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1.  HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials 
Swerdlow, Daniel I | Preiss, David | Kuchenbaecker, Karoline B | Holmes, Michael V | Engmann, Jorgen E L | Shah, Tina | Sofat, Reecha | Stender, Stefan | Johnson, Paul C D | Scott, Robert A | Leusink, Maarten | Verweij, Niek | Sharp, Stephen J | Guo, Yiran | Giambartolomei, Claudia | Chung, Christina | Peasey, Anne | Amuzu, Antoinette | Li, KaWah | Palmen, Jutta | Howard, Philip | Cooper, Jackie A | Drenos, Fotios | Li, Yun R | Lowe, Gordon | Gallacher, John | Stewart, Marlene C W | Tzoulaki, Ioanna | Buxbaum, Sarah G | van der A, Daphne L | Forouhi, Nita G | Onland-Moret, N Charlotte | van der Schouw, Yvonne T | Schnabel, Renate B | Hubacek, Jaroslav A | Kubinova, Ruzena | Baceviciene, Migle | Tamosiunas, Abdonas | Pajak, Andrzej | Topor-Madry, Romanvan | Stepaniak, Urszula | Malyutina, Sofia | Baldassarre, Damiano | Sennblad, Bengt | Tremoli, Elena | de Faire, Ulf | Veglia, Fabrizio | Ford, Ian | Jukema, J Wouter | Westendorp, Rudi G J | de Borst, Gert Jan | de Jong, Pim A | Algra, Ale | Spiering, Wilko | der Zee, Anke H Maitland-van | Klungel, Olaf H | de Boer, Anthonius | Doevendans, Pieter A | Eaton, Charles B | Robinson, Jennifer G | Duggan, David | Kjekshus, John | Downs, John R | Gotto, Antonio M | Keech, Anthony C | Marchioli, Roberto | Tognoni, Gianni | Sever, Peter S | Poulter, Neil R | Waters, David D | Pedersen, Terje R | Amarenco, Pierre | Nakamura, Haruo | McMurray, John J V | Lewsey, James D | Chasman, Daniel I | Ridker, Paul M | Maggioni, Aldo P | Tavazzi, Luigi | Ray, Kausik K | Seshasai, Sreenivasa Rao Kondapally | Manson, JoAnn E | Price, Jackie F | Whincup, Peter H | Morris, Richard W | Lawlor, Debbie A | Smith, George Davey | Ben-Shlomo, Yoav | Schreiner, Pamela J | Fornage, Myriam | Siscovick, David S | Cushman, Mary | Kumari, Meena | Wareham, Nick J | Verschuren, W M Monique | Redline, Susan | Patel, Sanjay R | Whittaker, John C | Hamsten, Anders | Delaney, Joseph A | Dale, Caroline | Gaunt, Tom R | Wong, Andrew | Kuh, Diana | Hardy, Rebecca | Kathiresan, Sekar | Castillo, Berta A | van der Harst, Pim | Brunner, Eric J | Tybjaerg-Hansen, Anne | Marmot, Michael G | Krauss, Ronald M | Tsai, Michael | Coresh, Josef | Hoogeveen, Ronald C | Psaty, Bruce M | Lange, Leslie A | Hakonarson, Hakon | Dudbridge, Frank | Humphries, Steve E | Talmud, Philippa J | Kivimäki, Mika | Timpson, Nicholas J | Langenberg, Claudia | Asselbergs, Folkert W | Voevoda, Mikhail | Bobak, Martin | Pikhart, Hynek | Wilson, James G | Reiner, Alex P | Keating, Brendan J | Hingorani, Aroon D | Sattar, Naveed
Lancet  2015;385(9965):351-361.
Summary
Background
Statins increase the risk of new-onset type 2 diabetes mellitus. We aimed to assess whether this increase in risk is a consequence of inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), the intended drug target.
Methods
We used single nucleotide polymorphisms in the HMGCR gene, rs17238484 (for the main analysis) and rs12916 (for a subsidiary analysis) as proxies for HMGCR inhibition by statins. We examined associations of these variants with plasma lipid, glucose, and insulin concentrations; bodyweight; waist circumference; and prevalent and incident type 2 diabetes. Study-specific effect estimates per copy of each LDL-lowering allele were pooled by meta-analysis. These findings were compared with a meta-analysis of new-onset type 2 diabetes and bodyweight change data from randomised trials of statin drugs. The effects of statins in each randomised trial were assessed using meta-analysis.
Findings
Data were available for up to 223 463 individuals from 43 genetic studies. Each additional rs17238484-G allele was associated with a mean 0·06 mmol/L (95% CI 0·05–0·07) lower LDL cholesterol and higher body weight (0·30 kg, 0·18–0·43), waist circumference (0·32 cm, 0·16–0·47), plasma insulin concentration (1·62%, 0·53–2·72), and plasma glucose concentration (0·23%, 0·02–0·44). The rs12916 SNP had similar effects on LDL cholesterol, bodyweight, and waist circumference. The rs17238484-G allele seemed to be associated with higher risk of type 2 diabetes (odds ratio [OR] per allele 1·02, 95% CI 1·00–1·05); the rs12916-T allele association was consistent (1·06, 1·03–1·09). In 129 170 individuals in randomised trials, statins lowered LDL cholesterol by 0·92 mmol/L (95% CI 0·18–1·67) at 1-year of follow-up, increased bodyweight by 0·24 kg (95% CI 0·10–0·38 in all trials; 0·33 kg, 95% CI 0·24–0·42 in placebo or standard care controlled trials and −0·15 kg, 95% CI −0·39 to 0·08 in intensive-dose vs moderate-dose trials) at a mean of 4·2 years (range 1·9–6·7) of follow-up, and increased the odds of new-onset type 2 diabetes (OR 1·12, 95% CI 1·06–1·18 in all trials; 1·11, 95% CI 1·03–1·20 in placebo or standard care controlled trials and 1·12, 95% CI 1·04–1·22 in intensive-dose vs moderate dose trials).
Interpretation
The increased risk of type 2 diabetes noted with statins is at least partially explained by HMGCR inhibition.
