Showing papers by "Sapienza University of Rome published in 2008"

Second consensus statement on the diagnosis of multiple system atrophy

Abstract: Background: A consensus conference on multiple system atrophy (MSA) in 1998 established criteria for diagnosis that have been accepted widely. Since then, clinical, laboratory, neuropathologic, and imaging studies have advanced the field, requiring a fresh evaluation of diagnostic criteria. We held a second consensus conference in 2007 and present the results here.Methods: Experts in the clinical, neuropathologic, and imaging aspects of MSA were invited to participate in a 2-day consensus conference. Participants were divided into five groups, consisting of specialists in the parkinsonian, cerebellar, autonomic, neuropathologic, and imaging aspects of the disorder. Each group independently wrote diagnostic criteria for its area of expertise in advance of the meeting. These criteria were discussed and reconciled during the meeting using consensus methodology.Results: The new criteria retain the diagnostic categories of MSA with predominant parkinsonism and MSA with predominant cerebellar ataxia to designate the predominant motor features and also retain the designations of definite, probable, and possible MSA. Definite MSA requires neuropathologic demonstration of CNS alpha-synuclein-positive glial cytoplasmic inclusions with neurodegenerative changes in striatonigral or olivopontocerebellar structures. Probable MSA requires a sporadic, progressive adult-onset disorder including rigorously defined autonomic failure and poorly levodopa-responsive parkinsonism or cerebellar ataxia. Possible MSA requires a sporadic, progressive adult-onset disease including parkinsonism or cerebellar ataxia and at least one feature suggesting autonomic dysfunction plus one other feature that may be a clinical or a neuroimaging abnormality.Conclusions: These new criteria have simplified the previous criteria, have incorporated current knowledge, and are expected to enhance future assessments of the disease.

The LHCb detector at the LHC

Abstract: The LHCb experiment is dedicated to precision measurements of CP violation and rare decays of B hadrons at the Large Hadron Collider (LHC) at CERN (Geneva). The initial configuration and expected performance of the detector and associated systems, as established by test beam measurements and simulation studies, is described.

Interaction ruling animal collective behavior depends on topological rather than metric distance: Evidence from a field study

Abstract: Numerical models indicate that collective animal behavior may emerge from simple local rules of interaction among the individuals. However, very little is known about the nature of such interaction, so that models and theories mostly rely on aprioristic assumptions. By reconstructing the three-dimensional positions of individual birds in airborne flocks of a few thousand members, we show that the interaction does not depend on the metric distance, as most current models and theories assume, but rather on the topological distance. In fact, we discovered that each bird interacts on average with a fixed number of neighbors (six to seven), rather than with all neighbors within a fixed metric distance. We argue that a topological interaction is indispensable to maintain a flock's cohesion against the large density changes caused by external perturbations, typically predation. We support this hypothesis by numerical simulations, showing that a topological interaction grants significantly higher cohesion of the aggregation compared with a standard metric one.

Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma.

Abstract: The time to progression among patients receiving bortezomib plus melphalan– prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan–prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P = 0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan–prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P = 0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%). Conclusions Bortezomib plus melphalan–prednisone was superior to melphalan–prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)

Identification and expansion of the tumorigenic lung cancer stem cell population.

Abstract: Lung carcinoma is often incurable and remains the leading cancer killer in both men and women. Recent evidence indicates that tumors contain a small population of cancer stem cells that are responsible for tumor maintenance and spreading. The identification of the tumorigenic population that sustains lung cancer may contribute significantly to the development of effective therapies. Here, we found that the tumorigenic cells in small cell and non-small cell lung cancer are a rare population of undifferentiated cells expressing CD133, an antigen present in the cell membrane of normal and cancer-primitive cells of the hematopoietic, neural, endothelial and epithelial lineages. Lung cancer CD133(+) cells were able to grow indefinitely as tumor spheres in serum-free medium containing epidermal growth factor and basic fibroblast growth factor. The injection of 10(4) lung cancer CD133(+) cells in immunocompromised mice readily generated tumor xenografts phenotypically identical to the original tumor. Upon differentiation, lung cancer CD133(+) cells acquired the specific lineage markers, while loosing the tumorigenic potential together with CD133 expression. Thus, lung cancer contains a rare population of CD133(+) cancer stem-like cells able to self-renew and generates an unlimited progeny of non-tumorigenic cells. Molecular and functional characterization of such a tumorigenic population may provide valuable information to be exploited in the clinical setting.

