Pregnant ewes were randomly assigned either to a normal control NC group (n = 8), or to groups given intravenous infusions of alcohol (or saline) from gestational days 4–41 (the first trimester-equivalent). A weekly binge-drinking pattern was modeled, with three consecutive days of infusions of saline SAL, 1.75 g/kg/day alcohol 1.75ALC, or 2.5 g/kg/day alcohol 2.5ALC followed by four days off. Infused ewes were randomly assigned to receive dietary supplements throughout pregnancy of choline (10 mg/kg/day) or placebo (n = 8 per group). Mean blood alcohol concentrations (BAC) were significantly higher in the 2.5ALC groups (287 mg/dL) than the 1.75ALC groups (197 mg/dL). Lamb cerebella were harvested on postnatal day 180 and processed for stereological counts of Purkinje cells. Both alcohol doses caused significant reductions in Purkinje number relative to NC and SAL-Placebo groups, confirming previous findings. Effects of choline supplementation depended on infusion group: it significantly protected against Purkinje cell loss in the 2.5ALC group, had no effect in the 1.75ALC group, and significantly reduced numbers in the SAL-Choline group (though neither the SAL-Choline nor the SAL-Placebo group differed from the NC group). The protection by choline evident only in the 2.5ALC group suggests that multiple, BAC-dependent mechanisms of cerebellar damage may be activated with alcohol exposure in the first trimester, and that choline may protect against pathogenic mechanisms that emerge at higher BACs. These outcomes extend the evidence that early choline supplementation can mitigate some neurodevelopmental defects resulting from binge-like PAE.
•Clinically relevant doses of choline have a potential therapeutic intervention for PAE.•Choline may protect against pathogenic mechanisms that emerge at higher BACs.•Early choline supplementation mitigates some neurodevelopmental defects from binge PAE.
The frequency of multiple fetuses has increased in human pregnancies due to assisted reproductive technologies. This translates into a greater proportion of premature and low-birth weight infants in ...the United States and worldwide. In addition, improvements in sheep breeding have resulted in new breeds with increased litter size but reduced fetal survival and birth weight. Currently, there are no treatments for preventing fetal growth restriction in humans or sheep (an established model for studying human fetal physiology) carrying multiple fetuses. In this work, Booroola Rambouillet ewes (FecB+/-) with 2-4 fetuses were fed a diet providing 100% of NRC-recommended nutrient requirements. Between d 100 and 121 of gestation, ewes received an i.v. bolus injection of either saline solution or 345 μmol arginine-HCl/kg body weight 3 times daily. The arginine treatment reduced (P < 0.05) the percentage of lambs born dead by 23% while increasing (P = 0.05) the percentage of lambs born alive by 59%. The i.v. administration of arginine enhanced (P < 0.05) the birth weights of quadruplets by 23% without affecting maternal body weight. The improved pregnancy outcome was associated with an increase in maternal plasma concentrations of arginine, ornithine, cysteine, and proline, as well as a decrease in circulating levels of ammonia and β-hydroxybutyrate. These novel results indicate that parenteral administration of arginine to prolific ewes ameliorated fetal mortality and growth retardation. Our findings provide support for experiments to assess the clinical use of arginine to enhance fetal growth and survival in women gestating multiple fetuses.
