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1.
Birth Defects Res ; 116(3): e2323, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38476117

RESUMO

BACKGROUND: Birth defects affect 1 in 33 infants in the United States and are a leading cause of infant mortality. Birth defects surveillance is crucial for informing public health action. The Massachusetts Birth Defects Monitoring Program (MBDMP) began collecting other pregnancy losses (OPLs) in 2011, including miscarriages (<20 weeks gestation) or elective terminations (any gestational age), in addition to live births and stillbirths (≥20 weeks gestation). We describe programmatic changes for adding OPLs and their impact on prevalence estimates. METHODS: Using population-based, statewide, data from the MBDMP (2012-2020), we assessed prevalence per 10,000 live births and 95% confidence intervals (CIs) with and without OPLs overall and for specific birth defects by time period, maternal age, and race/ethnicity. RESULTS: Including OPLs required amending a state statute and promulgating regulations, new data sources, and additional data processing, cleaning, and verification. Overall prevalence with OPLs increased from 257.4 (95% CI: 253.5-261.4) to 333.9 (95% CI: 329.4-338.4) per 10,000; increases were observed in all time periods, age, and race/ethnicity groups. After including OPLs, the prevalence increased for neural tube defects [3.2 (2.7-3.6) to 8.3 (7.6-9.0)], and trisomies 13 [0.5 (0.3-0.7) to 4.1 (3.6-4.6)], 18 [1.5 (1.2-1.9) to 8.2 (7.5-8.9)], and 21 [12.3 (11.4-13.2) to 28.9 (27.6-30.2)]. Cardiovascular defects increased slightly, while prevalence of eye/ear, respiratory, and gastrointestinal defects remained similar. CONCLUSIONS: Adding OPLs required substantial programmatic efforts and resulted in more complete case ascertainment, particularly for certain birth defects. More complete case ascertainment will allow for improved research, screening, and resource allocation.


Assuntos
Aborto Induzido , Defeitos do Tubo Neural , Gravidez , Lactente , Feminino , Humanos , Estados Unidos , Vigilância da População/métodos , Defeitos do Tubo Neural/epidemiologia , Idade Materna , Massachusetts
2.
Nutrients ; 16(5)2024 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-38474883

RESUMO

Folate, also known as vitamin B9, facilitates the transfer of methyl groups among molecules, which is crucial for amino acid metabolism and nucleotide synthesis. Adequate maternal folate supplementation has been widely acknowledged for its pivotal role in promoting cell proliferation and preventing neural tube defects. However, in the post-fortification era, there has been a rising concern regarding an excess maternal intake of folic acid (FA), the synthetic form of folate. In this review, we focused on recent advancements in understanding the influence of excess maternal FA intake on offspring. For human studies, we summarized findings from clinical trials investigating the effects of periconceptional FA intake on neurodevelopment and molecular-level changes in offspring. For studies using mouse models, we compiled the impact of high maternal FA supplementation on gene expression and behavioral changes in offspring. In summary, excessive maternal folate intake could potentially have adverse effects on offspring. Overall, we highlighted concerns regarding elevated maternal folate status in the population, providing a comprehensive perspective on the potential adverse effects of excessive maternal FA supplementation on offspring.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Defeitos do Tubo Neural , Animais , Camundongos , Humanos , Suplementos Nutricionais/efeitos adversos , Ácido Fólico/uso terapêutico , Defeitos do Tubo Neural/prevenção & controle , Família
3.
Birth Defects Res ; 116(3): e2321, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38457279

