Birth defects research. Part A, Clinical and molecular teratology最新文献_第6页

Effects of thyroxine exposure on the Twist 1 +/− phenotype: A test of gene–environment interaction modeling for craniosynostosis 甲状腺素暴露对Twist 1 +/−表型的影响:颅缝闭锁的基因-环境相互作用模型测试

Q Medicine

Birth defects research. Part A, Clinical and molecular teratology

Pub Date : 2016-07-20 DOI: 10.1002/bdra.23543

Emily L. Durham, R. Nicole Howie, Laurel Black, Grace Bennfors, Trish E. Parsons, Mohammed Elsalanty, Jack C. Yu, Seth M. Weinberg, James J. Cray Jr.

Background

Craniosynostosis, the premature fusion of one or more of the cranial sutures, is estimated to occur in 1:1800 to 2500 births. Genetic murine models of craniosynostosis exist, but often imperfectly model human patients. Case, cohort, and surveillance studies have identified excess thyroid hormone as an agent that can either cause or exacerbate human cases of craniosynostosis.

Methods

Here we investigate the influence of in utero and in vitro exogenous thyroid hormone exposure on a murine model of craniosynostosis, Twist 1 +/−.

Results

By 15 days post-natal, there was evidence of coronal suture fusion in the Twist 1 +/− model, regardless of exposure. With the exception of craniofacial width, there were no significant effects of exposure; however, the Twist 1 +/− phenotype was significantly different from the wild-type control. Twist 1 +/− cranial suture cells did not respond to thyroxine treatment as measured by proliferation, osteogenic differentiation, and gene expression of osteogenic markers. However, treatment of these cells did result in modulation of thyroid associated gene expression.

Conclusion

Our findings suggest the phenotypic effects of the genetic mutation largely outweighed the effects of thyroxine exposure in the Twist 1 +/− model. These results highlight difficultly in experimentally modeling gene–environment interactions for craniosynostotic phenotypes. Birth Defects Research (Part A) 106:803–813, 2016. © 2016 Wiley Periodicals, Inc.

颅缝闭合，即一条或多条颅缝的过早融合，估计发生在1:1800至2500的新生儿中。颅缝闭锁的遗传小鼠模型已经存在，但通常不能完美地模拟人类患者。病例、队列和监测研究已经确定过量的甲状腺激素是导致或加剧人类颅缝闭锁病例的一种因素。方法研究子宫内和体外外源性甲状腺激素暴露对小鼠颅缝闭锁模型Twist 1 +/−的影响。结果出生后15天，Twist 1 +/−模型中冠状缝合线融合的证据，无论暴露与否。除颅面宽度外，暴露无显著影响;然而，Twist 1 +/−表型与野生型对照有显著差异。通过增殖、成骨分化和成骨标志物的基因表达测量，Twist 1 +/ -颅缝合细胞对甲状腺素治疗没有反应。然而，这些细胞的治疗确实导致甲状腺相关基因表达的调节。结论在Twist 1 +/−模型中，基因突变的表型效应在很大程度上超过了甲状腺素暴露的影响。这些结果突出了在实验模拟基因-环境相互作用对颅缝闭合表型的困难。出生缺陷研究(A辑)(06):803 - 813,2016。©2016 Wiley期刊公司

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引用次数: 7

A 2015 global update on folic acid-preventable spina bifida and anencephaly 叶酸可预防脊柱裂和无脑畸形的2015年全球最新进展

Q Medicine

Birth defects research. Part A, Clinical and molecular teratology

Pub Date : 2016-07-15 DOI: 10.1002/bdra.23529

Annelise Arth, Vijaya Kancherla, Helena Pachón, Sarah Zimmerman, Quentin Johnson, Godfrey P. Oakley Jr

Background

Spina bifida and anencephaly are two major neural tube defects. They contribute substantially to perinatal, neonatal, infant, and under-five mortality and life-long disability. To monitor the progress toward the total prevention of folic acid-preventable spina bifida and anencephaly (FAP SBA), we examined their global status in 2015.

Methods

Based on existing data, we modeled the proportion of FAP SBA that are prevented in the year 2015 through mandatory folic acid fortification globally. We included only those countries with mandatory fortification that added at least 1.0 ppm folic acid as a fortificant to wheat and maize flour, and had complete information on coverage. Our model assumed mandatory folic acid fortification at 200 μg/day is fully protective against FAP SBA, and reduces the rate of spina bifida and anencephaly to a minimum of 0.5 per 1000 births.

RESULTS

Our estimates show that, in 2015, 13.2% (35,500 of approximately 268,700 global cases) of FAP SBA were prevented in 58 countries through mandatory folic acid fortification of wheat and maize flour. Most countries in Europe, Africa, and Asia were not implementing mandatory fortification with folic acid.

