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Corben L.A.,Murdoch Childrens Research Institute | Corben L.A.,Monash University | Delatycki M.B.,Murdoch Childrens Research Institute | Delatycki M.B.,University of Melbourne | And 7 more authors.
Journal of Neurology | Year: 2010

The cerebellar and spinocerebellar dysfunction seen in Friedreich ataxia (FRDA) has known effects on motor function. Recently, it was suggested that people with FRDA may also have impairment in motor planning, either because of cortical pathology or because of cerebello-cortical projections. Fifteen adults with FRDA and 15 matched controls completed a task requiring reciprocating movements between two buttons on a tapping board. Occasionally there was one of three "oddball" stimuli requiring reprogramming of movement. These were change in (1) direction, (2) extent or (3) direction and extent. We hypothesized that people with FRDA would have prolonged movement times due to their movement disorder, and that changes in preparation time would be affected in a way similar to controls, unless there was impairment in motor planning in FRDA. Movement execution and, to a lesser degree, movement preparation were impaired in individuals with FRDA. We argue this points to disturbed cortical function. There was a significant negative correlation between age of onset and all three reprogramming conditions, suggesting an impact of FRDA on developing motor planning. Future studies will be required to establish whether this dysfunction is due to cerebellar impairment interrupting cerebro-ponto- cerebello-thalamo-cerebral loops, primary cortical pathology or a combination of the two. © 2009 Springer-Verlag.


Shultz S.R.,University of Melbourne | Shultz S.R.,Florey Neurosciences Institute | Tan X.L.,University of Melbourne | Wright D.K.,University of Melbourne | And 9 more authors.
Journal of Neurotrauma | Year: 2014

Traumatic brain injury (TBI) is an international health concern with a complex pathogenesis resulting in major long-term neurological, neurocognitive, and neuropsychiatric outcomes. Although neuroinflammation has been identified as an important pathophysiological process resulting from TBI, the function of specific inflammatory mediators in the aftermath of TBI remains poorly understood. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an inflammatory cytokine that has been reported to have neuroprotective effects in various animal models of neurodegenerative disease that share pathological similarities with TBI. The importance of GM-CSF in TBI has yet to be studied, however. We examined the role of GM-CSF in TBI by comparing the effects of a lateral fluid percussion (LFP) injury or sham injury in GM-CSF gene deficient (GM-CSF-/-) versus wild-type (WT) mice. After a 3-month recovery interval, mice were assessed using neuroimaging and behavioral outcomes. All mice given a LFP injury displayed significant brain atrophy and behavioral impairments compared with those given sham-injuries; however, this was significantly worse in the GM-CSF-/- mice compared with the WT mice. GM-CSF-/- mice given LFP injury also had reduced astrogliosis compared with their WT counterparts. These novel findings indicate that the inflammatory mediator, GM-CSF, may have significant protective properties in the chronic sequelae of experimental TBI and suggest that further research investigating GM-CSF and its potential benefits in the injured brain is warranted. © Copyright 2014, Mary Ann Liebert, Inc. 2014.


Alaama J.,King Abdulaziz University | Smith T.D.,Florey Neurosciences Institute | Smith T.D.,University of Melbourne | Lo A.,Victorian Partnership for Advance Computing | And 6 more authors.
Human Mutation | Year: 2011

Genetic diseases are a pressing global health problem that requires comprehensive access to basic clinical and genetic data to counter. The creation of regional and international databases that can be easily accessed by clinicians and diagnostic labs will greatly improve our ability to accurately diagnose and treat patients with genetic disorders. The Human Variome Project is currently working in conjunction with human genetics societies to achieve this by establishing systems to collect every mutation reported by a diagnostic laboratory, clinic, or research laboratory in a country and store these within a national repository, or HVP Country Node. Nodes have already been initiated in Australia, Belgium, China, Egypt, Malaysia, and Kuwait. Each is examining how to systematically collect and share genetic, clinical, and biochemical information in a country-specific manner that is sensitive to local ethical and cultural issues. This article gathers cases of genetic data collection within countries and takes recommendations from the global community to develop a procedure for countries wishing to establish their own collection system as part of the Human Variome Project. We hope this may lead to standard practices to facilitate global collection of data and allow efficient use in clinical practice, research and therapy. © 2011 Wiley-Liss, Inc.