RESUMO

BACKGROUND: Folic acid is a micronutrient that is effective at preventing neural tube defects (NTDs). In 2016, the FDA authorized the voluntary fortification of corn masa flour (CMF) with folic acid to reduce disparities in NTDs among infants of women who do not regularly consume other fortified cereal grains, in particular Hispanic women of reproductive age (WRA). METHODS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to March 2020 assessing the impact of voluntary fortification of CMF on the folate status of Hispanic WRA. We analyzed folic acid usual intake and red blood cell (RBC) folate concentrations among non-pregnant, non-lactating Hispanic WRA, comparing pre-fortification (2011-2016) to post-fortification (2017-March 2020) data. RBC folate concentrations were used to create model-based estimation of NTD rates. RESULTS: The proportion of Hispanic WRA with folic acid usual intakes <400 µg/d did not change (2011-2016: 86.1% [95% Confidence Interval, CI: 83.7-88.5]; 2017-March 2020: 87.8% [95% CI: 84.8-90.7]; p = .38) nor did the proportion of Hispanic WRA with RBC folate below optimal concentrations (<748 nmol/L, 2011-2016: 16.0% [95% CI: 13.7-18.2]; 2017-March 2020: 18.1% [95% CI: 12.1-24.0]; p = 0.49). Model-based estimates of NTD rates suggest further improvements in the folate status of Hispanic WRA might prevent an additional 157 (95% Uncertainty Interval: 0, 288) NTDs/year. CONCLUSIONS: Voluntary fortification of CMF with folic acid has yet to have a significant impact on the folate status of WRA. Continued monitoring and further research into factors such as fortified product availability, community knowledge, and awareness of folic acid benefits would inform and improve future public health interventions.


Assuntos
Ácido Fólico , Defeitos do Tubo Neural , Feminino , Humanos , Inquéritos Nutricionais , Zea mays , Farinha , Alimentos Fortificados , Defeitos do Tubo Neural/prevenção & controle , Eritrócitos
4.
JAMA Netw Open ; 7(3): e241777, 2024 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-38457177

RESUMO

Importance: India has a disproportionately high prevalence of neural tube defects, including spina bifida and anencephaly (SBA), causing a high number of stillbirths, elective pregnancy terminations, and child mortality; India contributes a large proportion of the global burden of SBA. Thirty years after folic acid was shown to be effective in reducing SBA prevalence, only about one-quarter of such births are prevented globally through cereal grain fortification. Objective: To determine the association of folic acid-fortified iodized salt with serum folate concentrations among nonpregnant and nonlactating women of reproductive age. Design, Setting, and Participants: This nonrandomized controlled trial using a preintervention and postintervention design was conducted in 4 rural villages in Southern India from July 1 to November 30, 2022. All households in the villages agreed to participate in the study. Preintervention and postintervention serum folate levels were analyzed among study participants at baseline and after 4 months, respectively. Intervention: Consumption of approximately 300 µg/d of folic acid using double fortified salt (folic acid plus iodine). Median serum folate concentrations were assessed at baseline and 4 months. Main Outcomes and Measures: Change in median serum folate levels between baseline and study end point as the primary outcome of the study. Results: A total of 83 nonpregnant nonlactating women aged 20 to 44 years (mean [SD] age, 30.9 [5.1] years) were eligible for the study and provided serum samples for analysis at baseline and the end point of the intervention. The median serum folate concentration increased from 14.6 (IQR, 11.2-20.6) nmol/L at baseline to 54.4 (IQR, 43.5-54.4) nmol/L at end of study, a 3.7-fold increase from baseline to study end point. Two-tailed Wilcoxon signed rank test showed the median difference in preintervention and postintervention serum folate concentrations to be highly significant (P < .001). The participants found the salt acceptable in color and taste. Conclusions and Relevance: Use of folic acid-fortified iodized salt was associated with increased serum folate concentrations in women of reproductive age. This novel evidence can inform public health policy to accelerate SBA prevention. Trial Registration: ClinicalTrials.gov Identifier: NCT06174883.


