Showing papers by "University of Toronto published in 1997"
TL;DR: It is demonstrated that the cell capable of initiating human AML in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice) — termed the SCID leukemia-initiating cell, or SL-IC — possesses the differentiate and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell.
Abstract: On the subject of acute myeloid leukemia (AML), there is little consensus about the target cell within the hematopoietic stem cell hierarchy that is susceptible to leukemic transformation, or about the mechanism that underlies the phenotypic, genotypic and clinical heterogeneity. Here we demonstrate that the cell capable of initiating human AML in non-obese diabetic mice with severe combined immunodeficiency disease (NOD/SCID mice) - termed the SCID leukemia-initiating cell, or SL-IC - possesses the differentiative and proliferative capacities and the potential for self-renewal expected of a leukemic stem cell. The SL-ICs from all subtypes of AML analyzed, regardless of the heterogeneity in maturation characteristics of the leukemic blasts, were exclusively CD34++ CD38-, similar to the cell-surface phenotype of normal SCID-repopulating cells, suggesting that normal primitive cells, rather than committed progenitor cells, are the target for leukemic transformation. The SL-ICs were able to differentiate in vivo into leukemic blasts, indicating that the leukemic clone is organized as a hierarchy.
6,709 citations
TL;DR: New fluorescent indicators for Ca2+ that are genetically encoded without cofactors and are targetable to specific intracellular locations are constructed and dubbed ‘cameleons’.
Abstract: Important Ca2+ signals in the cytosol and organelles are often extremely localized and hard to measure. To overcome this problem we have constructed new fluorescent indicators for Ca2+ that are genetically encoded without cofactors and are targetable to specific intracellular locations. We have dubbed these fluorescent indicators 'cameleons'. They consist of tandem fusions of a blue- or cyan-emitting mutant of the green fluorescent protein (GFP), calmodulin, the calmodulin-binding peptide M13, and an enhanced green- or yellow-emitting GFP. Binding of Ca2+ makes calmodulin wrap around the M13 domain, increasing the fluorescence resonance energy transfer (FRET) between the flanking GFPs. Calmodulin mutations can tune the Ca2+ affinities to measure free Ca2+ concentrations in the range 10(-8) to 10(-2) M. We have visualized free Ca2+ dynamics in the cytosol, nucleus and endoplasmic reticulum of single HeLa cells transfected with complementary DNAs encoding chimaeras bearing appropriate localization signals. Ca2+ concentration in the endoplasmic reticulum of individual cells ranged from 60 to 400 microM at rest, and 1 to 50 microM after Ca2+ mobilization. FRET is also an indicator of the reversible intermolecular association of cyan-GFP-labelled calmodulin with yellow-GFP-labelled M13. Thus FRET between GFP mutants can monitor localized Ca2+ signals and protein heterodimerization in individual live cells.
3,248 citations
TL;DR: Simulations indicate that the lasso can be more accurate than stepwise selection in this setting and reduce the estimation variance while providing an interpretable final model in Cox's proportional hazards model.
Abstract: SUMMARY I propose a new method for variable selection and shrinkage in Cox’s proportional hazards model. My proposal minimizes the log partial likelihood subject to the sum of the absolute values of the parameters being bounded by a constant. Because of the nature of this constraint, it shrinks coeƒcients and produces some coeƒcients that are exactly zero. As a result it reduces the estimation variance while providing an interpretable final model. The method is a variation of the ‘lasso’ proposal of Tibshirani, designed for the linear regression context. Simulations indicate that the lasso can be more accurate than stepwise selection in this setting.
3,004 citations
TL;DR: Functional composition and functional diversity were the principal factors explaining plant productivity, plant percent nitrogen, plant total nitrogen, and light penetration in grassland plots.
Abstract: Humans are modifying both the identities and numbers of species in ecosystems, but the impacts of such changes on ecosystem processes are controversial. Plant species diversity, functional diversity, and functional composition were experimentally varied in grassland plots. Each factor by itself had significant effects on many ecosystem processes, but functional composition and functional diversity were the principal factors explaining plant productivity, plant percent nitrogen, plant total nitrogen, and light penetration. Thus, habitat modifications and management practices that change functional diversity and functional composition are likely to have large impacts on ecosystem processes.
2,762 citations
TL;DR: In this article, the authors present a compilation of trace element data from approximately sixty published works for NIST SRM 611 and NISTSRM 613 and provide useful new working values for these reference materials.
