A multi-organ analysis of the role of mTOR in fetal alcohol spectrum disorders.

Alcohol exposure during gestation can lead to fetal alcohol spectrum disorders (FASD), an array of cognitive and physical developmental impairments. Over the past two and a half decades, Mammalian Target of Rapamycin (mTOR) has emerged at the nexus of many fields of study, and has recently been implicated in FASD etiology. mTOR plays an integral role in modulating anabolic and catabolic activities, including protein synthesis and autophagy. These processes are vital for proper development and can have long lasting effects following alcohol exposure, such as impaired hippocampal and synapse formation, reduced brain size, as well as cognitive, behavioral, and memory impairments. We highlight recent advances in the field of FASD, primarily with regard to animal model discoveries and discuss the interaction between alcohol and mTOR in the context of various tissues, including brain, placenta, bone, and muscle, with respect to developmental alcohol exposure paradigms. The current review focuses on novel FASD research within the context of the mTOR signaling and sheds light on mechanistic etiologies at various biological levels including molecular, cellular, and functional, across multiple stages of development and illuminates the dichotomy between the different mTOR complexes and their unique signaling roles.

Distribution of Phosphatidylethanol in Maternal and Fetal Compartments After Chronic Gestational Binge Alcohol Exposure.

BACKGROUND: Phosphatidylethanol (PEth) is a promising biomarker for gestational alcohol exposure. Studies show PEth accumulation in maternal and fetal blood following alcohol exposure; however, distribution of specific PEth homologues (16:0/18:1, 16:0/18:2, 16:0/20:4) in maternal and fetal blood is unknown. Additionally, PEth levels in highly vulnerable FASD targets in maternal and fetal compartments remain unexplored. We hypothesized that all 3 major PEth homologues will be detectable in the maternal and fetal blood, the maternal uterine artery (a reproductive tissue that delivers oxygen and nutrients to fetoplacental unit), and fetal brain regions following gestational binge alcohol exposure and that homologue distribution profiles will be tissue-specific. METHODS: Pregnant rats received once-daily orogastric gavage of alcohol (Alcohol; BAC 216 mg/dl@4.5g/kg/d; BAC 289 mg/dl@6g/kg/d) or iso-caloric maltose dextrin (Pair-fed control) from gestation days (GD) 5 to 20 or 21. Following chronic exposure, maternal and fetal tissues were analyzed for PEth homologue concentrations utilizing LC-MS/MS technology. RESULTS: All 3 PEth homologues were detected in alcohol-exposed maternal blood, fetal blood, maternal uterine artery, and fetal brain regions (hippocampus, cerebral cortex, and cerebellum). In both maternal and fetal blood, respectively, PEth 16:0/18:2 was more abundant compared to 16:0/18:1 (p < 0.0001,~66%,↑; p = 0.0159, 20.4%↑) and 16:0/20:4 (p = 0.0072,~25%↑; p = 0.0187, 19.4%↑). Maternal PEth 16:0/20:4 was ~ 42% higher than 16:0/18:1 (p = 0.0015). Maternal PEth 16:0/18:2 and 16:0/20:4 were ~ 25%↑ and ~ 20%↑ higher than in fetal blood (p < 0.05). No homologue differences were detected in the maternal uterine artery. In all fetal brain regions, PEth 16:0/18:1 was significantly higher (p < 0.0001) than 16:0/18:2 (~48 to 78%↑) and 16:0/20:4 (~31 to 62%↑) concentrations. PEth 16:0/20:4 was ~ 18% higher than 16:0/18:1 (p < 0.05) in the fetal hippocampus and cortex. CONCLUSION: All major PEth homologues were detected in maternal and fetal blood following chronic gestational binge alcohol exposure; homologue distribution profiles were tissue-specific. This study also provides insights into PEth accumulation in critical FASD targets, specifically the maternal uterine artery and fetal brain.

Chronic Binge Alcohol Exposure During Pregnancy Alters mTOR System in Rat Fetal Hippocampus.