Assuntos
Iodo , Defeitos do Tubo Neural , Cloreto de Sódio na Dieta , Disrafismo Espinal , Gravidez , Criança , Feminino , Humanos , Adulto , Ácido Fólico/uso terapêutico , Alimentos Fortificados
6.
Birth Defects Res ; 116(3): e2328, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38450884

RESUMO

BACKGROUND: Two population-based case-control studies have reported an increased risk of neural tube defect (NTD)-affected pregnancies among women with low carbohydrate diet in the periconceptional period. Given that only two studies have investigated this association, it is unclear to what degree the findings could be impacted by residual confounding. Here, we further interrogated both studies that observed this association with the objective to identify factors from a much larger number of factors that might explain the association. METHODS: By employing a machine learning algorithm (random forest), we investigated a baseline set of over 200 variables. These analyses produced the top 10 variables in each data set for cases and controls that predicted periconceptional low carbohydrate intake. RESULTS: Examining those prediction variables with logistic regression modeling, we did not observe any particular variable that substantially contributed to the NTD-low carbohydrate association in either data set. CONCLUSIONS: If there are underlying factors that explain the association, our findings suggest that none of the 200+ variables we examined were sufficiently correlated with what that true explanatory exposure may be. Alternatively, our findings may suggest that there are other unidentified factor(s) at play, or the association observed in two independent data sets is directly related to low carbohydrate intake.


Assuntos
Algoritmos , Defeitos do Tubo Neural , Gravidez , Humanos , Feminino , Dieta com Restrição de Carboidratos , Aprendizado de Máquina
7.
J Transl Med ; 22(1): 257, 2024 Mar 09.
Artigo em Inglês | MEDLINE | ID: mdl-38461288

RESUMO

BACKGROUND: Neural Tube Defects (NTDs) are congenital malformations of the central nervous system resulting from the incomplete closure of the neural tube during early embryonic development. Neuroinflammation refers to the inflammatory response in the nervous system, typically resulting from damage to neural tissue. Immune-related processes have been identified in NTDs, however, the detailed relationship and underlying mechanisms between neuroinflammation and NTDs remain largely unclear. In this study, we utilized integrated multi-omics analysis to explore the role of neuroinflammation in NTDs and identify potential prenatal diagnostic markers using a murine model. METHODS: Nine public datasets from Gene Expression Omnibus (GEO) and ArrayExpress were mined using integrated multi-omics analysis to characterize the molecular landscape associated with neuroinflammation in NTDs. Special attention was given to the involvement of macrophages in neuroinflammation within amniotic fluid, as well as the dynamics of macrophage polarization and their interactions with neural cells at single-cell resolution. We also used qPCR assay to validate the key TFs and candidate prenatal diagnostic genes identified through the integrated analysis in a retinoic acid-induced NTDs mouse model. RESULTS: Our analysis indicated that neuroinflammation is a critical pathological feature of NTDs, regulated both transcriptionally and epigenetically within central nervous system tissues. Key alterations in gene expression and pathways highlighted the crucial role of STATs molecules in the JAK-STAT signaling pathway in regulating NTDs-associated neuroinflammation. Furthermore, single-cell resolution analysis revealed significant polarization of macrophages and their interaction with neural cells in amniotic fluid, underscoring their central role in mediating neuroinflammation associated with NTDs. Finally, we identified a set of six potential prenatal diagnostic genes, including FABP7, CRMP1, SCG3, SLC16A10, RNASE6 and RNASE1, which were subsequently validated in a murine NTDs model, indicating their promise as prospective markers for prenatal diagnosis of NTDs. CONCLUSIONS: Our study emphasizes the pivotal role of neuroinflammation in the progression of NTDs and underlines the potential of specific inflammatory and neural markers as novel prenatal diagnostic tools. These findings provide important clues for further understanding the underlying mechanisms between neuroinflammation and NTDs, and offer valuable insights for the future development of prenatal diagnostics.


Assuntos
Multiômica , Defeitos do Tubo Neural , Gravidez , Feminino , Animais , Camundongos , Doenças Neuroinflamatórias , Estudos Prospectivos , Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/induzido quimicamente , Sistema Nervoso Central/patologia
8.
BMC Pregnancy Childbirth ; 24(1): 114, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321376