Hogg M.N.,Royal Melbourne Hospital | Gibson S.,Australian Pain Society | Gibson S.,National Ageing Research Institute | Helou A.,Royal Prince Alfred Hospital | And 2 more authors.
Medical Journal of Australia | Year: 2012

Objectives: To document and describe outpatient persistent pain managementservices in Australia. Design, participants and setting: Systematic survey conducted between 1 December 2008 and 31 January 2010 of 57 services providing outpatient care to adult clients with persistent pain, plus five specialised paediatric services throughout Australia. Main outcome measures: Service structure, including funding processes; activity, including client numbers, access to specialised services (inpatient care, pain relief interventions); waiting times; and use of allied-health-professionalbased pain management programs. Results: Of 68 services identified, 57 participated in the study. The median waiting time from referral receipt to initial clinical assessment for a publicly funded outpatient adult pain management service was 150 days, compared with 38.5 days for a privately funded service (P <0.05). There was substantial variability among providers in range of services offered, including provision and duration of allied-health pain management programs. The level of service provision for children and rural patients is notably lower than that reported for urban adult constituents. Conclusions: Persistent pain management services are currently unable to meet service requirements adequately, and waiting times are more prolonged for publicly funded than privately funded services. Greater service provision is required in rural areas and for children.


Liu Y.R.,Royal Melbourne Hospital | Cardamone L.,Royal Melbourne Hospital | Hogan R.E.,Washington University in St. Louis | Gregoire M.-C.,Australian Nuclear Science and Technology Organisation | And 8 more authors.
Journal of Nuclear Medicine | Year: 2010

Traumatic brain injury (TBI) has a high incidence of long-term neurologic and neuropsychiatric morbidity. Metabolic and structural changes in rat brains were assessed after TBI using serial 18F-FDG PET and 3-dimensional MRI in vivo. Methods: Rats underwent lateral fluid percussion injury (FPI; n = 16) or a sham procedure (n = 11). PET and MR images were acquired at 1 wk and at 1, 3, and 6 mo after injury. Morphologic changes were assessed using MRI-based regions of interest, and hippocampal shape changes were assessed with large-deformation high-dimensional mapping. Metabolic changes were assessed using region-of-interest analysis and statistical parametric mapping with the flexible factorial analysis. Anxiety-like behavior and learning were assessed at 1, 3, and 6 mo after injury. Results: PET analyses showed widespread hypometabolism in injured rats, in particular involving the ipsilateral cortex, hippocampus, and amygdalae, present at 1 wk after FPI, most prominent at 1 mo, and then decreasing. Compared with the sham group, rats in the FPI group had decreased structural volume which progressively increased over 3-6 mo, occurring in the ipsilateral cortex, hippocampus, and ventricles after FPI (P < 0.05). Large-deformation high-dimensional mapping showed evolving hippocampal shape changes across the 6 mo after FPI. Injured rats displayed increased anxiety-like behavior (P < 0.05), but there were no direct correlations between the severity of the behavior abnormalities and functional or structural imaging changes. Conclusion: In selected brain structures, FPI induces early hypometabolism and delayed progressive atrophic changes that are dynamic and continue to evolve for months. These findings have implications for the understanding of the pathophysiology and evolution of long-term neurologic morbidity following TBI, and indicate an extended window for targeted neuroprotective interventions. Copyright © 2010 by the Society of Nuclear Medicine, Inc.


