Showing papers by "University of Toronto published in 2003"
Journal Article•
TL;DR: The identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation is reported.
Abstract: Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, there is overwhelming evidence in some malignancies that the tumor clone is heterogeneous with respect to proliferation and differentiation. In human leukemia, the tumor clone is organized as a hierarchy that originates from rare leukemic stem cells that possess extensive proliferative and self-renewal potential, and are responsible for maintaining the tumor clone. We report here the identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation. The increased self-renewal capacity of the brain tumor stem cell (BTSC) was highest from the most aggressive clinical samples of medulloblastoma compared with low-grade gliomas. The BTSC was exclusively isolated with the cell fraction expressing the neural stem cell surface marker CD133. These CD133+ cells could differentiate in culture into tumor cells that phenotypically resembled the tumor from the patient. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC.
4,899 citations
TL;DR: A novel graph theoretic clustering algorithm, "Molecular Complex Detection" (MCODE), that detects densely connected regions in large protein-protein interaction networks that may represent molecular complexes is described.
Abstract: Recent advances in proteomics technologies such as two-hybrid, phage display and mass spectrometry have enabled us to create a detailed map of biomolecular interaction networks. Initial mapping efforts have already produced a wealth of data. As the size of the interaction set increases, databases and computational methods will be required to store, visualize and analyze the information in order to effectively aid in knowledge discovery. This paper describes a novel graph theoretic clustering algorithm, "Molecular Complex Detection" (MCODE), that detects densely connected regions in large protein-protein interaction networks that may represent molecular complexes. The method is based on vertex weighting by local neighborhood density and outward traversal from a locally dense seed protein to isolate the dense regions according to given parameters. The algorithm has the advantage over other graph clustering methods of having a directed mode that allows fine-tuning of clusters of interest without considering the rest of the network and allows examination of cluster interconnectivity, which is relevant for protein networks. Protein interaction and complex information from the yeast Saccharomyces cerevisiae was used for evaluation. Dense regions of protein interaction networks can be found, based solely on connectivity data, many of which correspond to known protein complexes. The algorithm is not affected by a known high rate of false positives in data from high-throughput interaction techniques. The program is available from ftp://ftp.mshri.on.ca/pub/BIND/Tools/MCODE
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4,599 citations
University of Cambridge1, University of Toronto2, Yale University3, University of Iceland4, University of Melbourne5, Lund University6, National Institutes of Health7, Princess Anne Hospital8, The Chinese University of Hong Kong9, University of California, Irvine10, Pomeranian Medical University11, Helsinki University Central Hospital12, University of London13, Institute of Cancer Research14, St Mary's Hospital15
TL;DR: Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age and for variation in risk by mutation position for both genes, and some evidence for a reduction in risk in women from earlier birth cohorts is found.
Abstract: Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.
3,384 citations
TL;DR: The historical development of a from other indexes of internal consistency (split-half reliability and Kuder-Richardson 20) and four myths associated with a are discussed, including that it is a fixed property of the scale and that higher values are always preferred over lower ones.
Abstract: Cronbach's a is the most widely used index of the reliability of a scale. However, its use and interpretation can be subject to a number of errors. This article discusses the historical development of a from other indexes of internal consistency (split-half reliability and Kuder-Richardson 20) and discusses four myths associated with a: (a) that it is a fixed property of the scale, (b) that it measures only the internal consistency of the scale, (c) that higher values are always preferred over lower ones, and (d) that it is restricted to the range of 0 to 1. It provides some recommendations for acceptable values of a in different situations.
2,757 citations
TL;DR: In this paper, the theoretical micro-foundations of urban agglomeration economies are studied, based on sharing, matching, and learning mechanisms, and a handbook chapter is presented.
Abstract: This handbook chapter studies the theoretical micro-foundations of urban agglomeration economies. We distinguish three types of micro-foundations, based on sharing, matching, and learning mechanisms. For each of these three categories, we develop one or more core models in detail and discuss the literature in relation to those models. This allows us to give a precise characterisation of some of the main theoretical underpinnings of urban agglomeration economies, to discuss modelling issues that arise when working with these tools, and to compare different sources of agglomeration economies in terms of the aggregate urban outcomes they produce as well as in terms of their normative implications.
