Florey Department of Neuroscience and Mental Health - Research Publications

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    Genetics of Atrial Fibrillation and Possible Implications for Ischemic Stroke
    Lemmens, R ; Hermans, S ; Nuyens, D ; Thijs, V (HINDAWI LTD, 2011-01-01)
    Atrial fibrillation is the most common cardiac arrhythmia mainly caused by valvular, ischemic, hypertensive, and myopathic heart disease. Atrial fibrillation can occur in families suggesting a genetic background especially in younger subjects. Additionally recent studies have identified common genetic variants to be associated with atrial fibrillation in the general population. This cardiac arrhythmia has important public health implications because of its main complications: congestive heart failure and ischemic stroke. Since atrial fibrillation can result in ischemic stroke, one might assume that genetic determinants of this cardiac arrhythmia are also implicated in cerebrovascular disease. Ischemic stroke is a multifactorial, complex disease where multiple environmental and genetic factors interact. Whether genetic variants associated with a risk factor for ischemic stroke also increase the risk of a particular vascular endpoint still needs to be confirmed in many cases. Here we review the current knowledge on the genetic background of atrial fibrillation and the consequences for cerebrovascular disease.
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    Demographic and stroke-related factors as predictors of quality of acute stroke care provided by allied health professionals
    Luker, JA ; Bernhardt, J ; Grimmer-Somers, KA (DOVE MEDICAL PRESS LTD, 2011-01-01)
    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.
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    Does evidence really matter? Professionals' opinions on the practice of early mobilization after stroke
    Sjoholm, A ; Skarin, M ; Linden, T ; Bernhardt, J (DOVE MEDICAL PRESS LTD, 2011-01-01)
    INTRODUCTION: Early mobilization after stroke may be important for a good outcome and it is currently recommended in a range of international guidelines. The evidence base, however, is limited and clear definitions of what constitutes early mobilization are lacking. AIMS: To explore stroke care professionals' opinions about (1) when after stroke, first mobilization should take place, (2) whether early mobilization may affect patients' final outcome, and (3) what level of evidence they require to be convinced that early mobilization is beneficial. METHODS: A nine-item questionnaire was used to interview stroke care professionals during a conference in Sydney, Australia. RESULTS: Among 202 professionals interviewed, 40% were in favor of mobilizing both ischemic and hemorrhagic stroke patients within 24 hours of stroke onset. There was no clear agreement about the optimal time point beyond 24 hours. Most professionals thought that patients' final motor outcome (76%), cognitive outcome (57%), and risk of depression (75%) depends on being mobilized early. Only 19% required a large randomized controlled trial or a systematic review to be convinced of benefit. CONCLUSION: The spread in opinion reflects the absence of clear guidelines and knowledge in this important area of stroke recovery and rehabilitation, which suggests further research is required.
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    Age and gender as predictors of allied health quality stroke care
    Luker, JA ; Bernhardt, J ; Grimmer-Somers, KA (DOVE MEDICAL PRESS LTD, 2011-01-01)
    BACKGROUND: Improvement in acute stroke care requires the identification of variables which may influence care quality. The nature and impact of demographic and stroke-related variables on care quality provided by allied health (AH) professionals is unknown. AIMS: Our research explores the association of age and gender on an index of acute stroke care quality provided by AH professionals. METHODS: A retrospective clinical audit of 300 acute stroke patients extracted data on AH care, patients' age and gender. AH care quality was determined by the summed compliance with 20 predetermined process indicators. Our analysis explored relationships between this index of quality, age, and gender. Age was considered in different ways (as a continuous variable, and in different categories). It was correlated with care quality, using gender-specific linear and logistic regression models. Gender was then considered as a confounder in an overall model. RESULTS: No significant association was found for any treatment of age and the index of AH care quality. There were no differences in gender-specific models, and gender did not significantly adjust the age association with care quality. CONCLUSION: Age and gender were not predictors of the quality of care provided to acute stroke patients by AH professionals.
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    Alzheimer's disease and metals: a review of the involvement of cellular membrane receptors in metallosignalling.
    Amadoruge, PC ; Barnham, KJ (Hindawi Limited, 2011-03-02)
    Alzheimer's disease (AD) is a debilitating form of dementia. The hallmark protein associated with the disease is the amyloid beta (Aβ) peptide. Aggregation of Aβ has been shown to depend on interactions with metals. The recent studies now demonstrate that metals also play additional important roles in the disease process. Consequently, there may be benefit from modulating metal homeostasis. However, the role and subcellular location of metals within neurons is not well understood. There is growing evidence to suggest that metals can act at the site of cellular membrane receptors and affect cellular signaling by modulating the signal transduction of those receptors. The glutamatergic and cholinergic receptor systems, both well-known neurotransmitter systems affected in AD, have well-documented metal interactions, as do the tropomyosin-receptor kinase (Trk) family of receptors and the epidermal growth factor (EGF) receptor. In this paper, the metal interactions with these membrane receptor systems will be explored and thus the potential for membrane receptors as an intervention point in AD will be assessed.