Abstract: Microanalytical trace element techniques (such as ion probe or laser ablation ICP-MS) are hampered by a lack of well characterized, homogeneous standards. Two silicate glass reference materials produced by National Institute of Standards and Technology (NIST), NIST SRM 610 and NIST SRM 612, have been shown to be homogeneous and are spiked with up to sixty one trace elements at nominal concentrations of 500 μg g-1 and 50 μg g-1 respectively. These samples (supplied as 3 mm wafers) are equivalent to NIST SRM 611 and NIST SRM 613 respectively (which are supplied as 1 mm wafers) and are becoming more widely used as potential microanalytical reference materials. NIST however, only certifies up to eight elements in these glasses. Here we have compiled concentration data from approximately sixty published works for both glasses, and have produced new analyses from our laboratories. Compilations are presented for the matrix composition of these glasses and for fifty eight trace elements. The trace element data includes all available new and published data, and summaries present the overall average and standard deviation, the range, median, geometric mean and a preferred average (which excludes all data outside ± one standard deviation of the overall average). For the elements which have been certified, there is a good agreement between the compiled averages and the NIST data. This compilation is designed to provide useful new working values for these reference materials.
2,487 citations
TL;DR: In this article, a theory of stakeholder influences is proposed, which accommodates multiple, interdependent stakeholder demands and predicts how organizations respond to the simultaneous influence of multiple stakeholders.
Abstract: Stakeholder theory development has increased in recent years, in part because of its emphasis on explaining and predicting how an organization functions with respect to the relationships and influences existing in its environment. Thus far. most researchers have concentrated on dyadic relationships between individual stakeholders and a focal organization. Using social network analysis, I construct in this article a theory of stakeholder influences, which accommodates multiple, interdependent stakeholder demands and predicts how organizations respond to the simultaneous influence of multiple stakeholders.
2,393 citations
TL;DR: This study aimed to compare the reliability of three scoring systems, to compare live and bench formats and to assess construct validity of a test of operative skill.
Abstract: Background The technical skill of surgical trainees is not well assessed. This study aimed (1) to compare the reliability of three scoring systems, (2) to compare live and bench formats and (3) to assess construct validity of a test of operative skill.
Methods Parallel examinations of operative skill, one using live animals and one using simulations, were developed. Performance was graded using operation-specific checklists, detailed global rating forms and pass/fail judgements. Twenty surgical residents each took both formats.
Results Disattenuated correlations between live and bench scores were high (0.69–0.72). Mean inter-rater reliability across stations ranged from 0.64 to 0.72. Internal consistency was moderate to high (α: 0.61–0.74) for the live format using the checklist and for live and bench formats using global ratings. Global ratings discriminated between resident levels for both formats (bench: F(2,17) = 4.45, P < 0.05; live: F(2,17) = 3.5, P < 0.05), checklists did not.
Conclusion This preliminary study suggests that the Objective Structured Assessment of Technical Skill can reliably and validly assess surgical skills. Global ratings are a better method of assessment than task-specific checklists. Bench model simulation gives equivalent results to use of live animals for this test format.
2,160 citations
Book•
13 Jul 1997TL;DR: In this article, the basic magnetism in nature has been studied and the fundamental properties of magnetism have been discussed. But the authors focus on the magnetism of metamorphic and igneous rocks rather than extraterrestrial magnetism.
Abstract: Preface 1. Magnetism in nature 2. Fundamentals of magnetism 3. Terrestrial magnetic materials 4. Magnetostatic fields and energies 5. Elementary domain structure and hysteresis 6. Domain observations 7. Micromagnetic calculations 8. Single-domain thermoremanent magnetization 9. Multidomain thermoremanent magnetization 10. Viscous and thermoviscous magnetization 11. Isothermal magnetization and demagnetization 12. Pseudo-single-domain remanence 13. Crystallization remanent magnetization 14. Magnetism of igneous rocks and baked materials 15. Magnetism of sediments and sedimentary rocks 16. Magnetism of metamorphic rocks 17. Magnetism of extraterrestrial rocks References.
1,754 citations
TL;DR: This paper argues that a different kind of modelling and reasoning support is needed for the early phase of requirements engineering, which aims to model and analyze stakeholder interests and how they might be addressed, or compromised, by various system-and-environment alternatives.
