Longitudinal study of babies born to mothers enrolled in a preconception prospective pregnancy study: study design and methodology, New York State Angler cohort study.

Persistent environmental chemicals such as organochlorine pesticides and polychlorinated biphenyls (PCBs) have been associated with alterations in fetal development and child health including subtle differences in developmental status. Previous prospective studies have ascertained prenatal or postnatal exposures but none have been designed to assess exposures at critical windows including preconception. To address this gap, we followed infants born to mothers recruited prior to conception in the New York State Prospective Pregnancy Study to assess feasibility issues including acceptability of a relatively invasive study protocol during the child's first 2 years of life. Longitudinal measurements on health, development, and growth were obtained from 53 live-born infants; 49 families consented to standardized in-home neurodevelopmental and psychosocial evaluations at 12 and 24 months of age. Nineteen participating parents consented to the collection of blood from infants for lead thyroid and PCB levels. Despite the intensive data collection protocol over 2 years coupled with the mothers having completed an intensive prospective pregnancy protocol, we found parents readily open to continued participation in a longitudinal study involving their children. Suggestions for conducting in-home assessments include use of a consistent contact nurse, comprehensive parent-friendly developmental assessment tools with some interim assessment by parent report, and periodic team visits.

Differences in (G+C) content between species: a commentary on Forsdyke's "chromosomal viewpoint" of speciation.

Forsdyke (1999) has recently argued that differences in (G+C)%, or G+C content, may trigger new species formation. He further argues that the genic model has shortcomings that can be overcome by his "chromosomal" (hereafter, "G+C") model. We disagree on several counts. First, we do not accept that the genic model has the shortcomings suggested by Forsdyke. There is an abundance of empirical support for the contribution of individual genes, as well as of mapped chromosomal regions, to post-zygotic reproductive isolation (and Haldane's rule). Further, we argue that the G+C model suffers from the same theoretical difficulties as other speciation models based on underdominance. We also question the evidence Forsdyke uses to support his model. Finally, we describe analyses of G+C content in a well-studied model system of speciation (the Drosophila melanogaster species complex), the results of which are incompatible with the G+C model. Thus, while Forsdyke's G+C model cannot be explicitly ruled out, it is not directly supported by empirical data. In contrast, the genic model is well supported by empirical data, holds up on theoretical grounds, and does not require any assistance from the G+C model.

Cross-regulation of Hox genes in the Drosophila melanogaster embryo.

Cross-regulation of Homeotic Complex (Hox) genes by ectopic Hox proteins during the embryonic development of Drosophila melanogaster was examined using Gal4 directed transcriptional regulation. The expression patterns of the endogenous Hox genes were analyzed to identify cross-regulation while ectopic expression patterns and timing were altered using different Gal4 drivers. We provide evidence for tissue specific interactions between various Hox genes and demonstrate the induction of endodermal labial (lab) by ectopically expressed Ultrabithorax outside the visceral mesoderm (VMS). Similarly, activation and repression of Hox genes in the VMS from outside tissues seems to be mediated by decapentaplegic (dpp) gene activation. Additionally, we find that proboscipedia (pb) is activated in the epidermis by ectopically driven Sex combs reduced (Scr) and Deformed (Dfd); however, mesodermal pb expression is repressed by ectopic Scr in this tissue. Mutant analyses demonstrate that Scr and Dfd regulate pb in their normal domains of expression during embryogenesis. Ectopic Ultrabithorax and Abdominal-A repress only lab and Scr in the central nervous system (CNS) in a timing dependent manner; otherwise, overlapping expression in the CNS in tolerated. A summary of Hox gene cross-regulation by ectopically driven Hox proteins is tabulated for embryogenesis.

Extreme prematurity and school outcomes.

The purpose of this study was to assess the impact of extreme prematurity on three global measures of school outcomes. Using a matched cohort design, exposed infants comprised all surviving singleton infants < or = 28 weeks gestation born at one regional neonatal intensive care hospital between 1983 and 1986 (n = 132). Unexposed infants comprised randomly selected full-term infants (> or = 37 weeks gestation) frequency matched on date of birth, zip code and health insurance. All children were selected from a regional tertiary children's centre serving western New York population. Standardised telephone interviews elicited information on grade repetition, special education placement and use of school-based services. Unconditional logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) adjusted for potential confounders for children without major handicaps. Extreme prematurity was associated with a significant increase in risk of grade repetition (OR = 3.22; 95% CI = 1.63, 6.34), special education placement (OR = 3.16; 95% CI = 1.14, 8.76) and use of school-based services (OR = 4.56; 95% CI = 1.82, 11.42) in comparison with children born at term, even after controlling for age, race, maternal education, foster care placement and the matching factors. These findings suggest that survivors of extreme prematurity remain at risk of educational underachievement.

