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1.  Chlorpyrifos Exposure and Urban Residential Environment Characteristics as Determinants of Early Childhood Neurodevelopment 
We evaluated whether neighborhood characteristics correlated with early neurodevelopment and whether these characteristics confounded the previously reported association between exposure to chlorpyrifos (an organophosphate insecticide) and neurodevelopment.
We obtained prenatal addresses, chlorpyrifos exposure data, and 36-month Psychomotor Development Index (PDI) and Mental Development Index (MDI) scores for a birth cohort in New York City (born 1998–2002). We used data from the 2000 US Census to estimate measures of physical infrastructure, socioeconomic status, crowding, demographic composition, and linguistic isolation for 1-kilometer network areas around each child's prenatal address. Generalized estimating equations were adjusted for demographics, maternal education and IQ, prenatal exposure to tobacco smoke, caretaking environment quality, and building dilapidation.
Of 266 children included as participants, 47% were male, 59% were Dominican, and 41% were African American. For each standard deviation higher in neighborhood percent poverty, the PDI score was 2.6 points lower (95% confidence interval [CI]=−3.7, −1.5), and the MDI score was 1.7 points lower (95% CI=−2.6, −0.8). Neighborhood-level confounding of the chlorpyrifos-neurodevelopment association was not apparent.
Neighborhood context and chlorpyrifos exposure were independently associated with neurodevelopment, thus providing distinct opportunities for health promotion.
PMCID: PMC3000714  PMID: 20299657
2.  Randomized controlled trial of Family Nurture Intervention in the NICU: assessments of length of stay, feasibility and safety 
BMC Pediatrics  2013;13:148.
While survival rates for preterm infants have increased, the risk for adverse long-term neurodevelopmental and behavioral outcomes remains very high. In response to the need for novel, evidence-based interventions that prevent such outcomes, we have assessed Family Nurture Intervention (FNI), a novel dual mother-infant intervention implemented while the infant is in the Neonatal Intensive Care Unit (NICU). Here, we report the first trial results, including the primary outcome measure, length of stay in the NICU and, the feasibility and safety of its implementation in a high acuity level IV NICU.
The FNI trial is a single center, parallel-group, randomized controlled trial at Morgan Stanley Children’s Hospital for mothers and their singleton or twin infants of 26–34 weeks gestation. Families were randomized to standard care (SC) or (FNI). FNI was implemented by nurture specialists trained to facilitate affective communication between mother and infant during specified calming interactions. These interactions included scent cloth exchange, sustained touch, vocal soothing and eye contact, wrapped or skin-to-skin holding, plus family-based support interactions.
A total of 826 infants born between 26 and 34 weeks during the 3.5 year study period were admitted to the NICU. After infant and mother screening plus exclusion due to circumstances that prevented the family from participating, 373 infants were eligible for the study. Of these, we were unable to schedule a consent meeting with 56, and consent was withheld by 165. Consent was obtained for 150 infants from 115 families. The infants were block randomized to groups of N = 78, FNI and N = 72, SC. Sixteen (9.6%) of the randomized infants did not complete the study to home discharge, 7% of those randomized to SC and 12% of FNI infants. Mothers in the intervention group engaged in 3 to 4 facilitated one- to two-hour sessions/week. Intent to treat analyses revealed no significant difference between groups in medical complications. The mean length of stay was not significantly affected by the intervention.
There was no significant effect demonstrated with this intervention amount on the primary short-term outcome, length of stay. FNI can be safely and feasibly implemented within a level IV NICU.