Abstract: Requirements are usually understood as stating what a system is supposed to do, as apposed to how it should do it. However, understanding the organizational context and rationales (the "Whys") that lead up to systems requirements can be just as important for the ongoing success of the system. Requirements modelling techniques can be used to help deal with the knowledge and reasoning needed in this earlier phase of requirements engineering. However most existing requirements techniques are intended more for the later phase of requirements engineering, which focuses on completeness, consistency, and automated verification of requirements. In contrast, the early phase aims to model and analyze stakeholder interests and how they might be addressed, or compromised, by various system-and-environment alternatives. This paper argues, therefore, that a different kind of modelling and reasoning support is needed for the early phase. An outline of the i* framework is given as an example of a step in this direction. Meeting scheduling is used as a domain example.
1,743 citations
TL;DR: The hippocampal formation and related structures are involved in certain forms of memory (e.g. autobiographical episodic and spatial memory) for as long as they exist and contribute to the transformation and stabilization of other form of memory stored elsewhere in the brain.
1,743 citations
TL;DR: It is shown that a particular bootstrap method, the .632+ rule, substantially outperforms cross-validation in a catalog of 24 simulation experiments and also considers estimating the variability of an error rate estimate.
Abstract: A training set of data has been used to construct a rule for predicting future responses. What is the error rate of this rule? This is an important question both for comparing models and for assessing a final selected model. The traditional answer to this question is given by cross-validation. The cross-validation estimate of prediction error is nearly unbiased but can be highly variable. Here we discuss bootstrap estimates of prediction error, which can be thought of as smoothed versions of cross-validation. We show that a particular bootstrap method, the .632+ rule, substantially outperforms cross-validation in a catalog of 24 simulation experiments. Besides providing point estimates, we also consider estimating the variability of an error rate estimate. All of the results here are nonparametric and apply to any possible prediction rule; however, we study only classification problems with 0–1 loss in detail. Our simulations include “smooth” prediction rules like Fisher's linear discriminant fun...
TL;DR: Evidence supports a preliminary theory of episodic remembering, which holds that the prefrontal cortex plays a critical, supervisory role in empowering healthy adults with autonoetic consciousness-the capacity to mentally represent and become aware of subjective experiences in the past, present, and future.
Abstract: Adult humans are capable of remembering prior events by mentally traveling back in time to re-experience those events. In this review, the authors discuss this and other related capabilities, considering evidence from such diverse sources as brain imaging, neuropsychological experiments, clinical ob
Book•
28 Feb 1997TL;DR: The development and regulation of affects Graeme Taylor, Michael Bagby and James Parker as mentioned in this paper, along with the neurobiology of emotion, affect regulation and alexithymia.
Abstract: Foreword James S. Grotstein Acknowledgements Introduction Graeme Taylor 1. The development and regulation of affects Graeme Taylor, Michael Bagby and James Parker 2. Affect dysregulation and alexithymia Michael Bagby and Graeme Taylor 3. Measurement and validation of the alexithymia construct Michael Bagby and Graeme Taylor 4. Relations between alexithymia, personality, and affects James Parker and Graeme Taylor 5. The neurobiology of emotion, affect regulation and alexithymia James Parker and Graeme Taylor 6. Somatoform disorders Graeme Taylor 7. Anxiety and depressive disorders and a note on personality disorders Michael Bagby and Graeme Taylor 8. Substance use disorders Graeme Taylor 9. Eating disorders Graeme Taylor 10. Affects and alexithymia in medical illness and disease Graeme Taylor 11. Treatment considerations Graeme Taylor 12. Future directions James Parker, Michael Bagby and Graeme Taylor References Index.
TL;DR: In addition to their roles as inhibitors, the p21 family of proteins may also have roles as adaptor proteins that assemble and program kinase complexes for specific functions.
