Biomedical subjects

J M Fletcher

Publications and source records attributed to J M Fletcher.

At least 55 records · Page 3Linked to original sources

PubMed1999

Comorbidity of learning and attention disorders. Separate but equal.

Children with learning and attention disorders commonly present with symptoms of both types of disorders. In many children, this co-occurrence represents comorbid disorders that are separate but overlapping. Because of comorbidity, the presence of one disorder signals the need to evaluate for the other disorders. Evaluation and treatment approaches must address both disorders when present.

Attention Deficit Disorder with Hyperactivity↗

PubMed1999

Liver transplantation for citrullinaemia improves intellectual function.

BACKGROUND: Arginosuccinic acid synthetase (ASA) (EC 6.3.4.5) deficiency (citrullinaemia) (McKusick 215700) is a well-recognized cause of neonatal hyperammonaemic coma with poor long-term intellectual function, despite good medical management. METHODS: Cadaveric hepatic transplantation was performed in a 12-year-old boy with citrullinaemia under poor biochemical control. Subsequent development of fulminant hepatic failure necessitated a second cadaveric transplant. Psychometric assessments before and after transplantation were performed using a variety of age-appropriate tests. RESULTS: Normalization of plasma ammonium in our patient post transplantation has resulted in dramatic improvement in mental functioning and well-being and he now enjoys a normal diet. Psychometric assessment confirmed decline in his abilities prior to transplantation with particular post-transplantation improvement in perceptual organization and visuospatial abilities; these did not, however, return to normal. His family report considerable reduction in stress associated with the unpredictable nature of previous hyperammonaemic crises and recurrent hospitalization. CONCLUSIONS: Liver transplantation should be considered as an early therapeutic option in children with citrullinaemia to prevent ongoing cerebral insult associated with hyperammonaemia.

Amino Acid Metabolism, Inborn Errors↗

PubMed1999

Paired-associate learning in attention-deficit/hyperactivity disorder as a function of hyperactivity-impulsivity and oppositional defiant disorder.

A paired-associate learning (PAL) test was administered to 22 community volunteers without disruptive disorders and 197 children (7.5-13.5 years-old) presenting with the inattentive and combined subtypes of attention-deficit/hyperactivity disorder (ADHD) either in combination with or without oppositional defiant disorder (ODD). Participants were screened for learning disorders. In comparison to non-ADHD participants, children with ADHD achieved worse PAL and made errors rated as more acoustically and less semantically similar to the correct paired associates. These deficits were not related to hyperactivity-impulsivity or comorbid ODD. These results suggest that ADHD children are less competent at PAL and use less efficient learning strategies than their non-ADHD peers.

Adolescent↗

PubMed1999

Interhemispheric transfer of visual, auditory, tactile, and visuomotor information in children with hydrocephalus and partial agenesis of the corpus callosum.

Interhemispheric transfer was examined in 13 normal controls and in 13 children with hydrocephalus and partial agenesis of the corpus callosum involving a missing splenium associated with spina bifida meningomyelocele and aqueductal stenosis. Children with hydrocephalus demonstrated greater left visual-field superiority for forms indicative of difficulty in interhemispheric transfer of visual information. Interhemispheric transfer time (ITT) was somewhat longer in the children with hydrocephalus, but neither the ITT task nor the dichotic listening and tactile naming tasks provided clear evidence of difficulties in callosal transfer. Sensory and perceptual control tasks revealed similar visual acuity and monotic word perception but larger 2-point discrimination thresholds and poorer tactile matching.

Abnormalities, Multiple↗

PubMed1999

Executive functioning deficits in attention-deficit/hyperactivity disorder are independent of oppositional defiant or reading disorder.

OBJECTIVE: To evaluate deficits of executive functions in children with attention-deficit/hyperactivity disorder (ADHD) classified by type (combined [CT] or predominantly inattentive [IT]) and comorbidity with oppositional defiant disorder (ODD) and reading disorder (RD). METHOD: The Wisconsin Card Sorting Test (WCST) and Tower of Hanoi (TOH) were administered to 28 community volunteers and 359 children (7.5-13.5 years old) divided into ADHD types, RD, and ODD. RESULTS: ADHD/CT children solved fewer puzzles and violated more rules on the TOH than ADHD/IT or non-ADHD subjects. On the WCST there were no differences between diagnostic samples in perseverativeness, but ADHD/CT patients made more nonperseverative errors than ADHD/IT children. ODD was associated with moderately better TOH performance and RD with excessive rule breaks. CONCLUSIONS: Executive functioning deficits were found for only ADHD/CT children and were independent of comorbidity with RD or ODD.

