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Parkville, Australia

Bechdolf A.,University of Cologne | Bechdolf A.,University of Melbourne | Wood S.J.,University of Melbourne | Wood S.J.,University of Birmingham | And 13 more authors.
Psychiatry Research - Neuroimaging | Year: 2012

There are now numerous reports of neuroanatomical abnormalities in people with bipolar disorder. However, it remains unclear whether those abnormalities predate the onset of the illness. In this cross-sectional magnetic resonance imaging study, we assessed 11 young people clinically at ultra-high risk of development of psychosis (UHR), who all developed bipolar I or II disorder by follow-up (median time to onset 328. days - UHR-BP), 11 matched UHR participants, who had no psychiatric diagnosis after at least 12. months of follow-up (UHR-Well) and 11 matched healthy controls (HC). Our main outcome measures were amygdala, hippocampus, insula, lateral ventricular and whole brain volumes. Amygdala and insula volume reductions were more pronounced in the UHR-BP than in the UHR-Well and HC group. Lateral ventricle, whole-brain and hippocampal volumes did not differ between groups. If these findings are confirmed, they suggest that imaging investigations could help to distinguish people who will subsequently develop bipolar disorder from those who will not, at least in symptomatically enriched samples. © 2011 Elsevier Ireland Ltd. Source

Cheang M.Y.,Royal Melbourne Hospital | Manning N.,Royal Melbourne Hospital | Churilov L.,Florey Neuroscience Institute | Mitchell P.,Royal Melbourne Hospital | And 2 more authors.
Journal of Clinical Neuroscience | Year: 2014

Intravenous recombinant tissue plasminogen activator is associated with significant recanalisation failure in the setting of large artery occlusion. Endovascular treatment by stentriever achieves improved rates of recanalisation but its impact on clinical outcomes remains unclear. We hypothesise that successful recanalisation, unattentuated by age and stroke severity, is associated with improved clinical outcomes in patients treated with the Solitaire stentriever (ev3 Endovascular, Plymouth, MN, USA). We conducted a retrospective study of 60 consecutive acute ischaemic stroke patients treated with the Solitaire stentriever. The data included demographics, vascular risk factors, ictal onset time, National Institutes of Health Stroke Scale (NIHSS) score at presentation, angiographic findings, post-procedure imaging, and clinical follow-up. Recanalisation success was defined as a thrombolysis in cerebral infarction score (TICI) ≥ 2b. Good clinical outcome was defined as a modified Rankin Scale score (mRS) ≤ 2 at 3 months. Of the 60 patients, the mean age was 64.1 (standard deviation 13.4) years and 68.3% were men. Median NIHSS score at presentation was 18 (interquartile range 14-22). Successful recanalisation (TICI ≥ 2b) was achieved in 44 patients (73.3%). Of these 44 patients, 25 patients (56.8%) achieved mRS ≤ 2 at 3 months. Multiple logistic regression showed significant association between recanalisation success and improved clinical outcome (p = 0.019). Of all patients, four (6.7%) developed symptomatic intracranial haemorrhage. Overall mortality was 28.3%. In conclusion, the Solitaire stentriever was associated with improved recanalisation rates. We showed that successful recanalisation is associated with good clinical outcomes after adjustments for age, sex and stroke severity. © 2013 Elsevier Ltd. All rights reserved. Source

Dibbens L.M.,University of South Australia | De Vries B.,Leiden University | Donatello S.,Free University of Colombia | Heron S.E.,University of South Australia | And 33 more authors.
Nature Genetics | Year: 2013