2,032 citations
TL;DR: F fluorouracil-based adjuvant chemotherapy benefited patients with stage II or stage III colon cancer with microsatellite-stable tumors or tumors exhibiting low-frequency micros satellite instability but not those with tumors exhibiting high-frequencymicrosatellite instability.
Abstract: Background Colon cancers with high-frequency microsatellite instability have clinical and pathological features that distinguish them from microsatellite-stable tumors. We investigated the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II and stage III colon cancer. Methods Tumor specimens were collected from patients with colon cancer who were enrolled in randomized trials of fluorouracil-based adjuvant chemotherapy. Microsatellite instability was assessed with the use of mononucleotide and dinucleotide markers. Results Of 570 tissue specimens, 95 (16.7 percent) exhibited high-frequency microsatellite instability. Among 287 patients who did not receive adjuvant therapy, those with tumors displaying high-frequency microsatellite instability had a better five-year rate of overall survival than patients with tumors exhibiting microsatellite stability or low-frequency instability (hazard ratio for death, 0.31 [95 percent confi...
2,000 citations
1,640 citations
TL;DR: Locally linear embedding (LLE), an unsupervised learning algorithm that computes low dimensional, neighborhood preserving embeddings of high dimensional data, is described and several extensions that enhance its performance are discussed.
Abstract: The problem of dimensionality reduction arises in many fields of information processing, including machine learning, data compression, scientific visualization, pattern recognition, and neural computation. Here we describe locally linear embedding (LLE), an unsupervised learning algorithm that computes low dimensional, neighborhood preserving embeddings of high dimensional data. The data, assumed to be sampled from an underlying manifold, are mapped into a single global coordinate system of lower dimensionality. The mapping is derived from the symmetries of locally linear reconstructions, and the actual computation of the embedding reduces to a sparse eigenvalue problem. Notably, the optimizations in LLE---though capable of generating highly nonlinear embeddings---are simple to implement, and they do not involve local minima. In this paper, we describe the implementation of the algorithm in detail and discuss several extensions that enhance its performance. We present results of the algorithm applied to data sampled from known manifolds, as well as to collections of images of faces, lips, and handwritten digits. These examples are used to provide extensive illustrations of the algorithm's performance---both successes and failures---and to relate the algorithm to previous and ongoing work in nonlinear dimensionality reduction.
1,614 citations
TL;DR: As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival.
Abstract: background In hormone-dependent breast cancer, five years of postoperative tamoxifen therapy — but not tamoxifen therapy of longer duration — prolongs disease-free and overall survival. The aromatase inhibitor letrozole, by suppressing estrogen production, might improve the outcome after the discontinuation of tamoxifen therapy. methods We conducted a double-blind, placebo-controlled trial to test the effectiveness of five years of letrozole therapy in postmenopausal women with breast cancer who have completed five years of tamoxifen therapy. The primary end point was disease-free survival. results A total of 5187 women were enrolled (median follow-up, 2.4 years). At the first interim analysis, there were 207 local or metastatic recurrences of breast cancer or new primary cancers in the contralateral breast — 75 in the letrozole group and 132 in the placebo group — with estimated four-year disease-free survival rates of 93 percent and 87 percent, respectively, in the two groups (P ≤ 0.001 for the comparison of disease-free survival). A total of 42 women in the placebo group and 31 women in the letrozole group died (P=0.25 for the comparison of overall survival). Low-grade hot flashes, arthritis, arthralgia, and myalgia were more frequent in the letrozole group, but vaginal bleeding was less frequent. There were new diagnoses of osteoporosis in 5.8 percent of the women in the letrozole group and 4.5 percent of the women in the placebo group (P=0.07); the rates of fracture were similar. After the first interim analysis, the independent data and safety monitoring committee recommended termination of the trial and prompt communication of the results to the participants. conclusions As compared with placebo, letrozole therapy after the completion of standard tamoxifen treatment significantly improves disease-free survival.
1,538 citations
TL;DR: It is shown that even in treated patients who have had no detectable viremia for as long as 7 years, the reservoir decays so slowly that eradication is unlikely.
