Showing papers by "McGill University published in 1999"

Functional Characterization of the S. cerevisiae Genome by Gene Deletion and Parallel Analysis

Abstract: The functions of many open reading frames (ORFs) identified in genome-sequencing projects are unknown. New, whole-genome approaches are required to systematically determine their function. A total of 6925 Saccharomyces cerevisiae strains were constructed, by a high-throughput strategy, each with a precise deletion of one of 2026 ORFs (more than one-third of the ORFs in the genome). Of the deleted ORFs, 17 percent were essential for viability in rich medium. The phenotypes of more than 500 deletion strains were assayed in parallel. Of the deletion strains, 40 percent showed quantitative growth defects in either rich or minimal medium.

Bone marrow as a potential source of hepatic oval cells.

Abstract: Bone marrow stem cells develop into hematopoietic and mesenchymal lineages but have not been known to participate in production of hepatocytes, biliary cells, or oval cells during liver regeneration. Cross-sex or cross-strain bone marrow and whole liver transplantation were used to trace the origin of the repopulating liver cells. Transplanted rats were treated with 2-acetylaminofluorene, to block hepatocyte proliferation, and then hepatic injury, to induce oval cell proliferation. Markers for Y chromosome, dipeptidyl peptidase IV enzyme, and L21-6 antigen were used to identify liver cells of bone marrow origin. From these cells, a proportion of the regenerated hepatic cells were shown to be donor-derived. Thus, a stem cell associated with the bone marrow has epithelial cell lineage capability.

eIF4 Initiation Factors: Effectors of mRNA Recruitment to Ribosomes and Regulators of Translation

Abstract: ▪ Abstract Eukaryotic translation initiation factor 4F (eIF4F) is a protein complex that mediates recruitment of ribosomes to mRNA. This event is the rate-limiting step for translation under most circumstances and a primary target for translational control. Functions of the constituent proteins of eIF4F include recognition of the mRNA 5′ cap structure (eIF4E), delivery of an RNA helicase to the 5′ region (eIF4A), bridging of the mRNA and the ribosome (eIF4G), and circularization of the mRNA via interaction with poly(A)-binding protein (eIF4G). eIF4 activity is regulated by transcription, phosphorylation, inhibitory proteins, and proteolytic cleavage. Extracellular stimuli evoke changes in phosphorylation that influence eIF4F activity, especially through the phosphoinositide 3-kinase (PI3K) and Ras signaling pathways. Viral infection and cellular stresses also affect eIF4F function. The recent determination of the structure of eIF4E at atomic resolution has provided insight about how translation is initiat...

Increased insulin sensitivity and obesity resistance in mice lacking the protein tyrosine phosphatase-1B gene.

Abstract: Protein tyrosine phosphatase–1B (PTP-1B) has been implicated in the negative regulation of insulin signaling. Disruption of the mouse homolog of the gene encoding PTP-1B yielded healthy mice that, in the fed state, had blood glucose concentrations that were slightly lower and concentrations of circulating insulin that were one-half those of their PTP-1B+/+ littermates. The enhanced insulin sensitivity of the PTP-1B−/− mice was also evident in glucose and insulin tolerance tests. The PTP-1B−/− mice showed increased phosphorylation of the insulin receptor in liver and muscle tissue after insulin injection in comparison to PTP-1B+/+ mice. On a high-fat diet, the PTP-1B−/− and PTP-1B+/− mice were resistant to weight gain and remained insulin sensitive, whereas the PTP-1B+/+ mice rapidly gained weight and became insulin resistant. These results demonstrate that PTP-1B has a major role in modulating both insulin sensitivity and fuel metabolism, thereby establishing it as a potential therapeutic target in the treatment of type 2 diabetes and obesity.