BACKGROUND: Gestational alcohol exposure can contribute to fetal alcohol spectrum disorders (FASD), an array of cognitive, behavioral, and physical developmental impairments. Mammalian target of rapamycin (mTOR) plays a key role in regulating protein synthesis in response to neuronal activity, thereby modulating synaptic plasticity and long-term memory formation in the brain. Based on our previous quantitative mass spectrometry proteomic studies, we hypothesized that gestational chronic binge alcohol exposure alters mTOR signaling and downstream pathways in the fetal hippocampus. METHODS: Pregnant Sprague-Dawley rats were assigned to either a pair-fed control (PF-Cont) or a binge alcohol (Alcohol) treatment group. Alcohol dams were acclimatized via a once-daily orogastric gavage of 4.5 g/kg alcohol (peak BAC, 216 mg/dl) from GD 5-10 and progressed to 6 g/kg alcohol (peak BAC, 289 mg/dl) from GD 11-21. Pair-fed dams similarly received isocaloric maltose dextrin. RESULTS: In the Alcohol group, following this exposure paradigm, fetal body weight and crown-rump length were decreased. The phosphorylation level of mTOR (P-mTOR) in the fetal hippocampus was decreased in the Alcohol group compared with controls. Alcohol exposure resulted in dysregulation of fetal hippocampal mTORC1 signaling, as evidenced by an increase in total 4E-BP1 expression. Phosphorylation levels of 4E-BP1 and p70 S6K were also increased following alcohol exposure. P-mTOR and P-4E-BP1 were exclusively detected in the dentate gyrus and oriens layer of the fetal hippocampus, respectively. DEPTOR and RICTOR expression levels in the fetal hippocampus were increased; however, RAPTOR was not altered by chronic binge alcohol exposure. CONCLUSION: We conclude that chronic binge alcohol exposure during pregnancy alters mTORC1 signaling pathway in the fetal hippocampus. We conjecture that this dysregulation of mTOR protein expression, its activity, and downstream proteins may play a critical role in FASD neurobiological phenotypes.

Mechanisms Underlying Chronic Binge Alcohol Exposure-Induced Uterine Artery Dysfunction in Pregnant Rat.

BACKGROUND: A cardinal feature of fetal alcohol syndrome is growth restriction. Maternal uterine artery adaptations to pregnancy correlate with birthweight and survival. We hypothesized that gestational binge alcohol exposure impairs maternal uterine vascular function, affecting endothelial nitric oxide (NO)-mediated vasodilation. METHODS: Pregnant rats grouped as pair-fed control or binge alcohol exposed received a once-daily, orogastric gavage of isocaloric maltose-dextrin or alcohol, respectively. On gestational day 20, primary uterine arteries were isolated, cannulated, and connected to a pressure transducer, and functional studies were conducted by dual-chamber arteriography. Uterine arteries maintained at constant intramural pressure (90 mm Hg) were maximally constricted with thromboxane, and a dose-response for acetylcholine (Ach) was recorded. RESULTS: The alcohol group exhibited significantly impaired endothelium-dependent, Ach-induced uterine artery relaxation (↓∼30%). Subsequently, a dose-response was recorded following inhibition of endothelium-derived hyperpolarizing factor (apamin and TRAM-34) and prostacyclin (indomethacin). Ach-induced relaxation in the pair-fed control decreased by ~46%, and interestingly, relaxation in alcohol group further decreased by an additional ~48%, demonstrating that gestational binge alcohol impairs the NO system in the primary uterine artery. An endothelium-independent sodium nitroprusside effect was not observed. Immunoblotting indicated that alcohol decreased the level of endothelial excitatory P-Ser1177 endothelial NO synthase (eNOS) (p < 0.05) and total eNOS expression (p < 0.05) compared to both the normal and pair-fed controls. P-Ser1177 eNOS level was also confirmed by immunofluorescence imaging. CONCLUSIONS: This is the first study to demonstrate maternal binge alcohol consumption during pregnancy disrupts uterine artery vascular function via impairment of the eNOS vasodilatory system.

Placental Proteomics Reveal Insights into Fetal Alcohol Spectrum Disorders.

