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Biomedical subjects

D Bellinger

Publications and source records attributed to D Bellinger.

At least 19 recordsLinked to original sources
PubMed2006

A cumulative risk factor model for early identification of academic difficulties in premature and low birth weight infants.

OBJECTIVES: Premature and low birth weight children have a high prevalence of academic difficulties. This study examines a model comprised of cumulative risk factors that allows early identification of these difficulties. METHODS: This is a secondary analysis of data from a large cohort of premature (<37 weeks gestation) and LBW (<2500 g) children. The study subjects were 8 years of age and 494 had data available for reading achievement and 469 for mathematics. Potential predictor variables were categorized into 4 domains: sociodemographic, neonatal, maternal mental health and early childhood (ages 3 and 5). Regression analysis was used to create a model to predict reading and mathematics scores. RESULTS: Variables from all domains were significant in the model, predicting low achievement scores in reading (R (2) of 0.49, model p-value < .0001) and mathematics (R (2) of 0.44, model p-value < .0001). Significant risk factors for lower reading scores, were: lower maternal education and income, and Black or Hispanic race (sociodemographic); lower birth weight and male gender (neonatal); lower maternal responsivity (maternal mental health); lower intelligence, visual-motor skill and higher behavioral disturbance scores (early childhood). Lower mathematics scores were predicted by lower maternal education, income and age and Black or Hispanic race (sociodemographic); lower birth weight and higher head circumference (neonatal); lower maternal responsivity (maternal mental health); lower intelligence, visual-motor skill and higher behavioral disturbance scores (early childhood). CONCLUSIONS: Sequential early childhood risk factors in premature and LBW children lead to a cumulative risk for academic difficulties and can be used for early identification.

Child↗
PubMed2006

Delta-aminolevulinic acid dehydratase polymorphism and the relation between low level lead exposure and the Mini-Mental Status Examination in older men: the Normative Aging Study.

OBJECTIVE: To determine whether a polymorphism the in delta-aminolevulinic acid dehydratase (ALAD) gene modifies the neurotoxicity of lead in older adults. METHODS: The authors studied men participating in the Department of Veterans Affairs' Normative Aging Study, assessing their recent exposure to lead by measuring blood lead (n = 915) at each triennial clinic visit, and, beginning in 1991, assessing their cumulative exposure by measuring lead levels in tibia (n = 722) and patella (n = 720), using K-shell x ray fluorescence. Starting in 1993 and again at each triennial visit, the authors administered the Mini-Mental State Examination (MMSE) to assess their cognitive functioning. The relation of the lead biomarkers to MMSE score was evaluated and this association was compared among men who carried the variant allele, ALAD-2, versus men without the allele. RESULTS: Sixteen per cent of men carried the ALAD-2 allele. Median tibia and patella lead levels (first-third quartile) were 19 (13-28) and 27 (18-39) microg/g. Blood lead levels were consistent with non-occupational exposure: only 6% of men had levels > or =10 microg/dl. In multivariable adjusted analyses, higher levels of blood lead were associated with poorer performance on the MMSE. This association was most pronounced among ALAD-2 carriers, among whom a 3 microg/dl increment in blood lead (the interquartile range) was associated with a 0.26 point lower mean MMSE score (95% CI -0.54 to 0.01), compared with a 0.04 point lower score (95% CI -0.16 to 0.07) among non-carriers. The modest 0.22 point difference in these associations did not attain statistical significance, however (p(interaction) = 0.13). The associations between bone lead levels and MMSE score did not vary by ALAD-2 status. CONCLUSIONS: Although not statistically significant, these findings suggest that ALAD genotype may modify blood lead's adverse association with cognition among older men who had community exposures to lead. However, despite a relatively large sample size and the use of sensitive methods for measuring lead burden, the evidence overall was fairly weak.

Adult↗
PubMed2001

Children with adequate academic achievement scores referred for evaluation of school difficulties: information processing deficiencies.