Conclusion

Knowledge that folic acid prevents spina bifida and anencephaly has existed for 25 years, yet only a small fraction of FAP SBA is being prevented worldwide. Several countries still have 5- to 20-fold epidemics of FAP SBA. Implementation of mandatory fortification with folic acid offers governments a proven and rapid way to prevent FAP SBA-associated disability and mortality, and to help achieve health-related Sustainable Development Goals. Birth Defects Research (Part A) 106:520–529, 2016. © 2016 Wiley Periodicals, Inc.

背景:脊柱裂和无脑畸形是两种主要的神经管缺陷。它们在很大程度上导致围产期、新生儿、婴儿和五岁以下儿童死亡率和终身残疾。为了监测全面预防叶酸可预防的脊柱裂和无脑畸形(FAP SBA)的进展，我们在2015年调查了它们的全球状况。方法基于现有数据，我们建立了2015年全球通过强制性叶酸强化预防FAP SBA的比例模型。我们只纳入了那些在小麦和玉米粉中添加至少1.0 ppm叶酸作为强强剂的强制性强化国家，并有完整的覆盖信息。我们的模型假设每天200 μg的强制性叶酸强化可以完全预防FAP SBA，并将脊柱裂和无脑畸形的发生率降低到每1000个新生儿中至少0.5个。结果:我们的估计显示，2015年，58个国家通过强制强化小麦和玉米粉中的叶酸，预防了13.2%的FAP SBA(全球约268,700例病例中的35,500例)。欧洲、非洲和亚洲的大多数国家都没有实施强制性叶酸强化。结论叶酸预防脊柱裂和无脑畸形的知识已经存在了25年，但在世界范围内，只有一小部分FAP SBA被预防。一些国家仍有5至20倍的口蹄疫- SBA流行。强制性叶酸强化的实施为各国政府提供了一种行之有效的快速方法，以预防与FAP sba相关的残疾和死亡，并帮助实现与健康相关的可持续发展目标。出生缺陷研究(分册)，2016。©2016 Wiley期刊公司

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引用次数: 70

What is standing in the way of complete prevention of folate preventable neural tube defects? 是什么阻碍了叶酸可预防神经管缺陷的完全预防?

Q Medicine

Birth defects research. Part A, Clinical and molecular teratology

Pub Date : 2016-07-15 DOI: 10.1002/bdra.23518

James L. Mills, Aggeliki Dimopoulos, Regan L. Bailey

It is well known that there is a large gap between the number of neural tube defects (NTDs) that could be prevented by folic acid and the number that are actually being prevented. Arth and colleagues demonstrate just how large that gap is (Arth et al., 2016). The question is: why are so many potentially preventable NTDs not being prevented?

Campaigns recommending that women of childbearing age take folic acid supplements routinely and voluntary fortification programs have had only modest success at best (Khoshnood et al., 2015). Therefore, mandatory fortification has been instituted in almost 80 countries (Food Fortification Initiative, 2016). As Arth et al. demonstrate, many countries have not embraced the mandatory fortification approach, despite the fact that it has prevented an average of 40 to 50% of NTDs (Castillo-Lancellotti et al., 2013).

Concerns regarding the safety of folic acid fortification are one reason. Two major concerns are masking vitamin B12 deficiency and increasing cancer risk. It should be noted that the amount of folic acid people receive from fortified food in the United States, where fortification of enriched cereal grain products is mandatory, is an average of 163 micrograms per day in women of childbearing age, less than half the recommended dietary allowance (Tinker et al., 2010). This is sufficient to prevent folate-related NTDs (Mosley et al., 2009) but does not appear to cause masking of the hematological signs of vitamin B12 deficiency (Mills et al., 2003). A large meta-analysis of participants in folic acid trials demonstrated that, after an average of 5 years of follow-up, the relative risk for incident cancer was 1.06 with a 95% confidence interval of 0.99 to 1.13 (Vollset et al., 2013).

The authors noted that the 6% increase was not statistically significant and that trial participants were exposed to far higher doses than fortification would deliver. There was no significant increase in any individual cancers studied. Nonetheless, concerns persist regarding cancer risk (van Wijngaarden et al., 2014) and other possible but unproved risks (National Toxicology Program, 2015). It is important to note that the amount of folic acid needed to prevent NTDs is far less than the amount likely to cause adverse effects (Mills and Dimopoulos, 2015). Because NTDs are uncommon events and a small increase in cancer would affect a substantial number of people, some countries have been reluctant to require fortification. It should be noted, however, that mandatory fortification has caused a dramatic reduction in folate deficiency (Pfeiffer et al., 2012); so the benefit is not limited to a small group.