Luker J.A.,University of South Australia | Wall K.,Flinders Medical Center | Bernhardt J.,La Trobe University | Bernhardt J.,Florey Neurosciences Institute | And 2 more authors.
BMC Health Services Research | Year: 2011

Background: Evidence-based care should improve acute stroke outcomes with the same magnitude of effect for stroke patients of all ages. However, there is evidence to suggest that, in some instances, older stroke patients may receive poorer quality care than younger patients. Our aim was to systematically review evidence of the quality of care provided to patients with acute stroke related to their age. Quality of care was determined by compliance with recommended care processes. Methods. We systematically searched MEDLINE, CINAHL, ISI Web of Knowledge, Ageline and the Cochrane Library databases to identify publications (1995-2009) that reported data on acute stroke care process indicators by patient age. Data extracted included patient demographics and process indicator compliance. Included publications were critically appraised by two independent reviewers using the Critical Appraisal Skills Programme tool, and a comparison was made of the risk of bias according to studies' findings. The evidence base for reported process indicators was determined, and meta-analysis was undertaken for studies with sufficient similarity. Results: Nine from 163 potential studies met the inclusion criteria. Of the 56 process indicators reported, eleven indicators were evidence-based. Seven of these indicators (64%) showed significantly poorer care for older patients compared to younger ones, while younger patients received comparatively inferior care for only antihypertensive therapy at discharge. Our findings are limited by the variable methodological quality of included studies. Conclusion: Patients' age may be a factor in the care they receive after an acute stroke. However, the possible influence of patients' age on clinicians' decision-making must be considered in terms of the many complex issues that surround the provision of optimal care for older patients with acute stroke. © 2011 Luker et al; licensee BioMed Central Ltd.


Luker J.A.,University of South Australia | Bernhardt J.,La Trobe University | Bernhardt J.,Florey Neurosciences Institute | Grimmer-Somers K.A.,University of South Australia
Journal of Multidisciplinary Healthcare | Year: 2011

Background: We recently indicated that patient age on its own is not a determinant of quality of allied health care received after an acute stroke. It has not been tested whether other non- age variables influence care decisions made by allied health professionals. This paper explores demographic and stroke-related variables that are putatively associated with the quality of care provided to acute stroke patients by allied health professionals.Methods: Data were retrospectively audited from 300 acute stroke patient records regarding allied health care. Compliance with each of 20 indicators of allied health care quality was established. The influence of various demographic and stroke-related variables on each performance indicator was examined. We undertook a series of analyses using univariate logistic regression models to establish the influence of these variables on care quality.Results: Patient age had a significant correlation with only one process indicator (early mobilization). Seven variables, including stroke severity and level of dependence, were associated with patient age. The majority of these age proxies had significant associations with process indicator compliance. Correlations between non-age variables, in particular stroke severity and comorbidity, suggest the potential for complex confounding relationships between non-age variables and quality of allied health care.Conclusion: Compliance with individual indicators of allied health care was significantly associated with variables other than patient age, and included stroke severity, previous independence, comorbidities, day of admission, stroke unit admission, and length of stay. The inter-relationships between these non-age variables suggest that their influence on quality of care is complex. © 2011 Luker et al.


McOmish C.E.,Columbia University | McOmish C.E.,Florey Neurosciences Institute | McOmish C.E.,University of Melbourne | Lira A.,Columbia University | And 3 more authors.
Neuropsychopharmacology | Year: 2012

The need for safer, more effective therapeutics for the treatment of schizophrenia is widely acknowledged. To optimally target novel pharmacotherapies, in addition to establishing the mechanisms responsible for the beneficial effects of antipsychotics, the pathways underlying the most severe side effects must also be elucidated. Here we investigate the role of serotonin 2A (5-HT2A), serotonin 2C (5-HT 2C), and dopamine 2 receptors (D 2) in mediating adverse effects associated with canonical first- and second-generation antipsychotic drugs in mice. Wild-type (WT) and 5-HT 2A knockout (KO) mice treated with haloperidol, clozapine, and risperidone were assessed for locomotor activity and catalepsy. WT mice showed a marked reduction in locomotor activity following acute administration of haloperidol and high-dose risperidone, which was most likely secondary to the severe catalepsy caused by these compounds. Clozapine also dramatically reduced locomotor activity, but in the absence of catalepsy. Interestingly, 5-HT 2A KO mice were cataleptic following haloperidol and risperidone, but did not respond to clozapine's locomotor-suppressing effects. Restoration of 5-HT2A expression to cortical glutamatergic neurons re-instated the locomotor-suppressing effects of clozapine in the open field. In sum, we confirm that haloperidol and risperidone caused catalepsy in rodents, driven by strong antagonism of D 2. We also demonstrate that clozapine decreases locomotor activity in a 5-HT2A -dependent manner, in the absence of catalepsy. Moreover, we show that it is the cortical population of 5-HT2A that mediate the locomotor-suppressing effects of clozapine. © 2012 American College of Neuropsychopharmacology. All rights reserved.