Children (7-11 years old) with standardized academic achievement test scores in the normal range referred for evaluation of learning problems were compared to low-achieving children matched for age, sex, and nonverbal cognitive ability, and to children with no known history of learning difficulty matched for age, sex, and reading (all N = 65) on a battery of computerized tasks of nonverbal information processing. The normally achieving referred children performed similarly to the low-achieving group but worse than reading-matched nonreferred counterparts. These findings suggest that children who struggle in school yet perform adequately on standardized achievement measures can have heightened neurodevelopmental vulnerability. Implications are discussed with respect to the underlying substrate of learning disabilities, as well as their diagnosis, classification, and remediation.

Achievement↗
PubMed2001

Studies of lead exposure and the developing central nervous system: a reply to Kaufman.

Kaufman's critique of the lead-cognition hypothesis is a reiteration of well worn and weary claims raised many times in the past, primarily by spokespersons for the lead industry. They have been fully rebutted in the literature. The essence of these claims is that those studies showing an association between lead and IQ are flawed by uncontrolled confounding, multiple comparisons, and errors in measurement. Any effect of lead, Kaufman asserts, if present, is small. This response examines each of these issues and shows that they lack substance. Lead's negative impact on IQ persists in most modern studies after confounding has been controlled in many different statistical models. At least three metaanalyses have confirmed an effect of lead at low dose. Animal studies in which lead is given systematically, and the issue of confounding thereby avoided, demonstrate an unequivocal lead effect at similar doses to the human studies. The criticism of multiple comparisons similarly does not withstand examination. Measurement errors are nonsystematic and nondifferential. They are, therefore, null biasing. The actual size of the lead effect has been shown to be substantial, and to be found most prominently at the ends of the distribution. Kaufman says that lead requires study of diverse dimensions of intellect, but he restricts his scope to a sample of studies of lead and IQ, ignoring recent high quality studies that show a clear lead effect, and in those studies that he critiques he ignores data that contradict his position. His article adds nothing to the dialogue on lead neurotoxicity.

Comment↗
PubMed2000

Cognitive tests: interpretation for neurotoxicity? (Workshop summary).

The appropriate use and interpretation of cognitive tests presents important challenges to the toxicologist and to the risk assessor. For example, intelligence cannot be measured directly; rather intelligence is quantified indirectly by scoring responses (i.e., behaviors) to specific situations (problems). This workshop, "Cognitive Tests: Interpretation for Neurotoxicity?" provided an overview on the types of cognitive tests available and described approaches by which the validity of such tests can be assessed. Unlike many tools available to the toxicologist, cognitive tests have a particular advantage. Being noninvasive and species-neutral, the same test can be performed in different mammalian species. This enhances one's ability to assess the validity of test results. Criteria for test validity include comparable responses across species as well as similar disruption by the same neurotoxicant across species. Test batteries, such as the Operant Test Battery, have indicated remarkable similarity between monkeys and children with respect to performance of certain tasks involving, for example, short-term memory. Still, there is a need for caution in interpretation of such tests. In particular, cognitive tests, especially when performed in humans, are subject to confounding by a range of factors, including age, gender, and, in particular, education. Moreover, the ability of such tests to reflect intelligence must be considered. Certain aspects of intelligence, such as the ability to plan or carry out specific tasks, are not well reflected by many of the standard tests of cognition. Nonetheless, although still under development, cognitive tests do hold promise for reliably predicting neurotoxicity in humans.

Animals↗
PubMed1999

Persistent expression of canine factor IX in hemophilia B canines.

We previously demonstrated that direct intramuscular injection of recombinant adeno-associated virus (rAAV) carrying the human FIX (hFIX) cDNA can safely be administered to hemophilic B canines and express human factor IX protein; however, the functional activity of the hFIX protein could not be assessed due to anti-human FIX antibody (inhibitor) formation. To test the therapeutic efficacy of rAAV in hemophilic dogs, rAAV type 2 (rAAV2) carrying canine FIX (cFIX) cDNA was injected into the skeletal muscle of two dogs at doses of 1012-13particles. Circulating cFIX protein levels were maintained for 1 year at levels of 1-2% of normal. Hemostatic correction (WBCT and APTT) paralleled plasma FIX antigen levels. Both dogs still required plasma infusion for spontaneous and traumatic bleeding events. Inhibitors to cFIX protein were not detected in either animal by Bethesda assay. Neutralizing antibodies directed against AAV-2 capsid were pronounced and persistent. Vector DNA and mRNA transcripts were detected only at the injected skeletal muscle tissue. Analysis of both high and low molecular weight DNA identified both replicative episomal and integrated AAV species. These results demonstrate that persistent secretion of the FIX transgene protein, necessary for successful gene therapy of hemophilia B, can be achieved using the parvovirus-based rAAV vector

Animals↗
PubMed1999

Mother and teacher reports of ADHD symptoms: DSM-IV Questionnaire data.

