Stress Across Generations: DNA Methylation as a Potential Mechanism Underlying Intergenerational Effects of Stress in Both Post-traumatic Stress Disorder and Pre-clinical Predator Stress Rodent Models.

Although most humans will experience some type of traumatic event in their lifetime only a small set of individuals will go on to develop post-traumatic stress disorder (PTSD). Differences in sex, age, trauma type, and comorbidity, along with many other elements, contribute to the heterogenous manifestation of this disorder. Nonetheless, aberrant hypothalamus-pituitary-adrenal (HPA) axis activity, especially in terms of cortisol and glucocorticoid receptor (GR) alterations, has been postulated as a tenable factor in the etiology and pathophysiology of PTSD. Moreover, emerging data suggests that the harmful effects of traumatic stress to the HPA axis in PTSD can also propagate into future generations, making offspring more prone to psychopathologies. Predator stress models provide an ethical and ethologically relevant way to investigate tentative mechanisms that are thought to underlie this phenomenon. In this review article, we discuss findings from human and laboratory predator stress studies that suggest changes to DNA methylation germane to GRs may underlie the generational effects of trauma transmission. Understanding mechanisms that promote stress-induced psychopathology will represent a major advance in the field and may lead to novel treatments for such devastating, and often treatment-resistant trauma and stress-disorders.

Normative pediatric data for three tests of functional vision.

OBJECTIVE: To provide the normative pediatric data for three tests of functional vision. DESIGN: Prospective, cross-sectional study. PARTICIPANTS: The participants were 281 children between 3 and 5 years of age (mean 4.2 ± 0.8 years) participating in a preschool vision screening study. METHODS: Participants completed monocular testing with the Precision Vision Visual Acuity Testing (PVVAT) system, a computerized test of visual acuity. Stereoacuity was assessed using the Pass Test 3 Stereo Test. Noncycloplegic refractive error was measured using the Plusoptix S09 Vision Screener (PS09). The mean and 95% tolerance limits were determined for each test. RESULTS: Visual acuity improved significantly from 0.31 logMAR at 3 years to 0.18 logMAR at 5 years (p < 2.4 × 10-15). Stereoacuity improved from 104 arcsec at 3 years to 81 arcsec at 5 years (p = 0.0058). Spherical refractive error remained relatively stable at 0.29 D at 3 years and 0.24 D at 5 years (p = 0.543). Cylindrical refractive error was also relatively stable, measuring 0.39 D at 3 years and 0.31 D at 5 years (p = 0.109). CONCLUSIONS: Both visual acuity and stereoacuity improved significantly from 3 to 5 years of age. Note, however, that the norms obtained using the PVVAT system were somewhat lower than those reported in previous studies using other tests. The norms for the PS09 were stable and showed relatively good agreement with the manufacturer-suggested referral criteria.

Comparison of Patti Pics and Lea Symbols optotypes in children and adults.

PURPOSE: Although a great variety of pediatric tests of visual acuity exist, few have been compared directly within the same patients or have been evaluated directly against an adult gold standard. METHODS: Right eyes from 80 3- to 5-year-old preschoolers were tested at 3 m with the two current pediatric optotype tests-the Patti Pics and the Lea Symbols (Mass VAT versions)-that best adhere to the international standard for early eye and vision screening. For comparison, right eyes from 52 adults were tested under the same conditions with both pediatric tests and with a gold standard Mass VAT Sloan letter test. RESULTS: Compared with the Patti Pics, both children and adults showed relatively better and finer levels of visual acuity with Lea Symbols (0.07-0.11 logMAR better). Compared with Sloan letters, adults' acuity was also 0.09 logMAR better with the Lea Symbols but was virtually identical and also showed good statistical agreement with Patti Pics acuity. CONCLUSIONS: Although both pediatric tests show excellent testability, our data suggest that acuity values obtained with the Patti Pics optotypes are more consistent with those obtained with a gold standard visual acuity test used for older children and adults.

