Highlights of the Parkinson's Disease Foundation.
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Foundations↗
Biomedical subjects
R Elliott
Publications and source records attributed to R Elliott.
ATAR, a novel tumor necrosis factor receptor family member, signals through TRAF2 and TRAF5.
Members of tumor necrosis factor receptor (TNFR) family signal largely through interactions with death domain proteins and TRAF proteins. Here we report the identification of a novel TNFR family member ATAR. Human and mouse ATAR contain 283 and 276 amino acids, respectively, making them the shortest known members of the TNFR superfamily. The receptor is expressed mainly in spleen, thymus, bone marrow, lung, and small intestine. The intracellular domains of human and mouse ATAR share only 25% identity, yet both interact with TRAF5 and TRAF2. This TRAF interaction domain resides at the C-terminal 20 amino acids. Like most other TRAF-interacting receptors, overexpression of ATAR activates the transcription factor NF-kappaB. Co-expression of ATAR with TRAF5, but not TRAF2, results in synergistic activation of NF-kappaB, suggesting potentially different roles for TRAF2 and TRAF5 in post-receptor signaling.
Amino Acid Sequence↗
Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.
A novel secreted glycoprotein that regulates bone resorption has been identified. The protein, termed Osteoprotegerin (OPG), is a novel member of the TNF receptor superfamily. In vivo, hepatic expression of OPG in transgenic mice results in a profound yet nonlethal osteopetrosis, coincident with a decrease in later stages of osteoclast differentiation. These same effects are observed upon administration of recombinant OPG into normal mice. In vitro, osteoclast differentiation from precursor cells is blocked in a dose-dependent manner by recombinant OPG. Furthermore, OPG blocks ovariectomy-associated bone loss in rats. These data show that OPG can act as a soluble factor in the regulation of bone mass and imply a utility for OPG in the treatment of osteoporosis associated with increased osteoclast activity.
Amino Acid Sequence↗
Effects of methylphenidate on spatial working memory and planning in healthy young adults.
Previous studies of the effects of the psychomotor stimulant, methylphenidate, have concentrated on vigilance and reaction time tasks. In this study, the effects of methylphenidate on more complex aspects of cognition were studied using tasks from the CANTAB battery and related tests which have been shown to be sensitive to frontal lobe dysfunction. Twenty-eight young healthy men participated in a counterbalanced, double-blind, placebo-controlled study of the effects of methylphenidate. Cognitive assessment included tests of spatial working memory, planning, verbal fluency, attentional set-shifting and sustained attention. Methylphenidate had significant effects on performance of the tests of spatial working memory and planning but not on the attentional and fluency tests. When the drug was taken on the first test session, performance on the spatial tests was enhanced by the drug compared to placebo. However, when the drug was taken second, performance accuracy was impaired whereas response latencies were decreased. These results are consistent with a hypothesis that methylphenidate influences performance in two conflicting ways; enhancing executive aspects of spatial function on novel tasks but impairing previously established performance. This pattern of effects is discussed within the framework of dual, interacting arousal mechanisms.
Adult↗
Differential neural response to positive and negative feedback in planning and guessing tasks.
The neural mechanisms by which emotional and cognitive processing interact are unknown. Evidence from animal studies and neurological patients suggests that regions of the ventral striatum and orbitofrontal cortex, together with limbic structures such as the amygdala, are critical to such interactions. We used positron emission tomography to study the neural systems engaged by processing performance feedback under two conditions involving either a complex cognitive or a matched guessing task. The main activations associated with the processing of performance feedback under different task conditions involved foci in the medial caudate nucleus and the ventromedial orbitofrontal cortex. A differential modulation of these activations as a function of task type was observed. In particular the orbitofrontal activation associated with the presence of feedback was only seen in the guessing task. These data suggest that the ventral striatum and orbitofrontal cortex are involved in processing of feedback information, findings consistent with animal and neurological studies. We propose that differential activation associated with guessing compared to planning suggests enhanced neural processing of feedback when the outcome of a task is uncontrollable or when information must be assimilated across a number of trials to assess performance.
