PubMed Health⌕ Search

Biomedical subjects

G Dawson

Publications and source records attributed to G Dawson.

At least 19 recordsLinked to original sources
PubMed2003

Regional brain chemical alterations in young children with autism spectrum disorder.

OBJECTIVE: The authors evaluated regional brain chemistry for evidence of increased neuronal packing density in autism. METHODS: Forty-five 3- to 4-year-old children with autism spectrum disorder (ASD), 13 children with typical development (TD), and 15 children with delayed development (DD) were studied using dual-echo proton echoplanar spectroscopic imaging (32 x 32 matrix-1 cm(3) voxels) to measure brain chemical concentrations and relaxation times. Chemical quantification was corrected for tissue partial volume and relative measures of chemical relaxation (T(2r)) were calculated from the paired echoes. Measures from averaged and individual regions were compared using analysis of variance corrected for multiple comparisons. RESULTS: ASD subjects demonstrated reduced N-acetylaspartate (NAA) (-10%), creatine (Cre) (-8%), and myo-inositol (-13%) concentrations compared to TD controls and prolonged NAA T(2r) relative to TD (7%) and DD (9%) groups. Compared to DD subjects, children with ASD also demonstrated prolonged T(2r) for choline (10%) and Cre (9%). Regional analyses demonstrated subtle patterns of chemical alterations in ASD compared to the TD and DD groups. CONCLUSIONS: Brain chemical abnormalities are present in ASD at 3 to 4 years of age. However, the direction and widespread distribution of these abnormalities do not support hypothesis of diffuse increased neuronal packing density in ASD.

Age Distribution↗
PubMed2003

Placental, maternal serum and amniotic fluid molecular weight forms of inhibin A and pro-alphaC.

Previous studies have identified the presence of unidentified small molecular weight (mol wt) forms of inhibin and the pro-alphaC region of the inhibin alpha subunit in serum from women during late pregnancy. The aim of this study was to investigate if these gestational-related changes in mol wt forms arose from changing placental production. Pooled placental extracts, derived from normal healthy singleton pregnancies in the 1st, 2nd and 3rd trimesters of pregnancy, were fractionated by a combined immunoaffinity chromatography, preparative PAGE and electroelution procedure. Inhibin A, inhibin B and the pro-alphaC region of the inhibin alpha subunit were determined in the eluted fractions by specific ELISAs, with the profiles of immunoactivity characterized in terms of molecular size and percentage recovery. Inhibin B was undetectable in all samples. Mol wt peaks of 36k, 75K and 97K for inhibin A and 29k, 55K and 97K for pro-alphaC were detected in placental extracts across all three trimesters. The relative abundancy of small mol wt inhibin A forms (<30K) present in the placenta increased significantly in the third trimester placenta, increasing from 0.3 per cent in the first trimesters to 6 per cent in the third trimester (P=0.01, chi-squared test). The relative abundances of various mol wt forms of pro-alphaC was similar at all three gestations (P=0.67). In serum, small mol wt inhibin A and pro-alphaC forms accounted for 23.4 per cent and 37.4 per cent of inhibins, respectively, in the third trimester. These data suggest that the presence of small mol wt forms of both inhibin A and pro-alphaC in maternal serum is only partially attributed to placental production and/or secretion. We conclude that inhibin A and pro-alphaC inhibins in maternal serum are processed in late pregnancy by more than one mechanism to form low mol wt circulating forms of, as yet, undetermined structure.

Adult↗
PubMed2002

Brain structural abnormalities in young children with autism spectrum disorder.