A randomized trial of DHA intake during infancy: school readiness and receptive vocabulary at 2-3.5 years of age.

BACKGROUND: Studies investigating the effects of docosahexaenoic acid (DHA) in infant formula on language development yield conflicting results. No study to date has investigated the effects of DHA in infant formula on school readiness. AIM: To determine the effects of different dietary concentrations of DHA provided during the first 12 months of life on language development and school readiness. DESIGN: This was a double-masked, randomized, controlled, prospective trial. A total of 182 infants were enrolled at 1-9 days of age and assigned randomly to receive infant formula with one of four levels of DHA: control (0% DHA), 0.32% DHA, 0.64% DHA, or 0.96% DHA. All formulas with DHA also contained 0.64% arachidonic acid. One hundred forty-one children completed the 12-month feeding trial and were eligible for this study. Consent was obtained from 131 participants. School readiness was assessed at 2.5 years using the Bracken Basic Concept Scale-Revised (BBCS-R) and receptive vocabulary was assessed at 2 and 3.5 years using the Peabody Picture Vocabulary Test-Third Edition (PPVT-III). RESULTS: There were no diet group differences on any of the BBCS-R subscales. On the PPVT-III, the control group had higher raw scores and standard scores than both the 0.32% and 0.96% groups at 2 years of age. These differences were not evident at 3.5 years. CONCLUSIONS: Dietary DHA during the first year of life did not enhance school readiness or language development. Children who consumed infant formula with 0.32% and 0.96% DHA showed lower receptive vocabulary scores than controls at 2 but not 3.5 years of age.

Cognitive function in 18-month-old term infants of the DIAMOND study: a randomized, controlled clinical trial with multiple dietary levels of docosahexaenoic acid.

BACKGROUND: Studies investigating cognitive outcomes following docosahexaenoic acid (DHA) supplementation of infant formula yield conflicting results, perhaps due to inadequate dietary concentrations. AIM: To determine the optimal DHA concentration in term formula to support cognitive maturation. DESIGN: This was a double-masked, randomized, controlled, prospective trial. A total of 181 infants were enrolled at 1-9 days of age and assigned randomly to receive one of four term infant formulas with one of four levels of docosahexaenoic acid: Control (0% DHA), 0.32% DHA, 0.64% DHA, or 0.96% DHA. All DHA-supplemented formulas contained 0.64% arachidonic acid (ARA). Infants were fed the assigned formulas until 12 months of age. One hundred forty-one children completed the 12-month feeding trial and were eligible for this study. Cognitive function was assessed in 131 children at 18 months of age using the Bayley Scales of Infant Development II (BSID II). RESULTS: There were no diet group differences on the Mental Development Index (MDI), the Psychomotor Development Index (PDI), or the Behavior Rating Scale (BRS) of the BSID II. However, when the scores of children who received any of the three DHA-supplemented formulas were combined and compared to control children, a significant difference emerged: the MDI scores of DHA-supplemented children were higher (104.1 v. 98.4; p=0.02). CONCLUSIONS: These results suggest that dietary supplementation of DHA during the first year of life leads to enhanced cognitive development at 18 months of age. DHA concentration of 0.32% is adequate to improve cognitive function; higher concentrations did not confer additional benefit.

Vernier acuity cards: examination of development and screening validity.

