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Biomedical subjects

V A Anderson

Publications and source records attributed to V A Anderson.

At least 19 recordsLinked to original sources
PubMed2005

Identifying factors contributing to child and family outcome 30 months after traumatic brain injury in children.

OBJECTIVE: To examine the contributions of injury severity, physical and cognitive disability, child and family function to outcome 30 months after traumatic brain injury (TBI) in children. DESIGN: A prospective, longitudinal, between group design, comparing function before and after injury across three levels of injury severity. SUBJECTS: One hundred and fifty children, 3.0-12.11 years old, admitted to hospital with a diagnosis of TBI. The sample was divided according to injury severity: mild (n = 42), moderate (n = 70), severe (n = 38). Children with a history of neurological, developmental, and psychiatric disorders were excluded from participation. MAIN OUTCOME MEASURES: Post injury physical function, cognitive ability (incorporating intellect, memory, and attention), behavioural and family functioning, and level of family burden. RESULTS: A dose-response relation was identified for injury severity and physical and cognitive outcome, with significant recovery documented from acute to six months after TBI. Behavioural functioning was not related to injury severity, and where problems were identified, little recovery was noted over time. Family functioning remained unchanged from preinjury to post injury assessments. The level of family burden was high at both six and 30 months after injury, and was predicted by injury severity, functional impairment, and post injury child behavioural disturbance. CONCLUSIONS: These results suggest ongoing problems for the child and significant family burden 30 months after TBI. The nature and severity of the physical and cognitive problems are closely related to injury severity, with child and family function predicted by psychosocial and premorbid factors.

Adaptation, Psychological↗
PubMed2002

Engineered antibody for treating lymphoma.

One approach to improving the results of antibody treatment of posttransplant and other lymphomas is to alter the geometry of the antibody molecule so as to enhance its cytotoxicity. When antibody alights on a cell, cytotoxicity can be exerted by initiation of apoptotic signals at the cell surface, and by recruitment of effectors to specific sites on the antibody Fc region. Other routes to cytotoxicity have been described but their generality is debatable. The effectors consist of complement, and a series of potentially cytotoxic cells (macrophages, NK cells, neutrophils and others) bearing Fc-receptors (FcR). Recent evidence suggests that the FcR-bearing cells are the more important in dealing with antibody-coated autologous cells, including tumor cells. If the antibody happens to be of the host IgG class then its Fc region (Fcgamma) will contain a site for attachment of a non-cytotoxic FcR known as FcRB (the Brambell receptor): it is this receptor, present on endothelial cells, which recycles the molecule intact if it happens to be endocytosed and thus prolongs its metabolic life. Replacement of the mouse Fcgamma by human Fcgamma is expected to have three beneficial effects: better recruitment of human effector cells, better persistence of the antibody in extracellular fluid, and removal of a major source of immunogenic epitopes. Chemical manipulations of Fab'gamma and Fcgamma modules, linking them in different geometries via their hinge regions, offers constructs with further enhancements of cytotoxicity. These include Fab2Fc2, in which the presence of dual Fc regions enhances recruitment of both complement and cellular effectors; and bispecific antibody of the same modular formula in which one of the Fab arms is specific for tumor while the other is specific for, and recruits powerfully, a cellular effector.

Animals↗
PubMed2002

"Clockness" in the detection of dementia: a semantic-conceptual effect.

We studied aspects of clock cognition that might underlie the sensitivity of the CDT in screening for dementia of the Alzheimer type (DAT). Two groups, 15 patients with mild-moderate DAT and 15 controls, were assessed with the CDT and specially designed tests of clock-related cognition. Patients were impaired on the CDT, but they did not differ from controls in copying a clock face or selecting the correct representation of a given time. Patients were worse than controls at distinguishing between clock and nonclock objects, detecting anomalies in clocks, and in setting time irrespective of response format. These findings suggest that semantic-conceptual aspects of clock-related cognition are important in discriminating between patients with DAT and controls.

Aged↗
PubMed2001

Thioether-bonded constructs of Fab'gamma and Fc gamma modules utilizing differential reduction of interchain disulfide bonds.