Funding
The funding sources are cited at the end of the paper.
doi:10.1016/S0140-6736(14)61183-1
PMCID: PMC4322187  PMID: 25262344
2.  Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12 
Neurology  2014;83(8):678-685.
Objectives:
To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases.
Methods:
Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico “look-up” of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls.
Results:
In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07–1.13], p = 7.12 × 10−11) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90–1.17], p = 0.695).
Conclusion:
Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
doi:10.1212/WNL.0000000000000707
PMCID: PMC4150131  PMID: 25031287
3.  A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach 
PLoS Genetics  2014;10(7):e1004469.
Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10−7), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05–1.32); meta-analysis p = 2.6×10−8). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10−15; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.
Author Summary
Ischaemic stroke places an enormous burden on global healthcare. However, the disease processes that lead to stroke are not fully understood. Genome-wide association studies have recently established that common genetic variants can increase risk of ischaemic stroke and its subtypes. In this study, we aimed to identify novel genetic associations with ischaemic stroke and its subtypes by addressing the fact that younger onset cases may have a stronger genetic component, and using this information in our analyses. We identify a novel genetic variant on chromosome 11 (rs660599), which is associated with increased risk of large artery stroke. We also show that mRNA expression of the nearest gene (MMP12) is higher in arteries with the disease process underlying large artery stroke (atherosclerosis). Finally, we evaluate our novel analysis approach, and show that our method is likely to identify further associations with ischaemic stroke.
doi:10.1371/journal.pgen.1004469
PMCID: PMC4117446  PMID: 25078452
4.  Ipsilateral foetal-type posterior cerebral artery is associated with cognitive decline after carotid revascularisation 
BMC Neurology  2014;14:84.
Background
Stenosis of the internal carotid artery has been associated with cognitive impairment and decline. However, studies testing the effect of carotid revascularisation on cognition have had conflicting results. This may in part be explained by variation in the flow territory of the carotid artery. In 12 to 36% of the patients, the posterior cerebral artery is mainly or exclusively supplied by the internal carotid artery via a foetal-type posterior cerebral artery. In these patients, ipsilateral carotid artery stenosis is likely to result in a larger area with hypoperfusion than in case of a normal posterior cerebral artery. Patients with a foetal-type posterior cerebral artery could therefore benefit more from revascularisation. We compared the effects of carotid revascularisation on cognition between patients with a foetal-type and those with a normal posterior cerebral artery.
Methods
Patients with symptomatic internal carotid artery stenosis ≥ 50%, enrolled in the International Carotid Stenting Study (ICSS) at a single centre, underwent detailed neuropsychological examinations before and 6 months after revascularisation. Cognitive test results were standardized into z-scores, from which a cognitive sumscore was calculated. The primary outcome was the change in cognitive sumscore between baseline and follow-up. Changes in cognitive sumscore were compared between patients with an ipsilateral foetal-type and those with a normal posterior cerebral artery, as assessed with CT or MR angiography.
Results
Of 145 patients enrolled in ICSS at the centre during the study period, 98 had both angiography at baseline and neuropsychological examination at baseline and at 6-months follow-up. The cognitive sum score decreased by 0.28 (95% confidence interval, 0.10 to 0.45) in 13 patients with an ipsilateral foetal-type posterior cerebral artery and by 0.07 (95% CI, 0.002 to 0.15) in 85 patients with a normal posterior cerebral artery (mean difference, -0.20; 95% CI, -0.40 to -0.01). This did not change essentially after adjustment for baseline factors.
Conclusion
An ipsilateral foetal-type posterior cerebral artery appears to increase cognitive decline after carotid revascularisation. Our findings have to be reproduced in an independent study before further implications can be made.
doi:10.1186/1471-2377-14-84
PMCID: PMC4021499  PMID: 24739135
Angioplasty and stenting; Carotid endarterectomy; Symptomatic carotid stenosis; Cognition; Circle of Willis
5.  Intervention versus standard medical treatment in patients with symptomatic occlusion of the internal carotid artery: a randomised oxygen-15 PET study 
EJNMMI Research  2013;3:79.
Background
The aim of this randomised pilot study was to investigate the haemodynamic effects measured by oxygen-15 positron emission tomography (PET) of interventional treatment consisting of either endarterectomy or endovascular treatment of stenosed cerebropetal arteries, or tapering of antihypertensive medication in comparison with standard medical treatment alone in patients with symptomatic internal carotid artery (ICA) occlusion.
Methods
Twenty-three patients with symptomatic ICA occlusion underwent PET scanning at baseline and after 3 months. Twelve patients were randomised to intervention (either endarterectomy or endovascular treatment of stenosed cerebropetal arteries, or tapering of antihypertensive medication) and 11 to standard medical treatment alone. Primary outcome was a change in cerebral blood flow (CBF), cerebral blood volume (CBV) and/or oxygen extraction fraction (OEF) after 3 months measured by PET.
Results
There were no differences in changes in CBF, CBV or OEF between the two groups. Only patients with compromised perfusion at presentation showed a borderline significant increase in CBF of 2.8 mL/min/100 mL (95% confidence interval 0.0 to 5.7) after intervention (n = 7).
Conclusion
This pilot study shows that in patients with symptomatic ICA occlusion, oxygen-15 PET did not detect differences in improvement of CBF, CBV or OEF between interventional and standard treatment.
doi:10.1186/2191-219X-3-79
PMCID: PMC4029781  PMID: 24308868
Carotid artery diseases; Haemodynamics; Other cerebrovascular disease/stroke; PET
6.  The Basilar Artery International Cooperation Study (BASICS): study protocol for a randomised controlled trial 
Trials  2013;14:200.
Background
Despite recent advances in acute stroke treatment, basilar artery occlusion (BAO) is associated with a death or disability rate of close to 70%. Randomised trials have shown the safety and efficacy of intravenous thrombolysis (IVT) given within 4.5 h and have shown promising results of intra-arterial thrombolysis given within 6 h of symptom onset of acute ischaemic stroke, but these results do not directly apply to patients with an acute BAO because only few, if any, of these patients were included in randomised acute stroke trials.