BACKGROUND: Fetal alcohol spectrum disorders (FASD) describe many of the well-known neurodevelopmental deficits afflicting children exposed to alcohol in utero. The effects of alcohol on the maternal-fetal interface, especially the placenta, have been less explored. We herein hypothesized that chronic binge alcohol exposure during pregnancy significantly alters the placental protein profile in a rat FASD model. METHODS: Pregnant rats were orogastrically treated daily with alcohol (4.5 g/kg, gestational day [GD] 5 to 10; 6.0 g/kg, GD 11 to 19) or 50% maltose dextrin (isocalorically matched pair-fed controls). On GD 20, placentae were collected, flash-frozen, and stored until tissues were homogenized. Protein lysates were denatured, reduced, captured on a 10-kDa spin filter, and digested. Peptides were eluted, reconstituted, and analyzed by a Q Exactive™ Hybrid Quadrupole-Orbitrap™ mass spectrometer. RESULTS: Mass spectrometry (MS) analysis identified 2,285 placental proteins based on normalized spectral counts and 2,000 proteins by intensity-based absolute quantification. Forty-five placental proteins were significantly (p < 0.05) altered by gestational alcohol exposure by both quantification approaches. These included proteins directly related to alcohol metabolism; specific isoforms of alcohol dehydrogenase and aldehyde dehydrogenase were up-regulated in the alcohol group. Ingenuity analysis identified ethanol degradation as the most significantly altered canonical pathway in placenta, and fetal/organ development as most altered function, with increased risk for metabolic, neurological, and cardiovascular diseases. Physiological roles of the significantly altered proteins were related to early pregnancy adaptations, implantation, gestational diseases, fetal organ development, neurodevelopment, and immune functions. CONCLUSIONS: We conclude that the placenta is a valuable organ not only to understand FASD etiology but it may also serve as a diagnostic tool to identify novel biomarkers for detecting the outcome of fetal alcohol exposure. Placental MS analysis can offer sophisticated insights into identifying alcohol metabolism-related enzymes and regulators of fetal development.

Chronic binge alcohol exposure during pregnancy impairs rat maternal uterine vascular function.

BACKGROUND: Alcohol exposure during pregnancy results in an array of structural and functional abnormalities called fetal alcohol spectrum disorders (FASD). Alcohol dysregulates the exquisite coordination and regulation of gestational adaptations at the level of the uterine vasculature. We herein hypothesized that chronic binge-like alcohol results in uterine vascular dysfunction and impairs maternal uterine artery reactivity to vasoconstrictors and dilators. METHODS: We utilized a once-daily binge alcohol (4.5 g/kg body weight) exposure paradigm (gestational day 7 to 17) in a pregnant rat model system and investigated primary uterine artery function in response to vasoconstrictors and vasodilators utilizing wire myography. RESULTS: Alcohol (peak blood alcohol concentration, 216 mg/dl) produced uterine vascular dysfunction. Alcohol did not produce altered uterine vascular reactivity to α1 adrenergic agonist phenylephrine or the prostanoid thromboxane. However, alcohol specifically impaired acetylcholine (ACh)-mediated uterine artery vasodilation but exogenous endothelium-independent vasodilators like sodium nitroprusside exhibited no alcohol effect; ACh significantly decreased vessel relaxation (p = 0.003; ↓pD2 [negative log molar ACh concentration producing the half maximum response], -7.004 ± 0.215 vs. -6.310 ± 0.208; EMax [maximal ACh response], 92% vs. 75%). CONCLUSIONS: We conclude that moderate alcohol exposure impairs uterine vascular function in pregnant mothers. Alcohol specifically impairs agonist-induced uterine artery vasodilation. In summary, the maternal uterine compartment may play a significant role in the pathogenesis of FASD. Thus, the mechanistic targets of alcohol at the level of both the mother and the fetus need to be considered in order to develop effective therapeutic treatment strategies for FASD.

Characteristics of pediatric behavioral health emergencies in the prehospital setting.