PURPOSE: Because vernier acuity seems to be limited by the visual cortex, it possesses excellent potential as a clinical/screening tool to detect amblyopia in infants and toddlers. Thus, we developed the vernier acuity cards specifically for this age group. We compared developmental data gathered using this new test and the Teller Acuity Cards. In addition, we compared the clinical/screening validity of the two tests by testing children old enough to complete optotype acuity testing (6.2 ± 2.5 years). METHODS: Vernier acuity and grating acuity were assessed in 98 children and 18 adults with normal vision (age range = 2.8 months to 35.8 years). The developmental time course of the two visual functions was compared. In addition, vernier acuity and grating acuity were measured in 43 children with amblyopia and 30 nonamblyopic children with an amblyogenic condition. Each child's grating acuity and vernier acuity were classified as normal/abnormal based on age-appropriate norms. These classifications were compared with amblyopia diagnoses by crowded HOTV or Early Treatment Diabetic Retinopathy Study (ETDRS) testing. RESULTS: Vernier acuity and grating acuity follow different developmental time courses in normal infants and children. Vernier acuity is initially poorer than grating acuity but surpasses it by the age 5 years and is adult-like by the age 8 years. Compared with the Teller Acuity Cards, the vernier acuity cards yielded higher sensitivity (81 vs. 44%) and similar specificity (73 vs. 93%) and were more sensitive to all amblyopia subtypes/levels of severity. CONCLUSIONS: The developmental time course of vernier acuity differed from that of grating acuity, implying that it is not mediated by the retina. Also, the impressive validity of the vernier acuity cards suggests that they are an effective tool for detecting amblyopia.

Final version of the Distance Randot Stereotest: normative data, reliability, and validity.

PURPOSE: Measurement of distance stereoacuity may be useful in assessing strabismic patients, especially those with intermittent exotropia. We developed the Distance Randot Stereotest as an easily administered quantitative test for distance stereoacuity in children. By using a prototype, we reported testability, validity, and normative data. Here we report normative and validity data for the final, commercially available version of the test. METHOD: We administered both the Prototype and the Final Version Distance Randot Stereotest to 156 normal volunteers (2-40 years of age) and 77 strabismic patients (4-62 years of age). Test-retest data were collected for the Final Version. RESULTS: Normative Final Version scores were similar to those obtained with the Prototype; 96% were < or = 100 arcsec. Test-retests were identical in 82% and within one disparity level in 100%. Final Version scores were correlated with Prototype scores (rs = 0.64, p < 0.001). Among strabismic patients, 62.3% had abnormal stereoacuity; those with normal scores had incomitant or intermittent deviations. Nil stereoacuity was found in 27 patients, confirmed in 90.9% of retests; 17 had measurable stereoacuity, confirmed in 96.3% of retests. Patients with constant strabismus were more likely to have nil stereoacuity than patients who had intermittent strabismus (95% vs 12.2%). CONCLUSIONS: Distance Randot scores from normal subjects have low variability within each age group and high test-retest reliability. There is little overlap between Distance Randot scores from normal control and strabismic patients. The Distance Randot Stereotest is a sensitive measurement of binocular sensory status that may be useful in monitoring progression of strabismus and/or recovery after strabismus surgery.

The DIAMOND (DHA Intake And Measurement Of Neural Development) Study: a double-masked, randomized controlled clinical trial of the maturation of infant visual acuity as a function of the dietary level of docosahexaenoic acid.

BACKGROUND: The range of human milk docosahexaenoic acid (DHA) concentrations worldwide is much broader than the range explored in randomized clinical trials to date. OBJECTIVE: The primary objective was to determine the effect of 4 amounts of DHA supplementation on the visual acuity of formula-fed infants at 12 mo of age. Secondary objectives were to evaluate visual acuity maturation, red blood cell fatty acids, tolerance, anthropometric measures, and adverse events. DESIGN: This double-masked, randomized trial was conducted at 2 sites (Dallas and Kansas City). Three hundred forty-three healthy, term, formula-fed infants were enrolled at 1-9 d of age and were randomly assigned to be fed 1 of the following 4 infant formulas containing equivalent nutrient amounts, except for long-chain polyunsaturated fatty acids: control (0% DHA), 0.32% DHA, 0.64% DHA, or 0.96% DHA; DHA-supplemented formulas also provided 0.64% arachidonic acid. Visual acuity was measured by visual evoked potentials in 244 infants who completed the 12-mo primary outcome examination. RESULTS: Infants fed control formula had significantly poorer visual evoked potential visual acuity at 12 mo of age than did infants who received any of the DHA-supplemented formulas (P < 0.001). There were no significant differences in visual evoked potential visual acuity between the 3 amounts of DHA supplementation for either site at any age tested. CONCLUSIONS: DHA supplementation of infant formula at 0.32% of total fatty acids improves visual acuity. Higher amounts of DHA supplementation were not associated with additional improvement of visual acuity. This trial was registered at clinicaltrials.gov as NCT00753818.