We describe a two-stage preparation of chemically engineered Ab constructs, employing as modules Fab'gamma from mAb or rAb, and Fc from human normal IgG1. A multivalent, optionally multispecific F(ab')(n) core is formed in stage one, and one or more Fc modules added in stage two. Examples include bispecific Fab(2)Fc(2) (for simplicity, primes and Greek letters are omitted from names of final constructs) and trivalent Fab(3)Fc(2), which are designed to kill neoplastic cells. An essential element in the construction is the availability of the Fab' in two reduced forms, Fab'(-sulfhydryl (SH))(5) and Fab'-SH. The first is obtained by full reduction of the interchain disulfide bonds (SS) in the F(ab')(2) fragment of IgG. Fab'-SH is obtained by disulfide-interchange reactions on Fab'(-SH)(5), whereby the gamma-light SS is reconstituted, an unusual intrachain SS forms in the gamma-chain hinge, and one hinge SH remains. F(ab')(2) and F(ab')(3) cores are built using partially reduced modules, being given intermodular thioether links that resist reduction. These cores are then fully reduced, making available SH groups for addition of the Fcgamma modules. In the final constructs, all intermodular links embody tandem thioether bonds arising at hinge-region cysteines. Cytotoxic activities of representative constructs, and some enhancements deriving from multiple modules, are assessed. In guinea pigs, catabolism of Fab(2)Fc(2) yielded a t(1/2) similar to that of human IgG1, although the serum Fab(2)Fc(2) revealed some proteolytic breakdown not shown by the IgG1. Immunotherapy of a guinea-pig leukemia confirmed the ability of these constructs to kill target cells in vivo.

Animals↗
PubMed2001

Predictors of acute child and family outcome following traumatic brain injury in children.

OBJECTIVE: To examine the relative contributions of injury severity, level of physical and cognitive disability, child behavior and family function to short-term outcome 6 months following traumatic brain injury (TBI) in children. DESIGN: Prospective, longitudinal, between-group design, comparing preinjury and postinjury measures of functional outcome across three levels of injury severity. SUBJECTS: One hundred and twelve children, aged 2-12 years admitted to the Royal Children's Hospital, Melbourne, with a diagnosis of TBI. The sample was divided into three groups, according to injury severity: mild TBI (n = 31), moderate TBI (n = 52) and severe TBI (n = 29). Children with a history of neurologic, developmental and psychiatric disorder were excluded from participation. MAIN OUTCOME MEASURES: Levels of postinjury functioning in the following domains: physical function, cognitive ability (incorporating intellect, memory and attention), behavioral and family functioning, and level of family burden. RESULTS: A clear dose-response relationship for physical and cognitive outcomes was found, with severe TBI associated with greater impairment of physical, intellectual, memory and attentional function. For psychosocial outcome, results were less clearly linked to injury severity. Preinjury behavioral and family functioning were closely related to postinjury function in these domains, with an interaction identified between family function and child behavior at 6 months postinjury. Family functioning remained unchanged postinjury, although level of burden was high, and predicted by injury severity, functional impairment and postinjury behavioral disturbance. CONCLUSIONS: These results suggest ongoing functional problems for the child and significant family burden 6 months following TBI. The nature and severity of physical and cognitive problems are most closely related to injury severity, with family functioning and child behavior better predicted by psychosocial and premorbid factors.

Acute Disease↗
PubMed2001

Development of executive functions through late childhood and adolescence in an Australian sample.

Although there have been significant theoretical advances in the field of child neuropsychology, developmental features of adolescence have received less attention. Progress in clinical practice is restricted due to a lack of well-standardized, developmentally appropriate assessment techniques. This article addresses these issues in relation to executive skills. These abilities are targeted for 2 reasons: first, because they are often considered to be mature during late childhood and adolescence, despite limited investigation in this age range; and second, because of their central importance to efficient day-to-day functioning. Using a normative sample of 138 children, aged 11.0 to 17.11 years, this article plots the development of executive skills through late childhood and early adolescence and interprets progress in these skills with reference to current neurological and cognitive theory.

Adolescent↗
PubMed2000

Complement mediated cell death is associated with DNA fragmentation.

