Showing papers by "University of Toronto published in 1999"

OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis

Abstract: The tumour-necrosis-factor-family molecule osteoprotegerin ligand (OPGL; also known as TRANCE, RANKL and ODF) has been identified as a potential osteoclast differentiation factor and regulator of interactions between T cells and dendritic cells in vitro. Mice with a disrupted opgl gene show severe osteopetrosis and a defect in tooth eruption, and completely lack osteoclasts as a result of an inability of osteoblasts to support osteoclastogenesis. Although dendritic cells appear normal, opgl-deficient mice exhibit defects in early differentiation of T and B lymphocytes. Surprisingly, opgl-deficient mice lack all lymph nodes but have normal splenic structure and Peyer's patches. Thus OPGL is a new regulator of lymph-node organogenesis and lymphocyte development and is an essential osteoclast differentiation factor in vivo.

Rational approximation of frequency domain responses by vector fitting

Abstract: The paper describes a general methodology for the fitting of measured or calculated frequency domain responses with rational function approximations. This is achieved by replacing a set of starting poles with an improved set of poles via a scaling procedure. A previous paper (Gustavsen et al., 1997) described the application of the method to smooth functions using real starting poles. This paper extends the method to functions with a high number of resonance peaks by allowing complex starting poles. Fundamental properties of the method are discussed and details of its practical implementation are described. The method is demonstrated to be very suitable for fitting network equivalents and transformer responses. The computer code is in the public domain, available from the first author.

Impact of formal continuing medical education: do conferences, workshops, rounds, and other traditional continuing education activities change physician behavior or health care outcomes?

Abstract: ContextAlthough physicians report spending a considerable amount of time in continuing medical education (CME) activities, studies have shown a sizable difference between real and ideal performance, suggesting a lack of effect of formal CME.ObjectiveTo review, collate, and interpret the effect of formal CME interventions on physician performance and health care outcomes.Data SourcesSources included searches of the complete Research and Development Resource Base in Continuing Medical Education and the Specialised Register of the Cochrane Effective Practice and Organisation of Care Group, supplemented by searches of MEDLINE from 1993 to January 1999.Study SelectionStudies were included in the analyses if they were randomized controlled trials of formal didactic and/or interactive CME interventions (conferences, courses, rounds, meetings, symposia, lectures, and other formats) in which at least 50% of the participants were practicing physicians. Fourteen of 64 studies identified met these criteria and were included in the analyses. Articles were reviewed independently by 3 of the authors.Data ExtractionDeterminations were made about the nature of the CME intervention (didactic, interactive, or mixed), its occurrence as a 1-time or sequenced event, and other information about its educational content and format. Two of 3 reviewers independently applied all inclusion/exclusion criteria. Data were then subjected to meta-analytic techniques.Data SynthesisThe 14 studies generated 17 interventions fitting our criteria. Nine generated positive changes in professional practice, and 3 of 4 interventions altered health care outcomes in 1 or more measures. In 7 studies, sufficient data were available for effect sizes to be calculated; overall, no significant effect of these educational methods was detected (standardized effect size, 0.34; 95% confidence interval [CI], −0.22 to 0.97). However, interactive and mixed educational sessions were associated with a significant effect on practice (standardized effect size, 0.67; 95% CI, 0.01-1.45).ConclusionsOur data show some evidence that interactive CME sessions that enhance participant activity and provide the opportunity to practice skills can effect change in professional practice and, on occasion, health care outcomes. Based on a small number of well-conducted trials, didactic sessions do not appear to be effective in changing physician performance.

A method for designing primer sets for speciation studies in filamentous ascomycetes

Abstract: A simple method is described for designing primer sets that can amplify specific protein-encoding sequences in a wide variety of filamentous ascomycetes. Using this technique, we successfully desig...