OBJECTIVE: Diagnosis of attention-deficit/hyperactivity disorder (ADHD) is thought to be best accomplished by a multimodal approach. In many research and clinical settings, such extensive procedures may not be feasible. A screening instrument that could identify children meeting necessary (but not sufficient) criteria would permit selection of subgroups for more resource-intensive diagnostic procedures. METHOD: The Diagnostic Rating Scale (DRS) was completed by the mothers and teachers of 124 children referred to hospital-based clinics and 225 nonreferred children. The authors performed principal components analysis (PCA) on the questionnaire, compared the scores obtained by children from the 2 samples, and examined age and gender effects. Diagnoses derived from the DRS were not validated against structured diagnostic interviews. RESULTS: PCAs replicated the DSM-IV symptom combinations. Children from the referred sample exhibited more symptoms (p < .001) than children from the community sample. Boys were overrepresented among the children who received DRS-derived ADHD diagnoses. Girls were more likely (92%) to receive a diagnosis of ADHD, predominantly inattentive subtype, than other ADHD diagnoses. CONCLUSIONS: The results of this study provide preliminary support for the validity of the parent and teacher DRS as time- and resource-efficient screening instruments for examining symptoms associated with ADHD.

Attention Deficit Disorder with Hyperactivity↗
PubMed1997

Norepinephrine content in primary and secondary lymphoid organs is altered in rats with adjuvant-induced arthritis.

Chemical sympathectomy of secondary lymphoid organs with sparing of the hind limbs exacerbates adjuvant-induced arthritis (AA) in Lewis rats supporting a role for noradrenergic (NA) innervation of the immune system in AA pathology. The present study examines sympathetic innervation of lymphoid organs from Lewis rats 32 days after treatment with complete Freund's adjuvant (CFA) or vehicle using fluorescence histochemistry for localization of catecholamines (CA) and high-performance liquid chromatography with electrochemical detection (LCEC) for measurement for norepinephrine. The thymus from AA rats was significantly reduced in size, while secondary lymphoid organs, i.e., spleen and draining lymph nodes (DLN), were significantly enlarged compared with that seen in vehicle-treated controls. Fluorescence histochemistry revealed no apparent differences in the density of NA innervation, or the intensity of staining in sympathetic nerves in any of the secondary lymphoid organs from AA rats compared with that observed in control animals. However, there was an apparent increase in the density of NA nerve fibers in the thymus of AA rats. Norepinephrine (NE) concentration (pmol NE per g or mg wet weight), in the thymus from AA rats was significantly increased. Conversely, a significant decrease in splenic and lymph node NE concentration was measured in adjuvant-treated animals compared with that seen in vehicle-treated rats. Total NE content (pmol NE per whole organ weight) in lymphoid organs was not altered, except in popliteal lymph nodes (PLN), where it was increased. Collectively, our findings suggest that changes in NA innervation of lymphoid organs from AA rats result largely from increases or decreases in organ mass. Since NE released from NA nerves acts in a paracrine fashion, changes in lymphoid tissue volume that result from enhanced proliferation, migration, or cell death can make a significant difference in the availability of NE for interaction with immune target cells in these organs, even in the absence of a change in NE metabolism. Decreased thymic weight and increased spleen and lymph node weight should increase and decrease NE availability for interaction with target cells, respectively. Additionally, in PLN (a site where the highest concentration of antigen is encountered) an increase in total NE content suggests compensatory changes in NE metabolism.

Animals↗
PubMed1997

Residential lead-based-paint hazard remediation and soil lead abatement: their impact among children with mildly elevated blood lead levels.