In this study, we demonstrate for the first time that complement attack of target cells, in the presence of suitably high levels of serum, can induce the oligonucleosomal DNA fragmentation characteristic of apoptosis. This phenomenon requires membrane permeabilisation induced by formation of the complete membrane attack complex and relies on physiologically relevant levels of serum. TUNEL analysis detected complement mediated DNA fragmentation as early as 30 min after the addition of serum and electron microscopy confirmed that chromatin became condensed after complement attack. Various experiments implicate serum DNase I as the mediator of this DNA fragmentation. Intriguingly, membrane permeability induced by melittin gave rise to similar serum dependent DNA fragmentation. The implications of these results for the study of apoptosis in vitro and in vivo are discussed.

Animals↗
PubMed2000

Cognitive and academic outcome following cranial irradiation and chemotherapy in children: a longitudinal study.

Cranial irradiation therapy (CRT) and chemotherapy are associated with neurobehavioural deficits. Many studies have investigated late effects of these treatments, but few have evaluated changes in abilities over time. This study employed a longitudinal design to map abilities following these treatments. Three groups of children were studied: Group 1 (n = 35): children treated with CRT (18 Gy) + chemotherapy, aged 5 years or less at time of diagnosis; Group 2 (n = 19): children treated with chemotherapy alone, aged 5 years or less at time of diagnosis; Group 3 (n = 35): healthy children. All children were aged 7-13 years at time of initial assessment, with no pre-diagnosis history of neurologic, developmental, or psychiatric disorder. Intellectual and educational abilities were evaluated twice: T1, not less than 2 years post-treatment, and T2, 3 years later. Group 1 achieved poorest results at T1, with comparison groups performing similarly. At T2 group differences were maintained. For verbal skills differences remained stable. Group 1 exhibited deterioration on non-verbal and processing tasks, while comparison groups showed improved abilities. Group 1 exhibited increases in literacy skills, with educational intervention predicting progress. Results suggest cumulative deficits in non-verbal and information processing skills for children treated with CRT + chemotherapy, with other deficits remaining relatively stable over time. Improved literacy skills suggest that gains can occur with remediation.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2000

The implications of childhood bacterial meningitis for language development.

Bacterial meningitis is a life threatening infection of the central nervous system. This illness is most prevalent early in life when the healthy child is rapidly acquiring language. This study investigated whether children with a history of bacterial meningitis were at risk for language difficulties post illness. Thirty post-meningitic children, aged between 9 years 0 months and 11 years 0 months, participated in this study. Each subject was administered a measure of non-verbal cognitive ability and a range of language tasks. These children performed poorly on applied language tasks, which tap skills used in effective discourse. These deficits occurred despite age appropriate performances on measures of linguistic/grammatical knowledge. These findings clearly illustrate that bacterial meningitis has implications for ongoing language development, which emphasises the importance of long term follow up. In developmental terms, this discrepancy between verbal knowledge and problem solving represents a dissociation between language skills which develop early in life and those which emerge later. This pattern of results suggests that bacterial meningitis may result in a delay in language development. A young age at illness was identified as an additional risk factor for adverse outcome. This study highlights the need to inform parents/guardians that post-meningitic children are at risk for experiencing language difficulties throughout childhood.

Brain Damage, Chronic↗
PubMed2000

Recovery of memory function following traumatic brain injury in pre-school children.

Traumatic brain injury (TBI) may have a profound impact on a child's ongoing development. Various risk factors have been found to predict outcome, but considerable variability remains unexplained. This study used a prospective, longitudinal design to examine recovery of memory function following TBI within the pre school period. Ninety-six children with TBI were divided according to injury severity (mild, moderate, severe), and compared to age and SES matched healthy controls (n = 35). Children were evaluated acutely and at 6,12 and 18 months post-injury using intellectual and memory measures. Results showed a relationship between greater injury severity and poorer intellectual ability. This dose-response relationship was not clearly evident for memory function within the acute phase of recovery, but developed over time, with greater memory impairments evident for children with more severe TBI by 12 months post-injury. Children with mild TBI exhibited few memory problems. Findings are discussed in the context of theories of plasticity and recovery of function.

Amnesia↗
PubMed1999

Preparation of fcgamma for addition to sulfhydryl-expressing ligands with minimal disturbance of the hinge.