Abstract: The association of cdk4 with D-type cyclins to form functional kinase complexes is comparatively inefficient. This has led to the suggestion that assembly might be a regulated step. In this report we demonstrate that the CDK inhibitors pZl'^^'', p27^^^, and p57^^^^ all promote the association of cdk4 with the D-type cyclins. This effect is specific and does not occur with other cdk inhibitors or cdk-binding proteins. Both in vivo and in vitro, the abundance of assembled cdk4/cyclin D complex increases directly with increasing inhibitor levels. The promotion of assembly is not attributable to a simple cell cycle block and requires the function of both the cdk and cyclin-binding domains. Kinetic studies demonstrate that p21 and p27 lead to a 35- and 80-fold increase in K^, respectively, mostly because of a decrease in X^ff. At low concentrations, p21 promotes the assembly of active kinase complexes, whereas at higher concentrations, it inhibits activity. Moreover, immunodepletion experiments demonstrate that most of the active cdk4-associated kinase activity also associates with p21. To confirm these results in a natural setting, we examine the assembly of endogenous complexes in mammary epithelial cells after release from a GQ arrest. In agreement with our other data, cyclin Dl and p21 bind concomitantly to cdk4 during the in vivo assembly of cdk4/cyclin Dl complexes. This complex assembly occurs in parallel to an increase in cyclin Dl-associated kinase activity. Immunodepletion experiments demonstrate that most of the cellular cyclin Dl-associated kinase activity is also p21 associated. Finally, we find that all three CIP/KIP inhibitors target cdk4 and cyclin Dl to the nucleus. We suggest that in addition to their roles as inhibitors, the p21 family of proteins, originally identified as inhibitors, may also have roles as adaptor proteins that assemble and program kinase complexes for specific functions.
TL;DR: The data demonstrate that the preseniiin mutations cause a dominant gain of function and may induce AD by enhancing Aβ42 production, thus promoting cerebral β-amyloidosis.
Abstract: The mechanism by which mutations in the presenilin (PS) genes cause the most aggressive form of early-onset Alzheimer's disease (AD) is unknown, but fibroblasts from mutation carriers secrete increased levels of the amyloidogenic A beta 42 peptide, the main component of AD plaques. We established transfected cell and transgenic mouse models that coexpress human PS and amyloid beta-protein precursor (APP) genes and analyzed quantitatively the effects of PS expression on APP processing. In both models, expression of wild-type PS genes did not alter APP levels, alpha- and beta-secretase activity and A beta production. In the transfected cells, PS1 and PS2 mutations caused a highly significant increase in A beta 42 secretion in all mutant clones. Likewise, mutant but not wildtype PS1 transgenic mice showed significant overproduction of A beta 42 in the brain, and this effect was detectable as early as 2-4 months of age. Different PS mutations had differential effects on A beta generation. The extent of A beta 42 increase did not correlate with presenilin expression levels. Our data demonstrate that the presenilin mutations cause a dominant gain of function and may induce AD by enhancing A beta 42 production, thus promoting cerebral beta-amyloidosis.
TL;DR: Findings indicate that PrPC can exist in a Cu-metalloprotein form in vivo, and that its amino terminus contains the octapeptide PHGGGWGQ, which is among the best-preserved regions of mammalian PrPC.
Abstract: The normal cellular form of prion protein (PrPC) is a precursor to the pathogenic protease-resistant forms (PrPSc) believed to cause scrapie, bovine spongiform encephalopathy (BSE) and Creutzfeldt-Jakob disease. Its amino terminus contains the octapeptide PHGGGWGQ, which is repeated four times and is among the best-preserved regions of mammalian PrPC. Here we show that the amino-terminal domain of PrPC exhibits five to six sites that bind copper (Cu(II)) presented as a glycine chelate. At neutral pH, binding occurs with positive cooperativity, with binding affinity compatible with estimates for extracellular, labile copper. Two lines of independently derived PrPC gene-ablated (Prnp0/0) mice exhibit severe reductions in the copper content of membrane-enriched brain extracts and similar reductions in synaptosomal and endosome-enriched subcellular fractions. Prnp0/0 mice also have altered cellular phenotypes, including a reduction in the activity of copper/zinc superoxide dismutase and altered electrophysiological responses in the presence of excess copper. These findings indicate that PrPC can exist in a Cu-metalloprotein form in vivo.
Heidelberg University1, Loma Linda University2, Institute of Cancer Research3, Wellington Management Company4, University of Edinburgh5, Umeå University6, City of Hope National Medical Center7, University of Basel8, Memorial Sloan Kettering Cancer Center9, University of Toronto10, University of Groningen11
TL;DR: This paper presents the conclusions of a workshop entitled ‘Impact of Molecular Genetics on the Classification of Renal Cell Tumours’, which was held in Heidelberg in October 1996 and is applicable to routine diagnostic practice.