Trial registration NCT01439269
PMCID: PMC3851000  PMID: 24063360
Premature infant; NICU; Nurture; Safety; Feasibility; Length of stay
3.  Increased rate of sporadic and recurrent rare genic copy number variants in Parkinson's disease among Ashkenazi Jews 
To date, only one genome-wide study has assessed the contribution of copy number variants (CNVs) to Parkinson's disease (PD). We conducted a genome-wide scan for CNVs in a case–control dataset of Ashkenazi Jewish (AJ) origin (268 PD cases and 178 controls). Using high-confidence CNVs, we examined the global genome wide burden of large (≥100 kb) and rare (≤1% in the dataset) CNVs between cases and controls. A total of 986 such CNVs were observed in our dataset of 432 subjects. Overall global burden analyses did not reveal significant differences between cases and controls in CNV rate, distribution of deletions or duplications or number of genes affected by CNVs. Overall deletions (total CNV size and ≥2× frequency) were found 1.4 times more often in cases than in controls (P = 0.019). The large CNVs (≥500 kb) were also significantly associated with PD (P = 0.046, 1.24-fold higher in cases than in controls). Global burden was elevated for rare CNV regions. Specifically, for OVOS2 on Chr12p11.21, CNVs were observed only in PD cases (n = 7) but not in controls (P = 0.028) and this was experimentally validated. A total of 81 PD cases carried a rare genic CNV that was absent in controls. Ingenuity pathway analysis (IPA) identified ATXN3, FBXW7, CHCHD3, HSF1, KLC1, and MBD3 in the same disease pathway with known PD genes.
PMCID: PMC3782064  PMID: 24073418
Ashkenazi Jews; candidate genes; case–control study; CNV; Parkinson's disease
4.  Academic Achievement Varies With Gestational Age Among Children Born at Term 
Pediatrics  2012;130(2):e257-e264.
The goal of this study was to examine the degree to which children born within the “normal term” range of 37 to 41 weeks’ gestation vary in terms of school achievement.
This study analyzed data from 128 050 singleton births born between 37 and 41 weeks’ gestation in a large US city. Data were extracted from city birth records to assess a number of obstetric, social, and economic variables, at both the individual and community levels. Birth data were then matched with public school records of standardized city-wide third-grade reading and math tests. Specifically, we assessed (1) whether children born within the normal term range of 37 to 41 weeks’ gestation show differences in reading and/or math ability 8 years later as a function of gestational age, and (2) the degree to which a wide range of individual- and community-level social and biological factors mediate this effect.
Analyses revealed that gestational age within the normal term range was significantly and positively related to reading and math scores in third grade, with achievement scores for children born at 37 and 38 weeks significantly lower than those for children born at 39, 40, or 41 weeks. This effect was independent of birth weight, as well as a number of other obstetric, social, and economic factors.
Earlier normal term birth may be a characteristic considered by researchers, clinicians, and parents to help identify children who may be at risk for poorer school performance.
PMCID: PMC3408682  PMID: 22753563
gestational age; developmental outcomes; risk factors; school performance; reading achievement
5.  Relapse Risk after Discontinuation of Risperidone in Alzheimer’s Disease 
The New England journal of medicine  2012;367(16):1497-1507.
Among patients with Alzheimer’s disease who have had a response to antipsychotic medication for psychosis or agitation–aggression, the risk of a recurrence of symptoms after discontinuation of the medication has not been established.
Patients with Alzheimer’s disease and psychosis or agitation–aggression received open-label treatment with risperidone for 16 weeks. Those who had a response to risperidone therapy were then randomly assigned, in a double-blind fashion, to one of three regimens: continued risperidone therapy for 32 weeks (group 1), risperidone therapy for 16 weeks followed by placebo for 16 weeks (group 2), or placebo for 32 weeks (group 3). The primary outcome was the time to relapse of psychosis or agitation.
A total of 180 patients received open-label risperidone (mean dose, 0.97 mg daily). The severity of psychosis and agitation were reduced, although there was a mild increase in extrapyramidal signs; 112 patients met the criteria for response to treatment, of whom 110 underwent randomization. In the first 16 weeks after randomization, the rate of relapse was higher in the group that received placebo than in the groups that received risperidone (60% [24 of 40 patients in group 3] vs. 33% [23 of 70 in groups 1 and 2]; P = 0.004; hazard ratio with placebo, 1.94; 95% confidence interval [CI], 1.09 to 3.45; P = 0.02). During the next 16 weeks, the rate of relapse was higher in the group that was switched from risperidone to placebo than in the group that continued to receive risperidone (48% [13 of 27 patients in group 2] vs. 15% [2 of 13 in group 1]; P = 0.02; hazard ratio, 4.88; 95% CI, 1.08 to 21.98; P = 0.02). The rates of adverse events and death after randomization did not differ significantly among the groups, although comparisons were based on small numbers of patients, especially during the final 16 weeks.