Several other obstacles to mandatory fortification exist. Although European Union (EU) regulation No. 1925/2006 (European Commission, 2006) acknowledges the need for mandator

众所周知，叶酸可以预防的神经管缺陷(NTDs)的数量与实际预防的数量之间存在很大差距。Arth及其同事证明了这一差距有多大(Arth et al.， 2016)。问题是:为什么这么多本可预防的被忽视热带病没有得到预防?建议育龄妇女定期服用叶酸补充剂和自愿强化计划的运动充其量只取得了有限的成功(Khoshnood等人，2015)。因此，强制性强化已在近80个国家建立(食品强化倡议，2016)。正如Arth等人所证明的那样，许多国家尚未采用强制性强化方法，尽管它平均阻止了40%至50%的被忽视热带病(Castillo-Lancellotti等人，2013)。对叶酸强化安全性的担忧是原因之一。两个主要的担忧是掩盖维生素B12缺乏和增加癌症风险。值得注意的是，在美国，人们从强化食品中获得的叶酸量，在强化谷物产品是强制性的，育龄妇女平均每天摄入163微克，不到推荐膳食量的一半(Tinker等人，2010)。这足以预防叶酸相关的NTDs (Mosley等人，2009)，但似乎不会导致掩盖维生素B12缺乏的血液学症状(Mills等人，2003)。一项针对叶酸试验参与者的大型荟萃分析表明，在平均5年的随访后，癌症发生的相对风险为1.06,95%可信区间为0.99至1.13 (Vollset et al.， 2013)。作者指出，6%的增加在统计上并不显著，而且试验参与者暴露于比强化所能提供的剂量高得多的剂量。所研究的任何一种癌症的发病率都没有显著增加。尽管如此，人们仍然担心癌症风险(van Wijngaarden et al.， 2014)和其他可能但未经证实的风险(National Toxicology Program, 2015)。值得注意的是，预防ntd所需的叶酸量远远小于可能导致不良反应的量(Mills和Dimopoulos, 2015)。由于被忽视的热带病是不常见的事件，癌症的小幅增加会影响相当多的人，一些国家一直不愿要求强化。然而，应该指出的是，强制性强化导致叶酸缺乏症显著减少(Pfeiffer et al.， 2012);因此，这种益处并不局限于一小群人。强制设防还存在其他几个障碍。尽管欧洲联盟(欧盟)第1925/2006号条例(欧洲委员会，2006年)承认有必要在成员国强制强化食品中添加维生素，以解决公众健康问题，但一些国家反对操纵食品供应的想法。想要在整个欧盟销售商品的商人可能会选择不加强，以使他们的产品在这些国家更具吸引力。另一方面，在允许强化的国家中，广泛的自愿强化可能会造成将暴露量保持在安全范围内的问题。有人建议，自愿强化应作为强制性强化加以管制，以避免过度暴露。发展中国家在强制强化食品方面面临着一系列不同的问题。《战略文件:西太平洋地区在大米和小麦粉中添加维生素和矿物质》(《食品强化倡议》，2013年)的报告很好地概述了在实施之前需要解决的问题。在世界上的一些地区，找到一种可供大部分高危人群食用并可进行强化的食物可能是一个问题。谷物是在当地的小磨坊里碾磨的，获取叶酸并混合适量以确保安全有效的强化是一个严重的问题。大型工厂是防御工事的实际场所。当大磨坊生产大部分面粉时，小麦和玉米的强化相对容易，尽管设备成本可能是一个障碍。强化大米更为困难(美国国际开发署，2008年)。有些技术可能会生产出味道或外观令人无法接受的产品。如果大米被洗过或漂洗过，包衣也可能无效。热挤压技术可以生产出外观和口感正常的大米，并能很好地保留叶酸，但这种技术相对昂贵，需要在加工设备上进行大量投资。强制性强化必须在国家层面强制执行，以确保良好的覆盖范围，促进质量控制监测，并使所有制造商在生产成本方面处于平等地位。最后，在资源贫乏的国家，必须权衡叶酸强化与其他紧迫的公共卫生需求。 2013年，艾滋病毒/艾滋病估计造成150万人死亡(全球卫生观察站数据[2013]http://www.who.int/gho/hiv/epidemic_status/deaths/en/)。2013年，维生素A缺乏症导致约10.5万人死亡(Stevens et al.， 2015)。预防非传染性疾病的倡导者正在与预防其他死亡和残疾原因的干预措施竞争。在存在与营养缺乏有关的多重问题的地区，可以制定战略，用铁或维生素a等其他关键微量营养素进行强化。幸运的是，在混合中添加额外微量营养素的增量成本相当小。因此，可以根据国家的不同，将叶酸与维生素A和铁等其他关键微量营养素结合起来，从而提高叶酸强化的优先级。如果要预防所有与叶酸有关的热带病，就必须克服所有这些障碍。解决这些问题并非易事，需要工程师、化学家、立法者和公共卫生专家等广泛权威人士的专业知识。安全、有效的强制性强化项目在预防被忽视热带病方面的好处是有据可查的。降低叶酸缺乏性贫血的发病率是一个重要的附带好处。添加额外的微量营养素可大大降低由于缺乏其他微量营养素而导致的发病率和死亡率。简而言之，预防所有叶酸可预防的被忽视热带病并不容易，但这是一个值得追求的目标。