RESUMO

BACKGROUND: Folic acid supplementation is recommended for reducing the risk of birth defects. We aimed to assess the protective association of periconception folic acid supplements with birth defects in real-world setting. METHODS: This prospective, population-based cohort study utilized national preconception registered data of married Chinese couples planning a pregnancy within 6 months between 2010 and 2012 in Mainland China. Participated women are freely provided folic acid starting 3 months before conception till 3 months after conception. Birth defects were self-reported at 42 days postpartumn followup. R software (v4.0.2) was applied for statistical analyses. RESULTS: Complete data of 567,547 couples with pregnancy outcomes and folic acid supplementation were extracted for final analysis. A total of 74.7% women were with folic acid supplementation, and 599 birth defects were self-reported. The odd of birth defects was lower among women taking folic acid compared to their counterparts not taking (0.102% vs 0.116%, P < 0.001). In the multiple logistic regression analyses, the odd of birth defects was lower among couples with maternal folic acid supplementation (OR = 0.78, 95%CI: 0.66-0.95, P = 0.011), especially decreased odd of neural tube defects (NTDs) (OR = 0.56, 95%CI: 0.39-0.82, P = 0.003). This association was confirmed by 1:4 and 1:10 case control analysis. Odds of birth defects were significantly lower among women with folic acid supplementation more than 3 months before pregnancy (P < 0.001), and moreover, the odds of cleft (P = 0.007) and NTDs (P = 0.007) were of notable decrease. CONCLUSION: This retrospective case cohort study provides programmatic evidence for public health strategy-making to for reducing the risk of NTDs and clefts.


Assuntos
Ácido Fólico , Defeitos do Tubo Neural , Gravidez , Feminino , Humanos , Masculino , Estudos de Coortes , Estudos Prospectivos , Estudos Retrospectivos , Defeitos do Tubo Neural/prevenção & controle , Suplementos Nutricionais , China
9.
Nature ; 626(8001): 1042-1048, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38418917

RESUMO

The loss of the tail is among the most notable anatomical changes to have occurred along the evolutionary lineage leading to humans and to the 'anthropomorphous apes'1-3, with a proposed role in contributing to human bipedalism4-6. Yet, the genetic mechanism that facilitated tail-loss evolution in hominoids remains unknown. Here we present evidence that an individual insertion of an Alu element in the genome of the hominoid ancestor may have contributed to tail-loss evolution. We demonstrate that this Alu element-inserted into an intron of the TBXT gene7-9-pairs with a neighbouring ancestral Alu element encoded in the reverse genomic orientation and leads to a hominoid-specific alternative splicing event. To study the effect of this splicing event, we generated multiple mouse models that express both full-length and exon-skipped isoforms of Tbxt, mimicking the expression pattern of its hominoid orthologue TBXT. Mice expressing both Tbxt isoforms exhibit a complete absence of the tail or a shortened tail depending on the relative abundance of Tbxt isoforms expressed at the embryonic tail bud. These results support the notion that the exon-skipped transcript is sufficient to induce a tail-loss phenotype. Moreover, mice expressing the exon-skipped Tbxt isoform develop neural tube defects, a condition that affects approximately 1 in 1,000 neonates in humans10. Thus, tail-loss evolution may have been associated with an adaptive cost of the potential for neural tube defects, which continue to affect human health today.


Assuntos
Processamento Alternativo , Evolução Molecular , Hominidae , Proteínas com Domínio T , Cauda , Animais , Humanos , Camundongos , Processamento Alternativo/genética , Elementos Alu/genética , Modelos Animais de Doenças , Genoma/genética , Hominidae/anatomia & histologia , Hominidae/genética , Íntrons/genética , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Fenótipo , Isoformas de Proteínas/deficiência , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Proteínas com Domínio T/deficiência , Proteínas com Domínio T/genética , Proteínas com Domínio T/metabolismo , Cauda/anatomia & histologia , Cauda/embriologia , Éxons/genética
10.
J Med Case Rep ; 18(1): 69, 2024 Feb 04.
Artigo em Inglês | MEDLINE | ID: mdl-38310287