OBJECTIVE: Approximately 10% of emergency medical services (EMS) encounters in the United States are behavioral health related, but pediatric behavioral health EMS encounters have not been well characterized. We sought to describe demographic, clinical, and EMS system characteristics of pediatric behavioral health EMS encounters across the United States and to evaluate factors associated with sedative medication administration and physical restraint use during these encounters. METHODS: We conducted a retrospective cross-sectional study of pediatric (<18 years old) behavioral health EMS encounters from 2019 to 2020 using the National Emergency Medical Services Information System. Behavioral health encounters were defined using primary or secondary impression codes. We used multivariable logistic regression to identify factors associated with sedative medication administration and physical restraint use. RESULTS: Of 2,740,271 pediatric EMS encounters, 309,442 (11.3%) were for behavioral health. Of pediatric behavioral health EMS encounters, 85.2% of patients were 12-17 years old, 57.3% of patients were female, and 86.6% of encounters occurred in urban areas. Sedative medications and physical restraints were used in 2.2% and 3.0% of pediatric behavioral health EMS encounters, respectively. Sedative medication use was associated with the presence of developmental, communication, or physical disabilities relative to their absence (adjusted odds ratio [aOR] 3.38, 95% confidence interval [CI] 2.93-3.91) and with encounters in the West relative to the South (aOR 1.23, 95% CI 1.16-1.32). Physical restraint use was associated with encounters by patients 6-11 years old relative to those 12-17 years old (aOR 1.35, 95% CI 1.27-1.44), the West relative to the South (aOR 3.49, 95% CI 3.27-3.72), and private nonhospital EMS systems relative to fire departments (aOR 3.39, 95% CI 3.18-3.61). CONCLUSIONS: Among pediatric prehospital behavioral health EMS encounters, the use of sedative medications and physical restraint varies by demographic, clinical, and EMS system characteristics. Regional variation suggests opportunities may be available to standardize documentation and care practices during pediatric behavioral health EMS encounters.

In Vivo Administration of Phosphatidic Acid, a Direct Alcohol Target Rescues Fetal Growth Restriction and Maternal Uterine Artery Dysfunction in Rat FASD Model.

Fetal growth restriction is a hallmark of Fetal Alcohol Syndrome (FAS) and is accompanied by maternal uterine circulatory maladaptation. FAS is the most severe form of Fetal Alcohol Spectrum Disorder (FASD), a term for the range of conditions that can develop in a fetus when their pregnant mother consumes alcohol. Alcohol exerts specific direct effects on lipids that control fundamental developmental processes. We previously demonstrated that direct in vitro application of phosphatidic acid (PA, the simplest phospholipid and a direct target of alcohol exposure) to excised uterine arteries from alcohol-exposed rats improved vascular function, but it is unknown if PA can rescue end organ phenotypes in our FASD animal model. Pregnant Sprague-Dawley rats (n = 40 total dams) were gavaged daily from gestational day (GD) 5 to GD 19 with alcohol or maltose dextrin, with and without PA supplementation, for a total of four unique groups. To translate and assess the beneficial effects of PA, we hypothesized that in vivo administration of PA concomitant with chronic binge alcohol would reverse uterine artery dysfunction and fetal growth deficits in our FASD model. Mean fetal weights and placental efficiency were significantly lower in the binge alcohol group compared with those in the control (p < 0.05). However, these differences between the alcohol and the control groups were completely abolished by auxiliary in vivo PA administration with alcohol, indicating a reversal of the classic FAS growth restriction phenotype. Acetylcholine (ACh)-induced uterine artery relaxation was significantly impaired in the uterine arteries of chronic in vivo binge alcohol-administered rats compared to the controls (p < 0.05). Supplementation of PA in vivo throughout pregnancy reversed the alcohol-induced vasodilatory deficit; no differences were detected following in vivo PA administration between the pair-fed control and PA alcohol groups. Maximal ACh-induced vasodilation was significantly lower in the alcohol group compared to all the other treatments, including control, control PA, and alcohol PA groups (p < 0.05). When analyzing excitatory vasodilatory p1177-eNOS, alcohol-induced downregulation of p1177-eNOS was completely reversed following in vivo PA supplementation. In summary, these novel data utilize a specific alcohol target pathway (PA) to demonstrate a lipid-based preventive strategy and provide critical insights important for the development of translatable interventions.

The association of prehospital systemic corticosteroids with emergency department and in-hospital outcomes for patients with asthma exacerbations.

