Tammy Z. Movsas

Autism Spectrum Disorder is associated with ventricular enlargement in a Low Birth Weight Population

OBJECTIVE To determine the relation of neonatal cranial ultrasound abnormalities to autism spectrum disorders (ASD) in low birth weight (LBW) adult survivors, a population at increased ASD risk. STUDY DESIGN This is a secondary analysis of a prospectively-followed regional birth cohort of 1105 LBW infants systematically screened for perinatal brain injury with cranial ultrasound in the first week of life and later assessed for ASD using a two-stage process [screening at age 16 years (n = 623) followed by diagnostic assessment at age 21 years of a systematically selected subgroup of those screened (n = 189)]; 14 cases of ASD were identified. For this analysis, cranial ultrasound abnormalities were defined as ventricular enlargement (indicative of diffuse white matter injury), parenchymal lesions (indicative of focal white matter injury), and isolated germinal matrix/intraventricular hemorrhage. RESULTS Compared with no cranial ultrasound abnormalities, any type of white matter injury (ventricular enlargement and/or parenchymal lesion) tripled the risk for screening positively for ASD [3.0 (2.2, 4.1)]. However, the risk of being diagnosed with ASD depended on type of white matter injury. With ventricular enlargement, the risk of ASD diagnosis was almost seven-fold that of no cranial ultrasound abnormality [6.7 (2.3, 19.7)], and no elevated risk was found for parenchymal lesion without ventricular enlargement [1.8 (0.2, 13.6)]. Isolated germinal matrix/intraventricular hemorrhage did not increase risk for a positive ASD screen or diagnosis. CONCLUSION In LBW neonates, cranial ultrasound evidence of ventricular enlargement is a strong and significant risk factor for subsequent development of rigorously-diagnosed ASD.

Effect of Routine Vaccination on Aluminum and Essential Element Levels in Preterm Infants

ber that determines testis size and sperm production in adults. Sertoli cells develop during fetal and neonatal life and also at puberty when their number is definitively set. Our study suggests that breastfeeding is important for neonatal testes development because the inhibin B increase associated with breastfeeding was of the same magnitude as the proportion of Sertoli cells formed during the first year of life.5

Vitreous Levels of Luteinizing Hormone and VEGF are Strongly Correlated in Healthy Mammalian Eyes

ABSTRACT Purpose/Aim: Luteinizing hormone (LH) is known to function as a key regulator of vascular endothelial growth factor (VEGF) expression in reproductive organs. In recent years, LH has also been detected in human vitreous and LH receptors have been identified in human retina. This study was aimed to investigate a potential correlation between LH and VEGF levels in healthy mammalian eyes to provide supporting evidence of LH’s potential involvement in intraocular VEGF regulation. Methods: 18 bovine and 30 porcine eyes were procured from an abattoir and VEGF and LH levels were measured in the vitreous extracted from these eyes by commercially available bovine & porcine ELISA assay kits. Total protein of the vitreous was measured by using Micro BSA protein assay kit. Results: After total protein normalization, the Pearson Correlation Coefficients (PCC) showed a strong and significant correlation between LH and VEGF levels. (Bovine LH/VEGF PCC: 0.89, p < 0.001; Porcine LH/VEGF PCC: 0.80, p < 0.001). Linear regression analyses, adjusted for gender, showed significant linear relationships between LH and VEGF levels in both bovine and porcine vitreous. (Bovine: t-value = 7.69, p < 0.0001, adjusted r2 = .79; Porcine: t-value = 6.71, p < 0.001, adjusted r2 = .62) Conclusions: We show that VEGF and LH are strongly correlated in healthy, adult mammalian eyes. The robustness of the correlation is shown both by its strength of association and reproducibility in two species. Given that LH is well known to regulate VEGF levels in several tissue types, the LH/VEGF linear relationship in vitreous potentially implicates LH in homeostatic VEGF regulation of the eye. Because we also found that the correlation between LH and VEGF only became manifest when our targeted analytes were normalized by total amount of protein, preclinical and clinical investigators should consider normalizing analytes in vitreous by total protein when assessing potential correlations among them.