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    Functional Integration of Grafted Neural Stem Cell-Derived Dopaminergic Neurons Monitored by Optogenetics in an In Vitro Parkinson Model
    Tonnesen, J ; Parish, CL ; Sorensen, AT ; Andersson, A ; Lundberg, C ; Deisseroth, K ; Arenas, E ; Lindvall, O ; Kokaia, M ; Mattson, M (PUBLIC LIBRARY SCIENCE, 2011-03-04)
    Intrastriatal grafts of stem cell-derived dopamine (DA) neurons induce behavioral recovery in animal models of Parkinson's disease (PD), but how they functionally integrate in host neural circuitries is poorly understood. Here, Wnt5a-overexpressing neural stem cells derived from embryonic ventral mesencephalon of tyrosine hydroxylase-GFP transgenic mice were expanded as neurospheres and transplanted into organotypic cultures of wild type mouse striatum. Differentiated GFP-labeled DA neurons in the grafts exhibited mature neuronal properties, including spontaneous firing of action potentials, presence of post-synaptic currents, and functional expression of DA D₂ autoreceptors. These properties resembled those recorded from identical cells in acute slices of intrastriatal grafts in the 6-hydroxy-DA-induced mouse PD model and from DA neurons in intact substantia nigra. Optogenetic activation or inhibition of grafted cells and host neurons using channelrhodopsin-2 (ChR2) and halorhodopsin (NpHR), respectively, revealed complex, bi-directional synaptic interactions between grafted cells and host neurons and extensive synaptic connectivity within the graft. Our data demonstrate for the first time using optogenetics that ectopically grafted stem cell-derived DA neurons become functionally integrated in the DA-denervated striatum. Further optogenetic dissection of the synaptic wiring between grafted and host neurons will be crucial to clarify the cellular and synaptic mechanisms underlying behavioral recovery as well as adverse effects following stem cell-based DA cell replacement strategies in PD.
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    Evaluation of variation in the phosphoinositide-3-kinase catalytic subunit alpha oncogene and breast cancer risk
    Stevens, KN ; Garcia-Closas, M ; Fredericksen, Z ; Kosel, M ; Pankratz, VS ; Hopper, JL ; Dite, GS ; Apicella, C ; Southey, MC ; Schmidt, MK ; Broeks, A ; Van 't Veer, LJ ; Tollenaar, RAEM ; Fasching, PA ; Beckmann, MW ; Hein, A ; Ekici, AB ; Johnson, N ; Peto, J ; Silva, IDS ; Gibson, L ; Sawyer, E ; Tomlinson, I ; Kerin, MJ ; Chanock, S ; Lissowska, J ; Hunter, DJ ; Hoover, RN ; Thomas, GD ; Milne, RL ; Perez, JIA ; Gonzalez-Neira, A ; Benitez, J ; Burwinkel, B ; Meindl, A ; Schmutzler, RK ; Bartrar, CR ; Hamann, U ; Ko, YD ; Bruening, T ; Chang-Claude, J ; Hein, R ; Wang-Gohrke, S ; Doerk, T ; Schuermann, P ; Bremer, M ; Hillemanns, P ; Bogdanova, N ; Zalutsky, JV ; Rogov, YI ; Antonenkova, N ; Lindblom, A ; Margolin, S ; Mannermaa, A ; Kataja, V ; Kosma, V-M ; Hartikainen, J ; Chenevix-Trench, G ; Chen, X ; Peterlongo, P ; Bonanni, B ; Bernard, L ; Manoukian, S ; Wang, X ; Cerhan, J ; Vachon, CM ; Olson, J ; Giles, GG ; Baglietto, L ; McLean, CA ; Severi, G ; John, EM ; Miron, A ; Winqvist, R ; Pylkaes, K ; Jukkola-Vuorinen, A ; Grip, M ; Andrulis, I ; Knight, JA ; Glendon, G ; Mulligan, AM ; Cox, A ; Brock, IW ; Elliott, G ; Cross, SS ; Pharoah, PP ; Dunning, AM ; Pooley, KA ; Humphreys, MK ; Wang, J ; Kang, D ; Yoo, K-Y ; Noh, D-Y ; Sangrajrang, S ; Gabrieau, V ; Brennan, P ; Mckay, J ; Anton-Culver, H ; Ziogas, A ; Couch, FJ ; Easton, DF (NATURE PUBLISHING GROUP, 2011-12-06)
    BACKGROUND: Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival. The goal of this study was to evaluate the association between inherited variation in this oncogene and risk of breast cancer. METHODS: A single-nucleotide polymorphism from the PIK3CA locus that was associated with breast cancer in a study of Caucasian breast cancer cases and controls from the Mayo Clinic (MCBCS) was genotyped in 5436 cases and 5280 controls from the Cancer Genetic Markers of Susceptibility (CGEMS) study and in 30 949 cases and 29 788 controls from the Breast Cancer Association Consortium (BCAC). RESULTS: Rs1607237 was significantly associated with a decreased risk of breast cancer in MCBCS, CGEMS and all studies of white Europeans combined (odds ratio (OR)=0.97, 95% confidence interval (CI) 0.95-0.99, P=4.6 × 10(-3)), but did not reach significance in the BCAC replication study alone (OR=0.98, 95% CI 0.96-1.01, P=0.139). CONCLUSION: Common germline variation in PIK3CA does not have a strong influence on the risk of breast cancer.
