Clarifying the Ethics and Oversight of Chimeric Research.

This article is the lead piece in a special report that presents the results of a bioethical investigation into chimeric research, which involves the insertion of human cells into nonhuman animals and nonhuman animal embryos, including into their brains. Rapid scientific developments in this field may advance knowledge and could lead to new therapies for humans. They also reveal the conceptual, ethical, and procedural limitations of existing ethics guidance for human-nonhuman chimeric research.

Expanding the neurodevelopmental phenotype of PURA syndrome.

PURA syndrome is a recently described developmental encephalopathy presenting with neonatal hypotonia, feeding difficulties, global developmental delay, severe intellectual disability, and frequent apnea and epilepsy. We describe 18 new individuals with heterozygous sequence variations in PURA. A neuromotor disorder starting with neonatal hyptonia, but ultimately allowing delayed progression to walking, was present in nearly all individuals.

Exposure to Sodium Valproate during Pregnancy: Facial Features and Signs of Autism.

Background: Valproic acid (VPA) is the most teratogenic anticonvulsant drug in clinical use today. Children exposed prenatally to VPA have previously been shown to have dysmorphic craniofacial features, identified subjectively but not by anthropometric methods. Exposure to VPA has also been associated with an increased frequency of autism spectrum disorder (ASD).

exposures to environmental organic pollutants disrupt epigenetic marks linked to fetoplacental development.

While the developing fetus is largely shielded from the external environment through the protective barrier provided by the placenta, it is increasingly appreciated that environmental agents are able to cross and even accumulate in this vital organ for fetal development. To examine the potential influence of environmental pollutants on the placenta, we assessed the relationship between polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs), 1,1-dichloro-2,2-bis(p-chlorophenyl) ethylene (DDE) and several epigenetic marks linked to fetoplacental development. We measured / imprint control region methylation, and expression, loss of imprinting (LOI) and global DNA methylation levels in placenta ( = 116) collected in a formative research project of the National Children's Study to explore the relationship between these epigenetic marks and the selected organic environmental pollutants.

Shear Wave Elastography in the Living, Perfused, Post-Delivery Placenta.

The placenta is the critical interface between the mother and the developing fetus and is essential for survival and growth. Despite the widespread use of ultrasound imaging and Doppler in obstetrics and gynecology and the recent growth of elastographic technologies, little is known about the biomechanical (elastic shear wave) properties of the placenta and the range of normal and pathologic parameters that are present. This study uses a well-developed protocol for perfusing whole placentas, post-delivery, to maintain tissue integrity and function for hours.

Exploring the associations between microRNA expression profiles and environmental pollutants in human placenta from the National Children's Study (NCS).

The placenta is the principal regulator of the in utero environment, and disruptions to this environment can result in adverse offspring health outcomes. To better characterize the impact of in utero perturbations, we assessed the influence of known environmental pollutants on the expression of microRNA (miRNA) in placental samples collected from the National Children's Study (NCS) Vanguard birth cohort. This study analyzed the expression of 654 miRNAs in 110 term placentas.

Identification of novel mechanisms involved in generating localized vulvodynia pain.

Objective: Our goal was to gain a better understanding of the inflammatory pathways affected during localized vulvodynia, a poorly understood, common, and debilitating condition characterized by chronic pain of the vulvar vestibule.

Study Design: In a control matched study, primary human fibroblast strains were generated from biopsies collected from localized provoked vulvodynia (LPV) cases and from age- and race-matched controls. We then examined intracellular mechanisms by which these fibroblasts recognize pathogenic Candida albicans; >70% of vulvodynia patients report the occurrence of prior chronic Candida infections, which is accompanied by localized inflammation and elevated production of proinflammatory/pain-associated interleukin (IL)-6 and prostaglandin E2 (PGE2).

Site-specific mesenchymal control of inflammatory pain to yeast challenge in vulvodynia-afflicted and pain-free women.