The American College of Rheumatology nomenclature and case definitions for neuropsychiatric lupus syndromes

Abstract: OBJECTIVE To develop a standardized nomenclature system for the neuropsychiatric syndromes of systemic lupus erythematosus (NPSLE). METHODS An international, multidisciplinary committee representing rheumatology, neurology, psychiatry, neuropsychology, and hematology developed case definitions, reporting standards, and diagnostic testing recommendations. Before and after the meeting, clinician committee members assigned diagnoses to sets of vignettes randomly generated from a pool of 108 NPSLE patients. To assess whether the nomenclature system improved diagnostic agreement, a consensus index was developed and pre- and postmeeting scores were compared by t-tests. RESULTS Case definitions including diagnostic criteria, important exclusions, and methods of ascertainment were developed for 19 NPSLE syndromes. Recommendations for standard reporting requirements, minimum laboratory evaluation, and imaging techniques were formulated. A short neuropsychological test battery for the diagnosis of cognitive deficits was proposed. In the postmeeting exercise, a statistically significant improvement in diagnostic agreement was observed. CONCLUSION The American College of Rheumatology (ACR) Nomenclature for NPSLE provides case definitions for 19 neuropsychiatric syndromes seen in SLE, with reporting standards and recommendations for laboratory and imaging tests. It is intended to facilitate and enhance clinical research, particularly multicenter studies, and reporting. In clinical settings, consultation with other specialists may be required. It should be useful for didactic purposes but should not be used uncritically or as a substitute for a clinical diagnosis. The complete case definitions are available on the ACR World Wide Web site: http://www.rheumatology .org/ar/ar.html.

Nongenomic Transmission Across Generations of Maternal Behavior and Stress Responses in the Rat

Abstract: In the rat, variations in maternal care appear to influence the development of behavioral and endocrine responses to stress in the offspring. The results of cross-fostering studies reported here provide evidence for (i) a causal relationship between maternal behavior and stress reactivity in the offspring and (ii) the transmission of such individual differences in maternal behavior from one generation of females to the next. Moreover, an environmental manipulation imposed during early development that alters maternal behavior can then affect the pattern of transmission in subsequent generations. Taken together, these findings indicate that variations in maternal care can serve as the basis for a nongenomic behavioral transmission of individual differences in stress reactivity across generations.

Endotoxin-tolerant Mice Have Mutations in Toll-like Receptor 4 (Tlr4)

Abstract: Bacterial lipopolysaccharide (LPS) provokes a vigorous, generalized proinflammatory state in the infected host. Genetic regulation of this response has been localized to the Lps locus on mouse chromosome 4, through study of the C3H/HeJ and C57BL/10ScCr inbred strains. Both C3H/HeJ and C57BL/10ScCr mice are homozygous for a mutant Lps allele (Lpsd/d) that confers hyporesponsiveness to LPS challenge, and therefore exhibit natural tolerance to its lethal effects. Genetic and physical mapping of 1,345 backcross progeny segregating this mutant phenotype confined Lps to a 0.9-cM interval spanning 1.7 Mb. Three transcription units were identified within the candidate interval, including Toll-like receptor 4 (Tlr4), part of a protein family with members that have been implicated in LPS-induced cell signaling. C3H/HeJ mice have a point mutation within the coding region of the Tlr4 gene, resulting in a nonconservative substitution of a highly conserved proline by histidine at codon 712, whereas C57BL/ 10ScCr mice exhibit a deletion of Tlr4. Identification of distinct mutations involving the same gene at the Lps locus in two different hyporesponsive inbred mouse strains strongly supports the hypothesis that altered Tlr4 function is responsible for endotoxin tolerance.

Charged AdS black holes and catastrophic holography

Abstract: We compute the properties of a class of charged black holes in anti--de Sitter space-time, in diverse dimensions. These black holes are solutions of consistent Einstein-Maxwell truncations of gauged supergravities, which are shown to arise from the inclusion of rotation in the transverse space. We uncover rich thermodynamic phase structures for these systems, which display classic critical phenomena, including structures isomorphic to the van der Waals--Maxwell liquid-gas system. In that case, the phases are controlled by the universal ``cusp'' and ``swallowtail'' shapes familiar from catastrophe theory. All of the thermodynamics is consistent with field theory interpretations via holography, where the dual field theories can sometimes be found on the world volumes of coincident rotating branes.