Association Between Transient Hypothyroxinaemia of Prematurity and Adult Autism Spectrum Disorder in a Low-Birthweight Cohort: An Exploratory Study

BACKGROUND Transient hypothyroxinaemia of prematurity (THOP) is associated with increased risk of cerebral palsy and lower IQ in low-birthweight infants. This study explores whether THOP is also associated with increased risk of autism spectrum disorders (ASD). METHODS This secondary analysis uses data from a birth cohort of newborns weighing 500 -2000 g (n = 1105) who were followed to age 21 years, when they were assessed for ASD in the second of a two-stage process. Of the 187 assessed at age 21, 14 had ASD. Neonatal thyroxine results were available for 12/14 and 165/173 participants diagnosed with and without ASD, respectively. THOP was defined as thyroxine z-score <-2.6. Unadjusted relative risks (RR) and confidence intervals (CI) were calculated. RESULTS The mean neonatal thyroxine z-score in young adults diagnosed with ASD was 0.5 SD lower [95% CI -0.16, 1.06] than in those without ASD. Participants with THOP were at 2.5-fold greater risk of ASD (RR 2.5 [95% CI 0.7, 8.4]). While neither of these differences was statistically significant, in a secondary subgroup analysis of those whose mothers did not have hypertension during pregnancy, THOP significantly increased the RR for ASD (5.0 [95% CI 1.2, 20.5]). CONCLUSION While the primary relation between THOP and ASD found here is not statistically significant, the magnitude of association and significant relationship observed in the subgroup whose mothers did not have hypertension during pregnancy suggest that it is worthy of further investigation.

Confirmation of Luteinizing Hormone (LH) in Living Human Vitreous and the Effect of LH Receptor Reduction on Murine Electroretinogram

Luteinizing hormone (LH), produced in the anterior pituitary, has been detected in cadaver eyes and LH receptors (LHRs) have been identified in the retina, with the highest density in cone photoreceptors. Our aim was to confirm the presence of LH in the living, human eye as well as to examine the potential impact of a reduction in LHR signaling on visual processing. Vitreous samples were collected from 40 patients (23 diabetics, 17 non-diabetics) who were undergoing vitrectomies for various indications. LH concentration was quantified in each sample via an electro-chemiluminescence immunoassay and Meso Scale Discovery platform and normalized to total protein. In addition, full-field electroretinography (ERG) was performed on 11 adult LHR knockout heterozygous mice (B6;129X1-Lhcgrtm1Zmlei/J) and 11 wild types using the Celeris-Diagnosys system. The median LH values (pg/mg total protein) for non-diabetics, diabetics without proliferative diabetic retinopathy (PDR) and diabetics with PDR were 40.7, 41.9 and 167.8 respectively. LH levels were significantly higher in diabetics with PDR. In our ERG investigation, heterozygous LHRKOs were found to have significantly reduced amplitudes of a-wave and b-waves at high stimulus intensities with no significant change in a-wave or b-wave amplitudes at lower intensities; this is consistent with a selective impairment of cone-mediated responses. Our findings confirm LH is present in the adult human eye. Our findings also suggest that a reduction in LH receptor signaling negatively impacts visual processing of the cone photoreceptors. Overall, our study results support the theory that LH likely plays a physiologic role in the eye.

Pretreatment with Human Chorionic Gonadotropin Protects the Neonatal Brain against the Effects of Hypoxic-Ischemic Injury

Introduction Though the human fetus is exposed to placentally derived human chorionic gonadotropin (hCG) throughout gestation, the role of hCG on the fetal brain is unknown. Review of the available literature appears to indicate that groups of women with higher mean levels of hCG during pregnancy tend to have offspring with lower cerebral palsy (CP) risk. Given that newborn cerebral injury often precedes the development of CP, we aimed to determine whether hCG may protect against the neurodegenerative effects of neonatal brain injury. Methods We utilized the Rice–Vannucci model of neonatal cerebral hypoxia-ischemia (HI) in postnatal day 7 mice to examine whether intraperitoneal administration of hCG 15–18 h prior, 1 h after or immediately following HI decrease brain tissue loss 7 days after injury. We next studied whether hCG has pro-survival and trophic properties in neurons by exposing immature cortical and hippocampal neurons to hCG in vitro and examining neurite sprouting and neuronal survival prior and after glutamate receptor-mediated excitotoxic injury. Results We found that intraperitoneal injection of hCG 15 h prior to HI, but not at or 1 h after HI induction, resulted in a significant decrease in hippocampal and striatal tissue loss 7 days following brain injury. Furthermore, hCG reduced N-methyl-d-aspartate (NMDA)-mediated neuronal excitotoxicity in vitro when neurons were continuously exposed to this hormone for 10 days or when given at the time and following neuronal injury. In addition, continuous in vitro administration of hCG for 6–9 days increased neurite sprouting and basal neuronal survival as assessed by at least a 1-fold increase in MAP2 immunoreactivity and a 2.5-fold increase in NeuN + immunoreactivity. Conclusion Our findings suggest that hCG can decrease HI-associated immature neural degeneration. The mechanism of action for this neuroprotective effect may partly involve inhibition of NMDA-dependent excitotoxic injury. This study supports the hypothesis that hCG during pregnancy has the potential for protecting the developing brain against HI, an important CP risk factor.