Fibroblast strains were derived from 2 regions of the lower genital tract of localized provoked vulvodynia (LPV) cases and pain-free controls. Sixteen strains were derived from 4 cases and 4 controls, age and race matched, after presampling mechanical pain threshold assessments. Strains were challenged with 6 separate stimuli: live yeast species (Candida albicans, Candida glabrata, Candida tropicalis, and Saccharomyces cerevisiae), yeast extract (zymosan), or inactive vehicle.

Placental oxidative stress and decreased global DNA methylation are corrected by copper in the Cohen diabetic rat.

Fetal Growth Restriction (FGR) is a leading cause for long term morbidity. The Cohen diabetic sensitive rats (CDs), originating from Wistar, develop overt diabetes when fed high sucrose low copper diet (HSD) while the original outbred Sabra strain do not. HSD induced FGR and fetal oxidative stress, more prominent in the CDs, that was alleviated more effectively by copper than by the anti-oxidant vitamins C and E.

Selected persistent organic pollutants in human placental tissue from the United States.

Emerging and legacy environmental pollutants such as polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and organochlorine pesticide metabolite DDE are found in human placenta, indicating prenatal exposure, but data from the United States are sparse. We sought to determine concentrations of these compounds in human placentae as part of a formative research project conducted by the National Children's Study Placenta Consortium. A total of 169 tissue specimens were collected at different time points post delivery from 43 human placentae at three U.

The teratology society 2012-2017 strategic plan: pushing the boundaries.

The Teratology Society held its fourth strategic planning session in Albuquerque, NM, April 10-12, 2012, and launched the 2012-2017 Strategic Plan in conjunction with the 2012 annual meeting in Baltimore, MD. Building on the energy of the successful implementation of prior strategic plans (San Diego, 2007; Nashville,TN 2002; Cincinnati, OH 1998), session participants worked to identify barriers to success as a scientific society, as well as impending challenges and opportunities to which the Society needs to respond. The following report provides an overview of the Strategic Planning process, objectives, activities, and conclusions.

The effect of copper deficiency on fetal growth and liver anti-oxidant capacity in the Cohen diabetic rat model.

High sucrose low copper diet induces fetal growth restriction in the three strains of the Cohen diabetic rats: an inbred copper deficient resistant (CDr), an inbred copper deficient sensitive (CDs that become diabetic on high sucrose low copper diet -HSD) and an outbred Wistar derived Sabra rats. Although those growth restricted fetuses also exhibit increased oxidative stress, antioxidants do not restore normal growth. In the present study, we evaluated the role of copper deficiency in the HSD induced fetal growth restriction by adding to the drinking water of the rats 1 ppm or 2 ppm of copper throughout their pregnancy.

Valproic acid decreases urothelial cancer cell proliferation and induces thrombospondin-1 expression.

Background: Prevention of bladder cancer recurrence is a central challenge in the management of this highly prevalent disease. The histone deacetylase inhibitor valproic acid (sodium valproate) has anti-angiogenic properties and has been shown to decrease bladder cancer growth in model systems. We have previously shown reduced expression of thrombospondin-1 in a mouse model and in human bladder cancer relative to normal urothelium.

Hyperglycemia, hypoxia and their combination exert oxidative stress and changes in antioxidant gene expression: studies on cultured rat embryos.

Introduction: Hyperglycemia and hypoxia are well-known teratogens that may affect many animal species, including man. We hypothesize that a combination of hypoxia and hyperglycemia will increase embryonic damage produced by either factor individually. We investigated the interrelationship between hyperglycemia and hypoxia and their effects on genes involved in the balance of embryonic redox status.

The tampon test for vulvodynia treatment outcomes research: reliability, construct validity, and responsiveness.

Objective: A standardized tampon insertion and removal test, the Tampon Test provides an alternative to sexual intercourse pain as an outcome measure for vulvodynia research. We report upon the reliability, validity, and responsiveness to change of the Tampon Test as an outcome measure for vulvodynia clinical trials.

Methods: Outcome measures were assessed in women enrolled in the Vulvar Vestibulitis Clinical Trial, a randomized clinical trial of oral desipramine and topical lidocaine effectiveness.