Cognitive Work Analysis: Toward Safe, Productive, and Healthy Computer-Based Work

Abstract: This book describes, for the first time in pedagogical form, an approach to computer-based work in complex sociotechnical systems developed over the last 30 years by Jens Rasmussen and his colleagues at Riso National Laboratory in Roskilde, Denmark. This approach is represented by a framework called cognitive work analysis. Its goal is to help designers of complex sociotechnical systems create computer-based information support that helps workers adapt to the unexpected and changing demands of their jobs. In short, cognitive work analysis is about designing for adaptation. The book is divided into four parts. Part I provides a motivation by introducing three themes that tie the book together--safety, productivity, and worker health. The ecological approach that serves as the conceptual basis behind the book is also described. In addition, a glossary of terms is provided. Part II situates the ideas in the book in a broader intellectual context by reviewing alternative approaches to work analysis. The limitations of normative and descriptive approaches are outlined, and the rationale behind the formative approach advocated in this book is explored. Part III describes the concepts that comprise the cognitive work analysis framework in detail. Each concept is illustrated by a case study, and the implications of the framework for design and research are illustrated by example. Part IV unifies the themes of safety, productivity, and health, and shows why the need for the concepts in this book will only increase in the future. In addition, a historical addendum briefly describes the origins of the ideas described in the book.

Salt Tolerance Conferred by Overexpression of a Vacuolar Na+/H+ Antiport in Arabidopsis

Abstract: Agricultural productivity is severely affected by soil salinity. One possible mechanism by which plants could survive salt stress is to compartmentalize sodium ions away from the cytosol. Overexpression of a vacuolar Na+/H+antiport from Arabidopsis thaliana in Arabidopsisplants promotes sustained growth and development in soil watered with up to 200 millimolar sodium chloride. This salinity tolerance was correlated with higher-than-normal levels of AtNHX1transcripts, protein, and vacuolar Na+/H+(sodium/proton) antiport activity. These results demonstrate the feasibility of engineering salt tolerance in plants.

The pseudogap in high-temperature superconductors: an experimental survey

Abstract: We present an experimental review of the nature of the pseudogap in the cuprate superconductors. Evidence from various experimental techniques points to a common phenomenology. The pseudogap is seen in all high-temperature superconductors and there is general agreement on the temperature and doping range where it exists. It is also becoming clear that the superconducting gap emerges from the normal state pseudogap. The d-wave nature of the order parameter holds for both the superconducting gap and the pseudogap. Although an extensive body of evidence is reviewed, a consensus on the origin of the pseudogap is as lacking as it is for the mechanism underlying high-temperature superconductivity.

Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency

Abstract: Genes have a major role in the control of high-density lipoprotein (HDL) cholesterol (HDL-C) levels. Here we have identified two Tangier disease (TD) families, confirmed 9q31 linkage and refined the disease locus to a limited genomic region containing the gene encoding the ATP-binding cassette transporter (ABC1). Familial HDL deficiency (FHA) is a more frequent cause of low HDL levels. On the basis of independent linkage and meiotic recombinants, we localized the FHA locus to the same genomic region as the TD locus. Mutations in ABC1 were detected in both TD and FHA, indicating that TD and FHA are allelic. This indicates that the protein encoded by ABC1 is a key gatekeeper influencing intracellular cholesterol transport, hence we have named it cholesterol efflux regulatory protein (CERP).

Periodic mesoporous organosilicas with organic groups inside the channel walls

Abstract: Surfactant-mediated synthesis methods have attracted much interest for the production of inorganic mesoporous materials, which can, on removal of the surfactant template, incorporate polymeric, organic, inorganic and organometallic guests' in their pores 1,2 . These materials-initially made of silica 3-5 , but now also available in the form of other oxides 6-9 , sulphides 10,11 , phosphates 12 and metals 13 -could find application in fields ranging from catalysis, adsorption and sensing technology to nanoelectronics. The extension of surfactant-mediated synthesis to produce inorganic-organic hybrid material (that is, materials that contain organic groups as an integral part of their framework structure) promises access to an even wider range of application possibilities. Such hybrid materials have been produced in the form of amorphous silicates (xerogels) that indeed display unique properties different to those of the individual components 14-20 , but their random networks with broad pore-size distributions severely limit the shape and size selectivity of these materials. Mesoporous hybrid materials with periodic frameworks have been synthesized, but the organic groups are all terminally bonded to the pore surface, rather than incorporated into the pore walls 21-26 . Here we describe a periodic mesoporous organosilica containing bridge-bonded ethene groups directly integrated into the silica framework. We are able to solvent-extract and ion-exchange the surfactant templates to create a stable and periodic mesoporous ethenesilica with high surface area and ethene groups that are readily accessible for chemical reaction. Recent syntheses of similar periodic mesoporous organosilicas 27,28 and the ability to incorporate a variety of bridging organic and organometallic species raise the prospect of being able to fuse organic synthesis and inorganic materials chemistry to generate new materials with interesting chemical, mechanical electronic, optical and magnetic properties.

TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling

Abstract: Bone resorption and remodeling is an intricately controlled, physiological process that requires the function of osteoclasts. The processes governing both the differentiation and activation of osteoclasts involve signals induced by osteoprotegerin ligand (OPGL), a member of tumor necrosis factor (TNF) superfamily, and its cognate receptor RANK. The molecular mechanisms of the intracellular signal transduction remain to be elucidated. Here we report that mice deficient in TNF receptor-associated factor 6 (TRAF6) are osteopetrotic with defects in bone remodeling and tooth eruption due to impaired osteoclast function. Using in vitro assays, we demonstrate that TRAF6 is crucial not only in IL-1 and CD40 signaling but also, surprisingly, in LPS signaling. Furthermore, like TRAF2 and TRAF3, TRAF6 is essential for perinatal and postnatal survival. These findings establish unexpectedly diverse and critical roles for TRAF6 in perinatal and postnatal survival, bone metabolism, LPS, and cytokine signaling.

Quality End-of-Life Care: Patients' Perspectives

Abstract: ContextQuality end-of-life care is increasingly recognized as an ethical obligation of health care providers, both clinicians and organizations. However, this concept has not been examined from the perspective of patients.ObjectiveTo identify and describe elements of quality end-of-life care from the patient's perspective.DesignQualitative study using in-depth, open-ended, face-to-face interviews and content analysis.SettingToronto, Ontario.ParticipantsA total of 126 participants from 3 patient groups: dialysis patients (n = 48), people with human immunodeficiency virus infection (n = 40), and residents of a long-term care facility (n = 38).Outcome MeasuresParticipants' views on end-of-life issues.ResultsParticipants identified 5 domains of quality end-of-life care: receiving adequate pain and symptom management, avoiding inappropriate prolongation of dying, achieving a sense of control, relieving burden, and strengthening relationships with loved ones.ConclusionThese domains, which characterize patients' perspectives on end-of-life care, can serve as focal points for improving the quality of end-of-life care.

Autologous Transplantation of Bone Marrow Cells Improves Damaged Heart Function

Abstract: Background—Autologous bone marrow cells (BMCs) transplanted into ventricular scar tissue may differentiate into cardiomyocytes and restore myocardial function. This study evaluated cardiomyogenic differentiation of BMCs, their survival in myocardial scar tissue, and the effect of the implanted cells on heart function. Methods and Results—In vitro studies: BMCs from adult rats were cultured in cell culture medium (control) and medium with 5-azacytidine (5-aza, 10 μmol/L), TGFβ1 (10ng/mL), or insulin (1 nmol/L) (n=6, each group). Only BMCs cultured with 5-aza formed myotubules which stained positively for troponin I and myosin heavy chain. In vivo studies: a cryoinjury-derived scar was formed in the left ventricular free wall. At 3 weeks after injury, fresh BMCs (n=9), cultured BMCs (n=9), 5-aza–induced BMCs (n=12), and medium (control, n=12) were autologously transplanted into the scar. Heart function was measured at 8 weeks after myocardial injury. Cardiac-like muscle cells which stained positively for my...