OBJECTIVE: To explore the specific gross neuroanatomic substrates of this brain developmental disorder, the authors examine brain morphometric features in a large sample of carefully diagnosed 3- to 4-year-old children with autism spectrum disorder (ASD) compared with age-matched control groups of typically developing (TD) children and developmentally delayed (DD) children. METHODS: Volumes of the cerebrum, cerebellum, amygdala, and hippocampus were measured from three-dimensional coronal MR images acquired from 45 children with ASD, 26 TD children, and 14 DD children. The volumes were analyzed with respect to age, sex, volume of the cerebrum, and clinical status. RESULTS: Children with ASD were found to have significantly increased cerebral volumes compared with TD and DD children. Cerebellar volume for the ASD group was increased in comparison with the TD group, but this increase was proportional to overall increases in cerebral volume. The DD group had smaller cerebellar volumes compared with both of the other groups. Measurements of amygdalae and hippocampi in this group of young children with ASD revealed enlargement bilaterally that was proportional to overall increases in total cerebral volume. There were similar findings of cerebral enlargement for both girls and boys with ASD. For subregion analyses, structural abnormalities were observed primarily in boys, although this may reflect low statistical power issues because of the small sample (seven girls with ASD) studied. Among the ASD group, structural findings were independent of nonverbal IQ. In a subgroup of children with ASD with strictly defined autism, amygdalar enlargement was in excess of increased cerebral volume. CONCLUSIONS: These structural findings suggest abnormal brain developmental processes early in the clinical course of autism. Research currently is underway to better elucidate mechanisms underlying these structural abnormalities and their longitudinal progression.

Amygdala↗
PubMed2002

Molecular weight forms of inhibin A, inhibin B and pro-alphaC in maternal serum, amniotic fluid and placental extracts of normal and Down syndrome pregnancies.

BACKGROUND: Inhibin A, an established prenatal marker of Down syndrome (DS), exists in the maternal circulation in a number of isoforms. The present study explored whether specific inhibin A isoforms may be selectively increased in DS, offering the prospect of improved marker performance. METHODS: Second trimester maternal serum, placental extracts and amniotic fluid (AF) pools from both normal and DS pregnancies were fractionated by a combined immunoaffinity (IA) chromatography, preparative polyacrylamide gel electrophoresis (Prep-PAGE) and electroelution procedure. Inhibins A, B and pro-alphaC were determined in the eluted fractions by specific enzyme-linked immunosorbent assays (ELISAs) and the profiles of immunoactivity (IA) characterized in terms of molecular weight (MW) and percentage recovery. RESULTS: The MW patterns of inhibin A and pro-alphaC in maternal serum and AF were similar between DS and control pregnancies, both showing peaks between 25-40 k and approximately 65 k. AF contained, in addition, a higher proportion of <30 k inhibins A and B, and <25 k pro-alphaC forms. There were large differences in the inhibin forms present in DS placentae, with more 70 k and less 30-40 k inhibin A than in controls. CONCLUSIONS: The present data suggest that the processing, cleavage or secretion of inhibin MW forms by the DS placenta differs from normal. However, these differences are not reflected in maternal serum and so improvements in serum screening will not be afforded by measuring specific inhibin A isoforms.

Adult↗
PubMed2002

Comparison of buoyancy, passive and net active drag forces between Fastskin and standard swimsuits.

A cross-sectional comparison between the buoyancy, passive and net active drag force characteristics of full-length, Fastskin swimsuits with that of standard swimsuits was completed with nine Open National level swimmers (5 males and 4 females). Subjects were weighed in a hydrostatic tank and then towed via a mechanical winch on the surface and 0.4 m deep at 1.6, 2.2 and 2.8 m/s. The subjects performed a prone streamlined glide and maximum effort flutter kick at each towing velocity and depth. Hydrostatic weight differences between swimsuit types were not significant (p> 0.05. Fastskin passive drag values were significantly less than normal swimsuits during surface towing at 1.6 and 2.8 m/s: and at 0.4 m deep towing at 1.6, 2.2 and 2.8 m/s. Net active drag force values also were lower for the Fastskin suits when compared with those of normal swimsuits and a significant difference existed for surface towing at all three velocities of 1.6, 2.2 and 2.8 m/s. The full-length, Fastskin swimsuits created less total hydrodynamic resistance than normal swimsuits while providing no additional buoyancy benefits.