Recently the results of the Basilar Artery International Cooperation Study (BASICS), a prospective registry of patients with acute symptomatic BAO challenged the often-held assumption that intra-arterial treatment (IAT) is superior to IVT. Our observations in the BASICS registry underscore that we continue to lack a proven treatment modality for patients with an acute BAO and that current clinical practice varies widely.
Design
BASICS is a randomised controlled, multicentre, open label, phase III intervention trial with blinded outcome assessment, investigating the efficacy and safety of additional IAT after IVT in patients with BAO. The trial targets to include 750 patients, aged 18 to 85 years, with CT angiography or MR angiography confirmed BAO treated with IVT. Patients will be randomised between additional IAT followed by optimal medical care versus optimal medical care alone. IVT has to be initiated within 4.5 h from estimated time of BAO and IAT within 6 h. The primary outcome parameter will be favourable outcome at day 90 defined as a modified Rankin Scale score of 0–3.
Discussion
The BASICS registry was observational and has all the limitations of a non-randomised study. As the IAT approach becomes increasingly available and frequently utilised an adequately powered randomised controlled phase III trial investigating the added value of this therapy in patients with an acute symptomatic BAO is needed (clinicaltrials.gov: NCT01717755).
doi:10.1186/1745-6215-14-200
PMCID: PMC3728222  PMID: 23835026
Basilar artery occlusion; Basilar artery thrombosis; Intra-arterial treatment; Intravenous thrombolysis; Stroke
8.  Seventy-five genetic loci influencing the human red blood cell 
van der Harst, Pim | Zhang, Weihua | Leach, Irene Mateo | Rendon, Augusto | Verweij, Niek | Sehmi, Joban | Paul, Dirk S. | Elling, Ulrich | Allayee, Hooman | Li, Xinzhong | Radhakrishnan, Aparna | Tan, Sian-Tsung | Voss, Katrin | Weichenberger, Christian X. | Albers, Cornelis A. | Al-Hussani, Abtehale | Asselbergs, Folkert W. | Ciullo, Marina | Danjou, Fabrice | Dina, Christian | Esko, Tõnu | Evans, David M. | Franke, Lude | Gögele, Martin | Hartiala, Jaana | Hersch, Micha | Holm, Hilma | Hottenga, Jouke-Jan | Kanoni, Stavroula | Kleber, Marcus E. | Lagou, Vasiliki | Langenberg, Claudia | Lopez, Lorna M. | Lyytikäinen, Leo-Pekka | Melander, Olle | Murgia, Federico | Nolte, Ilja M. | O’Reilly, Paul F. | Padmanabhan, Sandosh | Parsa, Afshin | Pirastu, Nicola | Porcu, Eleonora | Portas, Laura | Prokopenko, Inga | Ried, Janina S. | Shin, So-Youn | Tang, Clara S. | Teumer, Alexander | Traglia, Michela | Ulivi, Sheila | Westra, Harm-Jan | Yang, Jian | Zhao, Jing Hua | Anni, Franco | Abdellaoui, Abdel | Attwood, Antony | Balkau, Beverley | Bandinelli, Stefania | Bastardot, François | Benyamin, Beben | Boehm, Bernhard O. | Cookson, William O. | Das, Debashish | de Bakker, Paul I. W. | de Boer, Rudolf A. | de Geus, Eco J. C. | de Moor, Marleen H. | Dimitriou, Maria | Domingues, Francisco S. | Döring, Angela | Engström, Gunnar | Eyjolfsson, Gudmundur Ingi | Ferrucci, Luigi | Fischer, Krista | Galanello, Renzo | Garner, Stephen F. | Genser, Bernd | Gibson, Quince D. | Girotto, Giorgia | Gudbjartsson, Daniel Fannar | Harris, Sarah E. | Hartikainen, Anna-Liisa | Hastie, Claire E. | Hedblad, Bo | Illig, Thomas | Jolley, Jennifer | Kähönen, Mika | Kema, Ido P. | Kemp, John P. | Liang, Liming | Lloyd-Jones, Heather | Loos, Ruth J. F. | Meacham, Stuart | Medland, Sarah E. | Meisinger, Christa | Memari, Yasin | Mihailov, Evelin | Miller, Kathy | Moffatt, Miriam F. | Nauck, Matthias | Novatchkova, Maria | Nutile, Teresa | Olafsson, Isleifur | Onundarson, Pall T. | Parracciani, Debora | Penninx, Brenda W. | Perseu, Lucia | Piga, Antonio | Pistis, Giorgio | Pouta, Anneli | Puc, Ursula | Raitakari, Olli | Ring, Susan M. | Robino, Antonietta | Ruggiero, Daniela | Ruokonen, Aimo | Saint-Pierre, Aude | Sala, Cinzia | Salumets, Andres | Sambrook, Jennifer | Schepers, Hein | Schmidt, Carsten Oliver | Silljé, Herman H. W. | Sladek, Rob | Smit, Johannes H. | Starr, John M. | Stephens, Jonathan | Sulem, Patrick | Tanaka, Toshiko | Thorsteinsdottir, Unnur | Tragante, Vinicius | van Gilst, Wiek H. | van Pelt, L. Joost | van Veldhuisen, Dirk J. | Völker, Uwe | Whitfield, John B. | Willemsen, Gonneke | Winkelmann, Bernhard R. | Wirnsberger, Gerald | Algra, Ale | Cucca, Francesco | d’Adamo, Adamo Pio | Danesh, John | Deary, Ian J. | Dominiczak, Anna F. | Elliott, Paul | Fortina, Paolo | Froguel, Philippe | Gasparini, Paolo | Greinacher, Andreas | Hazen, Stanley L. | Jarvelin, Marjo-Riitta | Khaw, Kay Tee | Lehtimäki, Terho | Maerz, Winfried | Martin, Nicholas G. | Metspalu, Andres | Mitchell, Braxton D. | Montgomery, Grant W. | Moore, Carmel | Navis, Gerjan | Pirastu, Mario | Pramstaller, Peter P. | Ramirez-Solis, Ramiro | Schadt, Eric | Scott, James | Shuldiner, Alan R. | Smith, George Davey | Smith, J. Gustav | Snieder, Harold | Sorice, Rossella | Spector, Tim D. | Stefansson, Kari | Stumvoll, Michael | Wilson Tang, W. H. | Toniolo, Daniela | Tönjes, Anke | Visscher, Peter M. | Vollenweider, Peter | Wareham, Nicholas J. | Wolffenbuttel, Bruce H. R. | Boomsma, Dorret I. | Beckmann, Jacques S. | Dedoussis, George V. | Deloukas, Panos | Ferreira, Manuel A. | Sanna, Serena | Uda, Manuela | Hicks, Andrew A. | Penninger, Josef Martin | Gieger, Christian | Kooner, Jaspal S. | Ouwehand, Willem H. | Soranzo, Nicole | Chambers, John C
Nature  2012;492(7429):369-375.