The majority of epilepsies are focal in origin, with seizures emanating from one brain region. Although focal epilepsies often arise from structural brain lesions, many affected individuals have normal brain imaging. The etiology is unknown in the majority of individuals, although genetic factors are increasingly recognized. Autosomal dominant familial focal epilepsy with variable foci (FFEVF) is notable because family members have seizures originating from different cortical regions. Using exome sequencing, we detected DEPDC5 mutations in two affected families. We subsequently identified mutations in five of six additional published large families with FFEVF. Study of families with focal epilepsy that were too small for conventional clinical diagnosis with FFEVF identified DEPDC5 mutations in approximately 12% of families (10/82). This high frequency establishes DEPDC5 mutations as a common cause of familial focal epilepsies. Shared homology with G protein signaling molecules and localization in human neurons suggest a role of DEPDC5 in neuronal signal transduction. © 2013 Nature America, Inc. All rights reserved. Source

Denham M.,University of Melbourne | Denham M.,Lund University | Thompson L.H.,Lund University | Thompson L.H.,Florey Neuroscience Institute | And 5 more authors.
Stem Cells | Year: 2010

Generation of mesencephalic dopamine (mesDA) neurons from human embryonic stem cells (hESCs) requires several stages of signaling from various extrinsic and intrinsic factors. To date, most methods incorporate exogenous treatment of Sonic hedgehog (SHH) to derive mesDA neurons. However, we and others have shown that this approach is inefficient for generating FOXA2+ cells, the precursors of mesDA neurons. As mesDA neurons are derived from the ventral floor plate (FP) regions of the embryonic neural tube, we sought to develop a system to derive FP cells from hESC. We show that forced expression of the transcription factor GLI1 in hESC at the earliest stage of neural induction, resulted in their commitment to FP lineage. The GLI1+ cells coexpressed FP markers, FOXA2 and Corin, and displayed exocrine SHH activity by ventrally patterning the surrounding neural progenitors. This system results in 63% FOXA2+ cells at the neural progenitor stage of hESC differentiation. The GLI1-transduced cells were also able to differentiate to neurons expressing tyrosine hydroxylase. This study demonstrates that GLI1 is a determinant of FP specification in hESC and describes a highly robust and efficient in vitro model system that mimics the ventral neural tube organizer. © AlphaMed Press. Source

Goh C.,Royal Melbourne Hospital | Churilov L.,University of Melbourne | Churilov L.,Florey Neuroscience Institute | Mitchell P.,Royal Melbourne Hospital | And 2 more authors.
American Journal of Neuroradiology | Year: 2013

BACKGROUND AND PURPOSE: Antiplatelet therapy is associated with decreased ischemic events after neurointerventional procedures. Antiplatelet resistance negates the protective effects of antiplatelet medication, leading to a higher incidence of ischemic events. A possible link between antiplatelet hyper-response and increased hemorrhagic complications has been inadequately investigated. We aimed to examine the correlation between antiplatelet hyper-response and the risk of hemorrhagic complications. MATERIALS AND METHODS: Patients who were treated with antiplatelet medications and underwent neurointerventional procedures were prospectively recruited. We collected the following data: demographics, vascular risk factors, antiplatelet and anticoagulation treatment, antiplatelet responsiveness, coagulation profile, and hemorrhagic complications. P2Y12 receptor-mediated platelet inhibition was tested by using the VerifyNow assay device. The primary end points were postprocedural major and minor hemorrhagic complications. Receiver operator characteristic analysis was used to evaluate the percentage of platelet inhibition as a diagnostic tool for bleeding events. The association between hemorrhage and percentage of platelet inhibition was investigated by using logistic regression modeling. RESULTS: Forty-seven patients were enrolled. The mean age was 56 ± 12 years, and 28% were men. Ten patients (21.3%) developed hemorrhagic complications. Clopidogrel response was higher in patients with a major bleeding complication compared with those with minor or no bleeding (median, 94% versus 24% platelet inhibition; P = .0084). Of the 7 patients (14.9%) defined as hyper-responders with ≥72% platelet inhibition, 42.8% had a major bleeding complication. CONCLUSIONS: Hyper-response to clopidogrel is associated with increased risk of hemorrhagic complications. Larger studies are urgently needed to validate a clinically useful threshold to define clopidogrel hyper-response and to examine the clinical effects of antiplatelet dosage adjustment. Source

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