RESUMO

BACKGROUND: Tight filum terminale is a rare and challenging condition to diagnose because it presents with nonspecific symptoms and unclear imaging findings. This report documents an atypical case of tight filum terminale. CASE PRESENTATION: The patient was a previously healthy Asian 18-year-old male presenting with recurrent upper extremity and back pain, initially treated as nonspecific musculoskeletal pain. Notably, the patient's symptoms were inconsistent with the dermatome, showing no correlation with his skin's sensory innervation areas. In contrast to typical tight filum terminale presentations focused on lower extremity and lumbar region disturbances, this patient experienced pain and weakness predominantly in the upper extremities and back, hypothesized to result from traction myelopathy exacerbated by thoracic disc herniation. Investigations including blood and nerve function tests were inconclusive. However, a magnetic resonance imaging scan revealed a combination of tight filum terminale and tiny thoracic disc herniation. A diagnosis of tethered spinal cord syndrome was confirmed following further tests and imaging. The filum terminale was surgically removed, resolving the symptoms at a 7-month follow-up. CONCLUSIONS: This case underlines the importance of including tight filum terminale as a differential diagnosis in cases of unexplained upper or lower extremity pain. Primary care practitioners, particularly those managing undefined symptoms, should consider tight filum terminale in their diagnostic approach.


Assuntos
Cauda Equina , Deslocamento do Disco Intervertebral , Defeitos do Tubo Neural , Masculino , Humanos , Adolescente , Cauda Equina/patologia , Deslocamento do Disco Intervertebral/diagnóstico , Deslocamento do Disco Intervertebral/diagnóstico por imagem , Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/patologia , Defeitos do Tubo Neural/cirurgia , Procedimentos Neurocirúrgicos/métodos , Imageamento por Ressonância Magnética , Dor
11.
Development ; 151(5)2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38300806

RESUMO

Defective tissue fusion during mammalian embryogenesis results in congenital anomalies, such as exencephaly, spina bifida and cleft lip and/or palate. The highly conserved transcription factor grainyhead-like 2 (Grhl2) is a crucial regulator of tissue fusion, with mouse models lacking GRHL2 function presenting with a fully penetrant open cranial neural tube, facial and abdominal clefting (abdominoschisis), and an open posterior neuropore. Here, we show that GRHL2 interacts with the soluble morphogen protein and bone morphogenetic protein (BMP) inhibitor noggin (NOG) to impact tissue fusion during development. The maxillary prominence epithelium in embryos lacking Grhl2 shows substantial morphological abnormalities and significant upregulation of NOG expression, together with aberrantly distributed pSMAD5-positive cells within the neural crest cell-derived maxillary prominence mesenchyme, indicative of disrupted BMP signalling. Reducing this elevated NOG expression (by generating Grhl2-/-;Nog+/- embryos) results in delayed embryonic lethality, partial tissue fusion rescue, and restoration of tissue form within the craniofacial epithelia. These data suggest that aberrant epithelial maintenance, partially regulated by noggin-mediated regulation of BMP-SMAD pathways, may underpin tissue fusion defects in Grhl2-/- mice.


Assuntos
Fenda Labial , Fissura Palatina , Defeitos do Tubo Neural , Animais , Camundongos , Proteínas Morfogenéticas Ósseas/metabolismo , Mamíferos/metabolismo , Tubo Neural/metabolismo , Receptores Nogo/metabolismo
12.
Nat Commun ; 15(1): 1642, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38388461

RESUMO

Folate supplementation reduces the occurrence of neural tube defects (NTDs), birth defects consisting in the failure of the neural tube to form and close. The mechanisms underlying NTDs and their prevention by folate remain unclear. Here we show that folate receptor 1 (FOLR1) is necessary for the formation of neural tube-like structures in human-cell derived neural organoids. FOLR1 knockdown in neural organoids and in Xenopus laevis embryos leads to NTDs that are rescued by pteroate, a folate precursor that is unable to participate in metabolism. We demonstrate that FOLR1 interacts with and opposes the function of CD2-associated protein, molecule essential for apical endocytosis and turnover of C-cadherin in neural plate cells. In addition, folates increase Ca2+ transient frequency, suggesting that folate and FOLR1 signal intracellularly to regulate neural plate folding. This study identifies a mechanism of action of folate distinct from its vitamin function during neural tube formation.