Measuring functional status and family support in older school-aged children with cerebral palsy: comparison of three instruments.

OBJECTIVE: To compare a pediatric and an adult version of a functional status measure and a family support measure for assessing school-age children with spastic cerebral palsy. DESIGN: A prospective study involved functional status measurements using the Pediatric Functional Independence Measure (WeeFIM), the Adult Functional Independence Measure (FIM), and a family support measure, the Amount of Assistance Questionnaire (AAQ). PARTICIPANTS: The feasibility sample consisted of 47 children aged 2 to 12 yrs with cerebral palsy. The study sample consisted of 20 children aged 7 to 16 yrs with spastic cerebral palsy (50% diplegia, 50% quadriplegia). INTERVENTIONS: Initial assessment interview included the WeeFIM, developmental milestones, educational achievement information, and the AAQ. Within 1 month, a follow-up phone interview using the FIM was completed. MAIN OUTCOME MEASURE: The WeeFIM and FIM measure independence in self-care, sphincter control, mobility, locomotion, communication, and social cognition. The AAQ measures the time and assistance required by a child in essential daily tasks. RESULTS: Pearson's correlation coefficient exceeded .97 for WeeFIM and FIM total score in the total sample as well as in two subgroups of children: those with diplegia and quadriplegia. Total scores in WeeFIM and FIM as well as domain scores were significantly different between children with diplegia and quadriplegia. Parental amount of assistance on the AAQ was significantly correlated with WeeFIM and FIM scores. CONCLUSION: Either the WeeFIM or FIM can be used for monitoring functional status through adolescence in children with spastic cerebral palsy. Functional limitations are highly related to requirements for parental assistance.

The embryonic expression pattern of labial, posterior homeotic complex genes and the teashirt homologue in an apterygote insect.

During embryogenesis of the fruit fly, Drosophila melanogaster, the homeotic genes are required to specify proper cell fates along the anterior-posterior axis of the embryo. We cloned partial cDNAs of homologues of the Drosophila homeotic gene teashirt and five of the homeotic-complex (HOM-C) genes from the thysanuran insect, Thermobia domestica, and assayed their embryonic expression patterns. The HOM-C genes we examined were labial, Antennapedia, Ultrabithorax, abdominal-A and Abdominal-B. As the expression pattern of these HOM-C genes is largely conserved among insects and as Thermobia is a member of a phylogenetically basal order of insects, we were able to infer their ancestral expression patterns in insects. We compare the expression patterns of the Thermobia HOM-C genes with their expression in Drosophila and other insects and discuss the potential roles these genes may have played in insect evolution. Interestingly, the teashirt homologue shows greater variability between Thermobia and Drosophila than any of the HOM-C genes. In particular, teashirt is not expressed strongly in the Thermobia abdomen, unlike Drosophila teashirt. We propose that teashirt expression has expanded posteriorly in Drosophila and contributed to a homogenization of the Drosophila larval thorax and abdomen.

Structure of the insect head in ontogeny and phylogeny: a view from Drosophila.

Evolutionary, developmental and insect biologists are currently using a three-pronged approach to study the evolution and development of the insect head. First, genetic manipulation of the fruit fly Drosophila melanogaster has led to the identification of many genes, including the segmentation and homeotic genes, that are important for embryonic pattern formation and development. Second, a comparison of orthologous gene expression patterns in other insects reveals that these regulatory genes are deployed in similar, yet distinct, patterns in different insects. Third, comparisons of embryonic morphology with gene expression patterns suggest that in general these genes promote a common insect body plan, but that variations in gene expression can often be correlated to variations in morphology. Here, we present a detailed review of the development of the cephalic ectoderm of Drosophila and extrapolate to development of a generalized insect head. Our analysis of the variations among insect species, in both morphology and gene expression patterns, conducted within an evolutionary framework supported by traditional phylogenies and paleontology provides the basis for hypotheses about the genetic factors governing morphologic and developmental evolution.

Evolution of the insect body plan as revealed by the Sex combs reduced expression pattern.