{"title":"What is standing in the way of complete prevention of folate preventable neural tube defects?","authors":"James L. Mills, Aggeliki Dimopoulos, Regan L. Bailey","doi":"10.1002/bdra.23518","DOIUrl":"10.1002/bdra.23518","url":null,"abstract":"<p>It is well known that there is a large gap between the number of neural tube defects (NTDs) that could be prevented by folic acid and the number that are actually being prevented. Arth and colleagues demonstrate just how large that gap is (Arth et al., <span>2016</span>). The question is: why are so many potentially preventable NTDs not being prevented?</p><p>Campaigns recommending that women of childbearing age take folic acid supplements routinely and voluntary fortification programs have had only modest success at best (Khoshnood et al., <span>2015</span>). Therefore, mandatory fortification has been instituted in almost 80 countries (Food Fortification Initiative, 2016). As Arth et al. demonstrate, many countries have not embraced the mandatory fortification approach, despite the fact that it has prevented an average of 40 to 50% of NTDs (Castillo-Lancellotti et al., <span>2013</span>).</p><p>Concerns regarding the safety of folic acid fortification are one reason. Two major concerns are masking vitamin B12 deficiency and increasing cancer risk. It should be noted that the amount of folic acid people receive from fortified food in the United States, where fortification of enriched cereal grain products is mandatory, is an average of 163 micrograms per day in women of childbearing age, less than half the recommended dietary allowance (Tinker et al., <span>2010</span>). This is sufficient to prevent folate-related NTDs (Mosley et al., <span>2009</span>) but does not appear to cause masking of the hematological signs of vitamin B12 deficiency (Mills et al., <span>2003</span>). A large meta-analysis of participants in folic acid trials demonstrated that, after an average of 5 years of follow-up, the relative risk for incident cancer was 1.06 with a 95% confidence interval of 0.99 to 1.13 (Vollset et al., <span>2013</span>).</p><p>The authors noted that the 6% increase was not statistically significant and that trial participants were exposed to far higher doses than fortification would deliver. There was no significant increase in any individual cancers studied. Nonetheless, concerns persist regarding cancer risk (van Wijngaarden et al., <span>2014</span>) and other possible but unproved risks (National Toxicology Program, 2015). It is important to note that the amount of folic acid needed to prevent NTDs is far less than the amount likely to cause adverse effects (Mills and Dimopoulos, <span>2015</span>). Because NTDs are uncommon events and a small increase in cancer would affect a substantial number of people, some countries have been reluctant to require fortification. It should be noted, however, that mandatory fortification has caused a dramatic reduction in folate deficiency (Pfeiffer et al., <span>2012</span>); so the benefit is not limited to a small group.</p><p>Several other obstacles to mandatory fortification exist. Although European Union (EU) regulation No. 1925/2006 (European Commission, 2006) acknowledges the need for mandator","PeriodicalId":8983,"journal":{"name":"Birth defects research. Part A, Clinical and molecular teratology","volume":"106 7","pages":"517-519"},"PeriodicalIF":0.0,"publicationDate":"2016-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1002/bdra.23518","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"34560361","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 4

In utero exposure to venlafaxine, a serotonin–norepinephrine reuptake inhibitor, increases cardiac anomalies and alters placental and heart serotonin signaling in the rat 在子宫内暴露于文拉法辛，一种血清素-去甲肾上腺素再摄取抑制剂，增加心脏异常和改变胎盘和心脏血清素信号

Q Medicine

Birth defects research. Part A, Clinical and molecular teratology

Pub Date : 2016-07-07 DOI: 10.1002/bdra.23537

Laetitia Laurent, Chunwei Huang, Sheila R. Ernest, Anick Berard, Cathy Vaillancourt, Barbara F. Hales

Background

Human studies are inconsistent with respect to an association between treatment with selective serotonin and serotonin–norepinephrine reuptake inhibitors (SSRI/SNRIs) and an increase in the incidence of congenital heart defects. Here we tested the hypothesis that in utero exposure to venlafaxine, a highly prescribed SNRI, increases the incidence of fetal heart defects and alters placental and fetal heart serotonin signaling in the rat.

Methods

Timed-pregnant Sprague Dawley rats were gavaged daily with venlafaxine hydrochloride (0, 3, 10, 30, or 100 mg/kg/day) from gestation day 8 to 20. On gestation day 21, fetuses were examined for external and internal malformations; placentas and fetal hearts were collected for the analysis of gene expression.

Results

Venlafaxine had no effect on the number of live fetuses, fetal body weights, or external morphology in the absence of maternal toxicity. However, venlafaxine significantly increased the placental index (fetal body/placental weight ratio) and the incidence of fetal cardiac anomalies. Venlafaxine exposure decreased placental expression of the serotonin transporter (SERT/Slc6a4) at the transcript and protein levels. In contrast, venlafaxine increased SERT expression in the hearts of female, but not male, fetuses. Expression of the serotonin 2B receptor (5-HT_2B/Htr2b) and of fibroblast growth factor 8 was induced in fetal hearts.

Conclusion

In utero venlafaxine exposure altered the placental index and induced fetal cardiac anomalies in rats. We propose that the increased incidence of cardiac anomalies is mediated through alterations in serotonin signaling in the placenta and fetal heart. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1044–1055, 2016. © 2016 Wiley Periodicals, Inc.