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    Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
    Sawcer, S ; Hellenthal, G ; Pirinen, M ; Spencer, CCA ; Patsopoulos, NA ; Moutsianas, L ; Dilthey, A ; Su, Z ; Freeman, C ; Hunt, SE ; Edkins, S ; Gray, E ; Booth, DR ; Potter, SC ; Goris, A ; Band, G ; Oturai, AB ; Strange, A ; Saarela, J ; Bellenguez, C ; Fontaine, B ; Gillman, M ; Hemmer, B ; Gwilliam, R ; Zipp, F ; Jayakumar, A ; Martin, R ; Leslie, S ; Hawkins, S ; Giannoulatou, E ; D'alfonso, S ; Blackburn, H ; Boneschi, FM ; Liddle, J ; Harbo, HF ; Perez, ML ; Spurkland, A ; Waller, MJ ; Mycko, MP ; Ricketts, M ; Comabella, M ; Hammond, N ; Kockum, I ; McCann, OT ; Ban, M ; Whittaker, P ; Kemppinen, A ; Weston, P ; Hawkins, C ; Widaa, S ; Zajicek, J ; Dronov, S ; Robertson, N ; Bumpstead, SJ ; Barcellos, LF ; Ravindrarajah, R ; Abraham, R ; Alfredsson, L ; Ardlie, K ; Aubin, C ; Baker, A ; Baker, K ; Baranzini, SE ; Bergamaschi, L ; Bergamaschi, R ; Bernstein, A ; Berthele, A ; Boggild, M ; Bradfield, JP ; Brassat, D ; Broadley, SA ; Buck, D ; Butzkueven, H ; Capra, R ; Carroll, WM ; Cavalla, P ; Celius, EG ; Cepok, S ; Chiavacci, R ; Clerget-Darpoux, F ; Clysters, K ; Comi, G ; Cossburn, M ; Cournu-Rebeix, I ; Cox, MB ; Cozen, W ; Cree, BAC ; Cross, AH ; Cusi, D ; Daly, MJ ; Davis, E ; de Bakker, PIW ; Debouverie, M ; D'hooghe, MB ; Dixon, K ; Dobosi, R ; Dubois, B ; Ellinghaus, D ; Elovaara, I ; Esposito, F ; Fontenille, C ; Foote, S ; Franke, A ; Galimberti, D ; Ghezzi, A ; Glessner, J ; Gomez, R ; Gout, O ; Graham, C ; Grant, SFA ; Guerini, FR ; Hakonarson, H ; Hall, P ; Hamsten, A ; Hartung, H-P ; Heard, RN ; Heath, S ; Hobart, J ; Hoshi, M ; Infante-Duarte, C ; Ingram, G ; Ingram, W ; Islam, T ; Jagodic, M ; Kabesch, M ; Kermode, AG ; Kilpatrick, TJ ; Kim, C ; Klopp, N ; Koivisto, K ; Larsson, M ; Lathrop, M ; Lechner-Scott, JS ; Leone, MA ; Leppa, V ; Liljedahl, U ; Bomfim, IL ; Lincoln, RR ; Link, J ; Liu, J ; Lorentzen, AR ; Lupoli, S ; Macciardi, F ; Mack, T ; Marriott, M ; Martinelli, V ; Mason, D ; McCauley, JL ; Mentch, F ; Mero, I-L ; Mihalova, T ; Montalban, X ; Mottershead, J ; Myhr, K-M ; Naldi, P ; Ollier, W ; Page, A ; Palotie, A ; Pelletier, J ; Piccio, L ; Pickersgill, T ; Piehl, F ; Pobywajlo, S ; Quach, HL ; Ramsay, PP ; Reunanen, M ; Reynolds, R ; Rioux, J ; Rodegher, M ; Roesner, S ; Rubio, JP ; Rueckert, I-M ; Salvetti, M ; Salvi, E ; Santaniello, A ; Schaefer, CA ; Schreiber, S ; Schulze, C ; Scott, RJ ; Sellebjerg, F ; Selmaj, KW ; Sexton, D ; Shen, L ; Simms-Acuna, B ; Skidmore, S ; Sleiman, PMA ; Smestad, C ; Sorensen, PS ; Sondergaard, HB ; Stankovich, J ; Strange, RC ; Sulonen, A-M ; Sundqvist, E ; Syvaenen, A-C ; Taddeo, F ; Taylor, B ; Blackwell, JM ; Tienari, P ; Bramon, E ; Tourbah, A ; Brown, MA ; Tronczynska, E ; Casas, JP ; Tubridy, N ; Corvin, A ; Vickery, J ; Jankowski, J ; Villoslada, P ; Markus, HS ; Wang, K ; Mathew, CG ; Wason, J ; Palmer, CNA ; Wichmann, H-E ; Plomin, R ; Willoughby, E ; Rautanen, A ; Winkelmann, J ; Wittig, M ; Trembath, RC ; Yaouanq, J ; Viswanathan, AC ; Zhang, H ; Wood, NW ; Zuvich, R ; Deloukas, P ; Langford, C ; Duncanson, A ; Oksenberg, JR ; Pericak-Vance, MA ; Haines, JL ; Olsson, T ; Hillert, J ; Ivinson, AJ ; De Jager, PL ; Peltonen, L ; Stewart, GJ ; Hafler, DA ; Hauser, SL ; McVean, G ; Donnelly, P ; Compston, A (NATURE PUBLISHING GROUP, 2011-08-11)
    Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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    Dietary patterns and risk of breast cancer