Promotion of atrial fibrillation by heart failure in dogs: atrial remodeling of a different sort.

Abstract: Background—Studies of atrial fibrillation (AF) due to atrial tachycardia have provided insights into the remodeling mechanisms by which “AF begets AF” but have not elucidated the substrate that initially supports AF before remodeling occurs. We studied the effects of congestive heart failure (CHF), an entity strongly associated with clinical AF, on atrial electrophysiology in the dog and compared the results with those in dogs subjected to rapid atrial pacing (RAP; 400 bpm) with a controlled ventricular rate (AV block plus ventricular pacemaker at 80 bpm). Methods and Results—CHF induced by 5 weeks of rapid ventricular pacing (220 to 240 bpm) increased the duration of AF induced by burst pacing (from 8±4 seconds in control dogs to 535±82 seconds; P<0.01), similar to the effect of 1 week of RAP (713±300 seconds). In contrast to RAP, CHF did not alter atrial refractory period, refractoriness heterogeneity, or conduction velocity at a cycle length of 360 ms; however, CHF dogs had a substantial increase in th...

Extinction rates of North American freshwater fauna

Abstract: Since 1900, 123 freshwater animal species have been recorded as extinct in North America. Hun- dreds of additional species of fishes, mollusks, crayfishes, and amphibians are considered imperiled. Using an exponential decay model, we derived recent and future extinction rates for North American freshwater fauna that are five times higher than those for terrestrial fauna. Assuming that imperiled freshwater species will not survive throughout the next century, our model projects a future extinction rate of 4% per decade, which sug- gests that North America's temperate freshwater ecosystems are being depleted of species as rapidly as tropi- cal forests.

Regulation of 4E-BP1 phosphorylation: a novel two-step mechanism

Abstract: The multisubunit eukaryotic translation initiation factor (eIF) 4F recruits 40S ribosomal subunits to the 5′ end of mRNA. The eIF4F subunit eIF4E interacts directly with the mRNA 5′ cap structure. Assembly of the eIF4F complex is inhibited by a family of repressor polypeptides, the eIF4E-binding proteins (4E-BPs). Binding of the 4E-BPs to eIF4E is regulated by phosphorylation: Hypophosphorylated 4E-BP isoforms interact strongly with eIF4E, whereas hyperphosphorylated isoforms do not. 4E-BP1 is hypophosphorylated in quiescent cells, but is hyperphosphorylated on multiple sites following exposure to a variety of extracellular stimuli. The PI3-kinase/Akt pathway and the kinase FRAP/mTOR signal to 4E-BP1. FRAP/mTOR has been reported to phosphorylate 4E-BP1 directly in vitro. However, it is not known if FRAP/mTOR is responsible for the phosphorylation of all 4E-BP1 sites, nor which sites must be phosphorylated to release 4E-BP1 from eIF4E. To address these questions, a recombinant FRAP/mTOR protein and a FRAP/mTOR immunoprecipitate were utilized in in vitro kinase assays to phosphorylate 4E-BP1. Phosphopeptide mapping of the in vitro-labeled protein yielded two 4E-BP1 phosphopeptides that comigrated with phosphopeptides produced in vivo. Mass spectrometry analysis indicated that these peptides contain phosphorylated Thr-37 and Thr-46. Thr-37 and Thr-46 are efficiently phosphorylated in vitro by FRAP/mTOR when 4E-BP1 is bound to eIF4E. However, phosphorylation at these sites was not associated with a loss of eIF4E binding. Phosphorylated Thr-37 and Thr-46 are detected in all phosphorylated in vivo 4E-BP1 isoforms, including those that interact with eIF4E. Finally, mutational analysis demonstrated that phosphorylation of Thr-37/Thr-46 is required for subsequent phosphorylation of several carboxy-terminal serum-sensitive sites. Taken together, our results suggest that 4E-BP1 phosphorylation by FRAP/mTOR on Thr-37 and Thr-46 is a priming event for subsequent phosphorylation of the carboxy-terminal serum-sensitive sites.