Assuntos
Ácido Fólico , Defeitos do Tubo Neural , Humanos , Ácido Fólico/metabolismo , Tubo Neural/metabolismo , Receptor 1 de Folato/genética , Receptor 1 de Folato/metabolismo , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Placa Neural/metabolismo
13.
Epigenomics ; 16(6): 419-426, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38410929

RESUMO

Neural tube defects (NTDs) are the most common congenital anomalies of the CNS. It is widely appreciated that both genetic and environmental factors contribute to their etiology. The inability to ascribe clear genetic patterns of inheritance to various NTD phenotypes suggests it is possible that epigenetic mechanisms are involved in the etiology of NTDs. In this context, the contribution of DNA methylation as an underlying contributing factor to the etiology of NTDs has been extensively reviewed. Here, an updated accounting of the evidence linking post-translational histone modifications to these birth defects, relying heavily upon studies in humans, and the possible molecular implications inferred from reports based on cellular and animal models, are presented.


Assuntos
Histonas , Defeitos do Tubo Neural , Animais , Humanos , Histonas/metabolismo , Código das Histonas , Defeitos do Tubo Neural/genética , Epigênese Genética , Metilação de DNA
14.
JAMA Intern Med ; 184(3): 242-251, 2024 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-38252426

RESUMO

Importance: Use of buprenorphine or methadone to treat opioid use disorder is recommended in pregnancy; however, their teratogenic potential is largely unknown. Objective: To compare the risk of congenital malformations following in utero exposure to buprenorphine vs methadone. Design, Setting, and Participants: This population-based cohort study used health care utilization data from publicly insured Medicaid beneficiaries in the US from 2000 to 2018. A total of 13 360 pregnancies with enrollment from 90 days prior to pregnancy start through 1 month after delivery and first trimester use of buprenorphine or methadone were included and linked to infants. Data were analyzed from July to December 2022. Exposure: A pharmacy dispensing of buprenorphine or a code for administration of methadone in the first trimester. Main Outcomes and Measures: Primary outcomes included major malformations overall and malformations previously associated with opioids (any cardiac malformations, ventricular septal defect, secundum atrial septal defect/nonprematurity-related patent foramen ovale, neural tube defects, clubfoot, and oral clefts). Secondary outcomes included other organ system-specific malformations. Risk differences and risk ratios (RRs) were estimated comparing buprenorphine with methadone, adjusting for confounders with propensity score overlap weights. Results: The cohort included 9514 pregnancies with first-trimester buprenorphine exposure (mean [SD] maternal age, 28.4 [4.6] years) and 3846 with methadone exposure (mean [SD] maternal age, 28.8 [4.7] years). The risk of malformations overall was 50.9 (95% CI, 46.5-55.3) per 1000 pregnancies for buprenorphine and 60.6 (95% CI, 53.0-68.1) per 1000 pregnancies for methadone. After confounding adjustment, buprenorphine was associated with a lower risk of malformations compared with methadone (RR, 0.82; 95% CI, 0.69-0.97). Risk was lower with buprenorphine for cardiac malformations (RR, 0.63; 95% CI, 0.47-0.85), including both ventricular septal defect (RR, 0.62; 95% CI, 0.39-0.98) and secundum atrial septal defect/nonprematurity-related patent foramen ovale (RR, 0.54; 95% CI, 0.30-0.97), oral clefts (RR, 0.65; 95% CI, 0.35-1.19), and clubfoot (RR, 0.55; 95% CI, 0.32-0.94). Results for neural tube defects were uncertain given low event counts. In secondary analyses, buprenorphine was associated with a decreased risk of central nervous system, urinary, and limb malformations but a greater risk of gastrointestinal malformations compared with methadone. These findings were consistent in sensitivity and bias analyses. Conclusions and Relevance: In this cohort study, the risk of most malformations previously associated with opioid exposure was lower in buprenorphine-exposed infants compared with methadone-exposed infants, independent of measured confounders. Malformation risk is one factor that informs the individualized patient decision regarding medications for opioid use disorder in pregnancy.