BACKGROUND: Timely administration of systemic corticosteroids is a cornerstone of asthma exacerbation treatment, yet little is known regarding potential benefits of prehospital administration by emergency medical services (EMS) clinicians. We examined factors associated with prehospital corticosteroid administration with hospitalization and hospital length of stay (LOS). METHODS: We performed a retrospective study of EMS encounters for patients 2-50 years of age with suspected asthma exacerbation from a national data set. We evaluated factors associated with systemic corticosteroid administration using generalized estimating equations. We performed propensity matching based on service level, age, encounter duration, vital signs, and treatments to evaluate the association of prehospital corticosteroid administration with hospitalization and LOS using weighted logistic regression. We evaluated the association of prehospital corticosteroid administration with admission using Bayesian models. RESULTS: Of 15,834 encounters, 4731 (29.9%) received prehospital systemic corticosteroids. Administration of corticosteroids was associated with older age; sex; urbanicity; advanced life support provider; vital sign instability; increasing doses of albuterol; and provision of ipratropium bromide, magnesium, epinephrine, and supplementary oxygen. Within the matched sample, prehospital corticosteroids were not associated with hospitalization (odds ratio [OR] 0.86, 95% confidence interval [CI] 0.73-1.01) or LOS (multiplier 0.76, 95% CI 0.56-1.05). Administration of corticosteroids was associated with lower odds of admission and shorter LOS in longer EMS encounters (>34 min), lower admission odds in patients with documented wheezing, and shorter LOS among patients treated with albuterol. In a Bayesian model with noninformative priors, the OR for admission among encounters given corticosteroids was 0.86 (95% credible interval 0.77-0.96). CONCLUSIONS: Prehospital systemic corticosteroid administration was not associated with hospitalization or LOS in the overall cohort of asthma patients treated by EMS, though they had a lower probability of admission within Bayesian models. Improved outcomes were noted among subgroups of longer EMS encounters, documented wheezing, and receipt of albuterol.

Untargeted and Targeted Blood Lipidomic Signature Profile of Gestational Alcohol Exposure.

Alcohol consumption has a close relationship with blood lipid levels in a nonpregnant state, with a myriad of effects on the liver; however, little is known about the interaction of alcohol and lipids in the context of fetal alcohol spectrum disorders (FASD). We herein aimed to determine the effect of alcohol on the lipid profile in a pregnant rat model, with a focus on FASD. Dry blood spots (50 µL) were obtained from rat maternal blood collected on gestational day (GD) 20, two hours after the last binge alcohol exposure (4.5 g/kg, GD 5-10; 6 g/kg, GD 11-20). The samples were then analyzed using high-throughput untargeted and targeted lipid profiling via liquid chromatography-tandem mass spectrometry (LC-MS/MS). In untargeted lipidomics, 73 of 315 identified lipids were altered in the alcohol group compared to the pair-fed controls; 67 were downregulated and 6 were upregulated. In targeted analysis, 57 of the 260 studied lipid subspecies were altered, including Phosphatidylcholine (PC), Phosphatidylethanolamine (PE), Phosphatidylglycerol (PG), Phosphatidic Acid (PA), Phosphatidylinositol (PI), and Phosphatidylserine (PS); 36 of these were downregulated and 21 lipid subspecies were upregulated. These findings suggest alcohol-induced dysregulation of lipids in the maternal blood of rats and provide novel insights into possible FASD mechanisms.

Impact of e-cigarette vaping aerosol exposure in pregnancy on mTOR signaling in rat fetal hippocampus.

Electronic cigarette (e-cig) use during pregnancy has become a major health concern in recent years and many view them as less harmful and may help quit or reduce combustible cigarettes. Implementing a state-of-the-art engineered vaping system, comprising an atomizer similar to those sold in vape shops, we aimed to utilize a translational e-cig inhalation delivery method to provide crucial information on the impact of prenatal e-cig aerosols on the developing brain hippocampal mTOR system in a rat model system. Gestational e-cig vaping significantly increased P-mTOR levels (p < 0.05) in the rat fetal hippocampi in the nicotine group (comprising of VG/PG + nicotine) compared to the control and the juice (comprising of VG/PG) groups. Total mTOR expression was not different among groups. Immunofluorescence imaging demonstrated P-mTOR was detected exclusively in the granule cells of the dentate gyrus of the fetal hippocampus. E-cig did not alter DEPTOR, but RAPTOR and RICTOR were higher (p < 0.05) in the Nicotine group. Gestational e-cig vaping with nicotine increased (p < 0.05) the activity and expression of 4EBP1, p70S6K, but decreased (p < 0.05) P-PKCα in the fetal hippocampi. In summary, dysregulation of mTORC1 and the related mTORC2, their activity, and downstream proteins together may play a critical role in e-cig-vaping-induced neurobiological phenotypes during development.

Medication Use in the Diagnostic Pediatric Lumbar Puncture.