Gastroenteropancreatic neuroendocrine tumours.

Abstract: Gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) are fairly rare neoplasms that present many clinical challenges. They secrete peptides and neuroamines that cause distinct clinical syndromes, including carcinoid syndrome. However, many are clinically silent until late presentation with mass effects. Investigation and management should be highly individualised for a patient, taking into consideration the likely natural history of the tumour and general health of the patient. Management strategies include surgery for cure (which is achieved rarely) or for cytoreduction, radiological intervention (by chemoembolisation and radiofrequency ablation), chemotherapy, and somatostatin analogues to control symptoms that result from release of peptides and neuroamines. New biological agents and somatostatin-tagged radionuclides are under investigation. The complexity, heterogeneity, and rarity of GEP NETs have contributed to a paucity of relevant randomised trials and little or no survival increase over the past 30 years. To improve outcome from GEP NETs, a better understanding of their biology is needed, with emphasis on molecular genetics and disease modeling. More-reliable serum markers, better tumour localisation and identification of small lesions, and histological grading systems and classifications with prognostic application are needed. Comparison between treatments is currently very difficult. Progress is unlikely to occur without development of centers of excellence, with dedicated combined clinical teams to coordinate multicentre studies, maintain clinical and tissue databases, and refine molecularly targeted therapeutics.

The status of the world's land and marine mammals: diversity, threat, and knowledge

Abstract: Knowledge of mammalian diversity is still surprisingly disparate, both regionally and taxonomically. Here, we present a comprehensive assessment of the conservation status and distribution of the world's mammals. Data, compiled by 1700+ experts, cover all 5487 species, including marine mammals. Global macroecological patterns are very different for land and marine species but suggest common mechanisms driving diversity and endemism across systems. Compared with land species, threat levels are higher among marine mammals, driven by different processes (accidental mortality and pollution, rather than habitat loss), and are spatially distinct (peaking in northern oceans, rather than in Southeast Asia). Marine mammals are also disproportionately poorly known. These data are made freely available to support further scientific developments and conservation action.

Identification of ALK as a major familial neuroblastoma predisposition gene

Abstract: Neuroblastoma is a childhood cancer that can be inherited, but the genetic aetiology is largely unknown. Here we show that germline mutations in the anaplastic lymphoma kinase (ALK) gene explain most hereditary neuroblastomas, and that activating mutations can also be somatically acquired. We first identified a significant linkage signal at chromosome bands 2p23-24 using a whole-genome scan in neuroblastoma pedigrees. Resequencing of regional candidate genes identified three separate germline missense mutations in the tyrosine kinase domain of ALK that segregated with the disease in eight separate families. Resequencing in 194 high-risk neuroblastoma samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the ten mutations map to critical regions of the kinase domain and were predicted, with high probability, to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK messenger RNA resulted in profound inhibition of growth in all cell lines harbouring mutant or amplified ALK, as well as in two out of six wild-type cell lines for ALK. Our results demonstrate that heritable mutations of ALK are the main cause of familial neuroblastoma, and that germline or acquired activation of this cell-surface kinase is a tractable therapeutic target for this lethal paediatric malignancy.