In patients with Alzheimer’s disease who had psychosis or agitation that had responded to risperidone therapy for 4 to 8 months, discontinuation of risperidone was associated with an increased risk of relapse.
PMCID: PMC3490406  PMID: 23075176
7.  Impact of Prenatal Chlorpyrifos Exposure on Neurodevelopment in the First 3 Years of Life Among Inner-City Children 
Pediatrics  2006;118(6):e1845-e1859.
The purpose of this study was to investigate the impact of prenatal exposure to chlorpyrifos on 3-year neurodevelopment and behavior in a sample of inner-city minority children.
As part of an ongoing prospective cohort study in an inner-city minority population, neurotoxicant effects of prenatal exposure to chlorpyrifos were evaluated in 254 children through the first 3 years of life. This report examined cognitive and motor development at 12, 24, and 36 months (measured with the Bayley Scales of Infant Development II) and child behavior at 36 months (measured with the Child Behavior Checklist) as a function of chlorpyrifos levels in umbilical cord plasma.
Highly exposed children (chlorpyrifos levels of >6.17 pg/g plasma) scored, on average, 6.5 points lower on the Bayley Psychomotor Development Index and 3.3 points lower on the Bayley Mental Development Index at 3 years of age compared with those with lower levels of exposure. Children exposed to higher, compared with lower, chlorpyrifos levels were also significantly more likely to experience Psychomotor Development Index and Mental Development Index delays, attention problems, attention-deficit/hyperactivity disorder problems, and pervasive developmental disorder problems at 3 years of age.
The adjusted mean 36-month Psychomotor Development Index and Mental Development Index scores of the highly and lower exposed groups differed by only 7.1 and 3.0 points, respectively, but the proportion of delayed children in the high-exposure group, compared with the low-exposure group, was 5 times greater for the Psychomotor Development Index and 2.4 times greater for the Mental Development Index, increasing the number of children possibly needing early intervention services.
PMCID: PMC3390915  PMID: 17116700
pesticides; chlorpyrifos; neurodevelopment; behavior problems
8.  Use of community-level data in the National Children’s Study to establish the representativeness of segment selection in the Queens Vanguard Site 
The WHO Multiple Exposures Multiple Effects (MEME) framework identifies community contextual variables as central to the study of childhood health. Here we identify multiple domains of neighborhood context, and key variables describing the dimensions of these domains, for use in the National Children’s Study (NCS) site in Queens. We test whether the neighborhoods selected for NCS recruitment, are representative of the whole of Queens County, and whether there is sufficient variability across neighborhoods for meaningful studies of contextual variables.
Nine domains (demographic, socioeconomic, households, birth rated, transit, playground/greenspace, safety and social disorder, land use, and pollution sources) and 53 indicator measures of the domains were identified. Geographic information systems were used to create community-level indicators for US Census tracts containing the 18 study neighborhoods in Queens selected for recruitment, using US Census, New York City Vital Statistics, and other sources of community-level information. Mean and inter-quartile range values for each indicator were compared for Tracts in recruitment and non-recruitment neighborhoods in Queens.
Across the nine domains, except in a very few instances, the NCS segment-containing tracts (N = 43) were not statistically different from those 597 populated tracts in Queens not containing portions of NCS segments; variability in most indicators was comparable in tracts containing and not containing segments.
In a diverse urban setting, the NCS segment selection process succeeded in identifying recruitment areas that are, as a whole, representative of Queens County, for a broad range of community-level variables.
PMCID: PMC3464806  PMID: 22668454
Neighborhood health; Social environment; Built environment; Children; Study design
9.  Neuropsychological profile of parkin mutation carriers with and without Parkinson disease: the CORE-PD study 
The cognitive profile of early onset Parkinson’s disease (EOPD) has not been clearly defined. Mutations in the parkin gene are the most common genetic risk factor for EOPD and may offer information about the neuropsychological pattern of performance in both symptomatic and asymptomatic mutation carriers.
EOPD probands and their first-degree relatives who did not have Parkinson’s disease (PD) were genotyped for mutations in the parkin gene and administered a comprehensive neuropsychological battery. Performance was compared between EOPD probands with (N=43) and without (N=52) parkin mutations. The same neuropsychological battery was administered to 217 first-degree relatives to assess neuropsychological function in individuals who carry parkin mutations but do not have PD.