Anaemia is a chief determinant of globalill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P <10−8, which together explain 4–9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
doi:10.1038/nature11677
PMCID: PMC3623669  PMID: 23222517
9.  Genetic risk factors for ischaemic stroke and its subtypes (the METASTROKE Collaboration): a meta-analysis of genome-wide association studies 
Traylor, Matthew | Farrall, Martin | Holliday, Elizabeth G | Sudlow, Cathie | Hopewell, Jemma C | Cheng, Yu-Ching | Fornage, Myriam | Ikram, M Arfan | Malik, Rainer | Bevan, Steve | Thorsteinsdottir, Unnur | Nalls, Mike A | Longstreth, WT | Wiggins, Kerri L | Yadav, Sunaina | Parati, Eugenio A | DeStefano, Anita L | Worrall, Bradford B | Kittner, Steven J | Khan, Muhammad Saleem | Reiner, Alex P | Helgadottir, Anna | Achterberg, Sefanja | Fernandez-Cadenas, Israel | Abboud, Sherine | Schmidt, Reinhold | Walters, Matthew | Chen, Wei-Min | Ringelstein, E Bernd | O'Donnell, Martin | Ho, Weang Kee | Pera, Joanna | Lemmens, Robin | Norrving, Bo | Higgins, Peter | Benn, Marianne | Sale, Michele | Kuhlenbäumer, Gregor | Doney, Alexander S F | Vicente, Astrid M | Delavaran, Hossein | Algra, Ale | Davies, Gail | Oliveira, Sofia A | Palmer, Colin N A | Deary, Ian | Schmidt, Helena | Pandolfo, Massimo | Montaner, Joan | Carty, Cara | de Bakker, Paul I W | Kostulas, Konstantinos | Ferro, Jose M | van Zuydam, Natalie R | Valdimarsson, Einar | Nordestgaard, Børge G | Lindgren, Arne | Thijs, Vincent | Slowik, Agnieszka | Saleheen, Danish | Paré, Guillaume | Berger, Klaus | Thorleifsson, Gudmar | Hofman, Albert | Mosley, Thomas H | Mitchell, Braxton D | Furie, Karen | Clarke, Robert | Levi, Christopher | Seshadri, Sudha | Gschwendtner, Andreas | Boncoraglio, Giorgio B | Sharma, Pankaj | Bis, Joshua C | Gretarsdottir, Solveig | Psaty, Bruce M | Rothwell, Peter M | Rosand, Jonathan | Meschia, James F | Stefansson, Kari | Dichgans, Martin | Markus, Hugh S
Lancet Neurology  2012;11(11):951-962.
Summary
Background
Various genome-wide association studies (GWAS) have been done in ischaemic stroke, identifying a few loci associated with the disease, but sample sizes have been 3500 cases or less. We established the METASTROKE collaboration with the aim of validating associations from previous GWAS and identifying novel genetic associations through meta-analysis of GWAS datasets for ischaemic stroke and its subtypes.
Methods
We meta-analysed data from 15 ischaemic stroke cohorts with a total of 12 389 individuals with ischaemic stroke and 62 004 controls, all of European ancestry. For the associations reaching genome-wide significance in METASTROKE, we did a further analysis, conditioning on the lead single nucleotide polymorphism in every associated region. Replication of novel suggestive signals was done in 13 347 cases and 29 083 controls.
Findings
We verified previous associations for cardioembolic stroke near PITX2 (p=2·8×10−16) and ZFHX3 (p=2·28×10−8), and for large-vessel stroke at a 9p21 locus (p=3·32×10−5) and HDAC9 (p=2·03×10−12). Additionally, we verified that all associations were subtype specific. Conditional analysis in the three regions for which the associations reached genome-wide significance (PITX2, ZFHX3, and HDAC9) indicated that all the signal in each region could be attributed to one risk haplotype. We also identified 12 potentially novel loci at p<5×10−6. However, we were unable to replicate any of these novel associations in the replication cohort.
Interpretation
Our results show that, although genetic variants can be detected in patients with ischaemic stroke when compared with controls, all associations we were able to confirm are specific to a stroke subtype. This finding has two implications. First, to maximise success of genetic studies in ischaemic stroke, detailed stroke subtyping is required. Second, different genetic pathophysiological mechanisms seem to be associated with different stroke subtypes.
Funding
Wellcome Trust, UK Medical Research Council (MRC), Australian National and Medical Health Research Council, National Institutes of Health (NIH) including National Heart, Lung and Blood Institute (NHLBI), the National Institute on Aging (NIA), the National Human Genome Research Institute (NHGRI), and the National Institute of Neurological Disorders and Stroke (NINDS).
doi:10.1016/S1474-4422(12)70234-X
PMCID: PMC3490334  PMID: 23041239
10.  Magnesium for aneurysmal subarachnoid haemorrhage (MASH-2): a randomised placebo-controlled trial 
Lancet  2012;380(9836):44-49.
Summary
Background
Magnesium sulphate is a neuroprotective agent that might improve outcome after aneurysmal subarachnoid haemorrhage by reducing the occurrence or improving the outcome of delayed cerebral ischaemia. We did a trial to test whether magnesium therapy improves outcome after aneurysmal subarachnoid haemorrhage.