The lumbar puncture (LP) is a common procedure in the pediatric emergency department. A retrospective review was conducted of patients who had LPs from 2012 to 2016 at 2 children's hospitals to (1) characterize medication use during the pediatric LP and (2) test the hypothesis that varied medication use influences LP outcome. Outcomes were defined as unsuccessful if the LP was documented as unsuccessful, had a cerebrospinal fluid (CSF) red blood cell (RBC) count >400 cells/µL, or if a second LP was performed within 24 hours. In total, 8463 patients were reviewed and 2806 (33%) were included in the study. We noted significant variation in LP medication use. When adjusted for patient demographics, location, weight, position, and provider experience, our regression model revealed that the use of fentanyl, ketamine, nitrous oxide, and propofol were best associated with LP success. These data suggest the need for a standardized LP medication protocol as provider choice in medication significantly influences LP outcome.

Rapid Development and Testing of a COVID-19 Vaccine Curriculum for Pediatricians.

BACKGROUND AND OBJECTIVES: As the coronavirus disease 2019 (COVID-19) pandemic evolves and vaccines become available to children, pediatricians must navigate vaccination discussions in the setting of rapidly changing vaccine recommendations and approvals. We developed and evaluated an educational curriculum for pediatricians to improve their knowledge about COVID-19 vaccines and confidence in communicating with patients and families about COVID-19 vaccines. METHODS: Five institutions collaborated to develop an online educational curriculum. Utilizing the collaboration's multidisciplinary expertise, we developed a 3-module curriculum focused on the SARS-CoV-2 virus and vaccine basics, logistics and administration of COVID-19 vaccine, and COVID-19 vaccine communication principles. Surveys administered to clinician participants before and after completion of the curriculum assessed knowledge and confidence; a follow-up survey 1 month after the post-survey assessed persistence of initial findings. RESULTS: A total of 152 pediatric providers participated; 72 completed both pre- and post-surveys. The median knowledge score improved from the pre-survey to the post-survey (79%-93%, P < .001). There was an increase in providers' confidence after completing the curriculum, which persisted in the follow-up survey. In the post-survey, 98% of participants had had the opportunity to discuss the COVID-19 vaccine with patients, and most clinicians reported that the modules decreased apprehension some or significantly. CONCLUSIONS: This project demonstrates rapid and feasible deployment of a curriculum providing up-to-date information to front-line clinicians responsible for having complex conversations about COVID-19 vaccine decision-making. Clinicians who completed this curriculum had sustained increased confidence and decreased levels of apprehension when discussing the COVID-19 vaccine.

Interaction of alcohol & phosphatidic acid in maternal rat uterine artery function.

Alcohol has been demonstrated to impair maternal uterine arterial adaptations in Fetal Alcohol Spectrum Disorder (FASD) animal models. However, the exact mechanism remains inconclusive. We hypothesized that phosphatidic acid (PA), a direct target of alcohol metabolism, would alleviate alcohol-induced vascular dysfunction of the maternal uterine artery. Mean fetal weight, and crown-rump length of the alcohol administered rats were ~9 % and 7.6 % lower than the pair-fed control pups, respectively. Acetylcholine (Ach)-induced uterine artery relaxation was significantly impaired in uterine arteries of alcohol-administered rats (P < 0.05). Supplementation of 10-5 M PA reversed alcohol-induced vasodilatory deficit; no difference was detected after PA treatment between pair-fed control and alcohol groups (P = 0.37). There was a significant interaction between PA concentrations and alcohol exposure (PA X Alcohol effect, P < 0.0001). Pair-wise comparisons showed a concentration-dependent vasodilatory effect on uterine arteries of the alcohol-administered rats, with % relaxation significantly improved at PA concentrations > 10-7 M (P < 0.05). Alcohol significantly reduced vasodilatory P-Ser1177 endothelial nitric oxide synthase (eNOS) levels in the uterine artery (↓90.7 %; P = 0.0029). PA treatment significantly reversed P-Ser1177 eNOS level in alcohol uterine arteries (153.7 %↑; P = 0.005); following ex vivo PA, there was no difference in P-Ser1177 eNOS levels between Control and Alcohol. Neither alcohol treatment nor PA affected total eNOS levels. Our data provide the first evidence of the interaction of alcohol and PA in rat maternal uterine artery vascular function and demonstrates PA's relationship with the eNOS system. Overall, the current study demonstrates that PA may be a promising therapeutic molecule of interest in alcohol-related gestational vascular dysfunction.

Effects of nutrition and gestational alcohol consumption on fetal growth and development.