The ALICE experiment at the CERN LHC

Abstract: ALICE (A Large Ion Collider Experiment) is a general-purpose, heavy-ion detector at the CERN LHC which focuses on QCD, the strong-interaction sector of the Standard Model. It is designed to address the physics of strongly interacting matter and the quark-gluon plasma at extreme values of energy density and temperature in nucleus-nucleus collisions. Besides running with Pb ions, the physics programme includes collisions with lighter ions, lower energy running and dedicated proton-nucleus runs. ALICE will also take data with proton beams at the top LHC energy to collect reference data for the heavy-ion programme and to address several QCD topics for which ALICE is complementary to the other LHC detectors. The ALICE detector has been built by a collaboration including currently over 1000 physicists and engineers from 105 Institutes in 30 countries. Its overall dimensions are 161626 m3 with a total weight of approximately 10 000 t. The experiment consists of 18 different detector systems each with its own specific technology choice and design constraints, driven both by the physics requirements and the experimental conditions expected at LHC. The most stringent design constraint is to cope with the extreme particle multiplicity anticipated in central Pb-Pb collisions. The different subsystems were optimized to provide high-momentum resolution as well as excellent Particle Identification (PID) over a broad range in momentum, up to the highest multiplicities predicted for LHC. This will allow for comprehensive studies of hadrons, electrons, muons, and photons produced in the collision of heavy nuclei. Most detector systems are scheduled to be installed and ready for data taking by mid-2008 when the LHC is scheduled to start operation, with the exception of parts of the Photon Spectrometer (PHOS), Transition Radiation Detector (TRD) and Electro Magnetic Calorimeter (EMCal). These detectors will be completed for the high-luminosity ion run expected in 2010. This paper describes in detail the detector components as installed for the first data taking in the summer of 2008.

Scalable and efficient provable data possession

Abstract: Storage outsourcing is a rising trend which prompts a number of interesting security issues, many of which have been extensively investigated in the past. However, Provable Data Possession (PDP) is a topic that has only recently appeared in the research literature. The main issue is how to frequently, efficiently and securely verify that a storage server is faithfully storing its client's (potentially very large) outsourced data. The storage server is assumed to be untrusted in terms of both security and reliability. (In other words, it might maliciously or accidentally erase hosted data; it might also relegate it to slow or off-line storage.) The problem is exacerbated by the client being a small computing device with limited resources. Prior work has addressed this problem using either public key cryptography or requiring the client to outsource its data in encrypted form.In this paper, we construct a highly efficient and provably secure PDP technique based entirely on symmetric key cryptography, while not requiring any bulk encryption. Also, in contrast with its predecessors, our PDP technique allows outsourcing of dynamic data, i.e, it efficiently supports operations, such as block modification, deletion and append.

First results from DAMA/LIBRA and the combined results with DAMA/NaI

Abstract: The highly radiopure ≃ 250 kg NaI(Tl) DAMA/LIBRA set-up is running at the Gran Sasso National Laboratory of the INFN. In this paper the first result obtained by exploiting the model independent annual modulation signature for Dark Matter (DM) particles is presented. It refers to an exposure of 0.53 ton×yr. The collected DAMA/LIBRA data satisfy all the many peculiarities of the DM annual modulation signature. Neither systematic effects nor side reactions able to account for the observed modulation amplitude and to contemporaneously satisfy all the several requirements of this DM signature are available. Considering the former DAMA/NaI and the present DAMA/LIBRA data all together (total exposure 0.82 ton×yr), the presence of Dark Matter particles in the galactic halo is supported, on the basis of the DM annual modulation signature, at 8.2 σ C.L.; in particular, in the energy interval (2–6) keV, the modulation amplitude is (0.0131±0.0016) cpd/kg/keV and the phase and the period are well compatible with June 2nd and one year, respectively.

Linking data to ontologies

Abstract: Many organizations nowadays face the problem of accessing existing data sources by means of flexible mechanisms that are both powerful and efficient. Ontologies are widely considered as a suitable formal tool for sophisticated data access. The ontology expresses the domain of interest of the information system at a high level of abstraction, and the relationship between data at the sources and instances of concepts and roles in the ontology is expressed by means of mappings. In this paper we present a solution to the problem of designing effective systems for ontology-based data access. Our solution is based on three main ingredients. First, we present a new ontology language, based on Description Logics, that is particularly suited to reason with large amounts of instances. The second ingredient is a novel mapping language that is able to deal with the so-called impedance mismatch problem, i.e., the problem arising from the difference between the basic elements managed by the sources, namely data, and the elements managed by the ontology, namely objects. The third ingredient is the query answering method, that combines reasoning at the level of the ontology with specific mechanisms for both taking into account the mappings and efficiently accessing the data at the sources.