Adolescent↗

PubMed1999

Persistence of dyslexia: the Connecticut Longitudinal Study at adolescence.

OBJECTIVE: The outcome in adolescence of children diagnosed as dyslexic during the early years of school was examined in children prospectively identified in childhood and continuously followed to young adulthood. This sample offers a unique opportunity to investigate a prospectively identified sample of adolescents for whom there is no question of the childhood diagnosis and in whom highly analytic measures of reading and language can be administered in adolescence. DESIGN: Children were recruited from the Connecticut Longitudinal Study, a cohort of 445 children representative of those children entering public kindergarten in Connecticut in 1983. Two groups were selected when the children were in grade 9: children who met criteria for persistent reading disability in grades 2 through 6 (persistently poor readers [PPR]; n = 21) and a comparison group of nondisabled children, subdivided into average readers (n = 35) and superior readers (n = 39). In grade 9, each child received a comprehensive assessment of academic, language, and other cognitive skills. RESULTS: Measures of phonological awareness (but not orthographic awareness) were most significant in differentiating the 3 reading groups, with smaller contributions from measures of word finding and digit-span. Academic measures that best separated good from poor readers were decoding and spelling, whereas measures of math and reading comprehension did not. Measures of phonological awareness, followed next by teacher rating of academic skills were the best predictors of decoding, reading rate, and reading accuracy. In contrast, the best predictor of reading comprehension was word finding, with digit span and socioeconomic status also contributing significantly. Using a growth curve model (quadratic model of growth to a plateau) all 3 groups demonstrated similar patterns of growth over time, with the superior group outperforming the average group, and the average group outperforming the PPR group. There was no evidence that the children in the PPR group catch up in their reading skills. CONCLUSIONS: Deficits in phonological coding continue to characterize dyslexic readers even in adolescence; performance on phonological processing measures contributes most to discriminating dyslexic and average readers, and average and superior readers as well. These data support and extend the findings of previous investigators indicating the continuing contribution of phonological processing to decoding words, reading rate, and accuracy and spelling. Children with dyslexia neither spontaneously remit nor do they demonstrate a lag mechanism for catching up in the development of reading skills. In adolescents, the rate of reading as well as facility with spelling may be most useful clinically in differentiating average from poor readers.

Adolescent↗

PubMed1998

Natural killer cell lysis of cytomegalovirus (CMV)-infected cells correlates with virally induced changes in cell surface lymphocyte function-associated antigen-3 (LFA-3) expression and not with the CMV-induced down-regulation of cell surface class I HLA.

CMV and other viruses down-regulate the cell surface expression of class I HLA, and while this allows them to evade CTL, it may make infected cells more susceptible to lysis by NK cells, due to the failure to engage class I inhibitory receptors on the NK cell. We studied CMV infection and found that fibroblasts infected with virus strains Towne, Toledo, Davis, and C1FE were refractory to NK lysis, while those infected with strains AD169, C1F, or R7 were susceptible. All viral strains down-regulated class I HLA to a similar extent, and we concluded that there was no evidence for any correlation between the latter and susceptibility to NK lysis. In contrast, there was a strong correlation between NK killing of CMV-infected cells and cell surface levels of lymphocyte function-associated antigen-3 (LFA-3). Fibroblasts infected with the Towne, Toledo, Davis, and C1FE strains of CMV down-regulated LFA-3 expression and were refractory to lysis, while strains AD169, C1F, and R7 up-regulated LFA-3 and were susceptible to NK killing. U373 MG (malignant glioma) cells expressed constitutively high levels of LFA-3 and were sensitive to NK lysis when infected with any of the above-listed CMV strains. We estimated that a minimum of between 29,000 and 71,000 LFA-3 molecules per target cell were needed for NK susceptibility. The effects on LFA-3 expression were due to immediate early/early viral gene products. We also demonstrated that fibroblasts infected with the strains Towne, Toledo, Davis, and C1FE expressed a ganciclovir-sensitive late CMV gene product, which delivered an inhibitory signal to NK cells.