Ventriculomegaly in very‐low‐birthweight infants with Down syndrome

The prevalence of Down syndrome in infants with fetal ventriculomegaly is 5% to 10%; however, the converse, the prevalence of cerebral ventriculomegaly in live‐born infants with Down syndrome, is not well established. Because cranial ultrasounds are performed on most very‐low‐birthweight (VLBW) infants (birthweight <1500g), our aim was to examine ultrasound abnormalities of VLBW infants to determine prevalence of ventriculomegaly and intraventricular hemorrhage (IVH) in VLBW infants with Down syndrome, and whether VLBW infants with Down syndrome are at higher risk for cranial ultrasound abnormalities, compared with the already elevated risk in other VLBW infants.

Trisomy 21 and Risk of Retinopathy of Prematurity

BACKGROUND AND OBJECTIVES: Trisomy 21 is known to decrease the risk of several (nonocular) angiogenic-mediated diseases. The objective of this study was to determine whether trisomy 21 can also be shown to be significantly protective against ocular angiogenic-mediated disorders such as retinopathy of prematurity (ROP). METHODS: A retrospective analysis of deidentified data from the Pediatrix BabySteps Clinical Warehouse. This large repository of neonatal data is approved for use in research studies by the Western Institutional Review Board. The study population consisted of 99 080 infants with very low birth weights (BWs; BW <1500 g), born between 1996 and 2013, cared for at >300 US NICUs, and who had been discharged alive from hospital. Statistical significance for unadjusted comparisons between groups was determined with Pearson’s χ2 test or Student’s t test. Logistic regression models were used to calculate the odds of ROP (of any stage) and advanced ROP (stage 3 or greater) for infants with trisomy 21 compared with all other infants. RESULTS: The prevalence of trisomy 21 was 0.3% in the study population (321 of 99 080). After adjustment for BW, gestational age, oxygen exposure, and other potential confounders, there was an odds ratio of 0.6 (95% confidence interval: 0.5–0.8) for ROP in infants with trisomy 21compared with other infants and an odds ratio of 0.4 (95% confidence interval: 0.1–0.9) for advanced-stage ROP. CONCLUSIONS: Trisomy 21 significantly decreases the odds for ROP in very low BW infant survivors. This study unmasks a potentially identifiable genetic component to ROP risk, paving the way for the development of a laboratory-based ROP screening tool.

Elimination of Signaling by the Luteinizing Hormone Receptor Reduces Ocular VEGF and Retinal Vascularization during Mouse Eye Development

ABSTRACT Purpose/Aim: Vascular endothelial growth factor (VEGF) dysregulation is implicated in the pathogenesis of retinopathy of prematurity (ROP). Identifying the factors that contribute to VEGF regulation during normal retinal vascularization is the key to ROP prevention. Currently, physiologic hypoxia is thought to be responsible for retinal VEGF regulation in utero. However, a potential hormonal contribution to VEGF regulation during eye development has not been fully investigated. The placental hormone, human chorionic gonadotropin and the pituitary hormone, and luteinizing hormone (LH) induce VEGF expression in several tissue types. Both of these gonadotropins activate the same LH receptor (LHR) in the human body; LHRs are expressed in the retina. In this study, we aimed to show that LHR signaling participates in VEGF regulation in the developing eye. Methods: When offspring from breeding pairs of LHR knockout mice (lhrkos) reached 21 days old, eyes and serum were extracted from homozygote lhrkos and wildtype (WT) siblings. VEGF levels were measured using Mouse VEGF Quantikine immunoassay kit. Retinas were incubated with isolectin for endothelial cell staining, flat mounted and imaged by confocal microscopy. Retinal vascular density was quantified using Imaris software. Some eyes were sectioned and stained for histopathologic review. Results: Ocular VEGF and retinal vascular volumes were significantly reduced by ~ 15% in lhrko eyes. Serum VEGF was not changed. The lhrko retinas did not display any anomalies. Conclusions: We provide evidence that LHR signaling plays a role in VEGF regulation and vascularization in the developing eye. Given that human preterm infants may have altered LHR-activity, the effect of gonadotropins on eye development should be further studied to identify novel strategies for ROP prevention.