Three randomized controlled trials of early long-chain polyunsaturated Fatty Acid supplementation on means-end problem solving in 9-month-olds.

This study examines whether feeding infants formula supplemented with long-chain polyunsaturated fatty acids (LCPUFA) improves cognitive function of 9-month-olds. Participants included 229 infants from 3 randomized controlled trials. Children received either formula supplemented with docosahexaenoic acid and arachidonic acid, or a control formula beginning at 1-5 days (12-month feeding study), or following 6 weeks (6-week-weaning study) or 4-6 months of breastfeeding (4-to 6-month weaning study). Infants were assessed with a 2-step problem solving task. In the 12-month feeding and 6-week weaning studies, supplemented children had more intentional solutions (successful task completions) and higher intention scores (goal-directed behaviors) than controls. These results suggest that LCPUFA supplementation improves means-end problem solving.

The teller acuity cards are effective in detecting amblyopia.

PURPOSE: Detection of amblyopia in infants and toddlers is difficult because the current clinical standard for this age group, fixation preference, is inaccurate. Although grating acuity represents an alternative, studies of preschoolers and schoolchildren report that it is not equivalent to the gold standard optotype acuity. Here, we examine whether the Teller Acuity Cards (TAC) can detect amblyopia effectively by testing children old enough (7.8 +/- 3.6 years) to complete optotype acuity testing. METHODS: Grating acuity was assessed monocularly in 45 patients with unilateral amblyopia, 44 patients at risk for amblyopia, and 37 children with no known vision disorders. Each child's grating acuity was classified as normal/abnormal based on age-appropriate norms. These classifications were compared with formal amblyopia diagnoses. RESULTS: Grating acuity was finer than optotype acuity among amblyopic eyes (medians: 0.28 vs. 0.40 logMAR, respectively, p < 0.0001) but not among fellow eyes (medians: 0.03 vs. 0.10 logMAR, respectively, p = 0.36). The optotype acuity-grating acuity discrepancy among amblyopic eyes was larger for cases of severe amblyopia than for moderate amblyopia (means: 0.64 vs. 0.18 logMAR, respectively, p = 0.0001). Nevertheless, most cases of amblyopia were detected successfully by the TAC, yielding a sensitivity of 80%. Furthermore, grating acuity was relatively sensitive to all amblyopia subtypes (69 to 89%) and levels of severity (79 to 83%). CONCLUSIONS: Although grating acuity is finer than optotype acuity in amblyopic eyes, most children with amblyopia were identified correctly suggesting that grating acuity is an effective clinical alternative for detecting amblyopia.

Phonological processing deficits and the acquisition of the alphabetic principle in a severely delayed reader: a case study.

At the end of first grade, TM did not know the alphabet and could read no words. He could not tap syllables in words, had difficulty producing rhyming words and retrieving the phonological representations of words, and he could not discriminate many phoneme contrasts. He learned letter-sound correspondences first for single-consonant onsets and then later for the final consonant in a word but had difficulty with letter-sound associations for vowels. TM's ability to select a printed word to match a spoken word on the basis of the initial or final letter and sound was interpreted as evidence of Ehri's phonetic-cue reading. Using the Glass Analysis method, the authors taught TM to read and he became an independent reader. We discuss how his phonological processing deficits contributed to his reading difficulties.