Intrauterine growth restriction (IUGR) is a major health problem worldwide that currently lacks an effective therapeutic solution. This study was conducted with an ovine IUGR model to test the ...hypothesis that parenteral administration of L-arginine (Arg) is effective in enhancing fetal growth. Beginning on d 28 of gestation, ewes were fed a diet providing 100% (control-fed) or 50% (underfed) of NRC-recommended nutrient requirements. Between d 60 of gestation and parturition, underfed ewes received i.v. infusions of saline or 155 μmol Arg-HCl/kg body weight 3 times daily, whereas control-fed ewes received only saline. The birth weights of lambs from saline-infused underfed ewes were 23% lower (P < 0.01) than those of lambs from control-fed dams. Administration of Arg to underfed ewes increased (P < 0.01) concentrations of Arg (69%), ornithine (55%), proline (29%), methionine (37%), leucine (36%), isoleucine (35%), cysteine (19%), and FFA (43%) in maternal serum, decreased maternal circulating levels of ammonia (18%) and triglycerides (32%), and enhanced birth weights of lambs by 21% compared with saline-infused underfed ewes. There was no difference in birth weights of lambs between the control-fed and the Arg-infused underfed ewes. These novel results indicate that parenteral administration of Arg to underfed ewes prevented fetal growth restriction and provide support for its clinical use to ameliorate IUGR in humans. The findings also lay a new framework for studying cellular and molecular mechanisms responsible for the beneficial effects of Arg in regulating conceptus growth and development.
Objective:
To review and assess available literature on the chemistry, pharmacology, pharmacodynamics, pharmacokinetics, clinical studies, adverse events, drug interactions, special populations, and ...dosing and administration for cangrelor, a product in late stage Phase II clinical trials.
Data Sources:
A literature search of MEDLINE (1966–March 2006), International Pharmaceutical Abstracts (1970–February 2006), and Cochrane database (first quarter 2006) was conducted using key terms of cangrelor, AR-C69931 MX, and P2Y12 receptor antagonist. Bibliographies of relevant articles were reviewed for additional references. The Medicines Company Web site was reviewed, and a company representative was contacted.
Study Selection and Data Extraction:
Available English-language literature, including abstracts, preclinical studies, clinical trials, and review articles, was reviewed.
Data Synthesis:
Cangrelor is a P2Y12 antagonist under development for treatment of acute coronary syndrome. Cangrelor has been studied as an intravenous infusion in doses of 2 or 4 μg/kg/min. It inhibits platelet aggregation with rapid onset and offset and does not require metabolism for therapeutic activity. Published Phase II trials have demonstrated safety and inhibition of platelet aggregation.
Conclusions:
Cangrelor is a promising investigational medication for inhibition of platelet aggregation in acute arterial coronary events. Phase II trials have shown safety and a greater inhibition of platelet aggregation over clopidogrel. Phase III trials will provide more definitive information on clinical efficacy and safety. Until then, the role of cangrelor is uncertain.
Background
Plasma or circulating miRNAs (cirmiRNAs) have potential diagnostic value as biomarkers for a range of diseases. Based on observations that ethanol (EtOH) altered intracellular miRNAs ...during development, we tested the hypothesis that plasma miRNAs were biomarkers for maternal alcohol exposure, and for past in utero exposure, in the neonate.
Methods
Pregnant sheep were exposed to a binge model of EtOH consumption resulting in an average peak blood alcohol content of 243 mg/dl, for a third‐trimester‐equivalent period from gestational day 4 (GD4) to GD132. MiRNA profiles were assessed by quantitative PCR analysis in plasma, erythrocyte, and leukocytes obtained from nonpregnant ewes, and plasma from pregnant ewes 24 hours following the last binge EtOH episode, and from newborn lambs, at birth on ~GD147.
Results
Pregnant ewe and newborn lamb cirmiRNA profiles were similar to each other and different from nonpregnant female plasma, erythrocyte, or leukocyte miRNAs. Significant changes in cirmiRNA profiles were observed in the EtOH‐exposed ewe and, at birth, in the in utero, EtOH‐exposed lamb. CirmiRNAs including miR‐9, ‐15b, ‐19b, and ‐20a were sensitive and specific measures of EtOH exposure in both pregnant ewe and newborn lamb. Additionally, EtOH exposure altered guide‐to‐passenger strand cirmiRNA ratios in the pregnant ewe, but not in the lamb.
Conclusions
Shared profiles between pregnant dam and neonate suggest possible maternal‐fetal miRNA transfer. CirmiRNAs are biomarkers for alcohol exposure during pregnancy, in both mother and neonate, and may constitute an important shared endocrine biomarker that is vulnerable to the maternal environment.
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