Action anticipation and motor resonance in elite basketball players

Abstract: We combined psychophysical and transcranial magnetic stimulation studies to investigate the dynamics of action anticipation and its underlying neural correlates in professional basketball players. Athletes predicted the success of free shots at a basket earlier and more accurately than did individuals with comparable visual experience (coaches or sports journalists) and novices. Moreover, performance between athletes and the other groups differed before the ball was seen to leave the model's hands, suggesting that athletes predicted the basket shot's fate by reading the body kinematics. Both visuo-motor and visual experts showed a selective increase of motor-evoked potentials during observation of basket shots. However, only athletes showed a time-specific motor activation during observation of erroneous basket throws. Results suggest that achieving excellence in sports may be related to the fine-tuning of specific anticipatory 'resonance' mechanisms that endow elite athletes' brains with the ability to predict others' actions ahead of their realization.

Aspirin and extended-release dipyridamole versus clopidogrel for recurrent stroke

Abstract: BACKGROUND: Recurrent stroke is a frequent, disabling event after ischemic stroke. This study compared the efficacy and safety of two antiplatelet regimens--aspirin plus extended-release dipyridamole (ASA-ERDP) versus clopidogrel. METHODS: In this double-blind, 2-by-2 factorial trial, we randomly assigned patients to receive 25 mg of aspirin plus 200 mg of extended-release dipyridamole twice daily or to receive 75 mg of clopidogrel daily. The primary outcome was first recurrence of stroke. The secondary outcome was a composite of stroke, myocardial infarction, or death from vascular causes. Sequential statistical testing of noninferiority (margin of 1.075), followed by superiority testing, was planned. RESULTS: A total of 20,332 patients were followed for a mean of 2.5 years. Recurrent stroke occurred in 916 patients (9.0%) receiving ASA-ERDP and in 898 patients (8.8%) receiving clopidogrel (hazard ratio, 1.01; 95% confidence interval [CI], 0.92 to 1.11). The secondary outcome occurred in 1333 patients (13.1%) in each group (hazard ratio for ASA-ERDP, 0.99; 95% CI, 0.92 to 1.07). There were more major hemorrhagic events among ASA-ERDP recipients (419 [4.1%]) than among clopidogrel recipients (365 [3.6%]) (hazard ratio, 1.15; 95% CI, 1.00 to 1.32), including intracranial hemorrhage (hazard ratio, 1.42; 95% CI, 1.11 to 1.83). The net risk of recurrent stroke or major hemorrhagic event was similar in the two groups (1194 ASA-ERDP recipients [11.7%], vs. 1156 clopidogrel recipients [11.4%]; hazard ratio, 1.03; 95% CI, 0.95 to 1.11). CONCLUSIONS: The trial did not meet the predefined criteria for noninferiority but showed similar rates of recurrent stroke with ASA-ERDP and with clopidogrel. There is no evidence that either of the two treatments was superior to the other in the prevention of recurrent stroke. (ClinicalTrials.gov number, NCT00153062.)

A genetic framework for the control of cell division and differentiation in the root meristem.

Abstract: Plant growth and development are sustained by meristems. Meristem activity is controlled by auxin and cytokinin, two hormones whose interactions in determining a specific developmental output are still poorly understood. By means of a comprehensive genetic and molecular analysis in Arabidopsis, we show that a primary cytokinin-response transcription factor, ARR1, activates the gene SHY2/IAA3 (SHY2), a repressor of auxin signaling that negatively regulates the PIN auxin transport facilitator genes: thereby, cytokinin causes auxin redistribution, prompting cell differentiation. Conversely, auxin mediates degradation of the SHY2 protein, sustaining PIN activities and cell division. Thus, the cell differentiation and division balance necessary for controlling root meristem size and root growth is the result of the interaction between cytokinin and auxin through a simple regulatory circuit converging on the SHY2 gene.