No significant differences in neuropsychological test performance were found between parkin carrier and non-carrier probands. Performance also did not differ between EOPD non-carriers and carrier subgroups (i.e. heterozygotes, compound heterozygotes/homozygotes). Similarly, no differences were found among unaffected family members across genotypes. Mean neuropsychological test performance was within normal range in all probands and relatives.
Carriers of parkin mutations, whether or not they have PD, do not perform differently on neuropsychological measures as compared to non-carriers. The cognitive functioning of parkin carriers over time warrants further study.
PMCID: PMC3366462  PMID: 21092386
Parkinson’s disease; genetics; neuropsychological assessment; genotype; PARK2; parkin mutation
10.  Family nurture intervention (FNI): methods and treatment protocol of a randomized controlled trial in the NICU 
BMC Pediatrics  2012;12:14.
The stress that results from preterm birth, requisite acute care and prolonged physical separation in the Neonatal Intensive Care Unit (NICU) can have adverse physiological/psychological effects on both the infant and the mother. In particular, the experience compromises the establishment and maintenance of optimal mother-infant relationship, the subsequent development of the infant, and the mother's emotional well-being. These findings highlight the importance of investigating early interventions that are designed to overcome or reduce the effects of these environmental insults and challenges.
This study is a randomized controlled trial (RCT) with blinded assessment comparing Standard Care (SC) with a novel Family Nurture Intervention (FNI). FNI targets preterm infants born 26-34 weeks postmenstrual age (PMA) and their mothers in the NICU. The intervention incorporates elements of mother-infant interventions with known efficacy and organizes them under a new theoretical context referred to collectively as calming activities. This intervention is facilitated by specially trained Nurture Specialists in three ways: 1) In the isolette through calming interactions between mother and infant via odor exchange, firm sustained touch and vocal soothing, and eye contact; 2) Outside the isolette during holding and feeding via the Calming Cycle; and 3) through family sessions designed to engage help and support the mother. In concert with infant neurobehavioral and physiological assessments from birth through 24 months corrected age (CA), maternal assessments are made using standard tools including anxiety, depression, attachment, support systems, temperament as well as physiological stress parameters. Quality of mother-infant interaction is also assessed. Our projected enrolment is 260 families (130 per group).
The FNI is designed to increase biologically important activities and behaviors that enhance maternally-mediated sensory experiences of preterm infants, as well as infant-mediated sensory experiences of the mother. Consequently, we are enlarging the testing of preterm infant neurodevelopment beyond that of previous research to include outcomes related to mother-infant interactions and mother-infant co-regulation. Our primary objective is to determine whether repeated engagement of the mother and her infant in the intervention's calming activities will improve the infant's developmental trajectory with respect to multiple outcomes. Our secondary objective is to assess the effectiveness of FNI in the physiological and psychological co-regulation of the mother and infant. We include aspects of neurodevelopment that have not been comprehensively measured in previous NICU interventions.
Trial Registration NCT01439269
PMCID: PMC3394087  PMID: 22314029
11.  Early Experiences and Predictors of Recruitment Success for the National Children's Study 
Pediatrics  2011;127(2):261-268.
We aimed to describe 17 months of experience with household recruitment of live births for the National Children's Study in Queens, a highly urban, diverse borough of New York City (NYC), and to assess predictors of recruitment success.
Recruitment data (enumeration, pregnancy screening of age-eligible women, identification of pregnancies, and consent) for the period of January 2009 through May 2010 were calculated. Geographic information systems were used to create 11 community-level variables for each of the 18 study segments where recruitment occurred, using US Census, NYC Office of Vital Statistics, NYC Department of City Planning, and NYC Police Department data. Recruitment yields were analyzed with respect to these variables at the segment level.
Enumeration identified 4889 eligible women, of whom 4333 (88.6%) completed the pregnancy screener. At least 115 births were lost because of an inability of the pregnancy screener to identify pregnant women, whereas another 115 could be expected to be lost because of missed enumerations and pregnancy screeners. The consent rate was 60.3%. Segments with higher percentages of low birth weight had higher enumeration, pregnancy screening, and consent rates.