The products of the HOM/Hox homeotic genes form a set of evolutionarily conserved transcription factors that control elaborate developmental processes and specify cell fates in many metazoans. We examined the expression of the ortholog of the homeotic gene Sex combs reduced (Scr) of Drosophila melanogaster in insects of three divergent orders: Hemiptera, Orthoptera and Thysanura. Our data reflect how the conservation and variation of Scr expression has affected the morphological evolution of insects. Whereas the anterior epidermal expression of Scr, in a small part of the posterior maxillary and all of the labial segment, is found to be in common among all four insect orders, the posterior (thoracic) expression domains vary. Unlike what is observed in flies, the Scr orthologs of other insects are not expressed broadly over the first thoracic segment, but are restricted to small patches. We show here that Scr is required for suppression of wings on the prothorax of Drosophila. Moreover, Scr expression at the dorsal base of the prothoracic limb in two other winged insects, crickets (Orthoptera) and milkweed bugs (Hemiptera), is consistent with Scr acting as a suppressor of prothoracic wings in these insects. Scr is also expressed in a small patch of cells near the basitarsal-tibial junction of milkweed bugs, precisely where a leg comb develops, suggesting that Scr promotes comb formation, as it does in Drosophila. Surprisingly, the dorsal prothoracic expression of Scr is also present in the primitively wingless firebrat (Thysanura) and the leg patch is seen in crickets, which have no comb. Mapping both gene expression patterns and morphological characters onto the insect phylogenetic tree demonstrates that in the cases of wing suppression and comb formation the appearance of expression of Scr in the prothorax apparently precedes these specific functions.

Structure of the insect head as revealed by the EN protein pattern in developing embryos.

The structure of the insect head has long been a topic of enjoyable yet endless debate among entomologists. More recently geneticists and molecular biologists trying to better understand the structure of the head of the Dipteran Drosophila melanogaster have joined the discourse extrapolating from what they have learned about Drosophila to insects in general. Here we present the results of an investigation into the structure of the insect head as revealed by the distribution of engrailed related protein (Engrailed) in the insect orders Diptera, Siphonaptera, Orthoptera and Hemiptera. The results of this comparative embryology in conjunction with genetic experiments on Drosophila melanogaster lead us to conclude: (1) The insect head is composed of six Engrailed accumulating segments, four postoral and two preoral. The potential seventh and eighth segments (clypeus or labrum) do not accumulate Engrailed. (2) The structure known as the dorsal ridge is not specific to the Diptera but is homologous to structures found in other insect orders. (3) A part of this structure is a single segment-like entity composed of labial and maxillary segment derivatives which produce the most anterior cuticle capable of taking a dorsal fate. The segments anterior to the maxillary segment produce only ventral structures. (4) As in Drosophila, the process of segmentation of the insect head is fundamentally different from the process of segmentation in the trunk. (5) The pattern of Engrailed accumulation and its presumed role in the specification and development of head segments appears to be highly conserved while its role in other pattern formation events and tissue-specific expression is variable. An overview of the pattern of Engrailed accumulation in developing insect embryos provides a basis for discussion of the generality of the parasegment and the evolution of Engrailed patterns.

Neurodevelopmental outcome of infants with hypoplastic left heart syndrome.

The neurodevelopmental outcome of hypoplastic left heart syndrome in infants remains unclear. All 11 survivors of staged surgical repair of hypoplastic left heart syndrome received standardized neurodevelopmental assessments at one regional children's hospital. Seven children (64%) had major developmental disabilities. Quality-of-life outcomes must be considered when management options for children with hypoplastic left heart syndrome are evaluated.

The Functional Independence Measure for Children (WeeFIM). Conceptual basis and pilot use in children with developmental disabilities.

Few tools are available to pediatricians for tracking and monitoring disability status in children. We describe the conceptual basis and pilot use of the Functional Independence Measure for Children (WeeFIM). Our pilot use of this instrument in children with limb deficiency, Down's syndrome, spina bifida, cerebral palsy, and extreme prematurity demonstrates that the WeeFIM is a valid measure for tracking disability in preschool age and middle childhood. The WeeFIM measures the impact of developmental strengths and difficulties on independence at home, in school, and in the community. This allows the pediatrician to prioritize interventions for enhancing comprehensive functional outcomes and supporting families.

Multivariate risks among extremely premature infants.

