Browsing by Subject "Birth defects"

Now showing 1 - 8 of 8
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    Embryonic Ethanol Exposure Dysregulates BMP and Notch Signaling, Leading to Persistent Atrio-Ventricular Valve Defects in Zebrafish
    (Plos, 2016-08-24) Sarmah, Swapnalee; Muralidharan, Pooja; Marrs, James A.; Department of Biology, School of Science
    Fetal alcohol spectrum disorder (FASD), birth defects associated with ethanol exposure in utero, includes a wide spectrum of congenital heart defects (CHDs), the most prevalent of which are septal and conotruncal defects. Zebrafish FASD model was used to dissect the mechanisms underlying FASD-associated CHDs. Embryonic ethanol exposure (3–24 hours post fertilization) led to defects in atrio-ventricular (AV) valvulogenesis beginning around 37 hpf, a morphogenetic event that arises long after ethanol withdrawal. Valve leaflets of the control embryos comprised two layers of cells confined at the compact atrio-ventricular canal (AVC). Ethanol treated embryos had extended AVC and valve forming cells were found either as rows of cells spanning the AVC or as unorganized clusters near the AV boundary. Ethanol exposure reduced valve precursors at the AVC, but some ventricular cells in ethanol treated embryos exhibited few characteristics of valve precursors. Late staged larvae and juvenile fish exposed to ethanol during embryonic development had faulty AV valves. Examination of AVC morphogenesis regulatory networks revealed that early ethanol exposure disrupted the Bmp signaling gradient in the heart during valve formation. Bmp signaling was prominent at the AVC in controls, but ethanol-exposed embryos displayed active Bmp signaling throughout the ventricle. Ethanol exposure also led to mislocalization of Notch signaling cells in endocardium during AV valve formation. Normally, highly active Notch signaling cells were organized at the AVC. In ethanol-exposed embryos, highly active Notch signaling cells were dispersed throughout the ventricle. At later stages, ethanol-exposed embryos exhibited reduced Wnt/β-catenin activity at the AVC. We conclude that early embryonic ethanol exposure alters Bmp, Notch and other signaling activities during AVC differentiation leading to faulty valve morphogenesis and valve defects persist in juvenile fish.
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    Esophageal Atresia With or Without Tracheoesophageal Fistula: Comorbidities, Genetic Evaluations, and Neonatal Outcomes
    (Springer Nature, 2023-02-08) Khattar, Divya; Suhrie, Kristen R.; Pediatrics, School of Medicine
    Objective: Esophageal atresia with or without tracheoesophageal fistula (EA/TEF) has a reported incidence of 1 in 3500 live births and requires intensive care and surgery. To evaluate the prevalence of a molecularly confirmed genetic etiology of EA/TEF in a level IV neonatal intensive care unit (NICU), focusing on genetic evaluation, diagnostic yield, and clinical outcomes of these neonates. Study design: A retrospective cohort study over a period of seven years was performed for all patients admitted with a diagnosis of EA/TEF. Automated data was extracted for demographic information and manual extraction was done to evaluate the frequency of associated anomalies, type of genetic evaluations and diagnoses, and outcomes at NICU discharge. Results: Sixty-eight infants met the inclusion criteria. The majority were male (n=42; 62%), born at >37 weeks' gestation (n=36; 53%), and had EA with distal TEF (n=54; 79%). Most (n=53; 78%) had additional associated congenital anomalies, but only 47 (69%) patients had a genetics evaluation performed and genetic testing was sent for 44 (65%) of those patients. The most common genetic testing performed was chromosomal microarray analysis (n=40; 59%), followed by chromosome analysis (n=11; 16%), and whole exome/genome sequencing (n=7; 10%). Five unique genetic diagnoses including CHARGE Syndrome, Fanconi Syndrome, EFTUD2-related mandibulofacial dysostosis, and two different chromosomal deletion syndromes were made for a total of nine (13%) patients in our cohort. The cohort suffered a high rate of morbidity and mortality during their NICU stay with important differences noted in isolated vs non-isolated EA/TEF. Twelve infants (18%) died prior to NICU discharge. Of those surviving, 40 (71%) infants had a primary repair, 37 (66%) infants required G or GJ feedings at NICU discharge, and eight (14%) patients were discharged on some type of respiratory support. Conclusion: In this high-risk cohort of EA/TEF patients cared for at a quaternary NICU, a majority were non-isolated and had some form of a genetic evaluation, but a minority underwent exome or genome sequencing. Given the high prevalence of associated anomalies, high mortality, and genetic disease prevalence in this cohort, we recommend standardization of phenotyping and genetic evaluation to allow for precision care and appropriate risk stratification.