OBJECTIVES: This prospective study describes the impact of residential lead-based-paint hazard remediations on children with mildly elevated blood lead levels. METHODS: Changes in blood lead levels were observed following paint hazard remediation alone and in combination with soil abatement. RESULTS: After adjustment for the confounding variables paint hazard remediation alone was associated with a blood lead increase of 6.5 micrograms/dL (P = 0.5), and paint hazard remediation combined with soil abatement was associated with an increase of 0.9 microgram/dL (P = 36). CONCLUSIONS: Lead-based-paint hazard remediation as performed in this study, is not an effective secondary prevention strategy among children with mildly elevated blood lead levels.

Boston↗
PubMed1996

Application of 6-hydroxydopamine into the fatpads surrounding the draining lymph nodes exacerbates adjuvant-induced arthritis.

Adjuvant-induced arthritis (AA) was examined in Lewis rats following local injection of 6-hydroxydopamine (6-OHDA) into the fatpads of the popliteal and inguinal lymph nodes which drain the hindlimbs (DLN). This method of 6-OHDA treatment resulted in noradrenergic (NA) denervation of DLN, spleen, and other organs in the peritoneal cavity, while sparing NA nerve fibers in the hindlimbs. Sympathectomy exacerbated the inflammation and osteopathic destruction of arthritic joints. Significant increases in dorsoplantar width in arthritic rats following denervation were observed by day 27 following immunization compared to nondenervated arthritic animals. Radiographic evaluation on day 27 after immunization confirmed the inflammation of soft tissue and revealed deterioration of bones of the ankle joint in both AA groups compared with the control groups; more extensive joint damage was apparent in arthritic rats following denervation compared to nondenervated arthritic rats. These findings suggest that the NA innervation of DLN and spleen (and possibly other organs of the peritoneal cavity) plays a regulatory role in the expression of AA. These data supports the hypothesis that absence of NA innervation in lymphoid organs during initiation, onset, and progression of the disease results in exacerbation of AA.

Adipose Tissue↗
PubMed1996

Biologically based, quantitative risk assessment of neurotoxicants.

The need for biologically based, quantitative risk assessment procedures for noncancer endpoints such as neurotoxicity has been discussed in reports by the United States Congress (Office of Technology Assessment, OTA), National Research Council (NRC), and a federal coordinating council. According to OTA, current attention and resources allocated to health risk assessment research are inadequate and not commensurate with its impact on public health and the economy. Methods to include continuous rather than dichotomous data for neurotoxicity endpoints, biomarkers of exposure and effects, and pharmacokinetic and mechanistic data have been proposed for neurotoxicity risk assessment but require further review and validation before acceptance. The purpose of this symposium was to examine procedures to enhance the risk assessment process for neurotoxicants and to discuss techniques to make the process more quantitative. Accordingly, a review of the currently used safety factor risk assessment approach for neurotoxicants is provided along with specific examples of how this process may be enhanced with the use of the benchmark dose approach. The importance of including physiologically based pharmacokinetic data in the risk assessment process and specific examples of this approach is presented for neurotoxicants. The role of biomarkers of exposure and effect and mechanistic information in the risk assessment process are also addressed. Finally, quantitative approaches with the use of continuous neurotoxicity data are demonstrated and the outcomes compared to those generated by currently used risk assessment procedures.

Biomarkers↗
PubMed1995

Models of delayed recovery.

After a biologic insult has impaired function of the developing central nervous system, recovery may not become apparent for years. Probability models adopted from the carcinogenesis, developmental neurobiology, learning decay, and stochastic process literatures are presented so that assumptions about apparent delays in the recovery process can be tested with data from longitudinal studies after a temporally circumscribed adverse event/exposure. This process of evaluating multiple models is exemplified with one data set. Nonlinear models of recovery are important because some children with early deficits first show improvement months to years later.

Brain↗
PubMed1995

A longitudinal study of chronic lead exposure and physical growth in Boston children.