Clothing↗
PubMed2001

Alpha-B crystallin gene (CRYAB) mutation causes dominant congenital posterior polar cataract in humans.

Congenital cataracts are an important cause of bilateral visual impairment in infants. In a four-generation family of English descent, we mapped dominant congenital posterior polar cataract to chromosome 11q22-q22.3. The maximum LOD score, 3.92 at recombination fraction 0, was obtained for marker D11S898, near the gene that encodes crystallin alpha-B protein (CRYAB). By sequencing the coding regions of CRYAB, we found in exon 3 a deletion mutation, 450delA, that is associated with cataract in this family. The mutation resulted in a frameshift in codon 150 and produced an aberrant protein consisting of 184 residues. This is the first report of a mutation, in this gene, resulting in isolated congenital cataract.

Amino Acid Sequence↗
PubMed2001

A TSM sensor investigation of low crystallinity cellulose films.

A thickness shear mode (TSM) quartz sensor has been used to characterize the substantivity, viscoelasticity, and mucoadhesive properties of low crystallinity cellulose (LCC) films. LCC is a novel pharmaceutical excipient that has been attributed with mucoadhesive properties. Thin films of LCC were deposited onto TSM sensors by a spin coating technique. The films were treated by passing water or 1.0% w/v mucin solution (pH 3.7 or 7.0) over the surface. Changes in the mass and viscosity of the film were observed by monitoring changes in the impedance spectra of the coated TSM sensors. Scanning electron micrographs (SEMs) of each film were used to assist the interpretation of the TSM sensor data. This study showed that LCC forms highly tenacious and viscoelastic films able to withstand prolonged (approximately 1 h) exposure to both water and mucin solution. Furthermore, these results indicate that the films may have mucoadhesive properties as LCC was found to bind significant (P<0.05) amounts of mucin in comparison with control measurements. Mucin binding to the LCC sensor was greater at pH 3.7 (P<0.05) than at pH 7.0, suggesting that the LCC formulation is mucoadhesive under these conditions.

Cellulose↗
PubMed2001

Increased extracellular magnesium modulates proliferation in fetal neural cells in culture.

Retrospective studies have shown that antenatal magnesium may decrease the risk of cerebral injury in preterm infants, leading to several ongoing trials of tocolytic magnesium as a neuroprotective agent. However, other studies have indicated that antenatal magnesium actually increases neonatal mortality, leaving it unclear if magnesium is protective or dangerous to preterm infants. This controversy may be secondary to our limited understanding about the mechanisms of magnesium's action on the fetal brain. We therefore investigated the effect of increasing extracellular magnesium on cultures of neurons from embryonic day 6 telencephalon. Conversion of MTT (3-(4,5-dimethyl, thiazol-2-yl)-2,5-diphenyltetrazolium bromide) by intact mitochondria was taken as a measure of cell viability. Nuclear incorporation of BrdU (5-bromo-2'-deoxyuridine) was taken as a measure of cell proliferation. Exposure of cultures for 24 h to a 4-fold increase in magnesium (3.3 mM) increased both overall cell viability (P<0.002) and proliferation (P<0.02) by approximately 50%. Proliferating cells showed characteristics of glial cell precursors but magnesium had no effect on mature astrocyte proliferation. Increased Akt activation was observed following magnesium treatment, comparable to that observed with the growth factor insulin, suggesting one mechanism for proliferation. However, when apoptosis was induced in these cultures with the phosphatidylinositol-3-kinase inhibitor wortmannin, magnesium significantly enhanced cell death. Thus under normal conditions in the fetus, magnesium may be a positive factor but during stress it may exacerbate cell injury. This is the first time increased extracellular magnesium has been shown to increase cell proliferation in neural cells in culture or suggested to induce Akt activation.

Androstadienes↗
PubMed2001

Prototype formation in autism.