Assuntos
Buprenorfina , Pé Torto Equinovaro , Forame Oval Patente , Cardiopatias Congênitas , Comunicação Interventricular , Defeitos do Tubo Neural , Transtornos Relacionados ao Uso de Opioides , Complicações na Gravidez , Gravidez , Lactente , Feminino , Humanos , Adulto , Metadona/efeitos adversos , Buprenorfina/efeitos adversos , Primeiro Trimestre da Gravidez , Estudos de Coortes , Pé Torto Equinovaro/complicações , Pé Torto Equinovaro/tratamento farmacológico , Forame Oval Patente/complicações , Forame Oval Patente/tratamento farmacológico , Complicações na Gravidez/tratamento farmacológico , Transtornos Relacionados ao Uso de Opioides/tratamento farmacológico , Analgésicos Opioides/efeitos adversos , Cardiopatias Congênitas/induzido quimicamente , Cardiopatias Congênitas/epidemiologia , Cardiopatias Congênitas/complicações , Defeitos do Tubo Neural/complicações , Defeitos do Tubo Neural/tratamento farmacológico , Comunicação Interventricular/complicações , Comunicação Interventricular/tratamento farmacológico
15.
Zool Res ; 45(2): 233-241, 2024 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-38287904

RESUMO

Neural tube defects (NTDs) are severe congenital neurodevelopmental disorders arising from incomplete neural tube closure. Although folate supplementation has been shown to mitigate the incidence of NTDs, some cases, often attributable to genetic factors, remain unpreventable. The SHROOM3 gene has been implicated in NTD cases that are unresponsive to folate supplementation; at present, however, the underlying mechanism remains unclear. Neural tube morphogenesis is a complex process involving the folding of the planar epithelium of the neural plate. To determine the role of SHROOM3 in early developmental morphogenesis, we established a neuroepithelial organoid culture system derived from cynomolgus monkeys to closely mimic the in vivo neural plate phase. Loss of SHROOM3 resulted in shorter neuroepithelial cells and smaller nuclei. These morphological changes were attributed to the insufficient recruitment of cytoskeletal proteins, namely fibrous actin (F-actin), myosin II, and phospho-myosin light chain (PMLC), to the apical side of the neuroepithelial cells. Notably, these defects were not rescued by folate supplementation. RNA sequencing revealed that differentially expressed genes were enriched in biological processes associated with cellular and organ morphogenesis. In summary, we established an authentic in vitro system to study NTDs and identified a novel mechanism for NTDs that are unresponsive to folate supplementation.


Assuntos
Proteínas do Citoesqueleto , Defeitos do Tubo Neural , Animais , Proteínas do Citoesqueleto/metabolismo , Tubo Neural/metabolismo , Macaca fascicularis , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Defeitos do Tubo Neural/veterinária , Células Neuroepiteliais/metabolismo , Ácido Fólico/metabolismo , Organoides , Citoesqueleto
16.
Genome Biol ; 25(1): 19, 2024 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-38225631

RESUMO

BACKGROUND: Neural tube defects (NTDs) are caused by genetic and environmental factors. ARMC5 is part of a novel ubiquitin ligase specific for POLR2A, the largest subunit of RNA polymerase II (Pol II). RESULTS: We find that ARMC5 knockout mice have increased incidence of NTDs, such as spina bifida and exencephaly. Surprisingly, the absence of ARMC5 causes the accumulation of not only POLR2A but also most of the other 11 Pol II subunits, indicating that the degradation of the whole Pol II complex is compromised. The enlarged Pol II pool does not lead to generalized Pol II stalling or a generalized decrease in mRNA transcription. In neural progenitor cells, ARMC5 knockout only dysregulates 106 genes, some of which are known to be involved in neural tube development. FOLH1, critical in folate uptake and hence neural tube development, is downregulated in the knockout intestine. We also identify nine deleterious mutations in the ARMC5 gene in 511 patients with myelomeningocele, a severe form of spina bifida. These mutations impair the interaction between ARMC5 and Pol II and reduce Pol II ubiquitination. CONCLUSIONS: Mutations in ARMC5 increase the risk of NTDs in mice and humans. ARMC5 is part of an E3 controlling the degradation of all 12 subunits of Pol II under physiological conditions. The Pol II pool size might have effects on NTD pathogenesis, and some of the effects might be via the downregulation of FOLH1. Additional mechanistic work is needed to establish the causal effect of the findings on NTD pathogenesis.