Fetal alcohol exposure can lead to a range of developmental disorders, including impaired fetal growth and development of multiple organ systems. These disorders are grouped under the term fetal alcohol spectrum disorders (FASDs). Adequate nutrition and a conducive intrauterine environment are essential for healthy fetal development. Nutrient deficiencies resulting from inadequate maternal nutrient ingestion may be compounded by alcohol-induced altered nutrient metabolism, placental clearance, and malabsorption. Alcohol-induced alteration of the intrauterine environment is the main source of developmental deficits and nutritional insufficiencies can worsen the effects on fetal development. In this review, we discuss studies examining the collective and interactive effects of nutrition (specifically iron, selenium, vitamin A, thiamine, zinc, folate, vitamin B12, choline, and amino acids) relative to gestational alcohol consumption and its effects on fetal growth and development. We also summarize scientific reports that tested potential benefits of micronutrient supplementation in animal models of fetal alcohol spectrum disorders and in humans. In summary, the deleterious effects of alcohol exposure in relation to nutrient homeostasis further validate that avoidance of alcohol consumption during pregnancy is the most effective way to mitigate the teratogenic effects of alcohol.

Comparative evaluation of clinical performance of ceramic and resin inlays, onlays, and overlays: A systematic review and meta analysis.

Background: Advances in adhesive technologies and escalation in esthetic demands have increased indications for tooth-colored, partial coverage restorations. Recently, material knowledge has evolved, new materials have been developed, and no systematic review has answered the question posed by practitioners: Is the clinical efficacy of resin or ceramic better, for inlay, onlay, and overlay in the long run? Aim: The aim of this systematic review and meta-analysis was to evaluate the clinical performance of ceramic and resin inlays, onlays, and overlays and to identify the complication types associated with the main clinical outcomes. Materials and Methods: Two reviewers (VN and AJ) searched PubMed, Embase, and Cochrane Central registry of controlled trials for published articles between 1983 and 2020 conforming to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for systematic reviews. Only clinical studies which met the following criteria were included (1) studies regarding ceramic and resin inlays, onlays, and overlays were included; (2) randomized controlled trials, retrospective or prospective studies conducted in humans; (3) studies with a dropout rate <50% 4) studies with a follow-up higher than 5 years. Results: Of 1718 articles, 21 articles were selected. At 5 years, the estimated survival rates for resin (n = 129) was 86%, feldspathic porcelain (n = 1048) was 90%, and glass ceramic (n = 2218) was 92%; at 10 years, the survival of resin was 75% (n = 115), feldspathic porcelain was 91% (n = 1829), and glass ceramic was 89% (n = 1075). Conclusion: The meta-regression indicated that ceramic partial coverage restorations (feldspathic porcelain and glass-ceramic) outperformed resin partial coverage restorations both at 5-year and 10-year follow-up. When compared between ceramic types, glass ceramics outperformed feldspathic porcelain at 5 years' follow-up and feldspathic porcelain outperformed glass ceramics at 10 years' follow-up. The failures were mostly due to fractures (6.2%), endodontic problems (3%), secondary caries (1.7%), and debonding which was 0.9%.

Impact of E-cig aerosol vaping on fetal and neonatal respiratory development and function.

Electronic cigarette (e-cig) use has increased over the past decade, and exposure to e-cig aerosols during pregnancy raises concern for maternal and fetal health. The developing fetal lung is known to be sensitive to prenatal tobacco product exposure. Utilizing a 3-pronged approach, we examined the effects of prenatal e-cig aerosols with, and without nicotine on respiratory development in a murine model. RNAseq analysis of fetal lungs revealed extensive dysregulation in gene expression. Morphologic assessment of distal airspaces in neonatal lungs display an emphysematic phenotype. Respiratory mechanics of neonates display signs of increased respiratory workload, with increased resistance and decreased compliance. These data are novel and provide evidence that prenatal e-cig exposure may result in altered lung function or development of disease.

Morphological alteration in rat hippocampal neuronal dendrites following chronic binge prenatal alcohol exposure.