背景:关于选择性5 -羟色胺和5 -羟色胺-去甲肾上腺素再摄取抑制剂(SSRI/SNRIs)治疗与先天性心脏缺陷发生率增加之间的关联，人类研究并不一致。在这里，我们测试了一个假设，即在子宫内暴露于文拉法辛(一种高度处方的SNRI)，会增加胎儿心脏缺陷的发生率，并改变大鼠胎盘和胎儿心脏血清素信号。方法妊娠第8 ~ 20天，定时妊娠大鼠每天灌胃盐酸文拉法辛0、3、10、30、100 mg/kg/d。妊娠第21天，检查胎儿的外部和内部畸形;采集胎盘和胎心进行基因表达分析。结果在无母体毒性的情况下，文拉法辛对活胎数、胎儿体重和体外形态均无影响。然而，文拉法辛显著增加胎盘指数(胎体/胎盘重量比)和胎儿心脏异常的发生率。文拉法辛暴露降低了胎盘血清素转运体(SERT/Slc6a4)在转录物和蛋白水平上的表达。相比之下，文拉法辛增加了女性胎儿心脏中SERT的表达，而不是男性胎儿。在胎儿心脏中诱导5-羟色胺2B受体(5-HT2B/Htr2b)和成纤维细胞生长因子8的表达。结论在子宫内暴露文拉法辛可改变大鼠胎盘指数，诱发胎儿心脏异常。我们认为心脏异常发生率的增加是通过胎盘和胎儿心脏中血清素信号的改变介导的。出生缺陷研究(上)，2016。©2016 Wiley期刊公司出生缺陷研究(A辑)106:1044-1055,2016。©2016 Wiley期刊公司

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引用次数: 23

Further evidence for deletions in 7p14.1 contributing to nonsyndromic cleft lip with or without cleft palate 进一步的证据表明，7p14.1基因缺失导致非综合征性唇裂伴或不伴腭裂

Q Medicine

Birth defects research. Part A, Clinical and molecular teratology

Pub Date : 2016-07-07 DOI: 10.1002/bdra.23539

Johanna Klamt, Andrea Hofmann, Anne C. Böhmer, Ann-Kathrin Hoebel, Lina Gölz, Jessica Becker, Alexander M. Zink, Markus Draaken, Alexander Hemprich, Martin Scheer, Gül Schmidt, Markus Martini, Michael Knapp, Elisabeth Mangold, Franziska Degenhardt, Kerstin U. Ludwig

Background

Nonsyndromic cleft with or without cleft palate (nsCL/P) is a common birth defect. Although genome-wide association studies (GWAS) have identified numerous risk variants, a considerable fraction of the genetic heritability remains unknown. The aim of the present study was to replicate a previous finding that de novo deletions in a 62 kb region of chromosome 7p14 are a risk factor for nsCL/P, using an independent cohort.

Methods

Data from a published case–control GWAS cohort of 399 patients and 1318 controls were used. Copy number variant (CNV) detection in the 62 kb candidate region of 7p14 was performed using QuantiSNP. Putative CNVs in probands were verified and validated by quantitative polymerase chain reaction. Segregation analyses were performed in family members for whom DNA was available.

Results

Within the 62 kb candidate region, a deletion of 7.4 kb showed association with nsCL/P (13/387 cases, 20/1300 controls, p_lowest = 0.024, odds ratio = 2.22). In all families with a sporadic case (n = 3), the deletion occurred de novo. In multiplex families, both incomplete segregation and incomplete penetrance were observed.

Conclusion

The present data support the hypothesis that deletions at 7p14 are a common risk factor for nsCL/P. Genome-wide CNV analyses in nsCL/P cohorts are warranted to explore the functional relevance of these deletions and their contribution to nsCL/P, and to determine exact breakpoints. Birth Defects Research (Part A) 106:767–772, 2016. © 2016 Wiley Periodicals, Inc.

背景:非综合征性腭裂伴或不伴腭裂(nsCL/P)是常见的先天性缺陷。尽管全基因组关联研究(GWAS)已经确定了许多风险变异，但相当一部分遗传能力仍然未知。本研究的目的是利用一个独立的队列来重复先前的发现，即7p14染色体62 kb区域的从头缺失是nsl /P的一个危险因素。方法数据来自已发表的病例对照GWAS队列，共399例患者和1318例对照。利用QuantiSNP对7p14的62 kb候选区域进行拷贝数变异(CNV)检测。先证物中假定的CNVs通过定量聚合酶链反应进行验证和验证。分离分析在可获得DNA的家庭成员中进行。结果在62 kb候选区域中，缺失7.4 kb与nsCL/P相关(13/387例，20/1300例对照，plowest = 0.024，优势比= 2.22)。在所有有散发性病例的家庭中(n = 3)，基因缺失都是从头开始的。在多重家族中，观察到不完全分离和不完全外显。结论目前的数据支持7p14缺失是nsCL/P常见危险因素的假设。在nsCL/P队列中进行全基因组CNV分析是有必要的，以探索这些缺失的功能相关性及其对nsCL/P的贡献，并确定确切的断点。出生缺陷研究(分册)(6):767 - 772,2016。©2016 Wiley期刊公司