We described previously a scheme for linking functionally intact human normal Fcgamma1, via a thioether linkage emerging from its hinge, to any molecule expressing a free sulfhydryl group (SH). The scheme entails reducing the Fc to release four SH from the two inter-gamma disulfide bonds (SS) in the hinge, blocking one SH by a stochastic alkylation, restoring by SS-interchange the inter-gamma SS whose two SH are still available, and attaching a bismaleimide linker to the one remaining SH. One thereby obtains Fc with a single maleimide group (Fc-maleimide) for attachment to the SH-displaying partner. Restoration of the inter-gamma SS is necessary if the final chimeric construct is to be able to activate the classical complement pathway. However, during this preparation of Fc-maleimide, there is apparently some SS-formation between non-homologous SH, so that not all hinges emerge with a reconstituted inter-gamma SS. To reduce this error we have modified the preparative procedure after investigating an initial partial reduction of the hinge, and reviewing the conditions for stochastic alkylation. During partial reduction by dithiothreitol, the two hinge SS were cleaved apparently randomly: there was no evidence for one bond being more susceptible to reduction than the other, and little indication that the reduction of one bond enhanced the susceptibility of the other. By limiting reduction to an average of one SS per molecule, and alkylation to 0.8 SH per molecule, a final Fc-maleimide product is obtained in which most of the molecules have passed through the entire preparation with one of their hinge SS, and by inference much of the hinge conformation, remaining intact.

Humans↗
PubMed1997

Conjugation of human Fc gamma in closed-hinge or open-hinge configuration to Fab'gamma and analogous ligands.

We describe a method for linking human normal Fc gamma1, via stable thioether bonds emerging from its hinge, to any molecule expressing a free sulfhydryl (SH) group. The Fc hinge may be closed by a disulfide (SS) bond or left open. Preparation begins with reduction of the Fc hinge to release four SH groups from its two parallel inter-gamma SS bonds. When the Fc is required in normal closed-hinge configuration, one SH group is alkylated with N-ethylmaleimide under limiting conditions, and one of the inter-gamma SS bonds is reconstituted by SS interchange. The residual SH group, to be used for linking, is left as a 4-dithiopyridyl group suitable for storage. When the Fc is required for conjugation the 4-dithiopyridyl is replaced by a metastable maleimidyl group, which reacts rapidly with SH on the partner molecule to form a tandem thioether link. If the partner is Ab Fab'gamma, linking to cysteines in the Fab'gamma hinge yields derivatives such as FabFc and FabFc2. Chimeric FabFc Abs (mouse Fab'gamma/human Fc gamma1) invoked cellular cytotoxicity in vitro, using human cell lines as targets and human lymphocytes as effectors, whether the Fc hinge was open or closed. The same Abs could kill the same targets by activating human complement, but only when the Fc hinge was closed. Both effector functions were enhanced by the presence of a second Fc in FabFc2. This method of Fc addition can be used to predict the performance of recombinant chimeric Abs and to provide novel molecular geometries.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1997

Predicting recovery from head injury in young children: a prospective analysis.

It has been argued that young children's brains are "plastic," and may sustain substantial brain insult with little loss of function. Recent research suggests that this notion may not apply for generalized cerebral pathology. The present study aimed to evaluate this proposition using a sample of 73 young children, divided into 3 groups: severe head injury (HI; N = 17); mild-moderate HI (N = 32); and noninjured controls (N = 24). Preinjury screening established equivalence across groups for age, sex, preinjury ability, behavioral adjustment, socioeconomic status, and family functioning. Children were evaluated as soon as possible postinjury, and again 12 months postinjury, in three domains: intellectual ability, language, and memory. Results indicated that severe HI was associated with substantial, persisting difficulties in all areas. In contrast, children with mild-moderate HI experienced fewer difficulties, and often performed similarly to controls, both acutely and 12 months postinjury. There was no evidence of differential recovery of function associated with injury severity, with performance increments consistent across groups and probably due to either age-appropriate developmental gains, or test-related practice effects. Poorer outcome at 12 months postinjury was predicted by injury severity primarily, with earlier age at injury, and premorbid ability associated with outcome in specific domains.

Age Factors↗
PubMed1996

Risk factors for adverse outcomes of bacterial meningitis.