Antibodies, Blocking↗

PubMed1998

Renal agenesis in mice homozygous for a gene trap mutation in the gene encoding heparan sulfate 2-sulfotransferase.

Heparan sulfate proteoglycans have been implicated in the presentation of a number of secreted signaling molecules to their signal-transducing receptors. We have characterized a gene trap mutation in the gene encoding a heparan sulfate biosynthetic enzyme, heparan sulfate 2-sulfotransferase (HS2ST). Transgenic mice were generated from embryonic stem cells harboring this insertion. lacZ reporter gene activity in heterozygous embryos demonstrates that the gene is expressed differentially during embryogenesis, presumably directing dynamic changes in heparan sulfate structure. Moreover, mice homozygous for the Hs2st gene trap allele die in the neonatal period, exhibiting bilateral renal agenesis and defects of the eye and the skeleton. Analysis of kidney development in Hs2st mutants reveals that the gene is not required for two early events-ureteric bud outgrowth from the Wolffian duct and initial induction of Pax-2 expression in the metanephric mesenchyme. It is required, however, for mesenchymal condensation around the ureteric bud and initiation of branching morphogenesis. Because 2-O-sulfation has been shown to influence the functional interactions of ligands with heparan sulfate in vitro, we discuss the possibility that the Hs2st mutant phenotype is a consequence of compromised interactions between growth factors and their signal-transducing receptors. These data provide the first genetic evidence that the regulated synthesis of differentially glycosylated proteoglycans can affect morphogenesis during vertebrate development.

Amino Acid Sequence↗

PubMed1998

X-linked adrenoleukodystrophy: the Australasian experience.

Our objective was to review the Australasian experience of X-linked adrenoleukodystrophy (ALD), to compare the spectrum of disease seen in Australasia with previously published data from elsewhere, and to assess the reliability of carrier testing. Study design was a retrospective review of records collected over a 15-year period, the setting was an international referral laboratory for the study of metabolic disease, and the subjects were all known cases of ALD diagnosed in Australia and New Zealand between 1981 and 1996 and their families. We estimate that the combined incidence of ALD and its variants in Australasia is at least 1.6 per 100,000. Of 95 affected males, 51 had cerebral adrenoleukodystrophy, 24 had adrenomyeloneuropathy, 15 had Addison's disease only, and 5 remained asymptomatic when last examined. However, the distribution of phenotypes among newly diagnosed patients has changed substantially over the last 15 years, with cerebral forms of the disease forming a decreasing proportion of new diagnoses. The measurement of plasma very long chain fatty acids (VLCFAs) alone detects 93% of women who can be proven to be carriers. The addition of genetic linkage studies or assay of VLCFAs in cultured fibroblasts improved this detection rate to the point that there were no obligate carriers who could not be detected using a combination of two or more techniques.

Adrenoleukodystrophy↗

PubMed1998

Functional disruption in the organization of the brain for reading in dyslexia.

Learning to read requires an awareness that spoken words can be decomposed into the phonologic constituents that the alphabetic characters represent. Such phonologic awareness is characteristically lacking in dyslexic readers who, therefore, have difficulty mapping the alphabetic characters onto the spoken word. To find the location and extent of the functional disruption in neural systems that underlies this impairment, we used functional magnetic resonance imaging to compare brain activation patterns in dyslexic and nonimpaired subjects as they performed tasks that made progressively greater demands on phonologic analysis. Brain activation patterns differed significantly between the groups with dyslexic readers showing relative underactivation in posterior regions (Wernicke's area, the angular gyrus, and striate cortex) and relative overactivation in an anterior region (inferior frontal gyrus). These results support a conclusion that the impairment in dyslexia is phonologic in nature and that these brain activation patterns may provide a neural signature for this impairment.

Brain↗

PubMed1998

Children's narratives following traumatic brain injury: linguistic structure, cohesion, and thematic recall.