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引用次数: 6

Prevalence, characteristics, and survival of children with esophageal atresia: A 32-year population-based study including 1,417,724 consecutive newborns. 食道闭锁儿童的患病率、特征和生存率:一项为期32年的基于人群的研究，包括1,417,724名连续新生儿。

Q Medicine

Birth defects research. Part A, Clinical and molecular teratology

Pub Date : 2016-07-01 DOI: 10.1002/bdra.23493

M. Cassina, Michele Ruol, R. Pertile, P. Midrio, S. Piffer, V. Vicenzi, M. Saugo, C. Stocco, P. Gamba, M. Clementi

BACKGROUNDEsophageal atresia (EA) is a congenital malformation of the upper gastrointestinal tract with an estimated prevalence varying from 1 in 2500 to 1 in 4500 births. The aim of this study was to describe the epidemiology of EA between 1981 and 2012 and evaluate patients' survival.METHODSThis study used data from a population-based Italian Congenital Malformation Registry. The survival status was ascertained by linking the registry records, vital records and the regional registries of patients. Kaplan-Meier methods were used to estimate survival probabilities up to 25 years and Cox proportional hazards regression was used to evaluate factors that affected survival.RESULTSA total of 407 cases of EA were identified among 1,417,724 total births. After the exclusion of cases with chromosomal anomalies, 49.9% of the patients presented with at least one associated congenital anomaly. The 25-year survival probability was 85.1% (95% confidence interval [CI], 80.8-89.4), with most deaths occurring during the first months of life. Patients' characteristics associated with decreased survival probability were low birth weight (hazard ratio, 3.7; 95% CI, 1.7-8.3) and presence of additional major defects (hazard ratio, 2.8; 95% CI, 1.3-6.0). A significant improvement in survival over the decades was observed for patients with nonisolated EA.CONCLUSIONThis study detected a significant improvement in survival of individuals with EA over the past decades and identified the strongest predictors of mortality. These results will be important for the planning of the clinical management and formulation of prognosis when EA is diagnosed in a newborn. Birth Defects Research (Part A) 106:542-548, 2016. © 2016 Wiley Periodicals, Inc.

食道闭锁(EA)是一种先天性上消化道畸形，估计患病率从1 / 2500到1 / 4500不等。本研究的目的是描述1981 - 2012年间EA的流行病学，并评估患者的生存率。方法:本研究使用的数据来自意大利先天性畸形登记处。生存状态确定通过连接登记记录，生命记录和患者的区域登记。Kaplan-Meier方法用于估计25年的生存概率，Cox比例风险回归用于评估影响生存的因素。结果在1417724例新生儿中，共发现407例EA。在排除有染色体异常的病例后，49.9%的患者至少伴有一种相关的先天性异常。25年生存率为85.1%(95%可信区间[CI]， 80.8-89.4)，大多数死亡发生在出生后的头几个月。与生存率降低相关的患者特征为低出生体重(风险比，3.7;95% CI, 1.7-8.3)和存在其他主要缺陷(风险比，2.8;95% ci, 1.3-6.0)。在过去的几十年里，非孤立性EA患者的生存率有了显著的提高。结论:本研究发现，在过去的几十年里，EA患者的生存率有了显著的提高，并确定了死亡率的最强预测因子。这些结果将是重要的规划临床管理和制定预后时，EA诊断为新生儿。出生缺陷研究(分册)(6):542-548,2016。©2016 Wiley期刊公司

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引用次数: 64

Obituary: Dr. Ed Lammer. 讣告:Ed Lammer博士。

Q Medicine

Birth defects research. Part A, Clinical and molecular teratology

Pub Date : 2016-07-01 DOI: 10.1002/bdra.23524

R. Finnell, G. Shaw

引用次数: 0

When the right (Drug) should be left: Prenatal drug exposure and heterotaxy syndrome. 右(药)时应左:产前药物暴露和异位综合征。