Assuntos
Proteínas do Domínio Armadillo , Defeitos do Tubo Neural , Disrafismo Espinal , Animais , Humanos , Camundongos , Proteínas do Domínio Armadillo/genética , Ácido Fólico/metabolismo , Camundongos Knockout , Mutação , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/epidemiologia , Disrafismo Espinal/genética
17.
Ultrasound Med Biol ; 50(4): 580-585, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38281887

RESUMO

OBJECTIVE: This study aimed to ascertain the conus medullaris position by counting the number of ossification centers in the vertebral bodies below the conus medullaris endpoint (N) and assess its utility in screening for closed spinal dysraphism and tethered cord syndrome. METHODS: A total of 900 normal fetuses and 146 fetuses with closed spinal dysraphism or tethered cord syndrome were included in this study. The N values were tallied and compared along the spinal longitudinal plane. The receiver operating characteristic curve was utilized, and the cut-off value of N was analyzed. RESULTS: The counting of N was successfully performed in 856 normal and 146 abnormal fetuses. In the normal group, an increase in N with gestational age was observed. Specifically, in the subgroup of 17-20 wk fetuses, N was ≥6 in 117 out of 131 cases. This figure increased to 211 out of 213 in 21-24 wk and 512 out of 512 in 25-41 wk, respectively. Cases with N ≥7 accounted for 715 out of 856 fetuses in the 17-41 wk range. In the abnormal group, N was less than 7 in 152 out of 163 fetuses, showing statistical differences between the two groups. With a cut-off value of 6.5, specificity and sensitivity reached 93.3% and 83.5%. CONCLUSIONS: The counting of N was found to be a straightforward and efficient method for evaluating the position of the conus medullaris.


Assuntos
Defeitos do Tubo Neural , Disrafismo Espinal , Humanos , Osteogênese , Medula Espinal/diagnóstico por imagem , Coluna Vertebral
20.
Womens Health (Lond) ; 20: 17455057231224176, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38279794

RESUMO

BACKGROUND: Several countries poorly adhere to the World Health Organization's recommendation of folic acid supplementation in the periconceptional period, especially in limited-resource settings. OBJECTIVE: The objective of this study was to investigate the prevalence of and the factors associated with folic acid usage in the periconceptional period among pregnant women at Gadarif Maternity Hospital in eastern Sudan. STUDY DESIGN: This is a cross-sectional study. METHODS: This study was conducted in eastern Sudan from April to September 2022. A total of 720 pregnant women in their first trimester were enrolled. The sociodemographic characteristics and clinical and obstetrical data of pregnant women in their first trimester were assessed using a face-to-face questionnaire. In addition, multivariate regression analysis was performed. RESULTS: In this study, the median (interquartile range) of the age and gravidity of the enrolled women was 26.3 (24.14-29.52) years and 2 (1-4), respectively. Of these 720 women, 423 (58.8%) used folic acid during the periconceptional period, while 27 (3.7%) women used folic acid in the preconceptional period. None of the investigated factors (age, residence, education, employment, body mass index, or gravidity) were associated with periconceptional use of folic acid. CONCLUSION: The study revealed a low prevalence of folic acid usage in preconceptional period among pregnant women in eastern Sudan. Additional efforts are needed to promote folic acid usage in the preconceptional period as well as in the first trimester.


Assuntos
Ácido Fólico , Defeitos do Tubo Neural , Feminino , Gravidez , Humanos , Masculino , Ácido Fólico/uso terapêutico , Estudos Transversais , Suplementos Nutricionais , Sudão/epidemiologia , Inquéritos e Questionários , Defeitos do Tubo Neural/epidemiologia , Defeitos do Tubo Neural/prevenção & controle
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