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1.  Mineral status of non-anemic Peruvian infants taking an iron and copper syrup with or without zinc from 6 to 18 months of age: a randomized controlled trial 
To evaluate changes in iron, zinc and copper status of non-anemic Peruvian infants receiving daily supplements with 10 mg iron, 0.5 mg copper with or without 10 mg zinc from 6 to 18 months of age.
Overall, 251 infants were randomized to one of two daily supplements. Venous blood draws at 6, 12, and 18 months were taken to characterize hemoglobin, plasma ferritin, zinc and copper concentrations. Urinary excretion of zinc was also measured at each time point. Repeated measures ANOVA was used to evaluate changes over time and by supplement type.
Both hemoglobin and copper concentrations increased significantly, while plasma ferritin decreased from 6 to 12 months of age (P < 0.05). Mean plasma zinc concentrations in the zinc treatment group were maintained over time, while that in the control group declined; differences by treatment were found at 12 and 18 months (P < 0.05). Urinary zinc concentration was increased in the zinc group at 12 months only. There was evidence that zinc treatment improved hemoglobin at 18 months of age (P = 0.09). Compliance with supplementation was high, with 81% of the intended dose consumed over the 12-month period.
Daily mineral supplementation over one year appears feasible and acceptable in this population, and a combined supplement can improve iron, zinc and copper status of infants at the same time.
PMCID: PMC3794366  PMID: 24103510
Zinc; iron; copper; supplements; infancy
2.  Scaffolds to Control Inflammation and Facilitate Dental Pulp Regeneration 
Journal of endodontics  2014;40(4 0):S6-12.
In dentistry, the maintenance of a vital dental pulp is of paramount importance, as teeth devitalized by root canal treatment may become more brittle and prone to structural failure over time. Advanced carious lesions can irreversibly damage the dental pulp by propagating a sustained inflammatory response throughout the tissue. While the inflammatory response initially drives tissue repair, sustained inflammation has an enormously destructive effect on the vital pulp, eventually leading to total necrosis of the tissue and necessitating its removal. The implications of tooth devitalization have driven significant interest in the development of bioactive materials that facilitate the regeneration of damaged pulp tissues by harnessing the capacity of the dental pulp for self-repair. In considering the process by which pulpitis drives tissue destruction, it is clear that an important step in supporting the regeneration of pulpal tissues is the attenuation of inflammation. Macrophages, key mediators of the immune response, may play a critical role in the resolution of pulpitis due to their ability to switch to a pro-resolution phenotype. This process can be driven by the resolvins, a family of molecules derived from fatty acids that show great promise as therapeutic agents. In this review, we outline the importance of preserving the capacity of the dental pulp to self-repair through the rapid attenuation of inflammation. Potential treatment modalities, such as shifting macrophages to a pro-resolving phenotype with resolvins are described, and a range of materials known to support the regeneration of dental pulp are presented.
PMCID: PMC4208618  PMID: 24698696
3.  Separable Attentional Predictors of Language Outcome 
The aim of this study was to examine the combined influences of infants attention and use of social cues in the prediction of their language outcomes. This longitudinal study measured infants' visual attention on a distractibility task (11 months), joint attention (14 months), and language outcomes (word –object association, 14 months; MBCDI vocabulary size and multi-word productions at 18 months of age). Path analyses were conducted for two different language outcomes. The analysis for vocabulary revealed unique direct prediction from infants' visual attention on a distractibility task (i.e., maintaining attention to a target event in the presence of competing events) and joint attention (i.e., more frequent response to tester's bids for attention) for larger vocabulary size at outcome; this model accounted for 48% of variance in vocabulary, after controlling for baseline communication status (assessed at 11 months). The analysis for multi-word productions yielded direct effects for infants' distractibility, but not joint attention; this model accounted for 45% of variance in multi-word productions, again after controlling for baseline communication status. Indirect effects were not significant in either model. Results are discussed in light of the unique predictive role of attentional factors and social/attention cues for emerging language.
PMCID: PMC4204017  PMID: 25342932
The current report provides a brief background introducing 30 years of research on LCPUFA and infant development, but focuses mainly on challenges for future studies. Infants fed formulas containing only vegetable fats were found to have lower docosahexaenoic acid (DHA, 22:6n-3) and arachidonic acid (ARA, 20:4n-6) status than infants fed human milk. Studies soon focused on efforts to improve LCPUFA status and evaluate functions suggested by early primate studies of DHA deficiency. Despite evidence for the importance of these fatty acids for development, particularly DHA, several recent meta-analyses conclude dietary supplementation does not enhance development. Future studies should employ 1) more finely grained measures of brain development as opposed to global measures; and 2) tests that evaluate development later in childhood when children are able to be tested on more complex behaviors (if found effective these would also be evidence of early brain programming). 3) Studies are needed to understand the cause of high variability in transfer of DHA to the fetus. Finally 4) the role of single nucleotide polymorphisms (SNPs) of the fatty acid desaturase genes (FADS1/2) of mother and infant needs study to determine how they affect requirements for these fatty acids by the fetus/infant.