Adult↗
A meta-analytic investigation of group treatment outcomes for sexually abused children.
OBJECTIVE: A meta-analytic review of outcome studies of group treatment for sexually abused children and adolescents was conducted to establish a quantitative measure of group treatment effectiveness for this population. METHOD: The psychological literature was searched for studies which met the following criteria: The effectiveness of group treatment for sexually abused children or adolescents was investigated, results were based on empirical measures, and sufficient statistical information was reported to calculate effect sized. This search resulted in 15 studies. Overall effect sized were then calculated for each study and an overall mean effect size across studies was calculated. Additionally, effect sizes were compared to assess for effects of group characteristics, response perspectives, and type of outcome variables used. RESULTS: The overall mean effect size across studies was .79. Effect size comparisons based on response perspective and outcome variable groupings yielded no significant differences. While statistically insignificant, a trend of larger effect sizes for groups comprised exclusively of females was found. CONCLUSIONS: Results from the current meta-analysis support the conclusion that effective group treatments for sexually abused children and adolescents exist and that the current meta-analysis can function as a comparison group for future researchers studying treatment outcome for this population. Suggestions for research are discussed.
Adolescent↗
Prefrontal dysfunction in depressed patients performing a complex planning task: a study using positron emission tomography.
INTRODUCTION: Patients with unipolar depression show impaired performance on the Tower of London planning task. Positron emission tomography, which has previously identified resting state blood flow abnormalities in depression, was used to investigate neural activity associated with performance of this task in depressed patients and normal controls. METHODS: Six patients with unipolar depression and six matched controls were scanned while performing easy and hard Tower of London problems in a one-touch computerized paradigm and while performing a perceptuomotor control task. RESULTS: The patients in this study showed an expected task-related performance deficit compared with normal subjects. In normal subjects, the task engaged a network of prefrontal cortex, anterior cingulate, posterior cortical areas and subcortical structures including the striatum, thalamus and cerebellum. Depressed patients failed to show significant activation in the cingulate and striatum; activation in the other prefrontal and posterior cortical regions was significantly attenuated relative to controls. Crucially, patients also failed to show the normal augmentation of activation in the caudate nucleus, anterior cingulate and right prefrontal cortex associated with increasing task difficulty. CONCLUSIONS: These findings provide evidence for cingulate, prefrontal and striatal dysfunction associated with impaired task performance in depression. The present results are consistent with a central role of cingulate dysfunction in depression as well as suggesting impaired frontostriatal function.
Adult↗
Examination-induced distress in a public examination at the completion of secondary schooling.
BACKGROUND: The context for this study was the Higher School Certificate examination in New South Wales, Australia. AIMS: The main research aim was to investigate the association between the Higher School Certificate, the reported distress and anxiety levels of the adolescent students who prepare for and sit for the examination, and various other internal and environmental variables. SAMPLE: The random sample consisted of 445 students in their last two years of secondary schooling, with approximately equal numbers of males and females from a diverse range of ethnic backgrounds. METHODS: Analysis was carried out using principal components analysis and multiple regression. RESULTS: The most significant contribution to distress associated with the examination was made by the personality trait, anxiety proneness. Lower socio-economic status, self-confidence, academic and verbal self-concepts and perceived ability to cope were also found, to a lesser extent, to be associated with increased distress. The interactions sex with ethnic background and year with ethnic background were of particular interest. Students who were male and had an English speaking background, and students in year 11 who had an English speaking background were least likely to experience distress than others in the context of the examination. CONCLUSIONS: Whilst results must be treated with caution, particular groups of students potentially vulnerable to distress were identified and directions for future research indicated.
Adolescent↗
Abnormal response to negative feedback in unipolar depression: evidence for a diagnosis specific impairment.