Q Medicine

Birth defects research. Part A, Clinical and molecular teratology

Pub Date : 2016-07-01 DOI: 10.1002/bdra.23497

Nicole R. van Veenendaal, C. Kusters, R. Oostra, J. Bergman, J. Cobben

BACKGROUNDRecent studies reported an association between prenatal propylthiouracil exposure and birth defects, including abnormal arrangement across the left-right body axis, suggesting an association with heterotaxy syndrome.METHODSThis case-control and case-finding study used data from 1981 to 2013 from the EUROCAT birth defect registry in the Northern Netherlands. First, we explored prenatal exposures in heterotaxy syndrome (cases) and Down syndrome (controls). Second, we describe the specific birth defects in offspring of mothers using propylthiouracil (PTU) prenatally.RESULTSA total of 66 cases with heterotaxy syndrome (incidence 12.1 per 100,000 pregnancies) and 783 controls with Down syndrome (143.3 per 100,000 pregnancies) were studied. No differences in intoxication use during pregnancy were found between cases and controls, including smoking (28.0% vs. 22.7%; p = 0.40), alcohol (14.0% vs. 26.9%; p = 0.052), and recreational drugs (0 vs. 0.3%; p = 1.00). We found an association between heterotaxy syndrome and prenatal drug exposure to follitropin-alfa (5.6% vs. 1.1%; p = 0.04), and drugs used in nicotine dependence (3.7% vs. 0.2%; p = 0.02). Five mothers used PTU during pregnancy and gave birth to a child with trisomy 18, renal abnormalities, or hypospadias and cardiac defects.CONCLUSIONThis study identified follitropin-alfa and drugs used in nicotine dependence as possible teratogens of heterotaxy syndrome. Our data suggest the possibility that there is an increased risk of birth defects (including renal, urological, and cardiac abnormalities) in children born among mothers taking PTU prenatally, but not for heterotaxy syndrome. Birth Defects Research (Part A) 106:573-579, 2016. © 2016 Wiley Periodicals, Inc.

最近的研究报道了产前丙硫尿嘧啶暴露与出生缺陷之间的关系，包括在左右体轴上的异常排列，这表明与异位综合征有关。方法本病例对照和病例发现研究使用了1981年至2013年荷兰北部EUROCAT出生缺陷登记处的数据。首先，我们探讨了异位综合征(病例)和唐氏综合征(对照组)的产前暴露。其次，我们描述了母亲在产前使用丙基硫脲嘧啶(PTU)的后代的特定出生缺陷。结果共纳入66例异位综合征(12.1 / 10万妊娠)和783例唐氏综合征(143.3 / 10万妊娠)对照。在怀孕期间，病例和对照组之间的中毒使用没有差异，包括吸烟(28.0%对22.7%;P = 0.40)、酒精(14.0% vs. 26.9%;P = 0.052)和娱乐性药物(0 vs. 0.3%;P = 1.00)。我们发现异位综合征与产前药物暴露于卵磷脂- α之间存在关联(5.6% vs 1.1%;P = 0.04)，以及尼古丁依赖的药物使用(3.7% vs. 0.2%;P = 0.02)。5位母亲在怀孕期间使用PTU，生下了一个患有18三体、肾脏异常或尿道下裂和心脏缺陷的孩子。结论本研究确定了卵磷脂- α和尼古丁依赖药物可能是异位综合征的致畸源。我们的数据表明，产前服用PTU的母亲所生的孩子有可能增加出生缺陷(包括肾脏、泌尿系统和心脏异常)的风险，但不存在异位综合征。出生缺陷研究(A辑)(06):573-579,2016。©2016 Wiley期刊公司

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引用次数: 5

Mechanism of pancreatic and liver malformations in human fetuses with short-rib polydactyly syndrome. 短肋多指畸形胎儿胰、肝畸形的发生机制。

Q Medicine

Birth defects research. Part A, Clinical and molecular teratology

Pub Date : 2016-07-01 DOI: 10.1002/bdra.23495

C. Loo, T. Pereira, M. Ramsing, I. Vogel, O. B. Petersen, G. Ramm

BACKGROUNDThe short-rib polydactyly (SRP) syndromes are rare skeletal dysplasias caused by abnormalities in primary cilia, sometimes associated with visceral malformations.METHODSThe pathogenesis of ductal plate malformation (DPM) varies in different syndromes and has not been investigated in SRP. We have studied liver development in five SRP fetuses and pancreatic development in one SRP fetus, with genetically confirmed mutations in cilia related genes, with and without DPMs, using the immunoperoxidase technique, and compared these to other syndromes with DPM.RESULTSAcetylated tubulin expression was abnormal in DPM in SRP, Meckel syndrome, and autosomal recessive polycystic kidney disease (ARPKD), confirming ciliary anomalies. SDF-1 was abnormally expressed in SRP and two of three cases of autosomal dominant polycystic kidney disease (ADPKD) but not ARPKD or Meckel. Increased density of quiescent hepatic stellate cells was seen in SRP, Meckel, one of three cases of ARPKD, and two of three cases of ADPKD with aberrant hepatocyte expression of keratin 19 in SRP and ADPKD. Immunophenotypic abnormalities were present even in fetal liver without fully developed DPMs. The SRP case with DPM and pancreatic malformations showed abnormalities in the pancreatic head (influenced by mesenchyme from the septum transversum, similar to liver) but not pancreatic body (influenced by mesenchyme adjacent to the notochord).CONCLUSIONIn SRP, there are differentiation defects of hepatocytes, cholangiocytes, and liver mesenchyme and, in rare cases, pancreatic mesenchymal anomalies. The morphological changes were subtle in early gestation but immunophenotypic abnormalities were present. Mesenchymal-epithelial interactions may contribute to the malformations. Birth Defects Research (Part A) 106:549-562, 2016. © 2016 Wiley Periodicals, Inc.