PMCID: PMC4188474  PMID: 24107504
5.  Pupil and Salivary Indicators of Autonomic Dysfunction in Autism Spectrum Disorder 
Developmental psychobiology  2012;55(5):10.1002/dev.21051.
Dysregulated tonic pupil size has been reported in Autism Spectrum Disorder (ASD). Among the possible sources of this dysregulation are disruptions in the feedback loop between norepinephrine (NE) and hypothalamic systems. In the current study, we examined afternoon levels of salivary alpha-amylase (sAA, a putative correlate of NE) and cortisol (used to assess stress-based responses) in two independent samples of children with ASD. We found a larger pupil size and lower sAA levels in ASD, compared to typical and clinical age-matched controls. This was substantiated at the individual level, as sAA levels were strongly correlated with tonic pupil size. Relatively little diurnal variation in sAA taken in the home environment in the ASD group was also observed, while typical controls showed a significant linear increase throughout the day. Results are discussed in terms of potential early biomarkers and the elucidation of underlying neural dysfunction in ASD.
PMCID: PMC3832142  PMID: 22644965
Autism Spectrum Disorder; Autonomic Nervous System; Pupil Size; Norepinephrine; Alpha-amylase; Cortisol; Eye-Tracking
6.  Attentional Control in Early and Later Bilingual Children 
Cognitive development  2013;28(3):233-246.
This study examined differences in attentional control among school-age children who were monolingual English speakers, early childhood Spanish-English bilinguals who began speaking both languages by age 3, and later childhood Spanish-English bilingual children who began speaking English after age 3. Children's attentional control was tested using the Attention Network Test (ANT). All language groups performed equally on ANT networks; however, when controlling for age and verbal ability, groups differed significantly on reaction time. Early bilingual children responded faster on the ANT compared to both monolingual and later bilingual children, suggesting an attentional monitoring advantage for early bilinguals. These results add to mounting evidence of advantaged cognitive functioning among bilinguals, and are consistent with the possibility that children who begin speaking a second language earlier in childhood have larger advantages due either to differential effects of acquiring a second language earlier during development or due to longer duration of bilingual experience.
PMCID: PMC4044912  PMID: 24910499
bilingualism; cognitive control; attentional monitoring; age of acquisition; Attention Network Test
7.  Infants’ Integration of Featural and Numerical Information 
Infant behavior & development  2012;35(4):10.1016/j.infbeh.2012.07.003.
The current study examined the integration of non-numerical (featural) and numerical information in 9-, 11-, and 13-month-old infants’ performance on a number discrimination task. Infants were habituated to pictures of objects (e.g., bowl, shoe) either in groups of two or three. In the test phase, infants saw both new and old objects in both groups of two and three. Nine-month-old infants discriminated number independent of the familiarity of the object, 11-month-old infants discriminated between familiar and novel objects (but not the number of objects), and 13-month-old infants discriminated between the familiar and novel objects only in the context of a familiar number of objects. These data suggest that early number representations are dissociated from featural information, and that the integration of these stimulus properties is a developmental process that occurs across the first year.
PMCID: PMC3832132  PMID: 22982269
8.  Your Eyes Say “No,” But Your Heart Says “Yes”: Behavioral and Psychophysiological Indices in Infant Quantitative Processing 
Behavioral indices (e.g., infant looking) are predominantly used in studies of infant cognition, but psychophysiological measures have been increasingly integrated into common infant paradigms. The current study reports a result in which behavioral measures and physiological measures were both incorporated in a task designed to study infant number discrimination. Seven-month-old infants were habituated to several sets of stimuli varying in object type, but of a constant numerical value (either 2 or 3 items). Although looking time to each of the test trials revealed no differences, differences in heart-rate defined measures of attention revealed infants’ ability to discriminate number. These findings imply that the inclusion of indices other than behavioral measures should become commonplace in studies of infant cognition.
PMCID: PMC3839846  PMID: 24285931
9.  Maternal DHA levels and Toddler Free-Play Attention 
Developmental neuropsychology  2009;34(2):159-174.
We investigated the relationship between maternal docosahexaenoic acid (DHA) levels at birth and toddler free-play attention in the second year. Toddler free-play attention was assessed at 12 and 18 months, and maternal erythrocyte (red-blood cell; RBC) phospholipid DHA (percentage of total fatty acids) was measured from mothers at delivery. Overall, higher maternal DHA status at birth was associated with enhanced attentional functioning during the second year. Toddlers whose mothers had high DHA at birth exhibited more total looking and fewer episodes of inattention during free-play than did toddlers whose mothers had low DHA at birth. Analyses also provided further information on changes in attention during toddlerhood. These findings are consistent with evidence suggesting a link between DHA and cognitive development in infancy and early childhood.