Abstract: Latent HIV-1 persists in resting memory CD4+ T cells, even in patients receiving highly active antiretroviral therapy (HAART). It has been unclear how stable this latent reservoir is and whether its persistence reflects replenishment by low-level viremia. Here we show that even in treated patients who have had no detectable viremia for as long as 7 years, the reservoir decays so slowly (t(1/2) = 44 months) that eradication is unlikely.
1,528 citations
TL;DR: The sequencing of complete genomes provides a list that includes the proteins responsible for cellular regulation, but this does not immediately reveal what these proteins do, nor how they are assembled into the molecular machines and functional networks that control cellular behavior.
Abstract: The sequencing of complete genomes provides a list that includes the proteins responsible for cellular regulation. However, this does not immediately reveal what these proteins do, nor how they are assembled into the molecular machines and functional networks that control cellular behavior. The regulation of many different cellular processes requires the use of protein interaction domains to direct the association of polypeptides with one another and with phospholipids, small molecules, or nucleic acids. The modular nature of these domains, and the flexibility of their binding properties, have likely facilitated the evolution of cellular pathways. Conversely, aberrant interactions can induce abnormal cellular behavior and disease. The fundamental properties of protein interaction domains are discussed in this review and in detailed reviews on individual domains at Science's STKE at http://www.sciencemag.org/cgi/content/full/300/5618/445/DC1.
Royal College of Surgeons in Ireland1, Cardiovascular Institute of the South2, University of Western Australia3, Joseph Fourier University4, University of Bonn5, University of Toronto6, Western General Hospital7, University of Padua8, Icahn School of Medicine at Mount Sinai9, University of Valencia10, Katholieke Universiteit Leuven11, National and Kapodistrian University of Athens12
TL;DR: In this paper, the accuracy of the conventional Riva-Rocci/Korotkoff technique of blood pressure measurement has been questioned and efforts have been made to improve the technique with automated devices.
Abstract: IntroductionOver the past 20 years or so, the accuracy of the conventional Riva-Rocci/Korotkoff technique of blood pressure measurement has been questioned and efforts have been made to improve the technique with automated devices. In the same period, recognition of the phenomenon of white-coat hype
TL;DR: This article found that corporations in countries where shareholders rights are not well protected hold up to twice as much cash as companies in countries with good shareholders protection, and that when shareholders protection is poor, factors that generally drive the need for cash holdings, such as investment opportunities and asymmetric information, actually become less important.
Abstract: Agency problems are an important determinant of corporate cash holdings. For a sample of more than 11,000 firms from 45 countries, we find that corporations in countries where shareholders rights are not well protected hold up to twice as much cash as corporations in countries with good shareholder protection. In addition, when shareholder protection is poor, factors that generally drive the need for cash holdings, such as investment opportunities and asymmetric information, actually become less important. These results are stronger after controlling for capital market development. Indeed, consistent with the importance of agency costs, we find that firms hold larger cash balances when access to funds is easier. Our evidence is consistent with the conjecture that investors in countries with poor shareholder protection cannot force managers to disgorge excessive cash balances.
TL;DR: In this article, the authors study the network activities of entrepreneurs through three phases of establishing a firm in four countries and find that entrepreneurs build networks that systematically vary by the phase of entrepreneurship, analyzing number of their discussion partners, and the time spent networking.
Abstract: We study network activities of entrepreneurs through three phases of establishing a firm in four countries. Entrepreneurs access people in their networks to discuss aspects of establishing and running a business. We find that entrepreneurs build networks that systematically vary by the phase of entrepreneurship, analyzing number of their discussion partners, and the time spent networking. Entrepreneurs talk with more people during the planning than other phases. Family members are present in their networks in all phases, particularly among those who took over an existing firm. However, women use their kin to a larger extent than men, and even more than men when they take over an existing firm. Experienced entrepreneurs have the same networking patterns as novices. Moreover, these networking patterns are the same in all countries. However, there are country differences in size of discussion networks and time spent networking.
TL;DR: This work develops an approach using Bayesian networks to predict protein-protein interactions genome-wide in yeast, and observes that at given levels of sensitivity, the predictions are more accurate than the existing high-throughput experimental data sets.