This study was designed to identify risk factors for mortality and morbidity of extremely premature infants born in the surfactant era. The study cohort included 194 infants born at < 29 weeks' gestation at one regional tertiary center between 1983 and 1986. Forty-one infants died. Blinded neurodevelopmental assessments were performed on 149 of 153 (97%) survivors at a mean age of 52 months. Thirty-one (21%) survivors had major impairments: 15 had mental retardation, 8 had multiple impairments, 7 had cerebral palsy, and 1 was blind. Logistic regression analysis identifies five significant risk factors for mortality: grade III or IV intraventricular hemorrhage, birth weight < 800 gm, 5-minute Apgar score < or = 3, male sex, and absence of surfactant therapy. Significant risk factors for any major impairment included sepsis (relative risks [RR] = 6.4), male sex (RR = 3.1), and nonwhite race (RR = 2.8). Hydrocephalus requiring shunting was a significant risk factor for cerebral palsy (RR = 16.4) and neonatal retardation (RR = 16.0). Nonwhite race (RR = 7.3), sepsis (RR = 6.8), and male sex (RR = 3.7) also were significant risk factors for mental retardation. Confirmation of these risk factors should facilitate development of targeted interventions for optimizing long-term outcome.

Predictors of mortality, morbidity, and disability in a cohort of infants < or = 28 weeks' gestation.

This study attempted to identify predictors for mortality, morbidity, disability, and educational handicap at age 4 years in a cohort of 194 infants born at 23 to 28 weeks' gestation at one regionalized tertiary center from 1983 to 1986. Forty-one infants died (21%); standardized neurodevelopmental and functional assessments were conducted on 149 of 153 (97%) survivors at a mean age of 52 months. Five significant predictors of death were identified with logistic regression analysis: gestational age 23 to 26 weeks, intraventricular hemorrhage grades 3 or 4, male gender, five-minute Apgar < or = 3, and absence of prophylactic calf lung surfactant extract. Significant predictors of neurodevelopmental morbidity included sepsis, male gender, and nonwhite race. Significant predictors of disability at age four included neurodevelopmental impairment and severe retinopathy of prematurity. Low socioeconomic status, nonwhite race and male gender were predictive of educational handicap. These findings suggest that outcomes may have distinct pathophysiologies. The role of biomedical events appears strongest for death.

Functional status of extremely preterm infants at kindergarten entry.

Functional status was formally assessed in 149 of 153 surviving members of an extremely preterm (< or = 28 weeks) birth cohort born at one tertiary center between 1983 and 1986. The children were observed in the completion of motor, speech and self-care tasks, and administered either the Vineland Daily Living Skills Scale (VDLS) or the Functional Independence Measure for children (WeeFIM). 31 children had major neurodevelopmental impairment. Only 5 per cent were considered to have severe functional limitation. The prevalence of functional limitation varied by definition: 11 children were limited using the WeeFIM instrument and 35 using the VDLS instrument. These findings suggest that the majority of extremely preterm children are functional at kindergarten entry, but will require continuous monitoring of academic skills.

Hypoxemia during oral feeding of children with severe cerebral palsy.

Oral feeding of children with severe dysphagia and multiple disabilities may result in hypoxemia. Pulse oximetry was used to monitor hemoglobin saturation (SpO2) during oral feeding of five children with multiple disabilities who were referred because of food refusal or coughing and fatigue during feeding. Modified barium videofluoroscopic swallow studies demonstrated deglutition abnormalities. SpO2 values were within the normal range at rest, but routine, upright oral feeding resulted in significant degrees of hypoxemia. The pharyngeal stage of deglutition was abnormal in all five children. In three, the periods of hypoxemia were dependent on food texture. Awareness of meal-time hypoxemia contributed to the decision to use gastrostomy-tube feedings for the other two children. Pulse oximetry during oral feeding should be considered for all children with severe dysphagia and multiple disabilities.

Kindergarten readiness after extreme prematurity.

OBJECTIVE: To assess kindergarten readiness among survivors of extreme prematurity and to identify predictors of special education requirements. DESIGN: Historic cohort design. SETTING: Regionalized tertiary pediatric center. PARTICIPANTS: One hundred forty-nine (97%) of 153 children who were alive at follow-up (mean +/- SD age, 52.7 +/- 9.9 months). SELECTION PROCEDURES: Study cohort included infants (gestation, 23 to 28 weeks), born between 1983 and 1986 (N = 194), who were alive at follow-up (N = 153, 79% survival). INTERVENTIONS: None. MEASUREMENTS AND RESULTS: Standardized neurodevelopmental and psychometric evaluations were administered by a multidisciplinary team that was blinded to the neonatal course. Thirty-one children (21%) had major neurodevelopmental impairments. By using the McCarthy Scales of Children's Abilities for children free of major impairments, 61 (63%) had one or more minor neurodevelopmental impairments noted. Half of the surviving children were thought to require special education resources at kindergarten entry. Multivariate logistic regression identified three significant predictors of special education: low socio-economic status, nonwhite race, and male gender. CONCLUSIONS: Social and demographic variables were associated with minor neurodevelopmental impairments and special education requirements among extremely premature children. Continued developmental follow-up and targeted interventions to reduce the risk of educational underachievement appear to be warranted.