Methods
We did this phase 3 randomised, placebo-controlled trial in eight centres in Europe and South America. We randomly assigned (with computer-generated random numbers, with permuted blocks of four, stratified by centre) patients aged 18 years or older with an aneurysmal pattern of subarachnoid haemorrhage on brain imaging who were admitted to hospital within 4 days of haemorrhage, to receive intravenous magnesium sulphate, 64 mmol/day, or placebo. We excluded patients with renal failure or bodyweight lower than 50 kg. Patients, treating physicians, and investigators assessing outcomes and analysing data were masked to the allocation. The primary outcome was poor outcome—defined as a score of 4–5 on the modified Rankin Scale—3 months after subarachnoid haemorrhage, or death. We analysed results by intention to treat. We also updated a previous meta-analysis of trials of magnesium treatment for aneurysmal subarachnoid haemorrhage. This study is registered with controlled-trials.com (ISRCTN 68742385) and the EU Clinical Trials Register (EudraCT 2006-003523-36).
Findings
1204 patients were enrolled, one of whom had his treatment allocation lost. 606 patients were assigned to the magnesium group (two lost to follow-up), 597 to the placebo (one lost to follow-up). 158 patients (26·2%) had poor outcome in the magnesium group compared with 151 (25·3%) in the placebo group (risk ratio [RR] 1·03, 95% CI 0·85–1·25). Our updated meta-analysis of seven randomised trials involving 2047 patients shows that magnesium is not superior to placebo for reduction of poor outcome after aneurysmal subarachnoid haemorrhage (RR 0·96, 95% CI 0·86–1·08).
Interpretation
Intravenous magnesium sulphate does not improve clinical outcome after aneurysmal subarachnoid haemorrhage, therefore routine administration of magnesium cannot be recommended.
Funding
Netherlands Heart Foundation, UK Medical Research Council.
doi:10.1016/S0140-6736(12)60724-7
PMCID: PMC3391717  PMID: 22633825
11.  Outcomes of basilar artery occlusion in patients aged 75 years or older in the Basilar Artery International Cooperation Study 
Journal of Neurology  2012;259(11):2341-2346.
Patients with an acute basilar artery occlusion (BAO) have a high risk of long-lasting disability and death. Only limited data are available on functional outcome in elderly patients with BAO. Using data from the Basilar Artery International Cooperation Study, we aimed to determine outcomes in patients ≥75 years. Primary outcome measure was poor functional outcome (modified Rankin scale score 4–6). Secondary outcomes were death, insufficient vessel recanalization (defined as thrombolysis in myocardial infarction score 0–1) and symptomatic intracranial hemorrhage (SICH). Patients were divided into four age-groups, based on quartiles: 18–54, 55–64, 65–74, and ≥75 years. Outcomes were compared between patients ≥75 years and patients aged 18–54 years. Risk ratios with corresponding 95 % confidence intervals (CI) were calculated and Poisson regression analyses were performed to calculate adjusted risk ratios (aRR). We included 619 patients [18–54 years n = 153 (25 %), 55–64 years n = 133 (21 %), 65–74 years n = 171 (28 %), and ≥75 years n = 162 (26 %)]. Compared with patients aged 18–54 years, patients ≥75 years were at increased risk of poor functional outcome [aRR 1.33 (1.14–1.55)] and death [aRR 2.47 (1.75–3.51)]. Nevertheless, 35/162 (22 %, 95 % CI 15–28 %) of patients ≥75 years had good functional outcome. No significant differences between age groups were observed for recanalization rate and incidence of SICH. Although patients ≥75 years with BAO have an increased risk of poor outcome compared with younger patients, a substantial group of patients ≥75 years survives with a good functional outcome.
Electronic supplementary material
The online version of this article (doi:10.1007/s00415-012-6498-2) contains supplementary material, which is available to authorized users.
doi:10.1007/s00415-012-6498-2
PMCID: PMC3484310  PMID: 22527236
Basilar artery occlusion; Age; Recanalization; Outcome; Mortality
12.  Trigger factors for rupture of intracranial aneurysms in relation to patient and aneurysm characteristics 
Journal of Neurology  2011;259(7):1298-1302.
Female gender, age above 60 years, and an aneurysm larger than 5 mm or location on the posterior circulation are associated with a higher rupture risk of intracranial aneurysms. We hypothesized that this association is explained by a higher susceptibility to (one of) the eight trigger factors that were recently identified. We included 250 patients with aneurysmal subarachnoid hemorrhage. We calculated relative risks (RR) with 95% confidence intervals (95% CI) of aneurysmal rupture for trigger factors according to sex, age, site, and size of the aneurysms by means of the case-crossover design. None of the triggers except for physical exercise differed according to patient and aneurysm characteristics. In the hour after exposure to physical exercise: (1) patients over the age of 60 have a six-times-higher risk of rupture (RR 13; 95% CI 6.3−26) than those of 60 years of age and under (RR 2.3; 1.3−4.1); (2) aneurysms at the internal carotid artery have a higher risk than those at other locations (RR 17; 7.8−37), but this was only statistically significant when compared to anterior communicating artery aneurysms (RR 3.2; 1.6−6.1); (3) aneurysms 5 mm or smaller had a higher risk of rupture (RR 9.5; 4.6−19) than larger aneurysms (RR 2.4; 1.3−4.3); and (4) women and men had similar risks. A higher susceptibility to exercise might explain part of the higher risk of rupture in older patients. Why women and patients with aneurysms larger than 5 mm or posterior circulation aneurysms have a higher risk of rupture remains to be settled.
doi:10.1007/s00415-011-6341-1
PMCID: PMC3390687  PMID: 22186848
Subarachnoid hemorrhage; Risk factors; Trigger factors; Intracranial aneurysm
13.  Occurrence and impact of delayed cerebral ischemia after coiling and after clipping in the International Subarachnoid Aneurysm Trial (ISAT) 
Journal of Neurology  2011;259(4):679-683.
Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage (SAH). We studied differences in incidence and impact of DCI as defined clinically after coiling and after clipping in the International Subarachnoid Aneurysm Trial. We calculated odds ratios (OR) for DCI for clipping versus coiling with logistic regression analysis. With coiled patients without DCI as the reference group, we calculated ORs for poor outcome at 2 months and 1 year for coiled patients with DCI and for clipped patients without, and with DCI. With these ORs, we calculated relative excess risk due to Interaction (RERI). Clipping increased the risk of DCI compared to coiling in the 2,143 patients OR 1.24, 95% confidence interval (95% CI 1.01–1.51). Coiled patients with DCI, clipped patients without DCI, and clipped patients with DCI all had higher risks of poor outcome than coiled patients without DCI. Clipping and DCI showed no interaction for poor outcome at 2 months: RERI 0.12 (95% CI −1.16 to 1.40) or 1 year: RERI −0.48 (95% CI −1.69 to 0.74). Only for patients treated within 4 days, coiling and DCI was associated with a poorer outcome at 1 year than clipping and DCI (RERI −2.02, 95% CI −3.97 to −0.08). DCI was more common after clipping than after coiling in SAH patients in ISAT. Impact of DCI on poor outcome did not differ between clipped and coiled patients, except for patients treated within 4 days, in whom DCI resulted more often in poor outcome after coiling than after clipping.
doi:10.1007/s00415-011-6243-2
PMCID: PMC3319891  PMID: 21947244
Subarachnoid hemorrhage; Delayed cerebral ischemia; Cerebral aneurysm
14.  Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials 
Lancet  2011;378(9791):584-594.
Summary
Background
The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials.
Methods
We established a collaboration of genetic studies consisting of 237 datasets including 59 995 individuals with data for homocysteine and 20 885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45 549 individuals, 2314 stroke events, 269 transient ischaemic attacks).
Findings
The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 μmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 μmol/L, −0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region.
Interpretation
In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption.
Funding
Full funding sources listed at end of paper (see Acknowledgments).
doi:10.1016/S0140-6736(11)60872-6
PMCID: PMC3156981  PMID: 21803414
15.  An early rise in body temperature is related to unfavorable outcome after stroke: data from the PAIS study 
Journal of Neurology  2010;258(2):302-307.
Subfebrile temperature or fever is present in about a third of patients on the first day after stroke onset and is associated with poor outcome. However, the temporal profile of this association is not well established. We aimed to assess the relationship between body temperature on admission as well as the change in body temperature from admission to 24 h thereafter and functional outcome and death. We analyzed data of 1,332 patients admitted within 12 h of stroke onset. The relation between body temperature on admission or the change in body temperature from admission to 24 h thereafter (adjusted for body temperature on admission) on the one hand and unfavorable outcome (death, or a modified Rankin Scale score >2) at 3 months on the other were expressed as odds ratio per 1.0°C increase in body temperature. Adjustments for potential confounders were made with a multiple logistic regression model. No relation was found between admission body temperature and poor outcome (aOR 1.06; 95% CI 0.85–1.32) and death (aOR 1.23; 95% CI 0.95–1.60). In contrast, increased body temperature in the first 24 h after stroke onset was associated with poor outcome (aOR 1.30; 95% CI 1.05–1.63) and death (aOR 1.51; 95% CI 1.15–1.98). An early rise in body temperature rather than high body temperature on admission is a risk factor for unfavorable outcome in patients with acute stroke.
doi:10.1007/s00415-010-5756-4
PMCID: PMC3036804  PMID: 20878419
Stroke; Body temperature; Clinical outcome
16.  Functional outcome and quality of life 5 and 12.5 years after aneurysmal subarachnoid haemorrhage 
Journal of Neurology  2010;257(12):2059-2064.
Patients who recover from aneurysmal subarachnoid haemorrhage (SAH) often remain disabled or have persisting symptoms with a reduced quality of life (QoL). We assessed functional outcome and QoL 5 and 12.5 years after SAH. In a consecutive series of 64 patients with mean age at SAH of 51 years, initial outcome assessments had been performed at 4 and 18 months after SAH. At the initial and current outcome assessments, functional outcome was measured with the modified Rankin Scale (mRS) and QoL with the SF-36 and a visual analogue scale (VAS). We studied the change in outcome measurements over time. We used the non-parametric Wilcoxon test to compare differences in mRS grades and calculated differences with corresponding 95% confidence intervals in the domain scores of the SF-36 and the VAS. After 5 years, seven patients had died and five patients had missing data. Compared with the 4-month follow-up, the mRS had improved in 29 of the 52 patients, remained similar in 19 patients. The overall QoL (SF-36 domains and VAS score) was better. At 12.5 years an additional six patients had died. Compared to the 4-month study, 25 of the 46 remaining patients had improved mRS, 12 had remained the same and in nine patients the mRS had worsened. Between the 5 and the 12.5 years follow-up, the improvement in mRS had decreased but patients reported overall a better QoL. Among long-time survivors, QoL may improve more than a decade after SAH.
doi:10.1007/s00415-010-5660-y
PMCID: PMC2999856  PMID: 20652302
Cerebral aneurysm; Subarachnoid haemorrhage; Quality of life
17.  Achieved serum magnesium concentrations and occurrence of delayed cerebral ischaemia and poor outcome in aneurysmal subarachnoid haemorrhage 
Background
Magnesium therapy probably reduces the frequency of delayed cerebral ischaemia (DCI) in subarachnoid haemorrhage (SAH) but uncertainty remains about the optimal serum magnesium concentration. We assessed the relationship between serum magnesium concentrations achieved with magnesium sulphate therapy 64 mmol/day and the occurrence of DCI and poor outcome in patients with SAH.
Methods
Differences in magnesium concentrations between patients with and without DCI and with and without poor outcome were calculated. Quartiles of last serum magnesium concentrations before the onset of DCI, or before the median day of DCI in patients without DCI, were related to the occurrence of DCI and poor outcome at 3 months using logistic regression.
Results
Compared with the lowest quartile of serum magnesium concentration (1.10–1.28 mmol/l), the risk of DCI was decreased in each of the higher three quartiles (adjusted odds ratio (OR) in each quartile 0.2; lower 95% CI 0.0 to 0.1; upper limit 0.8 to 0.9). The OR for poor outcome was 1.8 (95% CI 0.5 to 6.9) in the second quartile, 1.0 (95% CI 0.2 to 4.5) in the third quartile and 4.9 (95% CI 1.2 to 19.7) in the highest quartile.