We investigated the cross-sectional and longitudinal relationships between chronic exposure to lead and physical growth among a cohort of children reassessed 13 years after initial examination. We measured weight, height, and dentin lead levels of 270 children in 1975-78. In 1989-1990 we reexamined 79 of these children for measurement of weight, height, and bone lead levels by means of in vivo K X-ray fluorescence. To avoid potential confounding by race and chelation history, analysis was restricted to white subjects without a history of lead chelation therapy. A total of 236 subjects provided complete information for the study of cross-sectional relationship between dentin lead levels and changes in physical growth: 58 subjects for the study of longitudinal relationship between dentin lead levels and changes in physical growth and 54 subjects for the study of longitudinal relationship between bone lead levels and changes in physical growth. Dentin lead levels averaged 14.9 micrograms/g; tibia and patella lead levels averaged 1.2 and 5.0 micrograms/g, respectively. With control for potential confounders including age, sex, baseline body size, and mother's socioeconomic status, log10 dentin lead level was positively associated with body mass index as of 1975-1978 (beta = 1.02, p = 0.03) and increase in body mass index between 1975-78 and 1989-90 (beta = 2.65, p = 0.03). Bone lead levels were not significantly associated with physical growth. This is the first study relating chronic lead exposure to body mass index. The results suggest that chronic lead exposure in childhood may result in obesity that persists into adulthood.

Adolescent↗
PubMed1995

von Willebrand factor in plasma, platelets, and selected tissues of ferrets.

By standard laboratory methods the presence and activity of von Willebrand factor (vWF) was detected and characterized in the ferret (Mustela putorius furo); vWF in plasma, platelets, and selected tissues (thoracic aorta, cranial vena cava, thoracic portion of caudal vena cava, and lung) was documented. Activity, antigenic concentration, plasma multimeric distribution, and localization within tissues were similar to those features in other species. Two differences were apparent: multimeric distribution of platelet vWF was skewed toward the smaller molecular weight multimers, and mucous goblet, but not ciliated, cells of the bronchial epithelium stained positive for vWF. Larger molecular weight multimers were not released subsequent to administration of 1-deamino-8-D-arginine-vasopressin. The ferret may be a useful animal model in studying the role of vWF in hemostasis, thrombosis, and atherosclerosis. In particular, the role of small molecular weight multimers found in ferret platelets may provide further insight into the roles of platelet vWF multimeric distribution, platelet adhesion, and thrombosis.

Animals↗
PubMed1994

In vivo hepatic gene therapy: complete albeit transient correction of factor IX deficiency in hemophilia B dogs.

Hemophilia B is a bleeding disorder caused by mutations in the factor IX gene. The disorder is X-linked recessive with a prevalence of about 1 in 30,000 Caucasian males. Factor IX is naturally synthesized in the liver and secreted into blood. Here we report the construction of recombinant adenoviral vectors containing the canine factor IX cDNA that are capable of transducing hepatocytes in mice at high efficiencies in vivo without partial hepatectomy. The recombinant viral vector was used to treat hemophilia B dogs by direct vector infusion into the portal vasculature of deficient animals. Plasma factor IX concentrations in the treated hemophilia B dogs increased from 0 to 300% of the level present in normal dogs, resulting in complete amelioration of the disease as demonstrated by normal blood coagulation and hemostatic measurements. Although plasma factor IX concentration started to decline after a few days, therapeutic levels of factor IX persisted for 1-2 months in the treated animals. The results validate the principle of in vivo hepatic gene delivery to reconstitute the genetic deficiency in a large animal model and suggest that gene therapy is achievable when long-acting vectors are developed.

Adenoviridae↗
PubMed1994

Pre- and postnatal lead exposure and behavior problems in school-aged children.

The association between early lead exposure and later problem behaviors was evaluated prospectively in a cohort of 8-year-old children born during a 12-month period at one hospital. Lead levels in umbilical cord blood (means = 6.8 micrograms/dl, SD = 3.1) and the dentin of a shed deciduous tooth (means = 3.4 micrograms/g, SD = 2.4) provided measures of prenatal and postnatal exposure, respectively. Ratings on the Teacher Report Form of the Child Behavior Profile provided information about children's problem behaviors. Cord blood lead level was not associated with the overall prevalence or nature of problem behaviors. In both crude and adjusted analyses, tooth lead level was significantly associated with total problem behavior scores (approximately 2 points in T score per log unit increase in tooth lead). Significant tooth lead-associated increases in both internalizing and externalizing scores were also observed (approximately 1.5 points in T score per log unit increase). Weaker associations were noted between tooth lead level and the prevalence of "extreme" problem behavior scores. The extent to which these associations reflect residual confounding is uncertain. These data suggest, however, that social and emotional dysfunctions are correlates and may be expressions of increased lead exposure.

Child↗