Gelation of particles with short-range attraction

Abstract: Nanoscale or colloidal particles change the properties of materials, imparting solid-like behaviour to a wide variety of complex fluids. This behaviour arises when particles aggregate to form mesoscopic clusters and networks. Numerous scenarios for gelation have been proposed, but no consensus has emerged. Lu et al. report experiments showing that gelation of spherical particles with isotropic, short-range attractions is initiated by spinodal decomposition; this thermodynamic instability triggers the formation of density fluctuations, leading to spanning clusters that dynamically arrest to create a gel. This simple picture of gelation should apply to any particle system with short-range attractions. Solid-like behaviour arises in a wide variety of complex fluids upon gelation — aggregation of particles to form mesoscopic clusters and networks. The authors show that gelation of spherical particles with isotropic, short-range attractions is initiated by spinodal decomposition. Nanoscale or colloidal particles are important in many realms of science and technology. They can dramatically change the properties of materials, imparting solid-like behaviour to a wide variety of complex fluids1,2. This behaviour arises when particles aggregate to form mesoscopic clusters and networks. The essential component leading to aggregation is an interparticle attraction, which can be generated by many physical and chemical mechanisms. In the limit of irreversible aggregation, infinitely strong interparticle bonds lead to diffusion-limited cluster aggregation3 (DLCA). This is understood as a purely kinetic phenomenon that can form solid-like gels at arbitrarily low particle volume fraction4,5. Far more important technologically are systems with weaker attractions, where gel formation requires higher volume fractions. Numerous scenarios for gelation have been proposed, including DLCA6, kinetic or dynamic arrest4,7,8,9,10, phase separation5,6,11,12,13,14,15,16, percolation4,12,17,18 and jamming8. No consensus has emerged and, despite its ubiquity and significance, gelation is far from understood—even the location of the gelation phase boundary is not agreed on5. Here we report experiments showing that gelation of spherical particles with isotropic, short-range attractions is initiated by spinodal decomposition; this thermodynamic instability triggers the formation of density fluctuations, leading to spanning clusters that dynamically arrest to create a gel. This simple picture of gelation does not depend on microscopic system-specific details, and should thus apply broadly to any particle system with short-range attractions. Our results suggest that gelation—often considered a purely kinetic phenomenon4,8,9,10—is in fact a direct consequence of equilibrium liquid–gas phase separation5,13,14,15. Without exception, we observe gelation in all of our samples predicted by theory and simulation to phase-separate; this suggests that it is phase separation, not percolation12, that corresponds to gelation in models for attractive spheres.

Definition, assessment and treatment of wheezing disorders in preschool children: An evidence-based approach

Abstract: There is poor agreement on definitions of different phenotypes of preschool wheezing disorders. The present Task Force proposes to use the terms episodic (viral) wheeze to describe children who wheeze intermittently and are well between episodes, and multiple-trigger wheeze for children who wheeze both during and outside discrete episodes. Investigations are only needed when in doubt about the diagnosis. Based on the limited evidence available, inhaled short-acting beta(2)-agonists by metered-dose inhaler/spacer combination are recommended for symptomatic relief. Educating parents regarding causative factors and treatment is useful. Exposure to tobacco smoke should be avoided; allergen avoidance may be considered when sensitisation has been established. Maintenance treatment with inhaled corticosteroids is recommended for multiple-trigger wheeze; benefits are often small. Montelukast is recommended for the treatment of episodic (viral) wheeze and can be started when symptoms of a viral cold develop. Given the large overlap in phenotypes, and the fact that patients can move from one phenotype to another, inhaled corticosteroids and montelukast may be considered on a trial basis in almost any preschool child with recurrent wheeze, but should be discontinued if there is no clear clinical benefit. Large well-designed randomised controlled trials with clear descriptions of patients are needed to improve the present recommendations on the treatment of these common syndromes.

State of the art: using natriuretic peptide levels in clinical practice.