In a highly immigrant, urban setting, households could be approached for recruitment of women to participate in the National Children's Study with consent rates equal to those experienced in clinical settings. Refinement of the pregnancy screener and other recruitment materials presents an opportunity to optimize recruitment, improve the representativeness of study participants, and improve the cost-effectiveness of study execution.
PMCID: PMC3025422  PMID: 21262893
birth cohort; recruitment; longitudinal study; representative sampling
12.  The relationship of plasma Aβ levels to dementia in aging individuals with Down syndrome 
To study the relationship between plasma levels of amyloid β (Aβ) peptides and dementia in aging individuals with Down syndrome, we investigated the relationship among plasma Aβ, apolipoprotein E genotype and cognitive and clinical factors using baseline specimens form participants in an ongoing clinical trial in individuals with Down syndrome 50 years of age and older. Because of substantial skew in the distribution of peptide levels, analyses utilized log transformations of the data. The ratio of Aβ42 to Aβ40 was associated with the presence of dementia (p=0.003, df=196, F=9.37); this association persisted after adjustment for age, sex level of mental retardation and apolipoprotein E genotype. Consistent with recent reports regarding the effect of presenilin mutations on peptide generation, our finding supports the theory that the ratio of Aβ42 to Aβ40 rather than absolute levels of the peptides is important to the pathophysiology of Alzheimer's disease in genetically susceptible populations.
PMCID: PMC2787755  PMID: 19571732
Down syndrome; Aβ; Aβ40/42 ratio; dementia; Alzheimer's disease
13.  Prevalence of Essential Tremor in a Multiethnic, Community-Based Study in Northern Manhattan, New York, N.Y. 
Neuroepidemiology  2009;32(3):208-214.
Our aims were to: (1) estimate the prevalence of essential tremor (ET) in a community-based study in northern Manhattan, New York, N.Y., USA; (2) compare prevalence across ethnic groups, and (3) provide prevalence estimates for the oldest old.
This study did not rely on a screening questionnaire. Rather, as part of an in-person neurological evaluation, each participant produced several handwriting samples, from which ET diagnoses were assigned.
There were 1,965 participants (76.7 ± 6.9 years, range = 66–102 years); 108 had ET [5.5%, 95% confidence interval (CI) = 4.5–6.5%]. Odds of ET were robustly associated with Hispanic ethnicity versus white ethnicity [odds ratio (OR) = 2.19, 95% CI = 1.03–4.64, p = 0.04] and age (OR = 1.14, 95% CI = 1.03–1.26, p = 0.01), i.e. with every 1 year advance in age, the odds of ET increased by 14%. Prevalence reached 21.7% among the oldest old (age ≥95 years).
This study reports a significant ethnic difference in the prevalence of ET. The prevalence of ET was high overall (5.5%) and rose markedly with age so that in the oldest old, more than 1 in 5 individuals had this disease.
PMCID: PMC2744469  PMID: 19169043
Essential tremor; Epidemiology; Prevalence; Ethnicity; Clinical
14.  Prevalence of Essential Tremor in a Multi-Ethnic, Community-Based Study in Northern Manhattan, New York 
Neuroepidemiology  2009;32(3):208-214.
Our aims were to: (1) estimate the prevalence of essential tremor (ET) in a community-based study in northern Manhattan, New York, (2) compare prevalence across ethnic groups, and (3) provide prevalence estimates for the oldest old.
This study did not rely on a screening questionnaire. Rather, as part of an in-person neurological evaluation, each participant produced several handwriting samples, from which ET diagnoses were assigned.
There were 1,965 participants (76.7 ± 6.9 years, range = 66 – 102 years); 108 had ET (5.5%, 95% confidence interval [CI] = 4.5%–6.5%). Odds of ET were robustly associated with Hispanic ethnicity vs. White ethnicity (odds ratio [OR] = 2.19, 95% CI = 1.03–4.64, p = 0.04) and age (OR = 1.14, 95% CI = 1.03–1.26, p = 0.01)(i.e., with every 1 year advance in age, the odds of ET increased by 14%). Prevalence reached 21.7% among the oldest old (age ≥95 years).
This study reports a significant ethnic difference in the prevalence of ET. The prevalence of ET was high overall (5.5%) and rose markedly with age so that in the oldest old, more than one of five individuals had this disease.