Prevalence of amblyopia and other vision disorders in young Newfoundland and Labrador children.

BACKGROUND: Currently, there is a lack of adequate data on pediatric eye and vision disorders in Canada, particularly in the province of Newfoundland and Labrador. In the present study, we estimate the prevalence of eye and vision disorders among young children who participated in a vision screening program in the St. John's, Newfoundland, metropolitan region. METHODS: In daycare settings, 946 children (mean age 4.2 years) were screened with the latest tests of optics and functional vision. Those with suspected vision disorders were referred to an optometrist for a complete eye examination. From the results of these examinations, prevalence rates were estimated for several categories of vision disorders. RESULTS: Overall, we estimate that 14.0% of the children possessed significant vision disorders, the most prevalent of which were hyperopia, amblyopia, and strabismus (4.8%, 4.7%, and 4.3%, respectively). Myopia and anisometropia, on the other hand, were relatively rare (1.1% and 1.4%, respectively). In general, prevalence estimates are within the range of existing estimates from other developed nations. INTERPRETATION: Although the prevalence rates reported here must be interpreted cautiously because of methodological limitations, it appears that children in the present study do not possess an abnormally high prevalence of visual dysfunction. Nevertheless, because an estimated 14.0% of children tested had treatable vision disorders, early screening is clearly warranted in Newfoundland and Labrador.

Normative pediatric visual acuity using single surrounded HOTV optotypes on the Electronic Visual Acuity Tester following the Amblyopia Treatment Study protocol.

PURPOSE: To provide normative pediatric visual acuity data using HOTV optotypes presented on the Electronic Visual Acuity Tester following the Amblyopia Treatment Study (ATS) protocol. METHODS: Monocular testing was conducted on 384 healthy full-term children ranging from 3 to 10 years of age (mean, 5.4 years; SD, 1.8 years). A total of 373 children completed monocular testing of each eye. In addition, 23 adults (mean, 28.7 years; SD, 4.9 years) were tested for comparison. Both monocular visual acuity and interocular acuity differences were recorded. RESULTS: Mean visual acuity improved by slightly more than one line (0.12 logMAR) from 3 years of age to adulthood, increasing from 0.08 logMAR to -0.04 logMAR (F(6,400) = 26.3, p < 2.0 x 10(-26)). At all ages, mean interocular acuity difference was less than one line on a standard acuity chart (overall mean difference = 0.04 logMAR; SD, 0.06 logMAR). CONCLUSIONS: These results represent the first normative data reported for HOTV optotypes using the ATS protocol on the Electronic Visual Acuity Tester. These data may play an important role in clinical practice, screening, and clinical research.

Improvement in motor development following surgery for infantile esotropia.

PURPOSE: Infantile esotropia is associated with abnormal visual development and thus may delay the achievement of developmental milestones. Although early surgery can improve visual function, less is known about its effect on motor development. Here we address whether early surgery can improve motor development. METHODS: Recently, our lab devised the Infant Developmental Skills Survey, a 25-item questionnaire designed to assess sensorimotor and gross motor development. The questionnaire was completed by the parents of 3- to 10-month-old patients with infantile esotropia prior to surgery (n = 143) and the parents of 6- to 11-month-old patients following surgery (n = 58). A subset of parents (n = 40) completed the questionnaire both before and after surgery. For comparison, the questionnaire was completed by the parents of infants with normal ocular alignment (n = 194). RESULTS: Before surgery 4-, 5-, 6-, 7-, 9-, and 10-month-old patients showed delayed achievement of sensorimotor milestones (p < 0.01), and 5-, 9-, and 10-month-old patients demonstrated delayed attainment of gross motor milestones (p < 0.05) compared with normal children. However, following surgery, patients demonstrated a greater rate of sensorimotor development than age-matched controls (p < 0.0001) and caught up with normal children on both sensorimotor and gross motor skills. CONCLUSIONS: Prior to surgery, patients with infantile esotropia were delayed in their achievement of developmental milestones. However, following surgery, a comparison group of patients showed rapid development and possessed motor skills comparable to those of normal children, suggesting that early surgery is beneficial to both visual and motor development.