Narrative discourse and intellectual functioning were examined 3 years following traumatic brain injury (TBI) in children 1 to 8 years of age at the time of injury. The language-impaired TBI group (n = 9) had language deficits during the subacute stage of recovery; their performance was contrasted with that of a TBI comparison group equated on neurologic and demographic variables that did not show subacute language impairment (n = 8) and a sibling comparison group (n = 9). The language-impaired TBI group had lower Verbal and Full-Scale IQ scores and produced fewer words and utterances than the sibling group on a story retelling task; their stories were characterized by fewer complete referential and lexical ties and more referential errors, indicating difficulty conjoining meaning across sentences. The language-impaired TBI group recalled approximately one-third of the propositions needed to maintain the story theme and made more errors sequencing the propositions than either the TBI or the sibling comparison groups. Group differences were not obtained on the Performance IQ scores or on measures of rate or fluency of speech production, mazes, use of conjunctives, or naming errors. The discourse deficiencies of children with TBI and acute language impairment were most pronounced at the level of cognitive organization of the text reflecting text macrostructure and were least apparent at the level of lexical and sentential organization reflecting text microstructure. Results are discussed in terms of the vulnerability of developing language abilities to disruption by brain injury.

Brain Injuries↗

PubMed1998

Memory functions in children with early hydrocephalus.

Children with arrested, shunted, and no hydrocephalus were compared on verbal and nonverbal memory tasks assessing multiple components of memory. A gradient of severity was hypothesized, with the shunted hydrocephalus group expected to exhibit the most significant memory impairments and the arrested group expected to perform more poorly than children with no hydrocephalus. Etiologies of prematurity, spina bifida, and aqueductal stenosis were represented by 157 participants. Results supported the hypothesis; the shunted hydrocephalus group performed poorer on all memory measures. Differences for the arrested group were less frequently statistically significant relative to children with no hydrocephalus. Irrespective of etiology, the shunted hydrocephalus group exhibited a pattern of performance suggestive of encoding and retrieval deficits on both verbal and nonverbal tasks, showing a pervasive disturbance of memory processes.

Analysis of Variance↗

PubMed1998

Allogeneic CD34 selected peripheral stem cell transplant for Maroteaux-Lamy syndrome (mucopolysaccharidosis type VI): rapid haemopoietic and biochemical reconstitution.

Severe Maroteaux-Lamy syndrome is usually fatal in teenage or early adult life. Until recently, allogeneic bone marrow transplantation was the only form of enzyme replacement. We report the first successful transplant using CD34 selected, mobilised allogeneic blood cells for an inborn error of metabolism. A busulphan, cyclophosphamide, melphalan and antithymocyte globulin conditioning regimen was used as myeloablative therapy. Allogeneic CD34 selected granulocyte colony-stimulating factor (G-CSF)-mobilised blood cells from a HLA-identical sibling were used for the transplant. Haemopoietic reconstitution occurred on day 10 post-transplant with normal N-acetylgalactosamine-4-sulphatase levels. Infectious and graft-versus-host disease (GVHD) complications were minimal. We suggest that CD34 selected, mobilised allogeneic blood cells are a safe form of enzyme replacement therapy in Maroteaux-Lamy syndrome and should be considered in other metabolic diseases where the benefits of haemopoietic transplantation are proven.

Adolescent↗

PubMed1998

Academic achievement and academic placement following traumatic brain injury in children and adolescents: a two-year longitudinal study.

Prospective, longitudinal follow-up of academic status following pediatric traumatic brain injury (TBI) identified that patients with severe TBI (n = 33) obtained significantly lower reading recognition, spelling, and arithmetic scores than those with mild to moderate TBI (n = 28). Independent of injury severity, adolescents scored lower than children on computational arithmetic and reading comprehension subtests. Although all achievement scores increased significantly from the baseline evaluation to 6 months after the injury, no further change was noted from 6 months to 2 years. Despite average achievement test scores by 2 years after TBI, 79% of the severely injured patients had either failed a grade or received special educational assistance. Traditional achievement tests may be insensitive to posttraumatic academic deficits.

Achievement↗

PubMed1998

Colored overlays for visual perceptual deficits in children with reading disability and attention deficit/hyperactivity disorder: are they differentially effective?

The Transient Channel Deficit (TCD) model of reading disability was evaluated by examining the effects of color overlays on the reading ability of four groups of children (n = 15 each) with reading disability and comorbid conditions involving math and ADHD. These 60 children were evaluated for reading accuracy and rate on measures of word decoding and reading comprehension under three color transparency conditions (blue, red, no overlay). Results indicated that color overlays did not differentially affect the reading performance of individuals with and without reading disabilities. However, blue transparencies significantly improved reading comprehension in all groups, and reduced reading rate. These findings indicate that the TCD model may need to be reexamined. An alternative hypothesis for the observed effects, involving facilitation of attention processes, was posted.