Phenotypic Evolution — A Reaction Norm Perspective

Abstract: Every biologist interested in evolutionary biology should read this book. In a highly readable manner Schlichting and Pigliucci outline the present status of thinking on the importance of reaction norms in phenotypic evolution. The book has one central purpose, to propose and defend the proposition that to understand phenotypic evolution we must take into account phenotypic plasticity, not simply as an interesting peripheral phenomenon but as an integral part of the evolutionary process. Although I am already strongly biassed in this direction, I think that the authors produce an extremely strong case which should encourage more research in this fast- developing area. One of the great strengths of this book is that it presents an historical perspective, an assessment of the present state of thinking, and, the authors' own opinions on where future research should be directed.

Development of a multiple sclerosis functional composite as a clinical trial outcome measure

Abstract: The primary clinical outcome measure for evaluating multiple sclerosis in clinical trials has been Kurtzke's expanded disability status scale (EDSS). New therapies appear to favourably impact the course of multiple sclerosis and render continued use of placebo control groups more difficult. Consequently, future trials are likely to compare active treatment groups which will most probably require increased sample sizes in order to detect therapeutic efficacy. Because more responsive outcome measures will be needed for active arm comparison studies, the National Multiple Sclerosis Society's Advisory Committee on Cinical Trials of New Agents in Multiple Sclerosis appointed a Task Force that was charged with developing improved clinical outcome measures. This Task Force acquired contemporary clinical trial and historical multiple sclerosis data for meta-analyses of primary and secondary outcome assessments to provide a basis for recommending a new outcome measure. A composite measure encompassing the major clinical dimensions of arm, leg and cognitive function was identified and termed the multiple sclerosis functional composite (MSFC). The MSFC consists of three objective quantitative tests of neurological function which are easy to administer. Change in this MSFC over the first year of observation predicted subsequent change in the EDSS, suggesting that the MSFC is more sensitive to change than the EDSS. This paper provides details concerning the development and testing of the MSFC.

Encapsulation in the food industry: a review

Abstract: Encapsulation involves the incorporation of food ingredients, enzymes, cells or other materials in small capsules. Applications for this technique have increased in the food industry since the encapsulated materials can be protected from moisture, heat or other extreme conditions, thus enhancing their stability and maintaining viability. Encapsulation in foods is also utilized to mask odours or tastes. Various techniques are employed to form the capsules, including spray drying, spray chilling or spray cooling, extrusion coating, fluidized bed coating, liposome entrapment, coacervation, inclusion complexation, centrifugal extrusion and rotational suspension separation. Each of these techniques is discussed in this review. A wide variety of foods is encapsulated--flavouring agents, acids bases, artificial sweeteners, colourants, preservatives, leavening agents, antioxidants, agents with undesirable flavours, odours and nutrients, among others. The use of encapsulation for sweeteners such as aspartame and flavours in chewing gum is well known. Fats, starches, dextrins, alginates, protein and lipid materials can be employed as encapsulating materials. Various methods exist to release the ingredients from the capsules. Release can be site-specific, stage-specific or signalled by changes in pH, temperature, irradiation or osmotic shock. In the food industry, the most common method is by solvent-activated release. The addition of water to dry beverages or cake mixes is an example. Liposomes have been applied in cheese-making, and its use in the preparation of food emulsions such as spreads, margarine and mayonnaise is a developing area. Most recent developments include the encapsulation of foods in the areas of controlled release, carrier materials, preparation methods and sweetener immobilization. New markets are being developed and current research is underway to reduce the high production costs and lack of food-grade materials.