Individuals with autism have difficulty integrating information and generalizing previously learned concepts to new situations. It was hypothesized that these problems result from an underlying impairment in category formation. Persons with autism may not abstract a summary representation (a prototype) during category learning and, instead, may form categories by memorizing a list of rules. Children with autism, Down syndrome, and normal development participated in one set of category learning tasks that could be solved using a rule-based approach and a second set of tasks in which there was no rule that defined category membership (prototype tasks). In the rule-based tasks, all groups were successful at using a rule to learn a new category. In the prototype tasks, only the typically developing children were able to learn a new category. Neither the persons with autism nor the persons with Down syndrome appeared to develop a prototype during category learning. These data suggest that persons with autism and Down syndrome have difficulty categorizing new information by forming prototypes and, instead, tend to rely on a rule-based approach to learning.

Adolescent↗
PubMed2001

Role of palmitoyl-protein thioesterase in cell death: implications for infantile neuronal ceroid lipofuscinosis.

Infantile neuronal ceroid lipofuscinosis (INCL) is a childhood neurodegenerative disease caused by the selective death of cortical and retinal neurons as the result of an inherited palmitoyl-protein thioesterase 1 (PPT1) deficiency. Neuronal death is common to many lysosomal storage diseases but it occurs very early in INCL and we show here that inhibition of PPT1 increases the susceptibility of these cells to apoptotic cell death. Thus transient transfection of LA-N-5 neuroblastoma cells with a reverse-oriented (antisense) PPT1 (AS-PPT1) reduced PPT1 enzyme activity (as measured by an in vitro assay) and increased the susceptibility to apoptosis induced by C2 ceramide. Similarly, inhibition of PPT1 with a synthetic inhibitor (AcG-palmitoyl diaminoproprionate-VKIKK) (DAP1) (100 microM) increased the susceptibility of the cells to apoptosis induced by either C2-ceramide or etoposide and Adriamycin (doxorubicin), common chemotherapeutic agents used in the treatment of solid tumours. In contrast, overexpression of PPT1 led to increased resistance to cell death induced by these drugs.

Antibiotics, Antineoplastic↗
PubMed2000

Antisense palmitoyl protein thioesterase 1 (PPT1) treatment inhibits PPT1 activity and increases cell death in LA-N-5 neuroblastoma cells.

Infantile neuronal ceroid lipofuscinosis (INCL) is a childhood neurodegenerative disease caused by the selective death of cortical neurons and retinal degeneration, as the result of a palmitoyl protein thioesterase 1 (PPT1) deficiency. Recently, we showed that overexpression of PPT1 protects LA-N-5 human neuroblastoma cells against apoptotic death (Cho and Dawson [2000a] J. Neurochem. 74:1478-1488) and we now show that inhibition of PPT1 increases the susceptibility of these cells to apoptotic cell death. Transient transfection of LA-N-5 neuroblastoma cells with PPT1-FLAG resulted in a strong expression of PPT-FLAG-tagged protein as evidenced by Western blot analysis and immunofluorescence. Co-transfection of a reverse-oriented (antisense) PPT1 (AS-PPT1) decreased the expression of PPT-FLAG to almost zero, reduced PPT1 enzyme activity (as measured by an in vitro assay) and increased the susceptibility to apoptosis induced by C(2) ceramide. Similarly, inhibition of PPT1 with a synthetic inhibitor (AcG-palmitoyl diaminoproprionate-VKIKK) (DAP1) (100 microM) increased the susceptibility of the cells to apoptosis induced by either C(2)-ceramide or etoposide, a common chemotherapeutic agent used in the treatment of neuroblastoma. Cells stably overexpressing PPT1 were resistant to apoptosis induced by DAP1 suggesting that the inhibitor has a specific action and confirming that low levels of protein palmitoylation block the death pathway. Drugs that raise the level of protein palmitoylation are pro-apoptotic and PPT1 inhibition may enhance the killing efficacy of chemotherapeutic agents used to kill neuroblastoma-derived cells.