PMCID: PMC2744469  PMID: 19169043
essential tremor; epidemiology; prevalence; ethnicity; clinical
15.  Prenatal Insecticide Exposures and Birth Weight and Length among an Urban Minority Cohort 
Environmental Health Perspectives  2004;112(10):1125-1132.
We reported previously that insecticide exposures were widespread among minority women in New York City during pregnancy and that levels of the organophosphate chlorpyrifos in umbilical cord plasma were inversely associated with birth weight and length. Here we expand analyses to include additional insecticides (the organophosphate diazinon and the carbamate propoxur), a larger sample size (n = 314 mother–newborn pairs), and insecticide measurements in maternal personal air during pregnancy as well as in umbilical cord plasma at delivery. Controlling for potential confounders, we found no association between maternal personal air insecticide levels and birth weight, length, or head circumference. For each log unit increase in cord plasma chlorpyrifos levels, birth weight decreased by 42.6 g [95% confidence interval (CI), −81.8 to −3.8, p = 0.03] and birth length decreased by 0.24 cm (95% CI, −0.47 to −0.01, p = 0.04). Combined measures of (ln)cord plasma chlorpyrifos and diazinon (adjusted for relative potency) were also inversely associated with birth weight and length (p < 0.05). Birth weight averaged 186.3 g less (95% CI, −375.2 to −45.5) among newborns with the highest compared with lowest 26% of exposure levels (p = 0.01). Further, the associations between birth weight and length and cord plasma chlorpyrifos and diazinon were highly significant (p ≤ 0.007) among newborns born before the 2000–2001 U.S. Environmental Protection Agency’s regulatory actions to phase out residential use of these insecticides. Among newborns born after January 2001, exposure levels were substantially lower, and no association with fetal growth was apparent (p > 0.8). The propoxur metabolite 2-isopropoxyphenol in cord plasma was inversely associated with birth length, a finding of borderline significance (p = 0.05) after controlling for chlorpyrifos and diazinon. Results indicate that prenatal chlorpyrifos exposures have impaired fetal growth among this minority cohort and that diazinon exposures may have contributed to the effects. Findings support recent regulatory action to phase out residential uses of the insecticides.
PMCID: PMC1247388  PMID: 15238288
birth length; birth weight; insecticides; minority; prenatal; residential; urban; women
16.  Contemporary-use pesticides in personal air samples during pregnancy and blood samples at delivery among urban minority mothers and newborns. 
Environmental Health Perspectives  2003;111(5):749-756.
We have measured 29 pesticides in plasma samples collected at birth between 1998 and 2001 from 230 mother and newborn pairs enrolled in the Columbia Center for Children's Environmental Health prospective cohort study. Our prior research has shown widespread pesticide use during pregnancy among this urban minority cohort from New York City. We also measured eight pesticides in 48-hr personal air samples collected from the mothers during pregnancy. The following seven pesticides were detected in 48-83% of plasma samples (range, 1-270 pg/g): the organophosphates chlorpyrifos and diazinon, the carbamates bendiocarb and 2-isopropoxyphenol (metabolite of propoxur), and the fungicides dicloran, phthalimide (metabolite of folpet and captan), and tetrahydrophthalimide (metabolite of captan and captafol). Maternal and cord plasma levels were similar and, except for phthalimide, were highly correlated (p < 0.001). Chlorpyrifos, diazinon, and propoxur were detected in 100% of personal air samples (range, 0.7-6,010 ng/m(3)). Diazinon and propoxur levels were significantly higher in the personal air of women reporting use of an exterminator, can sprays, and/or pest bombs during pregnancy compared with women reporting no pesticide use or use of lower toxicity methods only. A significant correlation was seen between personal air level of chlorpyrifos, diazinon, and propoxur and levels of these insecticides or their metabolites in plasma samples (maternal and/or cord, p < 0.05). The fungicide ortho-phenylphenol was also detected in 100% of air samples but was not measured in plasma. The remaining 22 pesticides were detected in 0-45% of air or plasma samples. Chlorpyrifos, diazinon, propoxur, and bendiocarb levels in air and/or plasma decreased significantly between 1998 and 2001. Findings indicate that pesticide exposures are frequent but decreasing and that the pesticides are readily transferred to the developing fetus during pregnancy.
PMCID: PMC1241486  PMID: 12727605

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