Reconnection in a weakly stochastic field

Abstract: We examine the effect of weak, small-scale magnetic field structure on the rate of reconnection in a strongly magnetized plasma. This affects the rate of reconnection by reducing the transverse scale for reconnection flows and by allowing many independent flux reconnection events to occur simultaneously. Allowing only for the first effect and using Goldreich & Sridhar's model of strong turbulence in a magnetized plasma with negligible intermittency, we find a lower limit for the reconnection speed ~VA-3/16L3/4, where VA is the Alfven speed, L is the Lundquist number, and is the large-scale magnetic Mach number of the turbulence. We derive an upper limit of ~VA2 by invoking both effects. We argue that generic reconnection in turbulent plasmas will normally occur at close to this upper limit. The fraction of magnetic energy that goes directly into electron heating scales as -2/5L8/5, and the thickness of the current sheet scales as -3/5L-2/5. A significant fraction of the magnetic energy goes into high-frequency Alfven waves. The angle between adjacent field lines on the same side of the reconnection layer is ~-1/5L6/5 on the scale of the current sheet thickness. We claim that the qualitative sense of these conclusions, that reconnection is fast even though current sheets are narrow, is almost independent of the local physics of reconnection and the nature of the turbulent cascade. As the consequence of this the Galactic and solar dynamos are generically fast, i.e., do not depend on the plasma resistivity.

Efavirenz plus Zidovudine and Lamivudine, Efavirenz plus Indinavir, and Indinavir plus Zidovudine and Lamivudine in the Treatment of HIV-1 Infection in Adults

Abstract: Background Efavirenz is a nonnucleoside reverse-transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1). We compared two regimens containing efavirenz, one with a protease inhibitor and the other with two nucleoside reverse-transcriptase inhibitors, with a standard three-drug regimen. Methods The study subjects were 450 patients who had not previously been treated with lamivudine or any nonnucleoside reverse-transcriptase inhibitor or protease inhibitor. In this open-label study, patients were randomly assigned to one of three regimens: efavirenz (600 mg daily) plus zidovudine (300 mg twice daily) and lamivudine (150 mg twice daily); the protease inhibitor indinavir (800 mg every eight hours) plus zidovudine and lamivudine; or efavirenz plus indinavir (1000 mg every eight hours). Results Suppression of plasma HIV-1 RNA to undetectable levels was achieved in more patients in the group given efavirenz plus nucleoside reverse-transcriptase inhibitors than in the group given indinavir plus nucl...

Decreased Susceptibility of Streptococcus pneumoniae to Fluoroquinolones in Canada

Abstract: Background Fluoroquinolones are now recommended for the treatment of respiratory tract infections due to Streptococcus pneumoniae, particularly when the isolates are resistant to β-lactam antibiotics. Although pneumococci with reduced susceptibility to fluoroquinolones have been identified, their prevalence has not been determined in a defined population. Methods We performed susceptibility testing on 7551 isolates of S. pneumoniae obtained from surveillance in Canada in 1988 and from 1993 to 1998. Pneumococci with reduced susceptibility to fluoroquinolones (defined as a minimal inhibitory concentration of ciprofloxacin of at least 4 μg per milliliter) were further characterized. We also examined antibiotic prescriptions dispensed in Canadian retail pharmacies. Results Between 1988 and 1997, fluoroquinolone prescriptions increased from 0.8 to 5.5 per 100 persons per year. The prevalence of pneumococci with reduced susceptibility to fluoroquinolones increased from 0 percent in 1993 to 1.7 percent in 1997 a...