Prenatal alcohol exposure (PAE) may result in Fetal Alcohol Spectrum Disorders (FASD). The hippocampus has been recognized as a vulnerable target to alcohol-induced developmental damage. However, the effect of prenatal exposure to alcohol on dendritic morphological adaptations throughout the hippocampal fields in the developing brain still remains largely unknown in the context of FASD. We hypothesized that chronic binge alcohol exposure during pregnancy alters dendrite arborization throughout the developing rat hippocampus. Pregnant Sprague-Dawley rats were assigned to either a pair-fed control (PF-Cont) or a binge alcohol (Alcohol) treatment group. Alcohol dams were acclimatized via a once-daily orogastric gavage of 4.5 g/kg alcohol from gestational day (GD) 5-10 and progressed to 6 g/kg alcohol from GD 11-21. Pair-fed dams similarly received isocaloric maltose dextrin. After parturition, all dams received an ad libitum diet and nursed their offspring until postnatal day (PND) 10 when the pup brains were collected for morphological analysis. PAE increased dendritic arborization and complexities of CA1, CA2/3, and DG neurons in the PND 10 rat hippocampus. The number of primary dendrites, total dendritic length, and number of dendritic branches were significantly increased following PAE, and Sholl analysis revealed significantly more intersections of the dendritic processes in PND 10 offspring following PAE compared with those in the PF-Cont group. We conclude that chronic binge PAE significantly alters hippocampal dendritic morphology in the developing hippocampus. We conjecture that this morphological alteration in postnatal rat hippocampal dendrites following chronic binge prenatal alcohol exposure may play a critical role in FASD neurobiological phenotypes.

Impact of gestational electronic cigarette vaping on amino acid signature profile in the pregnant mother and the fetus.

BACKGROUND: Electronic cigarettes (e-cigs) are a form of tobacco product that has become increasingly popular over the past decade. Despite the known health consequences of tobacco product exposure during pregnancy, a substantial number of daily smokers will continue to smoke during pregnancy. Our current knowledge on the effects of e-cig aerosol exposure during pregnancy is limited to a small number of animal studies, which have identified several e-cig aerosol-induced disruptions to the physiology of normal development. METHODS: To further assess the impact of prenatal e-cig aerosol exposure on maternal and fetal health, we examined the amino acid signature profiles in maternal and fetal plasma, as well as in the fetal lungs, a sensitive target organ for prenatal tobacco product exposure. Pregnant Sprague Dawley rats were randomly assigned to one of three groups and were exposed to either e-cig aerosols containing nicotine, e-cig aerosols without nicotine, or room air. Dams were exposed utilizing a state-of-the-art custom engineered e-cig vaping system that is compatible with commercially available e-cig atomizers and enables a translational inhalation delivery method comparable to human vaping. RESULTS: We determined that gestational exposure to e-cig aerosols results in significant alterations to the amino acid profile in the maternal and fetal compartments, including the fetal lungs. The data shows a targeted disruption to the nitric oxide pathway, branched-chain amino acid metabolism, fetal protein synthesis, and urea cycle. CONCLUSION: The data presented herein provides additional support that gestational e-cig aerosol exposure can impact crucial biological processes and exemplifies the need for extensive research on exposure to e-cig aerosols.

Weight-for-Age Percentile as a Pediatric Predictor of Emergency Department Outcome.

This study is a retrospective cohort study that examines the association between weight-for-age percentile and pediatric admission incidence from the emergency department (ED) for all diagnoses. The charts of 1432 pediatric patients under 18 years with ED visits from 2013 to 2015 at a tertiary children's hospital were reviewed. Analyses of subject age/weight stratifications were performed, along with ED disposition, reason for visit, and Emergency Severity Index (ESI). Multivariable logistic regression models were used to evaluate the independent effect of weight-for-age percentile on ED disposition while controlling for age, ESI, and reason for visit. Underweight subjects were more likely to be admitted than their normal weight counterparts when analyzed overall (odds ratio [OR] = 2.58, P < .01) and by age: less than 2.0 years of age (OR = 2.04, P = .033), between 2.01 and 6.0 years of age (OR = 8.60, P = .004), and between 6.01 and 13.0 years of age (OR = 3.83, P = .053). Younger age (OR = 0.935, P < .001) and higher acuity (OR = 3.49, P < .001) were also significant predictors of admission. No significant associations were found between weight and likelihood of admission for patients older than 13.01 years or between overweight/obese weight categories and admission for any age subgroups. This study suggests that underweight children younger than 13 years are at higher risk to be admitted from the ED than their normal weight, overweight, and obese counterparts. Even when controlling for other key factors, such as the ESI, a lower weight-for-age percentile was a reliable predictor of hospitalization.