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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. Source


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. Source


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. Source


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. Source


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. Source

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