Abstract: We have developed an approach using Bayesian networks to predict protein-protein interactions genome-wide in yeast. Our method naturally weights and combines into reliable predictions genomic features only weakly associated with interaction (e.g., messenger RNAcoexpression, coessentiality, and colocalization). In addition to de novo predictions, it can integrate often noisy, experimental interaction data sets. We observe that at given levels of sensitivity, our predictions are more accurate than the existing high-throughput experimental data sets. We validate our predictions with TAP (tandem affinity purification) tagging experiments. Our analysis, which gives a comprehensive view of yeast interactions, is available at genecensus.org/intint.
Dartmouth College1, University of North Carolina at Chapel Hill2, University of Southern California3, University of Colorado Denver4, Veterans Health Administration5, Henry Ford Health System6, University of Toronto7, University of Iowa8, Cleveland Clinic9, University of Minnesota10, Emory University11
TL;DR: Low-dose aspirin has a moderate chemopreventive effect on adenomas in the large bowel, using generalized linear models to compute risk ratios and 95 percent confidence intervals.
Abstract: Background Laboratory and epidemiologic data suggest that aspirin has an antineoplastic effect in the large bowel. Methods We performed a randomized, double-blind trial of aspirin as a chemopreventive agent against colorectal adenomas. We randomly assigned 1121 patients with a recent history of histologically documented adenomas to receive placebo (372 patients), 81 mg of aspirin (377 patients), or 325 mg of aspirin (372 patients) daily. According to the protocol, follow-up colonoscopy was to be performed approximately three years after the qualifying endoscopy. We compared the groups with respect to the risk of one or more neoplasms (adenomas or colorectal cancer) at least one year after randomization using generalized linear models to compute risk ratios and 95 percent confidence intervals. Results Reported adherence to study medications and avoidance of nonsteroidal antiinflammatory drugs were excellent. Follow-up colonoscopy was performed at least one year after randomization in 1084 patients (97 perc...
TL;DR: The majority of cases in the SARS outbreak in the greater Toronto area were related to hospital exposure, and several features of the clinical presentation will be useful in raising the suspicion of SARS.
Abstract: ContextSevere acute respiratory syndrome (SARS) is an emerging infectious disease
that first manifested in humans in China in November 2002 and has subsequently
spread worldwide.ObjectivesTo describe the clinical characteristics and short-term outcomes of
SARS in the first large group of patients in North America; to describe how
these patients were treated and the variables associated with poor outcome.Design, Setting, and PatientsRetrospective case series involving 144 adult patients admitted to 10
academic and community hospitals in the greater Toronto, Ontario, area between
March 7 and April 10, 2003, with a diagnosis of suspected or probable SARS.
Patients were included if they had fever, a known exposure to SARS, and respiratory
symptoms or infiltrates observed on chest radiograph. Patients were excluded
if an alternative diagnosis was determined.Main Outcome MeasuresLocation of exposure to SARS; features of the history, physical examination,
and laboratory tests at admission to the hospital; and 21-day outcomes such
as death or intensive care unit (ICU) admission with or without mechanical
ventilation.ResultsOf the 144 patients, 111 (77%) were exposed to SARS in the hospital
setting. Features of the clinical examination most commonly found in these
patients at admission were self-reported fever (99%), documented elevated
temperature (85%), nonproductive cough (69%), myalgia (49%), and dyspnea (42%).
Common laboratory features included elevated lactate dehydrogenase (87%),
hypocalcemia (60%), and lymphopenia (54%). Only 2% of patients had rhinorrhea.
A total of 126 patients (88%) were treated with ribavirin, although its use
was associated with significant toxicity, including hemolysis (in 76%) and
decrease in hemoglobin of 2 g/dL (in 49%). Twenty-nine patients (20%) were
admitted to the ICU with or without mechanical ventilation, and 8 patients
died (21-day mortality, 6.5%; 95% confidence interval [CI], 1.9%-11.8%). Multivariable
analysis showed that the presence of diabetes (relative risk [RR], 3.1; 95%
CI, 1.4-7.2; P = .01) or other comorbid conditions
(RR, 2.5; 95% CI, 1.1-5.8; P = .03) were independently
associated with poor outcome (death, ICU admission, or mechanical ventilation).ConclusionsThe majority of cases in the SARS outbreak in the greater Toronto area
were related to hospital exposure. In the event that contact history becomes
unreliable, several features of the clinical presentation will be useful in
raising the suspicion of SARS. Although SARS is associated with significant
morbidity and mortality, especially in patients with diabetes or other comorbid
conditions, the vast majority (93.5%) of patients in our cohort survived.Published online May 6, 2003 (doi:10.1001/jama.289.21.JOC30885).