    Baglietto, L ; Krishnan, K ; Severi, G ; Hodge, A ; Brinkman, M ; English, DR ; McLean, C ; Hopper, JL ; Giles, GG (SPRINGERNATURE, 2011-02-01)
    BACKGROUND: Evidence is emerging that prudent/healthy dietary patterns might be associated with a reduced risk of breast cancer. METHODS: Using data from the prospective Melbourne Collaborative Cohort Study, we applied principal factor analysis to 124 foods and beverages to identify dietary patterns and estimated their association with breast cancer risk overall and by tumour characteristics using Cox regression. RESULTS: During an average of 14.1 years of follow-up of 20 967 women participants, 815 invasive breast cancers were diagnosed. Among the four dietary factors that we identified, only that characterised by high consumption of fruit and salad was associated with a reduced risk, with stronger associations observed for tumours not expressing oestrogen (ER) and progesterone receptors (PR). Compared with women in the lowest quintile of the factor score, the hazard ratio for women in the highest quintile was 0.92 (95% confidence interval (CI)=0.70-1.21; test for trend, P=0.5) for ER-positive or PR-positive tumours and 0.48 (95% CI=0.26-0.86; test for trend, P=0.002) for ER-negative and PR-negative tumours (test for homogeneity, P=0.01). CONCLUSION: Our study provides additional support for the hypothesis that a dietary pattern rich in fruit and salad might protect against invasive breast cancer and that the effect might be stronger for ER- and PR-negative tumours.
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    Sexually Dimorphic Serotonergic Dysfunction in a Mouse Model of Huntington's Disease and Depression
    Renoir, T ; Zajac, MS ; Du, X ; Pang, TY ; Leang, L ; Chevarin, C ; Lanfumey, L ; Hannan, AJ ; Hashimoto, K (PUBLIC LIBRARY SCIENCE, 2011-07-08)
    Depression is the most common psychiatric disorder in Huntington's disease (HD) patients. In the general population, women are more prone to develop depression and such susceptibility might be related to serotonergic dysregulation. There is yet to be a study of sexual dimorphism in the development and presentation of depression in HD patients. We investigated whether 8-week-old male and female R6/1 transgenic HD mice display depressive-like endophenotypes associated with serotonergic impairments. We also studied the behavioral effects of acute treatment with sertraline. We found that only female HD mice exhibited a decreased preference for saccharin as well as impaired emotionality-related behaviors when assessed on the novelty-suppressed feeding test (NSFT) and the forced-swimming test (FST). The exaggerated immobility time displayed by female HD in the FST was reduced by acute administration of sertraline. We also report an increased response to the 5-HT(1A) receptor agonist 8-OH-DPAT in inducing hypothermia and a decreased 5-HT(2A) receptor function in HD animals. While tissue levels of serotonin were reduced in both male and female HD mice, we found that serotonin concentration and hydroxylase-2 (TPH2) mRNA levels were higher in the hippocampus of males compared to female animals. Finally, the antidepressant-like effects of sertraline in the FST were blunted in male HD animals. This study reveals sex-specific depressive-related behaviors during an early stage of HD prior to any cognitive and motor deficits. Our data suggest a crucial role for disrupted serotonin signaling in mediating the sexually dimorphic depression-like phenotype in HD mice.