Abstract: This paper presents the conclusions of a workshop entitled 'Impact of Molecular Genetics on the Classification of Renal Cell Tumours', which was held in Heidelberg in October 1996. The focus on 'renal cell tumours' excludes any discussion of Wilms' tumour and its variants, or of tumours metastatic to the kidneys. The proposed classification subdivides renal cell tumours into benign and malignant parenchymal neoplasms and, where possible, limits each subcategory to the most commonly documented genetic abnormalities. Benign tumours are subclassified into metanephric adenoma and adenofibroma, papillary renal cell adenoma, and renal oncocytoma. Malignant tumours are subclassified into common or conventional renal cell carcinoma; papillary renal cell carcinoma; chromophobe renal cell carcinoma; collecting duct carcinoma, with medullary carcinoma of the kidney; and renal cell carcinoma, unclassified. This classification is based on current genetic knowledge, correlates with recognizable histological findings, and is applicable to routine diagnostic practice.
TL;DR: The concept that mechanical ventilation can have a significant influence on the inflammatory/anti-inflammatory milieu of the lung, and thus play a role in initiating or propagating a local, and possibly systemic inflammatory response, is supported.
Abstract: We examined the effect of ventilation strategy on lung inflammatory mediators in the presence and absence of a preexisting inflammatory stimulus. 55 Sprague-Dawley rats were randomized to either intravenous saline or lipopolysaccharide (LPS). After 50 min of spontaneous respiration, the lungs were excised and randomized to 2 h of ventilation with one of four strategies: (a) control (C), tidal volume (Vt) = 7 cc/kg, positive end expiratory pressure (PEEP) = 3 cm H2O; (b) moderate volume, high PEEP (MVHP), Vt = 15 cc/kg; PEEP = 10 cm H2O; (c) moderate volume, zero PEEP (MVZP), Vt = 15 cc/kg, PEEP = 0; or (d) high volume, zero PEEP (HVZP), Vt = 40 cc/kg, PEEP = 0. Ventilation with zero PEEP (MVZP, HVZP) resulted in significant reductions in lung compliance. Lung lavage levels of TNFalpha, IL-1beta, IL-6, IL-10, MIP-2, and IFNgamma were measured by ELISA. Zero PEEP in combination with high volume ventilation (HVZP) had a synergistic effect on cytokine levels (e.g., 56-fold increase of TNFalpha versus controls). Identical end inspiratory lung distention with PEEP (MVHP) resulted in only a three-fold increase in TNFalpha, whereas MVZP produced a six-fold increase in lavage TNFalpha. Northern blot analysis revealed a similar pattern (C, MVHP < MVZP < HVZP) for induction of c-fos mRNA. These data support the concept that mechanical ventilation can have a significant influence on the inflammatory/anti-inflammatory milieu of the lung, and thus may play a role in initiating or propagating a local, and possibly systemic inflammatory response.
Journal Article•
TL;DR: The evidence shows serious deficiencies in the adoption of CPGs in practice and future implementation strategies must overcome this failure through an understanding of the forces and variables influencing practice and through the use of methods that are practice- and community-based rather than didactic.
Abstract: OBJECTIVE: To recommend effective strategies for implementing clinical practice guidelines (CPGs). DATA SOURCES: The Research and Development Resource Base in Continuing Medical Education, maintained by the University of Toronto, was searched, as was MEDLINE from January 1990 to June 1996, inclusive, with the use of the MeSH heading "practice guidelines" and relevant text words. STUDY SELECTION: Studies of CPG implementation strategies and reviews of such studies were selected. Randomized controlled trials and trials that objectively measured physicians' performance or health care outcomes were emphasized. DATA EXTRACTION: Articles were reviewed to determine the effect of various factors on the adoption of guidelines. DATA SYNTHESIS: The articles showed that CPG dissemination or implementation processes have mixed results. Variables that affect the adoption of guidelines include qualities of the guidelines, characteristics of the health care professional, characteristics of the practice setting, incentives, regulation and patient factors. Specific strategies fell into 2 categories: primary strategies involving mailing or publication of the actual guidelines and secondary interventional strategies to reinforce the guidelines. The interventions were shown to be weak (didactic, traditional continuing medical education and mailings), moderately effective (audit and feedback, especially concurrent, targeted to specific providers and delivered by peers or opinion leaders) and relatively strong (reminder systems, academic detailing and multiple interventions). CONCLUSIONS: The evidence shows serious deficiencies in the adoption of CPGs in practice. Future implementation strategies must overcome this failure through an understanding of the forces and variables influencing practice and through the use of methods that are practice- and community-based rather than didactic.