Howell K.B.,Royal Childrens Hospital | Katanyuwong K.,Royal Childrens Hospital | MacKay M.T.,Royal Childrens Hospital | Bailey C.A.,Royal Childrens Hospital | And 6 more authors.
Epilepsia | Year: 2012

Purpose: Febrile infection-related epilepsy syndrome (FIRES) is an increasingly recognized epileptic syndrome that presents with multifocal refractory status epilepticus in previously normal children and evolves into a chronic, refractory, focal epilepsy with associated cognitive and behavioral difficulties. Herein we describe the features of the chronic epilepsy and critically review evidence for the etiology of this syndrome. Methods: Seven patients with FIRES were studied. The duration of follow-up in six survivors was 5-17 years. Clinical, electroencephalography (EEG), neuroimaging, and other investigative findings during the acute and chronic phases were reviewed. Key Findings: These previously normal children presented with a febrile illness and status epilepticus that was refractory to antiepileptic medications in all children, to immunotherapies (including immunoglobulin, corticosteroids, plasma exchange, and rituximab) in four, and to acute vagus nerve stimulation in one. Markers of cerebral inflammation were few and response to antiepileptic and immunomodulatory therapies was poor. Evolution to chronic epilepsy occurred without a silent period. Seizure characteristics in the chronic phase were strikingly stereotyped and similar to the acute phase, with head and eye version, unilateral facial jerking, asymmetric tonic posturing, and unilateral limb jerking in all patients. Electrographic ictal onset was lateralized in all recorded seizures, unilateral in one patient, and independent bilateral in three. Seizures were refractory to multiple antiepileptic medications in all patients and partly responsive to chronic vagus nerve stimulation in two patients. Moderate to severe intellectual impairment was noted in four patients, and borderline intellectual abilities were noted in two. Magnetic resonance imaging (MRI) in the chronic phase was normal in three patients and showed mild diffuse cortical atrophy and/or mild hippocampal atrophy or sclerosis in three. Significance: The similar perirolandic and perisylvian features of acute and chronic seizures, the lack of a silent period, the absence of evidence of cerebral inflammation, and the poor response to immunotherapies suggest FIRES is best conceptualized as a chronic epilepsy with explosive onset, not a remote-symptomatic epilepsy with an acute inflammatory antecedent. © 2011 International League Against Epilepsy.


Bouilleret V.,University of Melbourne | Cardamone L.,University of Melbourne | Liu C.,University of Melbourne | Koe A.S.,University of Melbourne | And 5 more authors.
Journal of Magnetic Resonance Imaging | Year: 2011

Purpose: To examine the long-term consequences of manganese exposure due to the use of manganese-enhanced magnetic resonance imaging (MEMRI) in a model of closed head injury, the fluid-percussion injury (FPI) model. Materials and Methods: Two groups of adult male Wistar rats (n = 72) were studied with either MEMRI, whereby rats receive MnCl 2 (100 mg/kg intraperitoneally) 24 hours prior to scanning, or standard MRI (sMRI) with no contrast agent. Rats from both groups underwent FPI or sham injury and were longitudinally assessed for 6 months for neurological toxicity using behavioral tests, EEG recording, and MRI scanning. Results: Regardless of whether they received FPI, MEMRI animals showed progressive signs of cerebral toxicity compared with sMRI rats, including significantly reduced weight gain, progressive brain volume decrease, and increased anxiety and depressive-like behaviors. Conclusion: Long-term structural and functional consequences of using manganese as a contrast agent for MRI can confound experimental outcomes and must be taken into account when designing longitudinal imaging studies using manganese-enhanced MRI. Copyright © 2011 Wiley-Liss, Inc.

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