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    Potential for elimination of folate and vitamin B12 deficiency in India using vitamin-fortified tea: a preliminary study
    (BMJ, 2021-06-23) Vora, Ravindra M.; Alappattu, Meryl J.; Zarkar, Apoorva D.; Soni, Mayur S.; Karmarkar, Santosh J.; Antony, Aśok C.; Medicine, School of Medicine
    Introduction: The majority of Indian women have a poor dietary folate and vitamin B12 intake resulting in their chronically low vitamin status, which contributes to anaemia and the high incidence of folate-responsive neural-tube defects (NTDs) in India. Although many countries have successfully deployed centrally-processed folate-fortified flour for prevention of NTDs, inherent logistical problems preclude widespread implementation of this strategy in India. Because tea-the second most common beverage worldwide (after water)-is consumed by most Indians every day, and appeared an ideal vehicle for fortification with folate and vitamin B12, we determined if daily consumption of vitamin-fortified tea for 2 months could benefit young women of childbearing-age in Sangli, India. Methods: Women (average age=20±2 SD) used teabags spiked with therapeutic doses of 1 mg folate plus either 0.1 mg vitamin B12 (Group-1, n=19) or 0.5 mg vitamin B12 (Group-2, n=19), or mock-fortified teabags (Group-0, n=5) to prepare a cup of tea every day for 2 months, following which their pre-intervention and post-intervention serum vitamin and haemoglobin concentrations were compared. Results: Most women had baseline anaemia with low-normal serum folate and below-normal serum vitamin B12 levels. After 2 months, women in both Group-1 and Group-2 exhibited significant increases in mean differences in pre-intervention versus post-intervention serum folate levels of 8.37 ng/mL (95% CIs 5.69 to 11.04, p<0.05) and 6.69 ng/mL (95% CI 3.93 to 9.44, p<0.05), respectively; however, Group-0 experienced an insignificant rise of 1.26 ng/mL (95% CI -4.08 to 0.16). In addition, over one-half and two-thirds of women in Group-1 and Group-2, respectively, exhibited increases in serum vitamin B12 levels over 300 pg/mL. There was also a significant post-interventional increase in the mean haemoglobin concentration in Group-1 of 1.45 g/dL (95% CI 0.64 to 2.26, p=0.002) and Group-2 of 0.79 g/dL (95% CI 0.11 to 1.42, p=0.027), which reflected a bona fide clinical response. Conclusion: Tea is an outstanding scalable vehicle for fortification with folate and vitamin B12 in India, and has potential to help eliminate haematological and neurological complications arising from inadequate dietary consumption or absorption of folate and vitamin B12.
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    Prevalence, trend, and associated risk factors for cleft lip with/without cleft palate: a national study on live births from 2016 to 2021
    (Springer Nature, 2024-01-07) Heydari, Mohammad‑Hossein; Sadeghian, Ali; Khadivi, Gita; Mustafa, Hiba J.; Javinani, Ali; Nadjmi, Nasser; Khojasteh, Arash; Obstetrics and Gynecology, School of Medicine
    Backgrounds: Cleft lip with or without cleft palate (CL/P) is the most common congenital craniofacial anomaly, including non-syndromic cleft lip with or without cleft palate and cleft palate only. Failure in the fusion of median and lateral nasal processes, the maxillary prominence, and soft tissues around the oral cavity can cause CL/P. Previously, the prevalence has been estimated to be 1 among every 1000 births in 2014 among American neonates and no other reports have been available since. Thus, this study aimed to calculate the prevalence and trend of isolated CL/P among American live births from 2016 to 2021 with its associated risk factors. Methods and materials: In this cross-sectional population-based retrospective study, we used live birth data provided by the National Center for Health Statistics (NCHS) from the Center for Disease Control and Prevention (CDC). We calculated the prevalence per 10,000 live births of isolated (non-syndromic) CL/P from 2016 to 2021. To examine risk factors for developing isolated CL/P, we used logistic regression modelling. Results: The total prevalence per 10,000 births from 2016 to 2021 was 4.88 (4.79-4.97), for both sexes, and 5.96 (5.82-6.10) for males, and 3.75 (3.64-3.87) for females. The prevalence did not show any consistent linear decreasing or increasing pattern. We found significant association between increased odds of developing isolated CL/P among cases with 20 to 24 year-old mothers (OR = 1.07, 1.01-1.13, p = 0.013), mothers who smoked 11 to 20 cigarettes per day (OR = 1.46, 1.33-1.60, p < 0.001), mothers with extreme obesity (OR = 1.32, 1.21-1.43, p < 0.001), mothers with grade II obesity (OR = 1.32, 1.23-1.42, p < 0.001), mothers with pre-pregnancy hypertension (OR = 1.17, 1.04-1.31, p = 0.009), mothers with pre-pregnancy diabetes mellitus (OR = 1.96, 1.71-2.25, p < 0.001), and mothers who used assisted reproductive technology (OR = 1.40, 1.18-1.66, p < 0.001). Conclusions: Our findings suggest a minuscule increase, albeit insignificant, in the trend of CL/P prevalence from 2016 to 2021. Developing CL/P had greater odds among mothers with pre-pregnancy diabetes, smoking, obesity, and pre-pregnancy hypertension mothers along with mothers who used assisted reproductive technology. Isolated CL/P had the highest prevalence in non-Hispanic Whites, American Indian or Alaskan Native and Native Hawaiian and Other Pacific Islanders.