TL;DR: In a placebo-controlled trial, treatment with natalizumab led to fewer inflammatory brain lesions and fewer relapses over a six-month period in patients with relapsing multiple sclerosis.
Abstract: Background In patients with multiple sclerosis, inflammatory brain lesions appear to arise from autoimmune responses involving activated lymphocytes and monocytes. The glycoprotein α4 integrin is expressed on the surface of these cells and plays a critical part in their adhesion to the vascular endothelium and migration into the parenchyma. Natalizumab is an α4 integrin antagonist that reduced the development of brain lesions in experimental models and in a preliminary study of patients with multiple sclerosis. Methods In a randomized, double-blind trial, we randomly assigned a total of 213 patients with relapsing–remitting or relapsing secondary progressive multiple sclerosis to receive 3 mg of intravenous natalizumab per kilogram of body weight (68 patients), 6 mg per kilogram (74 patients), or placebo (71 patients) every 28 days for 6 months. The primary end point was the number of new brain lesions on monthly gadolinium-enhanced magnetic resonance imaging during the six-month treatment period. Clinica...
TL;DR: The data demonstrate that tight regulation of VEGF-A signaling is critical for establishment and maintenance of the glomerular filtration barrier and strongly supports a pivotal role for VEGf-A in renal disease.
Abstract: Kidney disease affects over 20 million people in the United States alone. Although the causes of renal failure are diverse, the glomerular filtration barrier is often the target of injury. Dysregulation of VEGF expression within the glomerulus has been demonstrated in a wide range of primary and acquired renal diseases, although the significance of these changes is unknown. In the glomerulus, VEGF-A is highly expressed in podocytes that make up a major portion of the barrier between the blood and urinary spaces. In this paper, we show that glomerular-selective deletion or overexpression of VEGF-A leads to glomerular disease in mice. Podocyte-specific heterozygosity for VEGF-A resulted in renal disease by 2.5 weeks of age, characterized by proteinuria and endotheliosis, the renal lesion seen in preeclampsia. Homozygous deletion of VEGF-A in glomeruli resulted in perinatal lethality. Mutant kidneys failed to develop a filtration barrier due to defects in endothelial cell migration, differentiation, and survival. In contrast, podocyte-specific overexpression of the VEGF-164 isoform led to a striking collapsing glomerulopathy, the lesion seen in HIV-associated nephropathy. Our data demonstrate that tight regulation of VEGF-A signaling is critical for establishment and maintenance of the glomerular filtration barrier and strongly supports a pivotal role for VEGF-A in renal disease.
TL;DR: Wound bed preparation is the management of a wound in order to accelerate endogenous healing or to facilitate the effectiveness of other therapeutic measures to select the most appropriate intervention.
Abstract: The healing process in acute wounds has been extensively studied and the knowledge derived from these studies has often been extrapolated to the care of chronic wounds, on the assumption that nonhealing chronic wounds were simply aberrations of the normal tissue repair process. However, this approach is less than satisfactory, as the chronic wound healing process differs in many important respects from that seen in acute wounds. In chronic wounds, the orderly sequence of events seen in acute wounds becomes disrupted or “stuck” at one or more of the different stages of wound healing. For the normal repair process to resume, the barrier to healing must be identified and removed through application of the correct techniques. It is important, therefore, to understand the molecular events that are involved in the wound healing process in order to select the most appropriate intervention. Wound bed preparation is the management of a wound in order to accelerate endogenous healing or to facilitate the effectiveness of other therapeutic measures. Experts in wound management consider that wound bed preparation is an important concept with significant potential as an educational tool in wound management.
This article was developed after a meeting of wound healing experts in June 2002 and is intended to provide an overview of the current status, role, and key elements of wound bed preparation. Readers will be able to examine the following issues;
• the current status of wound bed preparation;
• an analysis of the acute and chronic wound environments;
• how wound healing can take place in these environments;
• the role of wound bed preparation in the clinic;
• the clinical and cellular components of the wound bed preparation concept;
• a detailed analysis of the components of wound bed preparation.