TL;DR: The use of cellular telephones in motor vehicles is associated with a quadrupling of the risk of a collision during the brief time interval involving a call, suggesting that having a cellular telephone may have had advantages in the aftermath of an event.
Abstract: Background Because of a belief that the use of cellular telephones while driving may cause collisions, several countries have restricted their use in motor vehicles, and others are considering such regulations. We used an epidemiologic method, the case–crossover design, to study whether using a cellular telephone while driving increases the risk of a motor vehicle collision. Methods We studied 699 drivers who had cellular telephones and who were involved in motor vehicle collisions resulting in substantial property damage but no personal injury. Each person's cellular-telephone calls on the day of the collision and during the previous week were analyzed through the use of detailed billing records. Results A total of 26,798 cellular-telephone calls were made during the 14-month study period. The risk of a collision when using a cellular telephone was four times higher than the risk when a cellular telephone was not being used (relative risk, 4.3; 95 percent confidence interval, 3.0 to 6.5). The relative ri...
TL;DR: This paper examined the role of the management team's international experience as such a mechanism for the internationalization of Canadian software product firms and found that internationally experienced management teams have a greater propensity to develop foreign strategic partners and to delay less in obtaining foreign sales after start-up, and that these behaviors are associated with a higher degree of internationalization.
Abstract: Why are some small and medium-sized enterprises (SMEs) more successful in selling outside their domestic markets than are other SMEs in the same industry? Although the traditional explanation is that firms can gain valuable knowledge and resources as they become older and larger, small and young firms are not necessarily disadvantaged if they develop other mechanisms to acquire the requisite knowledge and resources. We examine the role of the management team's international experience as such a mechanism, for the internationalization of Canadian software product firms. We show that internationally experienced management teams have a greater propensity to develop foreign strategic partners and to delay less in obtaining foreign sales after start-up, and that these behaviors are associated with a higher degree of internationalization.
01 Sep 1997
TL;DR: In terms of minimizing routing area, VPR outperforms all published FPGA place and route tools to which the authors can compare and presents placement and routing results on a new set of circuits more typical of today's industrial designs.
Abstract: We describe the capabilities of and algorithms used in a new FPGA CAD tool, Versatile Place and Route (VPR). In terms of minimizing routing area, VPR outperforms all published FPGA place and route tools to which we can compare. Although the algorithms used are based on previously known approaches, we present several enhancements that improve run-time and quality. We present placement and routing results on a new set of large circuits to allow future benchmark comparisons of FPGA place and route tools on circuit sizes more typical of today's industrial designs.
TL;DR: Circum circumcised infants showed a stronger pain response to subsequent routine vaccination than uncircumcised infants, and preoperative treatment with Emla attenuated the painresponse to vaccination.
TL;DR: Overall, findings suggest that clustering and switching are dissociable fluency components and that switching is related to frontal-lobe functioning.
Abstract: Although verbal fluency is a frequently used neuropsychological test, little is known about the underlying cognitive processes. The authors proposed that 2 important components of fluency performance are clustering (i.e., the production of words within semantic or phonemic subcategories) and switching (i.e., the ability to shift between clusters). In Experiment 1, correlational data from 54 older and 41 younger adults indicated that both components were highly correlated with the number of words generated on semantic fluency, whereas switching was more highly correlated than clustering with the number of words generated on phonemic fluency. On semantic fluency, younger participants generated more words and switched more frequently than older participants; on phonemic fluency, older participants produced larger clusters than younger participants. In Experiment 2, among 22 young adults, divided attention decreased the number of words generated and decreased switching on phonemic fluency only. Overall, findings suggest that clustering and switching are dissociable fluency components and that switching is related to frontal-lobe functioning.
TL;DR: It is suggested that differences in functional status can be statistically significant but below the threshold at which patients notice a difference in themselves relative to others; an awareness of the smallest difference in walking distance that is noticeable to patients may help clinicians interpret the effectiveness of symptomatic treatments for COPD.