The Tyrosine Kinase Negative Regulator c-Cbl as a RING-Type, E2-Dependent Ubiquitin-Protein Ligase

Abstract: Ubiquitination of receptor protein-tyrosine kinases (RPTKs) terminates signaling by marking active receptors for degradation. c-Cbl, an adapter protein for RPTKs, positively regulates RPTK ubiquitination in a manner dependent on its variant SRC homology 2 (SH2) and RING finger domains. Ubiquitin-protein ligases (or E3s) are the components of ubiquitination pathways that recognize target substrates and promote their ligation to ubiquitin. The c-Cbl protein acted as an E3 that can recognize tyrosine-phosphorylated substrates, such as the activated platelet-derived growth factor receptor, through its SH2 domain and that recruits and allosterically activates an E2 ubiquitin-conjugating enzyme through its RING domain. These results reveal an SH2-containing protein that functions as a ubiquitin-protein ligase and thus provide a distinct mechanism for substrate targeting in the ubiquitin system.

PRIMARY CONSUMER δ13C AND δ15N AND THE TROPHIC POSITION OF AQUATIC CONSUMERS

Abstract: Stable nitrogen isotope signatures (δ15N) are increasingly used to infer the trophic position of consumers in food web studies. Interpreting the δ15N of consumers relative to the δ15N characterizing the base of the food web provides a time-integrated measure of trophic position. We use primary consumers (trophic level 2) as baseline indicator organisms and investigate the variation in baseline δ15N values in 14 lakes in Ontario and Quebec. Values of δ15N ranged from −2 to +9‰ and varied significantly as a function of lake habitat (mean littoral = 1.6‰, pelagic = 3.1‰, profundal = 5.2 ‰). Stable carbon isotopic signatures (δ13C) of primary consumers decreased along this same habitat gradient (mean littoral = −23.8‰, pelagic = −28.4‰, profundal = −30.5‰). Primary consumer δ13C and a categorical lake variable explained 72% of the variability in primary consumer δ15N. This relationship was corroborated by primary consumer δ15N and δ13C data from the literature, indicating that habitat-specific variation in ba...

From the gate to the neuromatrix.

Abstract: The gate control theory's most important contribution to understanding pain was its emphasis on central neural mechanisms. The theory forced the medical and biological sciences to accept the brain as an active system that filters, selects and modulates inputs. The dorsal horns, too, were not merely passive transmission stations but sites at which dynamic activities (inhibition, excitation and modulation) occurred. The great challenge ahead of us is to understand brain function. I have therefore proposed that the brain possesses a neural network--the body-self neuromatrix--which integrates multiple inputs to produce the output pattern that evokes pain. The body-self neuromatrix comprises a widely distributed neural network that includes parallel somatosensory, limbic and thalamocortical components that subserve the sensory-discriminative. affective-motivational and evaluative-cognitive dimensions of pain experience. The synaptic architecture of the neuromatrix is determined by genetic and sensory influences. The 'neurosignature' output of the neuromatrix--patterns of nerve impulses of varying temporal and spatial dimensions--is produced by neural programs genetically build into the neuromatrix and determines the particular qualities and other properties of the pain experience and behavior. Multiple inputs that act on the neuromatrix programs and contribute to the output neurosignature include. (1) sensory inputs (cutaneous, visceral and other somatic receptors); (2) visual and other sensory inputs that influence the cognitive interpretation of the situation; (3) phasic and tonic cognitive and emotional inputs from other areas of the brain; (4) intrinsic neural inhibitory modulation inherent in all brain function; (5) the activity of the body's stress-regulation systems, including cytokines as well as the endocrine, autonomic, immune and opioid systems. We have traveled a long way from the psychophysical concept that seeks a simple one-to-one relationship between injury and pain. We now have a theoretical framework in which a genetically determined template for the body-self is modulated by the powerful stress system and the cognitive functions of the brain, in addition to the traditional sensory inputs.