Differential Galaxy Evolution in Cluster and Field Galaxies at z ≈ 0.3

Abstract: We measure spectral indexes for 1823 galaxies in the Canadian Network for Observational Cosmology 1 (CNOC1) sample of 15 X-ray luminous clusters at 0.18 5 A] but no [O II] emission [W0(O ) < 5 A], perhaps indicative of recently terminated star formation. The observed fraction of 4.4% ± 0.7% in the cluster sample is an overestimate due to a systematic effect that results from the large uncertainties on individual spectral index measurements. Corrected for this bias, we estimate that K+A galaxies make up only 2.1% ± 0.7% of the cluster sample and 0.1% ± 0.7% of the field. From the subsample of galaxies more luminous than Mr = -18.8 + 5 log h, which is statistically representative of a complete sample to this limit, the corrected fraction of K+A galaxies is 1.5% ± 0.8% in the cluster and 1.2% ± 0.8% in the field. Compared with the z ≈ 0.1 fraction of 0.30%, the fraction of K+A galaxies in the CNOC1 field sample is greater by perhaps a factor of 4, but with only 1 σ significance; no further evolution of this fraction is detectable over our redshift range. We compare our data with the results of PEGASE and GISSEL96 spectrophotometric models and conclude, from the relative fractions of red and blue galaxies with no [O II] λ3727 emission and strong Hδ absorption, that up to 1.9% ± 0.8% of the cluster population may have had its star formation recently truncated without a starburst. However, this is still not significantly greater than the fraction of such galaxies in the field, 3.1% ± 1.0%. Furthermore, we do not detect an excess of cluster galaxies that have unambiguously undergone starbursts within the last 1 Gyr. In fact, at 6.3% ± 2.1%, the A+em galaxies that Poggianti et al. have recently suggested are dusty starbursts are twice as common in the field as in the cluster environment. Our results imply that these cluster environments are not responsible for inducing starbursts; thus, the increase in cluster blue galaxy fraction with redshift may not be a strictly cluster-specific phenomenon. We suggest that the truncation of star formation in clusters may largely be a gradual process, perhaps due to the exhaustion of gas in the galactic disks over fairly long timescales; in this case differential evolution may result because field galaxies can refuel their disks with gas from extended halos, thus regenerating star formation, while cluster galaxies may not have such halos and so continue to evolve passively.

A unifying review of linear Gaussian models

Abstract: Factor analysis, principal component analysis, mixtures of gaussian clusters, vector quantization, Kalman filter models, and hidden Markov models can all be unified as variations of unsupervised learning under a single basic generative model. This is achieved by collecting together disparate observations and derivations made by many previous authors and introducing a new way of linking discrete and continuous state models using a simple nonlinearity. Through the use of other nonlinearities, we show how independent component analysis is also a variation of the same basic generative model.We show that factor analysis and mixtures of gaussians can be implemented in autoencoder neural networks and learned using squared error plus the same regularization term. We introduce a new model for static data, known as sensible principal component analysis, as well as a novel concept of spatially adaptive observation noise. We also review some of the literature involving global and local mixtures of the basic models and provide pseudocode for inference and learning for all the basic models.

Specific Coupling of NMDA Receptor Activation to Nitric Oxide Neurotoxicity by PSD-95 Protein

Abstract: The efficiency with whichN-methyl-d-aspartate receptors (NMDARs) trigger intracellular signaling pathways governs neuronal plasticity, development, senescence, and disease. In cultured cortical neurons, suppressing the expression of the NMDAR scaffolding protein PSD-95 (postsynaptic density–95) selectively attenuated excitotoxicity triggered via NMDARs, but not by other glutamate or calcium ion (Ca2+) channels. NMDAR function was unaffected, because receptor expression, NMDA currents, and 45Ca2+loading were unchanged. Suppressing PSD-95 blocked Ca2+-activated nitric oxide production by NMDARs selectively, without affecting neuronal nitric oxide synthase expression or function. Thus, PSD-95 is required for efficient coupling of NMDAR activity to nitric oxide toxicity, and imparts specificity to excitotoxic Ca2+ signaling.

A SMAD ubiquitin ligase targets the BMP pathway and affects embryonic pattern formation.

Abstract: The TGF-beta superfamily of proteins regulates many different biological processes, including cell growth, differentiation and embryonic pattern formation. TGF-beta-like factors signal across cell membranes through complexes of transmembrane receptors known as type I and type II serine/threonine-kinase receptors, which in turn activate the SMAD signalling pathway. On the inside of the cell membrane, a receptor-regulated class of SMADs are phosphorylated by the type-I-receptor kinase. In this way, receptors for different factors are able to pass on specific signals along the pathway: for example, receptors for bone morphogenetic protein (BMP) target SMADs 1, 5 and 8, whereas receptors for activin and TGF-beta target SMADs 2 and 3. Phosphorylation of receptor-regulated SMADs induces their association with Smad4, the 'common-partner' SMAD, and stimulates accumulation of this complex in the nucleus, where it regulates transcriptional responses. Here we describe Smurf1, a new member of the Hect family of E3 ubiquitin ligases. Smurf1 selectively interacts with receptor-regulated SMADs specific for the BMP pathway in order to trigger their ubiquitination and degradation, and hence their inactivation. In the amphibian Xenopus laevis, Smurf1 messenger RNA is localized to the animal pole of the egg; in Xenopus embryos, ectopic Smurf1 inhibits the transmission of BMP signals and thereby affects pattern formation. Smurf1 also enhances cellular responsiveness to the Smad2 (activin/TGF-beta) pathway. Thus, targeted ubiquitination of SMADs may serve to control both embryonic development and a wide variety of cellular responses to TGF-beta signals.