Antineoplastic Agents↗
PubMed2000

Galanin regulates the postnatal survival of a subset of basal forebrain cholinergic neurons.

The neuropeptide galanin colocalizes with choline acetyltransferase, the synthetic enzyme for acetylcholine, in a subset of cholinergic neurons in the basal forebrain of rodents. Chronic intracerebroventricular infusion of nerve growth factor induces a 3- to 4-fold increase in galanin gene expression in these neurons. Here we report the loss of a third of cholinergic neurons in the medial septum and vertical limb diagonal band of the basal forebrain of adult mice carrying a targeted loss-of-function mutation in the galanin gene. These deficits are associated with a 2-fold increase in the number of apoptotic cells in the forebrain at postnatal day seven. This loss is associated with marked age-dependent deficits in stimulated acetylcholine release, performance in the Morris water maze, and induction of long-term potentiation in the CA1 region of the hippocampus. These data provide unexpected evidence that galanin plays a trophic role to regulate the development and function of a subset of septohippocampal cholinergic neurons.

Animals↗
PubMed2000

Practice parameter: screening and diagnosis of autism: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Child Neurology Society [RETIRED].

Autism is a common disorder of childhood, affecting 1 in 500 children. Yet, it often remains unrecognized and undiagnosed until or after late preschool age because appropriate tools for routine developmental screening and screening specifically for autism have not been available. Early identification of children with autism and intensive, early intervention during the toddler and preschool years improves outcome for most young children with autism. This practice parameter reviews the available empirical evidence and gives specific recommendations for the identification of children with autism. This approach requires a dual process: 1) routine developmental surveillance and screening specifically for autism to be performed on all children to first identify those at risk for any type of atypical development, and to identify those specifically at risk for autism; and 2) to diagnose and evaluate autism, to differentiate autism from other developmental disorders.

Asperger Syndrome↗
PubMed2000

Selective phosphotyrosine phosphatase inhibition and increased ceramide formation is associated with B-cell death by apoptosis.

Bis(maltolato)oxovanadium(IV) (BMOV), a protein phosphotyrosine phosphatase inhibitor, selectively induced apoptosis (as quantitated by TUNEL staining) in a B-cell line (Ramos) but not in a T-cell line (Jurkat). The pattern of BMOV-induced protein tyrosine phosphorylation was different in B-cells versus T-cells. Further, BMOV induced a 2-fold increase in ceramide levels in B-cells but not in T-cells and this resembled the ceramide increase following activation of the B-cell antigen receptor. A 2-fold increase in the ratio of ceramide to sphingomyelin in B-cells treated with BMOV suggested that sphingomyelinase activation was the result of the sustained tyrosine phosphorylation of specific proteins and activated the cell death pathway.

Apoptosis↗
PubMed2000

Batten's disease: clues to neuronal protein catabolism in lysosomes.

Neuronal ceroid lipofuscinosis (Batten disease) encompasses a group of 8 or more inherited lysosomal storage diseases, with an overall frequency of 1 in 12,500 births. All are characterized by progressive blindness and dementia and were initially classified on the basis of age of onset, clinical phenotype and ultrastructural characterization of the storage material as granular osmiophilic deposits, curvilinear bodies or fingerprint bodies. Recent research has shown that the various forms of Batten disease result from mutations in at least 8 genes which code for proteins involved in different aspects of lysosomal protein catabolism. These include palmitoyl:protein thioesterase 1 (CLN1), tripeptidylpeptidase 1 (CLN2), cathepsin D (CLN8), and two membrane proteins of unknown function (CLN3 and CLN5). Biochemically, Batten disease is characterized by the accumulation in neurons and other cells of an autofluorescent pigment which has resisted many attempts at analysis. In this review we attempt to relate our current understanding of the nature of the storage material in Batten disease with this genetic information. We conclude that the 8 genes probably code for proteins which facilitate the degradation of post-translationally modified proteins in lysosomes, suggesting that the turnover of these proteins is highest in cortical neurons.

Animals↗