Discussion
Magnesium sulphate 64 mmol/day results in a stable risk reduction of DCI over a broad range of achieved serum magnesium concentrations, and strict titration of the dosage therefore does not seem necessary. However, concentrations ⩽1.28 mmol/l could decrease the effect on DCI while concentrations ⩾1.62 might have a negative effect on clinical outcome.
doi:10.1136/jnnp.2006.104042
PMCID: PMC2117699  PMID: 17135457
18.  Pulmonary edema and blood volume after aneurysmal subarachnoid hemorrhage: a prospective observational study 
Critical Care  2010;14(2):R43.
Introduction
Pulmonary edema (PED) is a severe complication after aneurysmal subarachnoid hemorrhage (SAH). PED is often treated with diuretics and a reduction in fluid intake, but this may cause intravascular volume depletion, which is associated with secondary ischemia after SAH. We prospectively studied intravascular volume in SAH patients with and without PED.
Methods
Circulating blood volume (CBV) was determined daily during the first 10 days after SAH by means of pulse dye densitometry. CBV of 60-80 ml/kg was considered normal. PED was diagnosed from clinical signs and characteristic bilateral pulmonary infiltrates on the chest radiograph. We compared CBV, cardiac index, and fluid balance between patients with and without PED with weighted linear regression, taking into account only measurements from the first day after SAH through to the day on which PED was diagnosed. Differences were adjusted for age, bodyweight, and clinical condition.
Results
In total, 102 patients were included, 17 of whom developed PED after a mean of 4 days after SAH. Patients developing PED had lower mean CBV (56.6 ml/kg) than did those without PED (66.8 ml/kg). The mean difference in CBV was -11.3 ml/kg (95% CI, -16.5 to -6.1); adjusted mean difference, -8.0 ml/kg (95% CI, -14.0 to -2.0). After adjusting, no differences were found in cardiac index or fluid balance between patients with and without PED.
Conclusions
SAH patients developing pulmonary edema have a lower blood volume than do those without PED and are hypovolemic. Measures taken to counteract pulmonary edema must be balanced against the risk of worsening hypovolemia.
Trial registration
NTR1255.
doi:10.1186/cc8930
PMCID: PMC2887155  PMID: 20331893
19.  Bilateral carotid artery occlusion with transient or moderately disabling ischaemic stroke: clinical features and long-term outcome 
Journal of Neurology  2009;256(10):1728-1735.
Information on the prognosis of patients with transient ischaemic attack or moderately disabling ischaemic stroke associated with bilateral internal carotid artery (ICA) occlusion is scarce. We prospectively studied 57 consecutive patients (46 men; mean age 60 ± 9 years) with bilateral ICA occlusion who had presented with unilateral transient or moderately disabling cerebral or retinal ischaemic symptoms. We determined the long-term risk of recurrent ischaemic stroke and the composite outcome of stroke, myocardial infarction or vascular death. Four patients had a recurrent ischaemic stroke during a mean follow-up of 5.9 years, resulting in an annual stroke rate of 1.2% (95% confidence interval (CI) 0.3–3.1). Risk factors for recurrent ischaemic stroke could not be identified. Eighteen patients suffered a stroke, myocardial infarction or vascular death, resulting in an annual rate for major vascular events of 5.3% (95% CI 3.1–8.3). Age and a history of ischaemic heart disease were significant risk factors for future vascular events. Patients with transient or moderately disabling symptoms of cerebral or retinal ischaemia associated with bilateral ICA occlusion have a relatively low risk of recurrent ischaemic stroke. Although this study was not designed to compare conservative treatment with surgical intervention, the favourable outcome suggests that a policy of medical therapy and control of risk factors may be justified in these patients.
doi:10.1007/s00415-009-5194-3
PMCID: PMC2758212  PMID: 19488672
Carotid artery diseases; Stroke; Collateral circulation; Follow-up studies
20.  Incorrect predictions, not incorrect statistics! 
Critical Care  2009;13(2):406.
doi:10.1186/cc7773
PMCID: PMC2689494  PMID: 19439047
21.  Nurses' prediction of volume status after aneurysmal subarachnoid haemorrhage: a prospective cohort study 
Critical Care  2008;12(6):R153.
Introduction
Patients who have suffered aneurysmal subarachnoid haemorrhage (SAH) often have derangements in blood volume, contributing to poor outcome. To guide fluid management, regular assessments of volume status must be conducted. We studied the ability of nursing staff to predict hypovolaemia or hypervolaemia, based on their interpretation of available haemodynamic data.
Methods
In a prospective cohort study, intensive care unit and medium care unit nurses, currently treating patients with recent SAH, were asked to predict present volume status. For their assessment they could use all available haemodynamic parameters (for example, heart rate, blood pressure, fluid balance). The nurses' assessments were compared with the actual circulating blood volume (CBV), as measured daily with pulse dye densitometry during the first 10 days after SAH. Normovolaemia was defined as a CBV of 60 to 80 ml/kg body weight; hypovolaemia as CBV under 60 ml/kg; severe hypovolaemia as CBV under 50 ml/kg and hypervolaemia as CBV above 80 ml/kg.
Results
A total of 350 combinations of volume predictions and CBV measurements were obtained in 43 patients. Prediction of hypovolaemia had a sensitivity of 0.10 (95% confidence interval [CI] = 0.06 to 0.16) and a positive predictive value of 0.37 (95% CI = 0.23 to 0.53) for actual hypovolaemia. The prediction of hypervolaemia had a sensitivity of 0.06 (95% CI = 0.01 to 0.16) and a positive predictive value of 0.06 (95% CI = 0.02 to 0.19) for actual hypervolaemia. Mean CBV was significantly lower in instances considered hypervolaemic than in instances considered normovolaemic.