Holography, thermodynamics, and fluctuations of charged AdS black holes

Abstract: The physical properties of Reissner-Nordstrom black holes in (n11)-dimensional anti-de Sitter spacetime are related, by a holographic map, to the physics of a class of n-dimensional field theories coupled to a background global current. Motivated by that fact, and the recent observations of the striking similarity between the thermodynamic phase structure of these black holes ~in the canonical ensemble! and that of the van der Waals-Maxwell liquid-gas system, we explore the physics in more detail. We study fluctuations and stability within the equilibrium thermodynamics, examining the specific heats and electrical permittivity of the holes, and consider the analogue of the Clayperon equation at the phase boundaries. Consequently, we refine the phase diagrams in the canonical and grand canonical ensembles. We study the interesting physics in the neighborhood of the critical point in the canonical ensemble. There is a second order phase transition found there, and that region is characterized by a Landau-Ginzburg model with A3 potential. The holographically dual field theories provide the description of the microscopic degrees of freedom which underlie all of the thermodynamics, as can be seen by examining the form of the microscopic fluctuations. @S0556-2821~99!06820-4#

Stable isotope evidence for the food web consequences of species invasions in lakes

Abstract: Species invasions pose a serious threat to biodiversity and native ecosystems1,2; however, predicting and quantifying the impacts of invasive species has proven problematic3,4,5,6. Here we use stable isotope ratios to document the food-web consequences of the invasion of two non-native predators, smallmouth bass and rock bass, into Canadian lakes. Invaded lakes had lower littoral prey-fish diversity and abundance than uninvaded reference lakes. Consistent with this difference, lake trout from invaded lakes had more negative δ13C values (-29.2‰ versus -27.4‰) and reduced trophic positions (3.3 versus 3.9) than those from reference lakes, indicating differences in food-web structure. Furthermore, a comparison of the pre- and post-invasion food webs of two recently invaded lakes showed that invasion was followed by substantial declines in littoral prey-fish abundance and the trophic position of lake trout, reflecting a shift in the diet of lake trout towards zooplankton and reduced dependence on littoral fish. This study demonstrates the use of stable isotope techniques to detect changes in food-web structure following perturbations; in this instance, bass-induced food-web shifts may have severe consequences for native species and ecosystems.

Surface terms as counterterms in the AdS-CFT correspondence

Abstract: We examine the recently proposed technique of adding boundary counterterms to the gravitational action for spacetimes which are locally asymptotic to anti--de Sitter spacetimes. In particular, we explicitly identify higher order counterterms, which allow us to consider spacetimes of dimensions $dl~7.$ As the counterterms eliminate the need of ``background subtraction'' in calculating the action, we apply this technique to study examples where the appropriate background was ambiguous or unknown: topological black holes, Taub-NUT-AdS and Taub-Bolt-AdS. We also identify certain cases where the covariant counterterms fail to render the action finite, and we comment on the dual field theory interpretation of this result. In some examples, the case of a vanishing cosmological constant may be recovered in a limit, which allows us to check results and resolve ambiguities in certain asymptotically flat spacetime computations in the literature.

Inbreeding depression in the wild

Abstract: Despite its practical application in conservation biology and evolutionary theory, the cost of inbreeding in natural populations of plants and animals remains to a large degree unknown. In this review we have gathered estimates of inbreeding depression (d) from the literature for wild species monitored in the field. We have also corrected estimates of d by dividing by F (coeAcient of inbreeding), to take into account the influence that the variation in F will have on d. Our data set includes seven bird species, nine mammal species, four species of poikilotherms (snakes, fish and snails) and 15 plant species. In total we obtained 169 estimates of inbreeding depression for 137 traits; 81 of those estimates included estimates of F. We compared our mammalian data (limited to those traits related to juvenile mortality) to the estimates for captive zoo species published by Ralls et al. (1988) to determine if, as predicted from the literature, natural estimates of inbreeding depression are higher than captive estimates. The mean d a SE (significantly diAerent from zero and not corrected for F) for homeotherms was 0.509 a 0.081; for poikilotherms, 0.201 a 0.039; and for plants, 0.331 a 0.038. Levels of inbreeding depression this high in magnitude will be biologically important under natural conditions. When we limited our data set to mortality traits for mammals and corrected for Fa0.25 (as is the case for the Ralls et al. data set), we found a significant diAerence between the two data sets; wild estimates had a substantially higher mean cost of inbreeding at F a 0.25: 2.155 (captive species: 0.314). Of the 169 estimates of d, 90 were significantly diAerent from zero, indicating that inbred wild species measured under natural conditions frequently exhibit moderate to high levels of inbreeding depression in fitness traits.