Abstract: Natriuretic peptide (NP) levels (B-type natriuretic peptide (BNP) and N-terminal proBNP) are now widely used in clinical practice and cardiovascular research throughout the world and have been incorporated into most national and international cardiovascular guidelines for heart failure. The role of NP levels in state-of-the-art clinical practice is evolving rapidly. This paper reviews and highlights ten key messages to clinicians: 1) NP levels are quantitative plasma biomarkers of heart failure (HF). 2) NP levels are accurate in the diagnosis of HF. 3) NP levels may help risk stratify emergency department (ED) patients with regard to the need for hospital admission or direct ED discharge. 4) NP levels help improve patient management and reduce total treatment costs in patients with acute dyspnoea. 5) NP levels at the time of admission are powerful predictors of outcome in predicting death and re-hospitalisation in HF patients. 6) NP levels at discharge aid in risk stratification of the HF patient. 7) NP-guided therapy may improve morbidity and/or mortality in chronic HF. 8) The combination of NP levels together with symptoms, signs and weight gain assists in the assessment of clinical decompensation in HF. 9) NP levels can accelerate accurate diagnosis of heart failure presenting in primary care. 10) NP levels may be helpful to screen for asymptomatic left ventricular dysfunction in high-risk patients.

Outcomes for COPD pharmacological trials: From lung function to biomarkers

Abstract: The American Thoracic Society/European Respiratory Society jointly created a Task Force on "Outcomes for COPD pharmacological trials: from lung function to biomarkers" to inform the chronic obstructive pulmonary disease research community about the possible use and limitations of current outcomes and markers when evaluating the impact of a pharmacological therapy. Based on their review of the published literature, the following document has been prepared with individual sections that address specific outcomes and markers, and a final section that summarises their recommendations.

Guidelines and good clinical practice recommendations for contrast enhanced ultrasound (CEUS) - Update 2008

Abstract: EFSUMB study group M. Claudon1, D. Cosgrove2, T. Albrecht3, L. Bolondi4, M. Bosio5, F. Calliada6, J.-M. Correas7, K. Darge8, C. Dietrich9, M. D'On ofrio10, D. H. Evans11, C. Filice12, L. Greiner13, K. Jäger14, N. de. Jong15, E. Leen16, R. Lencioni17, D. Lindsell18, A. Martegani19, S. Meairs20, C. Nolsøe21, F. Piscaglia22, P. Ricci23, G. Seidel24, B. Skjoldbye25, L. Solbiati26, L. Thorelius27, F. Tranquart28, H. P. Weskott29, T. Whittingham30

Modelling Myc inhibition as a cancer therapy

Abstract: Myc is a pleiotropic basic helix–loop–helix leucine zipper transcription factor that coordinates expression of the diverse intracellular and extracellular programs that together are necessary for growth and expansion of somatic cells1. In principle, this makes inhibition of Myc an attractive pharmacological approach for treating diverse types of cancer. However, enthusiasm has been muted by lack of direct evidence that Myc inhibition would be therapeutically efficacious, concerns that it would induce serious side effects by inhibiting proliferation of normal tissues, and practical difficulties in designing Myc inhibitory drugs. We have modelled genetically both the therapeutic impact and the side effects of systemic Myc inhibition in a preclinical mouse model of Ras-induced lung adenocarcinoma by reversible, systemic expression of a dominant-interfering Myc mutant. We show that Myc inhibition triggers rapid regression of incipient and established lung tumours, defining an unexpected role for endogenous Myc function in the maintenance of Ras-dependent tumours in vivo. Systemic Myc inhibition also exerts profound effects on normal regenerating tissues. However, these effects are well tolerated over extended periods and rapidly and completely reversible. Our data demonstrate the feasibility of targeting Myc, a common downstream conduit for many oncogenic signals, as an effective, efficient and tumour-specific cancer therapy.

Telmisartan to prevent recurrent stroke and cardiovascular events.

Abstract: BACKGROUND: Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke. METHODS: In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes. RESULTS: The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10). CONCLUSIONS: Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)