Parents' developmental perceptions and expectations for their high-risk infants.

This study examines the relationship between developmental outcomes of high-risk infants and parental perceptions and expectations. Parents of 209 consecutive high-risk infants were asked to provide their development interpretations and expectations before their infants received standard developmental assessments between April and October 1989. Moderate correlations between parents and professional assessments of motor and language skills were noted (p less than .05 to p less than .01). Most agreements occurred when infants were assessed as normal by professionals. Disagreements were common and occurred in all areas of development. These mismatches were not associated with gestational age at birth, neonatal complications, poverty, or estimates of parental experience. Professionals should take seriously any expressed developmental concerns by parents of high-risk infants. Expressed developmental concerns, however, cannot be relied on for developmental screening of high-risk infants.

Risk factors for major neurodevelopmental impairments and need for special education resources in extremely premature infants.

The purpose of this cohort study was to determine the incidence of and risk factors for major neurodevelopmental impairments among survivors of extreme prematurity. The study cohort comprised 100 infants born between 24 and 28 weeks of gestational age at one tertiary center from 1983 to 1984. Twenty-five infants (25%) died; 75 (75%) survived until follow-up (mean, 60 months). Standardized neurodevelopmental and psychometric assessments were performed in blind fashion on 68 of the 75 surviving children (91% follow-up). Informal assessments (parent, teacher, and physician reports) were obtained instead for seven (9%) children who had relocated outside of the area. Overall, 19 children (25%) had one or more major impairments: mental retardation, 9; cerebral palsy, 4; multiple impairments, 5; and blindness, 1. Despite a high prevalence of impairments, 95% of children (n = 71) were functionally independent [corrected]. Special educational resources were definitely necessary for seven (9%) and possibly needed for 36 (48%) additional children. Univariate analyses revealed four significant risk factors for cerebral palsy: hydrocephalus (relative risk = 12.2), grades III and IV intraventricular hemorrhage (relative risk = 5.8), 5-minute Apgar score lower than 7 (relative risk = 5.7), and bronchopulmonary dysplasia (relative risk = 5.5). Hydrocephalus was the only significant risk factor observed for mental retardation (relative risk = 5.4). Risk factors predicting a need for special education resources included sepsis (relative risk = 24.9), low socioeconomic status (relative risk = 16.3), and nonwhite race (relative risk = 3.0). Thus our data suggest that biomedical factors appear to confer the greatest risk of major impairments; sociodemographic factors appear to have a significant impact on educational risk in extremely premature infants who do not die. Continued follow-up with biomedical and developmental-social interventions appears warranted to decrease the risk of educational underachievement in this population.

Pneumonia caused by coliforms and Pseudomonas aeruginosa.

The diagnosis and treatment of 20 hospital patients seen in the past year with proven pneumonia caused by coliforms and Pseudomonas aeruginosa are discussed. Predisposing factors and methods for improving laboratory and clinical diagnosis are analysed, the main problem being to discriminate between genuine pneumonia caused by these organisms and mere contamination of sputum samples resulting from colonization of the upper respiratory tract following broad-spectrum chemotherapy. Overall initial chemotherapy with gentamicin cured 75% (15 out of 20) of the patients in spite of unfavourable underlying pathology. Where gentamicin was given in adequate dosage, which in practice meant that dose which produced peak serum concentrations of 8 mug/ml or more, the cure rate was 91% (11 out of 12). In those patients achieving (measured) peak serum concentrations of less than 8 mug/ml the cure rate was only 33% (4 out of 12). These figures include four patients who failed to respond to doses of gentamicin producing peak concentrations of 5-0-6-0 mug/ml in each case. These patients responded promptly to higher doses (or accumulation), producing peak serum concentrations of 8 mug/ml or more and were then cured within three to five days. Toxicity from gentamicin was not observed in any patient. These results indicate that it is necessary to monitor gentamicin therapy by laboratory assay to ensure adequate dosage and that peak serum concentrations of 8 mug/ml or more are significantly correlated with successful treatment of pneumonia caused by coliforms and Ps. aeruginosa.