Development of a functional measure for persons with Alzheimer's disease: the disability assessment for dementia.

Abstract: Objectives This article describes the development of an assessment of functional disability for use with proxy-respondents of community-dwelling persons who have Alzheimer's disease as well as a study testing its reliability. Method Panels composed of health care professionals and caregivers of persons with Alzheimer's disease were used to develop the Disability Assessment for Dementia (DAD). Fifty-nine caregivers participated in the refinement of the content and the testing of reliability. Results The DAD includes 40 items: 17 related to basic self-care and 23 to instrumental activities of daily living. It demonstrated a high degree of internal consistency (Cronbach's alpha = .96) and excellent interrater (N = 31, ICC = .95) and test-retest (N = 45, ICC = .96) reliability. In addition, it was found not to have gender bias. Conclusion This instrument may help clinicians and caregivers of the population with Alzheimer's disease make decisions regarding the choice of suitable interventions.

Outcomes of total hip and knee replacement: preoperative functional status predicts outcomes at six months after surgery.

Abstract: Objective To determine whether patients with knee or hip osteoarthritis (OA) who have worse physical function preoperatively achieve a postoperative status that is similar to that of patients with better preoperative function. Methods This study surveyed an observational cohort of 379 consecutive patients with definite OA who were without other inflammatory joint diseases and were undergoing either total hip or knee replacement in a US (Boston) and a Canadian (Montreal) referral center. Questionnaires on health status (the Short Form 36 and Western Ontario and McMaster Universities Osteoarthritis Index) were administered preoperatively and at 3 and 6 months postoperatively. Physical function and pain due to OA were deemed the most significant outcomes to study. Results Two hundred twenty-two patients returned their questionnaires. Patients in the 2 centers were comparable in age, sex, time to surgery, and proportion of hip/knee surgery. The Boston group had more education, lower comorbidity, and more cemented knee prostheses. Patients undergoing hip or knee replacement in Montreal had lower preoperative physical function and more pain than their Boston counterparts. In patients with lower preoperative physical function, function and pain were not improved postoperatively to the level achieved by those with higher preoperative function. This was most striking in patients undergoing total knee replacement. Conclusion Surgery performed later in the natural history of functional decline due to OA of the knee, and possibly of the hip, results in worse postoperative functional status.

Two Polymorphic Variants of Wild-Type p53 Differ Biochemically and Biologically

Abstract: The wild-type p53 protein exhibits a common polymorphism at amino acid 72, resulting in either a proline residue (p53Pro) or an arginine residue (p53Arg) at this position. Despite the difference that this change makes in the primary structure of the protein resulting in a difference in migration during sodium dodecyl sulfate-polyacrylamide gel electrophoresis, no differences in the biochemical or biological characteristics of these wild-type p53 variants have been reported. We have recently shown that p53Arg is significantly more susceptible than p53Pro to the degradation induced by human papillomavirus (HPV) E6 protein. Moreover, this may result in an increased susceptibility to HPV-induced tumors in homozygous p53Arg individuals. In further investigating the characteristics of these p53 variants, we now show that both forms are morphologically wild type and do not differ in their ability to bind to DNA in a sequence-specific manner. However, there are a number of differences between the p53 variants in their abilities to bind components of the transcriptional machinery, to activate transcription, to induce apoptosis, and to repress the transformation of primary cells. These observations may have implications for the development of cancers which harbor wild-type p53 sequences and possibly for the ability of such tumors to respond to therapy, depending on their p53 genotype.