背景:短肋多指综合征是由初级纤毛异常引起的罕见的骨骼发育不良，有时与内脏畸形有关。方法导管板畸形(DPM)的发病机制在不同的证候中存在差异，尚未在SRP中进行研究。我们使用免疫过氧化物酶技术研究了5例SRP胎儿的肝脏发育和1例SRP胎儿的胰腺发育，这些胎儿有纤毛相关基因突变，有或没有DPM，并将这些与其他DPM综合征进行了比较。结果SRP、Meckel综合征和常染色体隐性多囊肾病(ARPKD)患者DPM中sacetylated微管蛋白表达异常，证实纤毛异常。SDF-1在SRP和三分之二的常染色体显性多囊肾病(ADPKD)中异常表达，但在ARPKD或Meckel中不表达。在SRP、Meckel (ARPKD三例中的一例)和ADPKD三例中的两例中可见静止的肝星状细胞密度增加，SRP和ADPKD中角蛋白19的肝细胞表达异常。即使在没有完全发育的dpm的胎儿肝脏中也存在免疫表型异常。伴有DPM和胰腺畸形的SRP病例显示胰腺头部(受横隔间质影响，类似于肝脏)异常，但胰腺体(受脊索附近间质影响)未见异常。结论SRP存在肝细胞、胆管细胞和肝间质分化缺陷，少见胰腺间质异常。妊娠早期形态变化轻微，但存在免疫表型异常。间充质-上皮相互作用可能导致畸形。出生缺陷研究(A辑)(06):549-562,2016。©2016 Wiley期刊公司

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引用次数: 1

Childhood cancer in children with congenital anomalies in Oklahoma, 1997 to 2009. 1997年至2009年俄克拉何马州先天性畸形儿童患癌症的情况。

Q Medicine

Birth defects research. Part A, Clinical and molecular teratology

Pub Date : 2016-07-01 DOI: 10.1002/bdra.23494

Amanda E. Janitz, B. Neas, Janis E Campbell, Anne E Pate, J. Stoner, S. Magzamen, J. Peck

BACKGROUNDData-linkage studies have reported an association between congenital anomalies and childhood cancer. However, few studies have focused on the differences in the effect of congenital anomalies on cancer as a function of attained age. We aimed to examine associations between anomalies and childhood cancer as a function of attained age among children born in Oklahoma.METHODSData were obtained from the Oklahoma State Department of Health from 1997 to 2009 (n = 591,235). We linked Vital Statistics records for singleton deliveries to the Oklahoma Birth Defects Registry and the Oklahoma Central Cancer Registry using name and birth date. To assess the relation between anomalies and childhood cancer, we used Cox regression analysis allowing for a nonproportional hazards for anomalies as a function of age.RESULTSThere were 23,368 (4.0%) children with anomalies and 531 (0.1%) children with cancer. When considering 3-year age intervals, we detected an increased hazard of any childhood cancer in children with anomalies compared with those without anomalies before 1 year of age (hazard ratio, 14.1; 95% confidence interval, 8.3-23.7) and at 3 years of age (hazard ratio, 2.3; 95% confidence interval, 1.6-3.2). The increased hazard declined with increasing time since birth, with the effect diminished by 6 years of age.CONCLUSIONOur results were consistent with previous studies indicating an increased rate of childhood cancer among children with anomalies at younger ages. Furthermore, our study added a methodological refinement of assessing the effect of anomalies as a function of attained age. Birth Defects Research (Part A) 106:633-642, 2016. © 2016 Wiley Periodicals, Inc.

背景数据链接研究已经报道了先天性异常和儿童癌症之间的关联。然而，很少有研究关注先天性异常对癌症的影响随年龄的变化。我们的目的是研究在俄克拉何马州出生的儿童中，异常和儿童癌症之间的关系作为达到年龄的函数。方法数据来自1997 - 2009年俄克拉荷马州卫生部(n = 591,235)。我们使用姓名和出生日期将单胎分娩的生命统计记录与俄克拉何马州出生缺陷登记处和俄克拉何马州中央癌症登记处联系起来。为了评估异常与儿童癌症之间的关系，我们使用Cox回归分析，允许异常的非比例风险作为年龄的函数。结果异常患儿23368例(4.0%)，癌变患儿531例(0.1%)。当考虑3年的年龄间隔时，我们发现在1岁之前，与没有异常的儿童相比，有异常的儿童患任何儿童癌症的风险都增加(风险比，14.1;95%可信区间，8.3-23.7)和3岁时(风险比，2.3;95%置信区间，1.6-3.2)。随着出生时间的增加，增加的危险性下降，6岁时影响减弱。结论:我们的研究结果与先前的研究一致，表明在年龄较小的异常儿童中儿童癌症发病率增加。此外，我们的研究增加了评估异常影响作为达到年龄的函数的方法改进。出生缺陷研究(A辑)(06):633-642,2016。©2016 Wiley期刊公司

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引用次数: 21