OBJECTIVES: To assess in further detail the specific form of motivational impairment influencing neuropsychological performance in depression-oversensitivity to perceived failure. The present study considers two questions: firstly whether this is specific to depression and secondly how the effect relates to clinical features. METHODS: Unipolar depressed patients and matched controls were assessed on two neuropsychological tests giving explicit performance feedback. The data were analysed in two separate studies to consider the questions above. The first study considered the specificity of the effect to depressed patients, using data on the same tests collected from other patient groups. The second study was a longitudinal assessment of the depressed patients on clinical recovery to determine whether the effect is specific to the depressed state. RESULTS: The effect was not seen in non-depressed patient groups, either neurological or psychiatric groups. The longitudinal study showed a residual abnormal response to negative feedback on clinical recovery. CONCLUSIONS: Abnormal response to negative feedback is specific to a primary diagnosis of depression and may be a trait rather than a state factor of the disorder. These results are discussed in relation to the putative neuropathology of depression and also to cognitive and behavioural accounts of the disorder. The findings presented here have important implications for establishing a link between mood and cognition in unipolar depression.
Adult↗
Lack of autoimmune serological reactions in rodent models of insulin dependent diabetes mellitus.
Spontaneous insulitis with insulin-dependent diabetes mellitus (IDDM) in rodent models, the BB rat and NOD mouse, has clarified the pathogenesis of and guided decisions on interventional therapy for human IDDM. However, the occurrence in such models of a standard marker of human IDDM, autoantibodies to beta islet cell constituents, has been controversial. Hence we assessed diabetes-prone rodents for the frequencies of raised levels of auto-antibodies to glutamic acid decarboxylase GAD (anti-GAD), insulin and heat shock protein 65 (HSP-65) in relation to levels in non-diabetes-prone animals and levels in human diabetic sera. Assays were performed sequentially at various ages of life. The immunoassays used for anti-GAD and anti-insulin were those validated for sensitivity and specificity for detection of the corresponding autoantibodies in human IDDM sera at international workshops. Positive controls included human IDDM sera with reactivity with GAD or insulin and, for mouse anti-GAD, the highly reactive monoclonal antibody, GAD-6. The results were that levels of autoantibodies in diabetes-prone BB rats or NOD mice to the "IDDM-relevant' autoantigens in our panel did not exceed levels in control rats or mice, and were much lower than levels in humans with IDDM. We conclude that the BB rat and NOD mouse represent a model, but not a facsimile, of human IDDM and that therapeutic successes in such models should be interpreted with caution in relation to interventional therapy for human IDDM.
Animals↗
Molecular epidemiology of IDDM in the Western Pacific Rim Region. WHO DiaMond Molecular Epidemiology Sub-Project Group.
HLA-DQA11 and DQB1 alleles coding for arginine (R) in position 52, and an amino acid other than aspartic acid (ND) in position 57, respectively, are strong genetic markers for IDDM in Caucasians. However, their contribution to the occurrence of the disease in Asian populations is less clear. As part of the WHO DiaMond Molecular Epidemiology Sub-Project, HLA-DQ molecular typing was performed for IDDM cases and non-diabetic controls from three populations in the Western Pacific Rim Region where incidence rates have been established (Hokkaido, Japan; Seoul, Korea; Auckland, New Zealand). DQA1*R homozygosity was significantly associated with IDDM in all areas. DQB1*ND homozygosity was also related to IDDM in Korea and New Zealand, but not in Japan. Individuals who were homozygous for DQA1*R and DQB1*ND were at highest IDDM risk in Korea and New Zealand, with the most striking findings in Auckland. In Japan, individuals carrying two DQA1*R, but only one DQB1*ND allele, were most likely to develop IDDM. These data revealed considerable genetic heterogeneity between Japan and Korea and suggest that DQA1*R and DQB1*ND alleles may explain a larger proportion of IDDM incidence in Caucasian compared to Asian populations.
Alleles↗
Neuropsychological impairments in unipolar depression: the influence of perceived failure on subsequent performance.