(WOUND REP REG 2003;11:1–28)
Journal Article•
TL;DR: The psychological and occupational impact of this event within a large hospital in the first 4 weeks of the SARS outbreak and the subsequent administrative and mental health response is described.
Abstract: Background: The outbreak of severe acute respiratory syndrome (SARS) in Toronto, which began on Mar. 7, 2003, resulted in extraordinary public health and infection control measures. We aimed to describe the psychological and occupational impact of this event within a large hospital in the first 4 weeks of the outbreak and the subsequent administrative and mental health response. Methods: Two principal authors met with core team members and mental health care providers at Mount Sinai Hospital, Toronto, to compile retrospectively descriptions of the experiences of staff and patients based on informal observation. All authors reviewed and analyzed the descriptions in an iterative process between Apr. 3 and Apr. 13, 2003. Results: In a 4-week period, 19 individuals developed SARS, including 11 health care workers. The hospital’s response included establishing a leadership command team and a SARS isolation unit, implementing mental health support interventions for patients and staff, overcoming problems with logistics and communication, and overcoming resistance to directives. Patients with SARS reported fear, loneliness, boredom and anger, and they worried about the effects of quarantine and contagion on family members and friends. They experienced anxiety about fever and the effects of insomnia. Staff were adversely affected by fear of contagion and of infecting family, friends and colleagues. Caring for health care workers as patients and colleagues was emotionally difficult. Uncertainty and stigmatization were prominent themes for both staff and patients. Interpretation: The hospital’s response required clear communication, sensitivity to individual responses to stress, collaboration between disciplines, authoritative leadership and provision of relevant support. The emotional and behavioural reactions of patients and staff are understood to be a normal, adaptive response to stress in the face of an overwhelming event.
University of Pennsylvania1, New York University2, National Institutes of Health3, National Institute for Health and Welfare4, Cardiff University5, University of Bonn6, Johns Hopkins University School of Medicine7, Harvard University8, Rutgers University9, University of Medicine and Dentistry of New Jersey10, Columbia University11, University of Louisville12, University College London13, Uppsala University14, University of Utah15, University of California, Irvine16, Queen's University Belfast17, Virginia Commonwealth University18, University of California, Los Angeles19, University of Helsinki20, University of Geneva21, University of Queensland22, Icahn School of Medicine at Mount Sinai23, University of Iowa24, Washington University in St. Louis25, University of Toronto26
TL;DR: The GSMA produced significant genomewide evidence for linkage on chromosome 2q and suggests that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
Abstract: Schizophrenia is a common disorder with high heritability and a 10-fold increase in risk to siblings of probands. Replication has been inconsistent for reports of significant genetic linkage. To assess evidence for linkage across studies, rank-based genome scan meta-analysis (GSMA) was applied to data from 20 schizophrenia genome scans. Each marker for each scan was assigned to 1 of 120 30-cM bins, with the bins ranked by linkage scores (1 = most significant) and the ranks averaged across studies (R(avg)) and then weighted for sample size (N(sqrt)[affected casess]). A permutation test was used to compute the probability of observing, by chance, each bin's average rank (P(AvgRnk)) or of observing it for a bin with the same place (first, second, etc.) in the order of average ranks in each permutation (P(ord)). The GSMA produced significant genomewide evidence for linkage on chromosome 2q (PAvgRnk<.000417). Two aggregate criteria for linkage were also met (clusters of nominally significant P values that did not occur in 1,000 replicates of the entire data set with no linkage present): 12 consecutive bins with both P(AvgRnk) and P(ord)<.05, including regions of chromosomes 5q, 3p, 11q, 6p, 1q, 22q, 8p, 20q, and 14p, and 19 consecutive bins with P(ord)<.05, additionally including regions of chromosomes 16q, 18q, 10p, 15q, 6q, and 17q. There is greater consistency of linkage results across studies than has been previously recognized. The results suggest that some or all of these regions contain loci that increase susceptibility to schizophrenia in diverse populations.
TL;DR: A framework for learning robust, adaptive, appearance models to be used for motion-based tracking of natural objects to provide robustness in the face of image outliers, while adapting to natural changes in appearance such as those due to facial expressions or variations in 3D pose.