Adolescent↗

PubMed1998

Cytomegalovirus-infected endothelial cells recruit neutrophils by the secretion of C-X-C chemokines and transmit virus by direct neutrophil-endothelial cell contact and during neutrophil transendothelial migration.

Infection of endothelial cells with an endothelial cell-tropic clinical isolate of cytomegalovirus (CMV), C1FE, induced enhanced production of the neutrophil chemoattractant C-X-C chemokines interleukin-8 and GROalpha. Infected endothelial cell supernatants induced neutrophil chemotaxis in a transendothelial migration assay. Neutrophils acquired the CMV structural protein pp65 following either coculture with infected endothelial cells or transmigration through infected endothelium. The lack of CMV p72 expression in the neutrophils indicated that viral replication had not occurred in these cells. Of importance, neutrophils acquired infectious CMV during transmigration across infected endothelium and were subsequently able to transmit infectious virus to fibroblasts. Thus, CMV-infected endothelial cells can recruit neutrophils by the secretion of C-X-C chemokines and can transmit the virus to them by direct cell-to-cell contact and during neutrophil transendothelial migration, suggesting that the neutrophil-endothelial cell interaction plays an important role in virus dissemination in vivo.

Cell Communication↗

PubMed1998

Carcinoma of the male breast: a review and recommendations for management.

BACKGROUND: Male breast cancer is rare and experience of it in any single institution is limited. The aim of this study was to evaluate the presentation, management and outcome of male patients with breast cancer treated at Concord Repatriation General Hospital hospital over a 38-year period and to determine a best-practice protocol based on the results and a review of the literature. METHODS: A total of 42 patients were retrospectively reviewed, pathology slides were re-examined and reclassified where necessary. Outcome was assessed and compared with results obtained from a literature review. RESULTS: A trend towards less radical surgery has emerged. Overall 5-year survival was 50%, but, due to the late age at presentation, more than half the deaths were non-breast cancer related. One quarter of the patients presented with locally advanced or metastatic disease. CONCLUSIONS: The presentation, diagnosis pathology and outcome of breast cancer are similar in men and women, although the disease occurs at a later age in men. Radical surgery is not required in order to gain local control, but knowledge of axillary node status is important in determining prognosis and the need for adjuvant therapy.

Adult↗

PubMed1998

Neuroimaging, physical, and developmental findings after inflicted and noninflicted traumatic brain injury in young children.

OBJECTIVE: To characterize neuroimaging, physical, neurobehavioral, and developmental findings in children with inflicted and noninflicted traumatic brain injury (TBI) and to identify characteristic features of inflicted TBI. METHODS AND PATIENTS: Forty children, 0 to 6 years of age, hospitalized for TBI who had no documented history of previous brain injury were enrolled in a prospective longitudinal study. TBI was categorized as either inflicted (n = 20) or noninflicted (n = 20) based on the assessment of hospital and county protective services. Glasgow Coma Scale scores and neonatal history were comparable in both groups. OUTCOME MEASURES: Acute computed tomography/magnetic resonance imaging studies and physical findings were evaluated. Glasgow Outcome Scale scores, cognitive development, and motor functioning were assessed an average of 1.3 months after TBI. chi2 analyses assessed differences in the distribution of findings in the inflicted and noninflicted TBI groups. RESULTS: Signs of preexisting brain injury, including cerebral atrophy, subdural hygroma, and ex vacuo ventriculomegaly, were present in 45% of children with inflicted TBI and in none of the children with noninflicted TBI. Subdural hematomas and seizures occurred significantly more often in children with inflicted TBI. Intraparenchymal hemorrhage, edema, skull fractures, and cephalohematomas were similar in both groups. Retinal hemorrhage was only identified in the inflicted TBI group. Glasgow Outcome Scale scores indicated a significantly less favorable outcome after inflicted than noninflicted TBI. Mental deficiency was present in 45% of the inflicted and 5% of the noninflicted TBI groups. CONCLUSIONS: Characteristic features of inflicted TBI included acute computed tomography/magnetic resonance imaging findings of preexisting brain injury, extraaxial hemorrhages, seizures, retinal hemorrhages, and significantly impaired cognitive function without prolonged impairment of consciousness.

Brain Damage, Chronic↗