The CANTAB battery of neuropsychological tests was used to compare the performance of 28 patients with unipolar depression with that of 22 age and IQ matched controls. The patients were impaired on almost all tests studied with deficits in pattern and spatial recognition memory, matching to sample, spatial span, spatial working memory and planning. Most of the patients showed at least some impairment and deficits were seen across cognitive domains. An important finding was the detrimental effect of failure on subsequent performance; having solved one problem incorrectly, patients were far more likely than controls to fail the subsequent problem. Superimposed on the general deficits, there were also specific deficits in executive tasks characteristic of frontostriatal dysfunction and deficits in mnemonic tasks characteristic of temporal lobe dysfunction. This combination of a specific form of motivational deficit, resulting in oversensitivity to negative feedback, and superimposed specific neuropsychological deficits were correlated with severity of depression. The most significant correlations were seen between mnemonic deficits and clinical rating scores. Comparisons of the deficits seen in the depressed patients in this study with other patient groups assessed with the CANTAB neuropsychological battery, showed that one of the hypotheses of the neuropsychological deficits in depression, that of "frontosubcortical' or "frontostriatal' dysfunction, was not supported. These findings are discussed in relation to the likely neural substrates of depression.
Adult↗
Neuropsychology--dementia and affective disorders.
The neuropsychology of dementia and depression is surveyed with a focus on dementia of Alzheimer type (DAT) and depression in old age. Some of the main cognitive deficits in DAT are identified as loss of memory for events and attentional or executive deficit. The course of deterioration across various cognitive domains in DAT is consistent with a posterior-to-anterior spread of pathology in the cerebral cortex. Depressed, elderly patients exhibit a generalised profile of deficits, with impairments in tests shown to be sensitive to temporal or frontal cortex dysfunction. The depressed also exhibit a specific deficit in response to negative feedback (failure) which may contribute to different forms of cognitive dysfunctioning. Gross similarities in the deficits presented by subjects in depression or DAT necessitate a search for qualitative differences between the two, in order to facilitate their differential diagnosis: one such difference is the reversibility of certain of the cognitive deficits following recovery from depression.
Brain↗
Multivariate allometric scaling of men's world indoor rowing championship performance.
The World Indoor Rowing Championship (WIRC) is based on the time (T) to row a simulated 2500 m on a rowing ergometer. In the WIRC there are separate age categories but only two weight classes: light and heavyweight, thus penalizing those just heavier and those significantly lighter than the cut-off weight. Multivariate allometric scaling (MAS) provides an expression of performance free of the confounding effect of more than one scaling variable. We used MAS to scale T by height (H) and age (A) to create a new index of rowing performance, T*H(-a)*A(-b). Subjects were 148 male competitors from the 1995 WIRC. MAS indicated that T*H*A(-0.06) expresses T free of the confounding effect of H and A. We also scaled T only by H on those subjects, A < 40, (N = 109). Results showed that T*H is an optimal and particularly feasible scaling of T. Use of either convention dramatically changed race results. In conclusion, we recommend use of either the T.H (17 < or = A < or = 39) or T*H*A(-0.06) conventions to adjust WIRC performance in adult males.
Age Factors↗
Report of the Fifth International Workshop on Human Chromosome 11 Mapping 1996.
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Chromosome Mapping↗
Neuropsychological deficits in tests of executive function in asymptomatic and symptomatic HIV-1 seropositive men.
There has been much debate about the exact nature and time of onset of the cognitive impairments associated with infection by the human immunodeficiency virus type 1 (HIV-1). Studies to date have not reached consistent conclusions. The present study comprised 22 asymptomatic and 18 symptomatic HIV-1 seropositive men, whose only risk factor for contraction of the virus was sexual intercourse, and 18 seronegative controls matched for age and IQ. Subjects were given computerized neuropsychological tests from the CANTAB battery, which assessed visuospatial memory, attention and executive function. Both the asymptomatic and the symptomatic HIV-1 seropositive subjects showed a selective pattern of deficits relative to the controls. In addition, the seropositive subjects were subtly but significantly impaired on tests of executive function but unimpaired on certain tests of visual memory. This finding supports an hypothesis that frontostriatal dysfunction occurs in HIV-1 infected individuals prior even to the expression of clinical symptoms.
Adult↗
The neuropsychology of schizophrenia: relations with clinical and neurobiological dimensions.
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Brain Mapping↗