Abstract: We propose a framework for learning robust, adaptive, appearance models to be used for motion-based tracking of natural objects. The model adapts to slowly changing appearance, and it maintains a natural measure of the stability of the observed image structure during tracking. By identifying stable properties of appearance, we can weight them more heavily for motion estimation, while less stable properties can be proportionately downweighted. The appearance model involves a mixture of stable image structure, learned over long time courses, along with two-frame motion information and an outlier process. An online EM-algorithm is used to adapt the appearance model parameters over time. An implementation of this approach is developed for an appearance model based on the filter responses from a steerable pyramid. This model is used in a motion-based tracking algorithm to provide robustness in the face of image outliers, such as those caused by occlusions, while adapting to natural changes in appearance such as those due to facial expressions or variations in 3D pose.
TL;DR: In this article, the authors used a unique and rich database in conjunction with mapping software to measure the geographic extent of agglomerative externalities and found that industrial organization affects the benefits of the benefits.
Abstract: This paper makes two contributions to the empirical literature on agglomeration economies. First, the paper uses a unique and rich database in conjunction with mapping software to measure the geographic extent of agglomerative externalities. Previous papers have been forced to assume that agglomeration economies are club goods that operate at a metropolitan scale. Second, the paper tests for the existence of organizational agglomeration economies of the kind studied qualitatively by Saxenian (1994). This is a potentially important source of increasing returns that previous empirical work has not considered. Results indicate that localization economies attenuate rapidly and that industrial organization affects the benefits of agglomeration.
TL;DR: SARS appears to be of viral origin, with patterns suggesting droplet or contact transmission, and the role of human metapneumovirus, a novel coronavirus, or both requires further investigation.
Abstract: background Severe acute respiratory syndrome (SARS) is a condition of unknown cause that has recently been recognized in patients in Asia, North America, and Europe. This report summarizes the initial epidemiologic findings, clinical description, and diagnostic findings that followed the identification of SARS in Canada. methods SARS was first identified in Canada in early March 2003. We collected epidemiologic, clinical, and diagnostic data from each of the first 10 cases prospectively as they were identified. Specimens from all cases were sent to local, provincial, national, and international laboratories for studies to identify an etiologic agent. results The patients ranged from 24 to 78 years old; 60 percent were men. Transmission occurred only after close contact. The most common presenting symptoms were fever (in 100 percent of cases) and malaise (in 70 percent), followed by nonproductive cough (in 100 percent) and dyspnea (in 80 percent) associated with infiltrates on chest radiography (in 100 percent). Lymphopenia (in 89 percent of those for whom data were available), elevated lactate dehydrogenase levels (in 80 percent), elevated aspartate aminotransferase levels (in 78 percent), and elevated creatinine kinase levels (in 56 percent) were common. Empirical therapy most commonly included antibiotics, oseltamivir, and intravenous ribavirin. Mechanical ventilation was required in five patients. Three patients died, and five have had clinical improvement. The results of laboratory investigations were negative or not clinically significant except for the amplification of human metapneumovirus from respiratory specimens from five of nine patients and the isolation and amplification of a novel coronavirus from five of nine patients. In four cases both pathogens were isolated. conclusions SARS is a condition associated with substantial morbidity and mortality. It appears to be of viral origin, with patterns suggesting droplet or contact transmission. The role of human metapneumovirus, a novel coronavirus, or both requires further investigation.
TL;DR: The rod–cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions such as pupillary light reflex and circadian photo-entrainment.
Abstract: In the mammalian retina, besides the conventional rod-cone system, a melanopsin-associated photoreceptive system exists that conveys photic information for accessory visual functions such as pupillary light reflex and circadian photo-entrainment. On ablation of the melanopsin gene, retinal ganglion cells that normally express melanopsin are no longer intrinsically photosensitive. Furthermore, pupil reflex, light-induced phase delays of the circadian clock and period lengthening of the circadian rhythm in constant light are all partially impaired. Here, we investigated whether additional photoreceptive systems participate in these responses. Using mice lacking rods and cones, we measured the action spectrum for phase-shifting the circadian rhythm of locomotor behaviour. This spectrum matches that for the pupillary light reflex in mice of the same genotype, and that for the intrinsic photosensitivity of the melanopsin-expressing retinal ganglion cells. We have also generated mice lacking melanopsin coupled with disabled rod and cone phototransduction mechanisms. These animals have an intact retina but fail to show any significant pupil reflex, to entrain to light/dark cycles, and to show any masking response to light. Thus, the rod-cone and melanopsin systems together seem to provide all of the photic input for these accessory visual functions.