Abstract: Functional status measurements are often difficult to interpret because small differences may be statistically significant but not clinically significant. How much does the Six Minute Walk test (6MW) need to differ to signify a noticeable difference in walking ability for patients with chronic obstructive pulmonary disease (COPD)? We studied individuals with stable COPD (n = 112, mean age = 67 yr, mean FEV1 = 975 ml) and estimated the smallest difference in 6MW distances that was associated with a noticeable difference in patients' subjective comparison ratings of their walking ability. We found that the 6MW was significantly correlated with patients' ratings of their walking ability relative to other patients (r = 0.59, 95% confidence interval [CI]: 0.54 to 0.63). Distances needed to differ by 54 m for the average patient to stop rating themselves as "about the same" and start rating themselves as either "a little bit better" or "a little bit worse" (95% CI: 37 to 71 m). We suggest that differences in functional status can be statistically significant but below the threshold at which patients notice a difference in themselves relative to others; an awareness of the smallest difference in walking distance that is noticeable to patients may help clinicians interpret the effectiveness of symptomatic treatments for COPD.
TL;DR: Biophysical studies suggest that partly folded intermediates are involved in fibrillogenesis, and this may be relevant to amyloidosis generally.
Abstract: Tissue deposition of soluble proteins as amyloid fibrils underlies a range of fatal diseases. The two naturally occurring human lysozyme variants are both amyloidogenic, and are shown here to be unstable. They aggregate to form amyloid fibrils with transformation of the mainly helical native fold, observed in crystal structures, to the amyloid fibril cross-beta fold. Biophysical studies suggest that partly folded intermediates are involved in fibrillogenesis, and this may be relevant to amyloidosis generally.
TL;DR: The OSATS demonstrates high reliability and construct validity, suggesting that it can effectively measure residents' technical ability outside the operating room using bench model simulations.
Abstract: Background A new approach to testing operative technical skills, the Objective Structured Assessment of Technical Skill (OSATS), formally assesses discrete segments of surgical tasks using bench model simulations. This study examines the interstation reliability and construct validity of a large-scale administration of the OSATS. Methods A 2-hour, eight-station OSATS was administered to 48 general surgery residents. Residents were assessed at each station by one of 48 surgeons who evaluated the resident using two methods of scoring: task-specific checklists and global rating scales. Results lnterstation reliability was 0.78 for the checklist score, and 0.85 for the global score. Analysis of variance revealed a significant effect of training for both the checklist score, F(3,44) = 20.08, P Conclusions The OSATS demonstrates high reliability and construct validity, suggesting that we can effectively measure residents' technical ability outside the operating room using bench model simulations.
TL;DR: The results suggest that the discoidin-related DDR tyrosine kinases are novel collagen receptors with the potential to control cellular responses to the extracellular matrix.
TL;DR: Detailed flow cytometric analysis of the marrow of highly engrafted mice demonstrated both lymphoid and myeloid differentiation, as well as the retention of a significant fraction of CD34(+) CD38(-) cells, which should be useful for identification of the cellular and molecular mechanisms that regulate primitive human hematopoietic cells.
Abstract: The purification of primitive human hematopoietic stem cells has been impaired by the absence of repopulation assays. By using a stringent two-step strategy involving depletion of lineage-positive cells followed by fluorescence-activated cell sorting, we have purified a cell population that is highly enriched for cells capable of multilineage repopulation in nonobese diabetic/severe combined immunodeficient (NOD/SCID) recipients. These SCID-repopulating cells (SRCs) were exclusively found in a cell fraction that expressed high levels of CD34 and no CD38. Through limiting dilution analysis using Poisson statistics, we calculated a frequency of 1 SRC in 617 CD34+ CD38− cells. The highly purified SRC were capable of extensive proliferation in NOD/SCID mice. Mice transplanted with 1 SRC (at limiting cell doses) were able to produce approximately 400,000 progeny 6 weeks after the transplant. Detailed flow cytometric analysis of the marrow of highly engrafted mice demonstrated both lymphoid and myeloid differentiation, as well as the retention of a significant fraction of CD34+ CD38− cells. These highly purified fractions should be useful for identification of the cellular and molecular mechanisms that regulate primitive human hematopoietic cells. Moreover, the ability to detect and purify primitive cells provides a means to develop conditions for maintaining and/or expanding these cells during in vitro culture.
TL;DR: It is demonstrated that cells lacking Flk1 are unable to reach the correct location to form blood islands, suggesting that FlK1 is involved in the movement of cells from the posterior primitive streak to the yolk sac and, possibly, to the intraembryonic sites of early hematopoiesis.