PMCID: PMC3752039  PMID: 19267293
10.  Docosahexaenoic acid and cognitive function: Is the link mediated by the autonomic nervous system? 
Docosahexaenoic acid is a long-chain polyunsaturated fatty acid that is found in large quantity in the brain and which has repeatedly been observed to be related in positive ways to both cognitive function and cardiovascular health. The mechanisms through which docosahexaenoic acid affects cognition are not well understood, but in this article, we propose a hypothesis that integrates the positive effects of docosahexaenoic acid in the cognitive and cardiovascular realms through the autonomic nervous system. The autonomic nervous system is known to regulate vital functions such as heart rate and respiration, and has also been linked to basic cognitive components related to arousal and attention. We review the literature from this perspective, and delineate the predictions generated by the hypothesis. In addition, we provide new data showing a link between docosahexaenoic acid and fetal heart rate that is consistent with the hypothesis.
PMCID: PMC3751406  PMID: 18930644
11.  Visual attention and autistic behavior in infants with fragile X syndrome 
Fragile X syndrome (FXS) is the leading known inherited cause of intellectual disability and the most common known biological cause of autism. Approximately 25% to 50% of males with FXS meet full diagnostic criteria for autism. Despite the high comorbidity between FXS and autism and the ability to diagnose FXS prenatally or at birth, no studies have examined indicators of autism in infants with FXS. The current study focused on indices of visual attention, one of the earliest and most robust behavioral indicators of autism in idiopathic (non-FXS) autism. Analyses revealed lower HR variability, shallower HR decelerations, and prolonged look durations in 12-month old infants with FXS that were correlated with severity of autistic behavior but not mental age.
PMCID: PMC3743218  PMID: 21720726
fragile X; autism; early detection; heart rate; visual attention; high-risk infants
12.  Larger Tonic Pupil Size in Young Children With Autism Spectrum Disorder 
Developmental psychobiology  2009;51(2):207-211.
The symptoms of Autism Spectrum Disorder (ASD) have been suggested to manifest from atypical functioning of the autonomic nervous system (ANS), leading to altered arousal and atypical processing of salient stimuli. Coherent with this, persons with ASD show heightened autonomic activity, sleep difficulties, and structural and neurochemical alterations within the ANS. Recently, we observed decreased pupil responses to human faces in children with ASD. In the current study, we found differences in baseline (tonic) pupil size, with the ASD group exhibiting a larger pupil size than age-matched controls. Pupil responses are sensitive and reliable measures of ANS functioning, thus, this finding highlights the role of the ANS, and may provide clues about underlying neuropathology.
PMCID: PMC3744086  PMID: 18988196
autism spectrum disorder; pupillometry; autonomic nervous system; arousal; eye-tracking; early identification
A subset (~3–5%) of patients with cystic fibrosis (CF) develops severe liver disease (CFLD) with portal hypertension.
To assess whether any of 9 polymorphisms in 5 candidate genes (SERPINA1, ACE, GSTP1, MBL2, and TGFB1) are associated with severe liver disease in CF patients.
Design, Setting, and Participants
A 2-stage design was used in this case–control study. CFLD subjects were enrolled from 63 U.S., 32 Canadian, and 18 CF centers outside of North America, with the University of North Carolina at Chapel Hill (UNC) as the coordinating site. In the initial study, we studied 124 CFLD patients (enrolled 1/1999–12/2004) and 843 CF controls (patients without CFLD) by genotyping 9 polymorphisms in 5 genes previously implicated as modifiers of liver disease in CF. In the second stage, the SERPINA1 Z allele and TGFB1 codon 10 genotype were tested in an additional 136 CFLD patients (enrolled 1/2005–2/2007) and 1088 CF controls.
Main Outcome Measures
We compared differences in distribution of genotypes in CF patients with severe liver disease versus CF patients without CFLD.
The initial study showed CFLD to be associated with the SERPINA1 (also known as α1-antiprotease and α1-antitrypsin) Z allele (P value=3.3×10−6; odds ratio (OR) 4.72, 95% confidence interval (CI) 2.31–9.61), and with transforming growth factor β-1 (TGFB1) codon 10 CC genotype (P=2.8×10−3; OR 1.53, CI 1.16–2.03). In the replication study, CFLD was associated with the SERPINA1 Z allele (P=1.4×10−3; OR 3.42, CI 1.54–7.59), but not with TGFB1 codon 10. A combined analysis of the initial and replication studies by logistic regression showed CFLD to be associated with SERPINA1 Z allele (P=1.5×10−8; OR 5.04, CI 2.88–8.83).