OBJECTIVE: To identify risk factors for adverse outcomes from bacterial meningitis. METHODOLOGY: From a cohort of 166 children with bacterial meningitis who were studied prospectively, 130/158 (82%) survivors underwent neurological, neuropsychological, audiological and behaviour assessments 5-9 years following their illness. RESULTS: Major adverse outcomes included B/166 (4.8%) deaths and severe neurological, intellectual or audiological sequelae in 11/130 (8.5%) children followed. Another 24 (18.5%) had cognitive, auditory or behaviour disorders. Bivariate analysis found age < or = 12 months, tertiary referral, symptoms > 24 h before diagnosis, seizures, focal neurological signs, deteriorating conscious state in hospital, Streptococcus pneumoniae infection and serum sodium concentration < 130 mmol/L were associated with adverse outcomes. Multivariate analysis showed age < or = 12 months, symptoms > 24 h, seizures after 72 h in hospital and focal neurological signs as independent risk factors. These were present in 18/19 (95%) children with major sequelae, but absent in 9/24 (37.5%) children with minor disabilities. CONCLUSIONS: As minor disabilities following meningitis cannot be predicted, all survivors require assessment during their early school years.

Adolescent↗
PubMed1995

Adverse outcomes of bacterial meningitis in school-age survivors.

OBJECTIVE: To determine the outcomes of bacterial meningitis in school-age survivors. DESIGN: Prospective cohort study. SETTING: Teaching pediatric hospital. CHILDREN: During 1983 through 1986, 158 meningitis survivors, ages 3 months to 14 years, treated at a single center were enrolled. Between 1991 and 1993, 130 children, 82% of the original cohort, were evaluated at a mean age of 8.4 years and a mean of 6.7 years after their meningitis. OUTCOME MEASURES: Blinded neurologic, neuropsychologic, audiologic, behavior, and socio-demographic assessments were compared with those from grade- and sex-matched control children. Multivariate analyses adjusted for age at testing and socio-demographic variables. RESULTS: There was a systematic increase in risk of abnormality or poorer functioning for children with meningitis, compared with control children, across all categories tested, which was significant for fine motor function, Intelligence quotient (IQ) scores, and tests of school behavior, neuropsychologic function, and auditory figure-ground differentiation. Eleven children who had experienced meningitis (8.5%) had major deficits (IQ < 70, seizures, hydrocephalus, spasticity, blindness, or severe to profound hearing loss); a further 24 (18.5%) cases and 14 (10.8%) control children had minor deficits (IQ 70 to 80, inability to read, mild to moderate hearing loss, abnormalities in speech discrimination, or school behavior problems). Overall, children who had meningitis were at greater risk (26.9%) for disability. Children with acute neurologic complications had more adverse outcomes than those with uncomplicated meningitis and control children (39% vs 18% vs 11%, respectively). CONCLUSIONS: One in four school-age meningitis survivors has either serious and disabling sequelae or a functionally important behavior disorder, neuropsychologic or auditory dysfunction adversely affecting academic performance. As a group, survivors function less well than their classroom peers, and risk is greatest for, but not confined to, those who had acute neurologic complications. All survivors require careful follow-up, at least until school age.

Adolescent↗
PubMed1988

The plant activation of m-phenylenediamine by Tradescantia clone 03 and clone 4430 cells in liquid suspension culture.

In this study, we expanded the use of the genus Tradescantia to investigate the plant activation of promutagens and further refine the methodology of the plant cell/microbe coincubation assay. Liquid suspension cell cultures of Tradescantia clone 03 and Tradescantia clone 4430 were used to activate the promutagen m-phenylenediamine into a mutagenic compound which was detected by Salmonella typhimurium strain TA98 in the plant cell/microbe coincubation assay. Optimum treatment parameters were established for both plant cell lines. Optimum was defined as the lowest concentration or shortest time period that provided consistently positive results and high rates of revertants. Preliminary experiments with both cell lines defined 2.5 mumoles m-phenylenediamine per plate as the optimum concentration to be used in the determination of the optimal coincubation period and the optimal concentration of plant cells. These experiments also determined the optimal physiological stage at which both clones should be used in the coincubation assay. Differences were found in the optimal of coincubation (1h for clone 03, 2 h for clone 4430) and growth stage (mid-log for clone 03, mid- to late-log for clone 4430). Similar activation responses were seen for both clones when the concentration of plant cells (mg/ml) was varied. Under optimized conditions, clone 03 cells demonstrated an approximately 10% higher activation response than clone 4430.

Biotransformation↗