Growing Y-junction carbon nanotubes

Abstract: The synthesis of connections between two or more different carbon nanotubes is an important step in the development of carbon nanotube-based electronic devices and circuits1,2,3,4. But this is difficult to achieve using conventional methods to grow carbon nanotubes5 because the straight tube structure cannot be controllably altered along its length. Various ideas for post-growth modifications have been suggested6, but these have been hard to implement and are prone to defects. Here we use nano-structured template channels to grow individual Y-junction carbon-nanotube heterostructures by the pyrolysis of acetylene with cobalt catalysis.

Calreticulin: one protein, one gene, many functions.

Abstract: The endoplasmic reticulum (ER) plays a critical role in the synthesis and chaperoning of membrane-associated and secreted proteins. The membrane is also an important site of Ca(2+) storage and release. Calreticulin is a unique ER luminal resident protein. The protein affects many cellular functions, both in the ER lumen and outside of the ER environment. In the ER lumen, calreticulin performs two major functions: chaperoning and regulation of Ca(2+) homoeostasis. Calreticulin is a highly versatile lectin-like chaperone, and it participates during the synthesis of a variety of molecules, including ion channels, surface receptors, integrins and transporters. The protein also affects intracellular Ca(2+) homoeostasis by modulation of ER Ca(2+) storage and transport. Studies on the cell biology of calreticulin revealed that the ER membrane is a very dynamic intracellular compartment affecting many aspects of cell physiology.

Pulse inversion Doppler: a new method for detecting nonlinear echoes from microbubble contrast agents

Abstract: A novel technique for the selective detection of ultrasound contrast agents, called pulse inversion Doppler, has been developed. In this technique, a conventional Doppler or color Doppler pulse sequence is modified by inverting every second transmit pulse. Either conventional or harmonic Doppler processing is then performed on the received echoes. In the resulting Doppler spectra, Doppler shifts from linear and nonlinear scattering are separated into two distinct regions that can be analyzed separately or combined to estimate the ratio of nonlinear to linear scattering from a region of tissue. The maximum Doppler shift that can be detected is 1/2 the normal Nyquist limit. This has the advantage over conventional harmonic Doppler that it can function over the entire bandwidth of the echo signal, thus achieving superior spatial resolution in the Doppler image. In vitro measurements comparing flowing agent and cellulose particles suggest that pulse inversion Doppler can provide 3 to 10 dB more agent to tissue contrast than harmonic imaging with similar pulses. Similar measurements suggest that broadband pulse inversion Doppler can provide up to 16 dB more contrast than broadband conventional Doppler. Nonlinear propagation effects limit the maximum contrast obtainable with both harmonic and pulse inversion Doppler techniques.

Salt Tolerance and Crop Potential of Halophytes

Abstract: Although they represent only 2% of terrestrial plant species, halophytes are present in about half the higher plant families and represent a wide diversity of plant forms. Despite their polyphyletic origins, halophytes appear to have evolved the same basic method of osmotic adjustment: accumulation of inorganic salts, mainly NaCl, in the vacuole and accumulation of organic solutes in the cytoplasm. Differences between halophyte and gly-cophyte ion transport systems are becoming apparent. The pathways by which Na+ and Cl− enters halophyte cells are not well understood but may involve ion channels and pinocytosis, in addition to Na+ and Cl− transporters. Na+ uptake into vacuoles requires Na+/H+ antiporters in the tonoplast and H+ ATPases and perhaps PPi ases to provide the proton motive force. Tonoplast antiporters are constitutive in halophytes, whereas they must be activated by NaCl in salt-tolerant glycophytes, and they may be absent from salt-sensitive glycophytes. Halophyte vacuoles may have a modified...