Heterogeneous association between engrailed-2 and autism in the CPEA network.

Autism is a neurodevelopmental disorder characterized by an early onset of abnormal social, communicative, and repetitive behavior. Engrailed-2 (EN2) was identified as an autism candidate gene because its influence on cerebellar development in mice parallels neurodevelopmental abnormalities seen in individuals with autism. Studies investigating association between markers at EN2 (chr7q36), a location associated with language disorders, and autism reveal mixed findings.

Mapping autism risk loci using genetic linkage and chromosomal rearrangements.

Autism spectrum disorders (ASDs) are common, heritable neurodevelopmental conditions. The genetic architecture of ASDs is complex, requiring large samples to overcome heterogeneity. Here we broaden coverage and sample size relative to other studies of ASDs by using Affymetrix 10K SNP arrays and 1,181 [corrected] families with at least two affected individuals, performing the largest linkage scan to date while also analyzing copy number variation in these families.

Head circumference and height in autism: a study by the Collaborative Program of Excellence in Autism.

Data from 10 sites of the NICHD/NIDCD Collaborative Programs of Excellence in Autism were combined to study the distribution of head circumference and relationship to demographic and clinical variables. Three hundred thirty-eight probands with autism-spectrum disorder (ASD) including 208 probands with autism were studied along with 147 parents, 149 siblings, and typically developing controls. ASDs were diagnosed, and head circumference and clinical variables measured in a standardized manner across all sites.

Induction of the homeotic gene Hoxa1 through valproic acid's teratogenic mechanism of action.

Background: Valproic acid (VPA) exposure in utero has been associated with an increased risk of both neural tube defects and autism spectrum disorders (ASDs). The terata induced by VPA suggest interference with pattern formation. Retinoic acid produces similar terata and is known to act in part by increasing the expression of Hoxa1.

Evidence for multiple loci from a genome scan of autism kindreds.

We performed a genome-wide linkage scan using highly polymorphic microsatellite markers. To minimize genetic heterogeneity, we focused on sibpairs meeting the strict diagnosis of autism. In our primary analyses, we observed a strong linkage signal (P=0.

Autism and the serotonin transporter: the long and short of it.

Autism is a neurodevelopmental disorder manifesting early in childhood. Some symptoms of autism are alleviated by treatment with selective serotonin reuptake inhibitors, which are known to interact with the serotonin transporter. Moreover, variation in the gene that encodes the transporter (SLC6A4), especially the HTTLPR locus, is known to modulate its expression.

The teratology of autism.

Autism spectrum disorders affect behaviors that emerge at ages when typically developing children become increasingly social and communicative, but many lines of evidence suggest that the underlying alterations in the brain occur long before the period when symptoms become obvious. Studies of the behavior of children in the first year of life demonstrate that symptoms are often detectable in the first 6 months. The environmental factors known to increase the risk of autism have critical periods of action during embryogenesis.

Impact of genetic variation in interleukin-1 receptor antagonist and melanocortin-1 receptor genes on vulvar vestibulitis syndrome.

Objective: To investigate the risk of vulvar vestibulitis syndrome (VVS) in the presence of specific genetic variants (polymorphisms) that affect chronic inflammation, pain and skin color.

Study Design: For a retrospective, case-control study performed at a university-based ambulatory gynecologic service, 36 consecutive VVS cases and 69 consecutive pain-free controls were selected. Polymerase chain reaction products containing genetic variants of 2 genes, the interleukin-1 receptor antagonist (IL1RN) and melanocortin-1 receptor (MC1R), were analyzed by 2 independent techniques, gel electrophoresis and direct sequencing.

Alleles of a reelin CGG repeat do not convey liability to autism in a sample from the CPEA network.

A recent study by Persico et al. [2001: Mol Psychiatry 6:150-159] suggests alleles of a CGG polymorphism, just 5' of the reelin gene (RELN) initiator codon, confer liability for autism, especially alleles bearing 11 or more CGG repeats (long alleles). The association is consistent across both a case-control and family-based sample.