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    Rapid Genome Sequencing Shows Diagnostic Utility In Infants With Congenital Heart Defects
    (Research Square, 2024-03-20) Durbin, Matthew D.; Helvaty, Lindsey R.; Posorske, Alyx; Zhang, Samuel; Huang, Manyan; Li, Ming; Abreu, Daniel; Fairman, Korre; Geddes, Gabrielle C.; Helm, Benjamin M.; Landis, Benjamin J.; McEntire, Alexis; Mitchell, Dana K.; Ware, Stephanie M.; Pediatrics, School of Medicine
    Congenital heart disease (CHD) is the most common birth defect and a leading cause of infant mortality. CHD often has a genetic etiology and recent studies demonstrate utility in genetic testing. In clinical practice, decisions around genetic testing choices continue to evolve, and the incorporation of rapid genome sequencing (rGS) in CHD has not been well studied. Though smaller studies demonstrate the value of rGS, they also highlight the burden of results interpretation. We analyze genetic testing in CHD at two time-points, in 2018 and 2022-2023, across a change in clinical testing guidelines from chromosome microarray (CMA) to rGS. Analysis of 421 hospitalized infants with CHD demonstrated consistent genetic testing across time. Overall, after incorporation of rGS in 2022-2023, the diagnostic yield was 6.8% higher compared to 2018, and this pattern was consistent across all patient subtypes analyzed. In 2018, CMA was the most common test performed, with diagnostic results for CHD in 14.3%, while in 2022-2023, rGS was the most frequent test performed, with results diagnostic for CHD in 16.9%. Additionally, rGS identified 44% more unique genetic diagnoses than CMA. This is the largest study to highlight the value of rGS in CHD and has important implications for management.
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    The Unresolved Tragedy of Neural-Tube Defects in India: The Case for Folate- and Vitamin-B12-Fortified Tea for Prevention
    (Wolters Kluwer, 2022) Vora, Ravindra Motilal; Antony, Asok C.; Medicine, School of Medicine
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    ZIKV Inhibitors Based on Pyrazolo[3,4- d]pyridazine-7-one Core: Rational Design, In Vitro Evaluation, and Theoretical Studies
    (American Chemical Society, 2023-12-14) De Tran, Quang; Nguyen, Cuong Quoc; Dang, Quang Le; Nguyen, Thi Hong Minh; Hue, Bui Thi Buu; Le, Minh Uyen Thi; Tuan, Nguyen Trong; Thanh, Nguyen Quoc Chau; Men, Tran Thanh; Quan, Pham Minh; Tuan, Nguyen Duy; Cam, Thai Thi; Thuy, Nguyen Thi Thu; Hau, Vu Thi Bich; Binh, Tran Duy; Nguyen, Hong Phuong; Surgery, School of Medicine
    The Zika virus (ZIKV) is believed to cause birth defects, and no anti-ZIKV drugs have been approved by medical organizations to date. Starting from antimicrobial lead compounds with a pyrazolo[3,4-d]pyridazine-7-one scaffold, we synthesized 16 derivatives and screened their ability to interfere with ZIKV infection utilizing a cell-based phenotypic assay. Of these, five compounds showed significant inhibition of ZIKV with a selective index value greater than 4.6. In particular, compound 9b showed the best anti-ZIKV activity with a selectivity index of 22.4 (half-maximal effective concentration = 25.6 μM and 50% cytotoxic concentration = 572.4 μM). Through the brine shrimp lethality bioassay, 9b, 10b, 12, 17a, and 19a showed median lethal dose values in a range of 87.2-100.3 μg/mL. Compound 9b was also targeted to the NS2B-NS3 protease of ZIKV using molecular docking protocols, in which it acted as a noncompetitive inhibitor and strongly bound to five key amino acids (His51, Asp75, Ser135, Ala132, Tyr161). Utilizing the pharmacophore model of 9b, the top 20 hits were identified as prospective inhibitors of NS2B-NS3 protease, and six of them were confirmed for their stability with the protease via redocking and molecular dynamics simulations.