Conclusions
Assessment of haemodynamic condition in patients with SAH by intensive care unit or medium care unit nurses does not adequately predict hypovolaemia or hypervolaemia, as measured using pulse dye densitometry. Fluid therapy after SAH may require guidance with more advanced techniques than interpretation of usual haemodynamic parameters.
doi:10.1186/cc7142
PMCID: PMC2646318  PMID: 19046461
22.  Correction: PAIS: paracetamol (acetaminophen) in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN74418480] 
Background
The Paracetamol (Acetaminophen) In Stroke (PAIS) study is a phase III multicenter, double blind, randomized, placebo-controlled clinical trial of high-dose acetaminophen in patients with acute stroke. The trial compares treatment with a daily dose of 6 g acetaminophen, started within 12 hours after the onset of symptoms, with matched placebo. The purpose of this study is to assess whether treatment with acetaminophen for 3 days will result in improved functional outcome through a modest reduction in body temperature and prevention of fever.
The previously planned statistical analysis based on a dichotomization of the scores on the modified Rankin Scale (mRS) may not make the most efficient use of the available baseline information. Therefore, the planned primary analysis of the PAIS study has been changed from fixed dichotomization of the mRS to a sliding dichotomy analysis.
Methods
Instead of taking a single definition of good outcome for all patients, the definition is tailored to each individual patient's baseline prognosis on entry into the trial.
Conclusion
The protocol change was initiated because of both advances in statistical approaches and to increase the efficiency of the trial by improving statistical power.
Trial Registration
Current Controlled Trials [ISCRTN74418480]
doi:10.1186/1471-2261-8-29
PMCID: PMC2600816  PMID: 18983661
23.  Caveolin-1 Influences Vascular Protease Activity and Is a Potential Stabilizing Factor in Human Atherosclerotic Disease 
PLoS ONE  2008;3(7):e2612.
Caveolin-1 (Cav-1) is a regulatory protein of the arterial wall, but its role in human atherosclerosis remains unknown. We have studied the relationships between Cav-1 abundance, atherosclerotic plaque characteristics and clinical manisfestations of atherosclerotic disease.We determined Cav-1 expression by western blotting in atherosclerotic plaques harvested from 378 subjects that underwent carotid endarterectomy. Cav-1 levels were significantly lower in carotid plaques than non-atherosclerotic vascular specimens. Low Cav-1 expression was associated with features of plaque instability such as large lipid core, thrombus formation, macrophage infiltration, high IL-6, IL-8 levels and elevated MMP-9 activity. Clinically, a down-regulation of Cav-1 was observed in plaques obtained from men, patients with a history of myocardial infarction and restenotic lesions. Cav-1 levels above the median were associated with absence of new vascular events within 30 days after surgery [0% vs. 4%] and a trend towards lower incidence of new cardiovascular events during longer follow-up. Consistent with these clinical data, Cav-1 null mice revealed elevated intimal hyperplasia response following arterial injury that was significantly attenuated after MMP inhibition. Recombinant peptides mimicking Cav-1 scaffolding domain (Cavtratin) reduced gelatinase activity in cultured porcine arteries and impaired MMP-9 activity and COX-2 in LPS-challenged macrophages. Administration of Cavtratin strongly impaired flow-induced expansive remodeling in mice.This is the first study that identifies Cav-1 as a novel potential stabilizing factor in human atherosclerosis. Our findings support the hypothesis that local down-regulation of Cav-1 in atherosclerotic lesions contributes to plaque formation and/or instability accelerating the occurrence of adverse clinical outcomes. Therefore, given the large number of patients studied, we believe that Cav-1 may be considered as a novel target in the prevention of human atherosclerotic disease and the loss of Cav-1 may be a novel biomarker of vulnerable plaque with prognostic value.
doi:10.1371/journal.pone.0002612
PMCID: PMC2432041  PMID: 18596970
24.  Hemicraniectomy after middle cerebral artery infarction with life-threatening Edema trial (HAMLET). Protocol for a randomised controlled trial of decompressive surgery in space-occupying hemispheric infarction 
Trials  2006;7:29.
Background
Patients with a hemispheric infarct and massive space-occupying brain oedema have a poor prognosis. Despite maximal conservative treatment, the case fatality rate may be as high as 80%, and most survivors are left severely disabled. Non-randomised studies suggest that decompressive surgery reduces mortality substantially and improves functional outcome of survivors. This study is designed to compare the efficacy of decompressive surgery to improve functional outcome with that of conservative treatment in patients with space-occupying supratentorial infarction
Methods
The study design is that of a multi-centre, randomised clinical trial, which will include 112 patients aged between 18 and 60 years with a large hemispheric infarct with space-occupying oedema that leads to a decrease in consciousness. Patients will be randomised to receive either decompressive surgery in combination with medical treatment or best medical treatment alone. Randomisation will be stratified for the intended mode of conservative treatment (intensive care or stroke unit care). The primary outcome measure will be functional outcome, as determined by the score on the modified Rankin Scale, at one year.
doi:10.1186/1745-6215-7-29
PMCID: PMC1570365  PMID: 16965617
25.  PAIS: paracetamol (acetaminophen) in stroke; protocol for a randomized, double blind clinical trial. [ISCRTN 74418480] 
Background
In patients with acute stroke, increased body temperature is associated with large lesion volumes, high case fatality, and poor functional outcome. A 1°C increase in body temperature may double the odds of poor outcome. Two randomized double-blind clinical trials in patients with acute ischemic stroke have shown that treatment with a daily dose of 6 g acetaminophen (paracetamol) results in a small but rapid and potentially worthwhile reduction of 0.3°C (95% CI: 0.1–0.5) in body temperature. We set out to test the hypothesis that early antipyretic therapy reduces the risk of death or dependency in patients with acute stroke, even if they are normothermic.
Methods/design
Paracetamol (Acetaminophen) In Stroke (PAIS) is a randomized, double-blind clinical trial, comparing high-dose acetaminophen with placebo in 2500 patients. Inclusion criteria are a clinical diagnosis of hemorrhagic or ischemic stroke and the possibility to start treatment within 12 hours from onset of symptoms. The study will have a power of 86% to detect an absolute difference of 6% in the risk of death or dependency at three months, and a power of 72% to detect an absolute difference of 5%, at a 5% significance level.
Discussion
This is a simple trial, with a drug that only has a small effect on body temperature in normothermic patients. However, when lowering body temperature with acetaminophen does have the expected effectiveness, 20 patients will have to be treated to prevent dependency or death in one.
doi:10.1186/1471-2261-5-24
PMCID: PMC1208871  PMID: 16109181

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