TL;DR: This review covers Förster theory for donor-acceptor pairs and electronic coupling for singlet-singlet, triplet-triplet, and superexchange-mediated energy transfer and includes the transition density picture of Coulombic coupling as well as electronic coupling between molecular aggregates (excitons).
Abstract: The current state of understanding of molecular resonance energy transfer (RET) and recent developments in the field are reviewed. The development of more general theoretical approaches has uncovered some new principles underlying RET processes. This review brings many of these important new concepts together into a generalization of Forster's original theory. The conclusions of studies investigating the various approximations in Forster theory are summarized. Areas of present and future activity are discussed. The review covers Forster theory for donor-acceptor pairs and electronic coupling for singlet-singlet, triplet-triplet, and superexchange-mediated energy transfer. This includes the transition density picture of Coulombic coupling as well as electronic coupling between molecular aggregates (excitons). Spectral overlaps and ensemble energy transfer rates in disordered aggregates, the role of dielectric properties of the medium, weak versus strong coupling, and new models for energy transfer in complex molecular assemblies are also described.
TL;DR: Proteomics is the study of the function of all expressed proteins and further technological improvements, organization of international proteomics projects and open access to results are needed for proteomics to fulfil its potential.
Abstract: Proteomics is the study of the function of all expressed proteins Tremendous progress has been made in the past few years in generating large-scale data sets for protein-protein interactions, organelle composition, protein activity patterns and protein profiles in cancer patients But further technological improvements, organization of international proteomics projects and open access to results are needed for proteomics to fulfil its potential
TL;DR: A synthesis of functional neuroimaging studies examining regional metabolic and blood flow changes in depression is presented in the context of a testable limbic-cortical network model, seen as a critical step towards future development of evidenced-based algorithms that will optimize the diagnosis and treatment of individual depressed patients.
Abstract: While characterization of pathogenetic mechanisms underlying major depression is a fundamental aim of neuroscience research, an equally critical clinical goal is to identify biomarkers that might improve diagnostic accuracy and guide treatment selection for individual patients. To this end, a synthesis of functional neuroimaging studies examining regional metabolic and blood flow changes in depression is presented in the context of a testable limbic-cortical network model. 'Network' dysfunction combined with active intrinsic compensatory processes is seen to explain the heterogeneity of depressive symptoms observed clinically, as well as variations in pretreatment scan patterns described experimentally. Furthermore, the synchronized modulation of these dysfunctional limbic-cortical pathways is considered critical for illness remission, regardless of treatment modality. Testing of response-specific functional relationships among regional 'nodes' within this network using multivariate approaches is discussed, with a perspective aimed at identifying biomarkers of treatment non-response, relapse risk and disease vulnerability. Characterization of adaptive and maladaptive functional interactions among these pathways is seen as a critical step towards future development of evidenced-based algorithms that will optimize the diagnosis and treatment of individual depressed patients.
TL;DR: Compared with a bare metal stent, paclitaxel-eluting stents reduced in-stent neointimal formation and restenosis and improved 12-month clinical outcome of patients with single de novo coronary lesions.
Abstract: Background— Early clinical studies demonstrated the feasibility of local paclitaxel delivery in reducing restenosis after treatment of de novo coronary lesions in small patient populations. Methods and Results— We conducted a randomized, double-blind trial of 536 patients at 38 medical centers evaluating slow-release (SR) and moderate-release (MR) formulations of a polymer-based paclitaxel-eluting stent (TAXUS) for revascularization of single, primary lesions in native coronary arteries. Cohort I compared TAXUS-SR with control stents, and Cohort II compared TAXUS-MR with a second control group. The primary end point was 6-month percent in-stent net volume obstruction measured by intravascular ultrasound. Secondary end points were 6-month angiographic restenosis and 6- and 12-month incidence of major adverse cardiac events, a composite of cardiac death, myocardial infarction, and repeat revascularization. At 6 months, percent net volume obstruction within the stent was significantly lower for TAXUS stents ...