Randot Preschool Stereoacuity Test: normative data and validity.

INTRODUCTION: The Randot Preschool Stereoacuity Test is a widely used three-book test for the assessment of binocular status. Using a prototype, we previously reported high testability in children as young as 3 years, validity data, and some normative data. Here we report extensive normative and validity data for the final version of the test. In addition, we report normative data for a new, fourth book that adds finer disparities. METHODS: The Randot Preschool Stereoacuity Test was administered to 4355 normal children aged 3 to 18 years and 39 adults in multiple settings. In addition, the Randot Preschool Stereoacuity Test along with the new, fourth book that added 30 arcsec and 20 arcsec disparity levels was administered to 1402 normal children aged 3 to 18 years and 33 normal adults. Both the four-book Randot((R)) Preschool Stereoacuity Test and the Randot circles were administered to 242 patients with amblyogenic conditions aged 3 to 18 years. RESULTS: Mean normal stereoacuity improved from 100 arcsec at 3 years of age to 60 arcsec by 5 years and 40 arcsec by 7 years. The lower limit of normal was 400 arcsec at 3 years, 200 arcsec at 4 years, and 60 arcsec at 7 years. Using the new four-book version, further improvement in mean stereoacuity could be appreciated beyond 7 years of age to 30 arcsec in the 11- to 18-year-old and adult groups. Among the 242 patients, Randot Preschool Stereoacuity Test stereoacuity was strongly associated with Randot circle stereoacuity (chi(2) = 261.0, p < 0.001). CONCLUSIONS: Normative data for the Randot Preschool Stereoacuity Test show a monotonic improvement of stereoacuity from age 3 years through the teen years. Patient data support the validity of the Randot Preschool Stereoacuity Test.

Accuracy of the contrast sensitivity card test for infants: retest variability and prediction of spatial resolution.

PURPOSE: We assessed the retest variability of a new contrast sensitivity (CS) card procedure and its ability to predict spatial resolution. METHODS: Twenty-four 3-month-olds were tested twice with the CS cards and once with the Teller acuity cards (TAC) within a single session. RESULTS: Coefficient of repeatability (COR) analysis revealed that retest variability of the new cards is superior to that of an earlier prototype at low to mid spatial frequencies. Furthermore, retest variability is comparable to that of infant visual evoked potential studies and the Vistech 6500, a chart commonly used to measure CS in adults. Finally, estimates of visual acuity based on the CS cards were consistent with those provided by the TAC (although CS-based estimates were generally lower overall). CONCLUSIONS: Given its reliability and accuracy, the new CS card procedure has good potential as a clinical tool for assessing spatial vision in infants and toddlers.

Improving the effectiveness of the infant contrast sensitivity card procedure.

Based on results from an earlier prototype, custom software and printing techniques were developed to construct a new card-based test of contrast sensitivity (CS) for nonverbal subjects. Compared with the prototype, the new CS card test contains three improvements: (1) larger, more salient test gratings; (2) higher contrast warm-up cards for each spatial frequency set; and (3) smaller contrast step size between adjacent cards. The success of the new cards was evaluated by testing 3.5- and 12-month-old human infants. Results indicated that the new version of the test required little time to complete (mean, 6.5 min) and provided accurate estimates of visual acuity. Also, group contrast sensitivity functions (CSFs) showed substantial development from 3.5 to 12 months of age. Surprisingly, however, group CSFs obtained with the new cards were lower than those obtained with the prototype, a discrepancy that may be due to differences in space average luminance between the two sets of cards. In all, the new CS card procedure possesses several merits that give it potential as an option for assessing spatial vision in infants, toddlers, and subjects with multiple impairments.