The SERPINA1 Z allele is a risk factor for liver disease in CF. Patients who carry the Z allele are at greater odds (OR ~5) to develop severe liver disease with portal hypertension.
PMCID: PMC3711243  PMID: 19738092
14.  Is the Measure the Message: The BSID and Nutritional Interventions 
Pediatrics  2012;129(6):1166-1167.
PMCID: PMC3362912  PMID: 22641756
15.  Long Chain Polyunsaturated Fatty Acid Supplementation in Infancy Reduces Heart Rate and Positively Affects Distribution of Attention 
Pediatric research  2011;70(4):406-410.
A double-blind, randomized, controlled, parallel-group prospective trial was conducted to determine whether a dose-response existed for four different levels of docosahexaenoic acid (DHA) supplementation on the cognitive performance of infants. A total of 122 term infants were fed one of four different formulas varying in their DHA composition (0.00%, 0.32%, 0.64% and 0.96% of total fatty acids as DHA) from birth to 12 months. The three DHA-supplemented formulas also contained 0.64% of total fatty acids as arachidonic acid (ARA, 20:4n-6). Infants were tested at 4, 6, and 9 months of age on a visual habituation protocol that yielded both behavioral and psychophysiological indices of attention. Infants in all DHA+ARA-supplemented conditions had lower heart rates than those in the unsupplemented condition; there was no dose-response for this effect. The distribution of time that infants spent in different phases of attention (a cognitive index derived from the convergence of behavioral and cardiac responses) varied as a function of dosage. Infants supplemented at the two lower DHA doses spent proportionately more time engaged in active stimulus processing than infants fed the unsupplemented formula, while infants fed the highest dose were intermediate and did not differ from any other group.
PMCID: PMC3172991  PMID: 21705959
16.  Now, Pay Attention! The Effects of Instruction on Children's Attention 
We investigated the effects of instructions to “stay on task” on preschoolers' attention and cognitive performance in the face of either incomprehensible or comprehensible distraction. Three- and 4-year-olds completed problem-solving tasks while a distracting event played continuously in the background, under conditions of (a) no instruction, (b) moderate instruction, or (c) frequent instruction to “stay on task.” Under conditions where an incomprehensible distractor was present, any amount of instruction reduced looking to the distracting event. Under conditions where a comprehensible distractor was present, however, frequent instruction was the most effective in increasing looking to the task and decreasing looking to the distracting event.
PMCID: PMC3015160  PMID: 21218123
17.  Habituation Revisited: An Updated and Revised Description of the Behavioral Characteristics of Habituation 
The most commonly cited descriptions of the behavioral characteristics of habituation come from two papers published almost 40 years ago (Thompson and Spencer, 1966; Groves and Thompson, 1970). In August 2007, the authors of this review, who study habituation in a wide range of species and paradigms, met to discuss their work on habituation and to revisit and refine the characteristics of habituation. This review offers a re-evaluation of the characteristics of habituation in light of these discussions. We made substantial changes to only a few of the characteristics, usually to add new information and expand upon the description rather than to substantially alter the original point.
PMCID: PMC2754195  PMID: 18854219
18.  Infant Visual Habituation 
The use of visual habituation in the study of infant cognition and learning is reviewed. This article traces the history of the technique, underlying theory, and procedural variation in its measurement. In addition, we review empirical findings with respect to the cognitive processes that presumably contribute to habituation, studies of developmental course and long-term prediction, as well as recent attempts to address or explain the phenomenon of visual habituation through the use of mathematical or quantitative models. The review ends with an appeal for a return to the study of habituation per se as a valid measure of infant learning, rather than relegating the phenomenon to its use as a technique for familiarizing infants in procedures testing for discrimination or recognition.
PMCID: PMC2758574  PMID: 18620070
19.  Structure and Continuity of Intellectual Development in Early Childhood 
Intelligence  2009;37(1):106-113.
We evaluated over 200 participants semiannually from 12 to 48 months of age on measures of intellectual (Bayley Scales, Stanford-Binet Scale) and verbal (MacArthur-Bates Inventory, Peabody Picture Vocabulary Test) status. Structural equation modeling and hierarchical linear (growth curve) analyses were applied to address the nature of development and individual differences during this time. Structural analyses showed a strong and robust simplex model from infancy to the preschool period, with no evidence of qualitative reorganizations or discontinuities. Growth-curve modeling revealed significant associations between level factors across the early and later measures of cognition, providing further evidence of continuity; the growth trajectory from the Bayley through 24 months predicted growth in a nonverbal factor, but not in a verbal factor. Altogether, the findings reveal continuous and stable development in intellectual function from late infancy through the preschool years. Additionally, the high level of continuity demonstrated across these ages was observed to be largely independent of growth in vocabulary.
PMCID: PMC2631272  PMID: 20046219

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