Showing papers by "Université de Montréal published in 2004"

Genome sequence of the Brown Norway rat yields insights into mammalian evolution

Abstract: The laboratory rat (Rattus norvegicus) is an indispensable tool in experimental medicine and drug development, having made inestimable contributions to human health. We report here the genome sequence of the Brown Norway (BN) rat strain. The sequence represents a high-quality 'draft' covering over 90% of the genome. The BN rat sequence is the third complete mammalian genome to be deciphered, and three-way comparisons with the human and mouse genomes resolve details of mammalian evolution. This first comprehensive analysis includes genes and proteins and their relation to human disease, repeated sequences, comparative genome-wide studies of mammalian orthologous chromosomal regions and rearrangement breakpoints, reconstruction of ancestral karyotypes and the events leading to existing species, rates of variation, and lineage-specific and lineage-independent evolutionary events such as expansion of gene families, orthology relations and protein evolution.

Semi-supervised Learning by Entropy Minimization

Abstract: We consider the semi-supervised learning problem, where a decision rule is to be learned from labeled and unlabeled data. In this framework, we motivate minimum entropy regularization, which enables to incorporate unlabeled data in the standard supervised learning. Our approach includes other approaches to the semi-supervised problem as particular or limiting cases. A series of experiments illustrates that the proposed solution benefits from unlabeled data. The method challenges mixture models when the data are sampled from the distribution class spanned by the generative model. The performances are definitely in favor of minimum entropy regularization when generative models are misspecified, and the weighting of unlabeled data provides robustness to the violation of the "cluster assumption". Finally, we also illustrate that the method can also be far superior to manifold learning in high dimension spaces.

Serum Procalcitonin and C-Reactive Protein Levels as Markers of Bacterial Infection: A Systematic Review and Meta-analysis

Abstract: A meta-analysis was performed to evaluate the accuracy of determination of procalcitonin (PCT) and C-reactive protein (CRP) levels for the diagnosis of bacterial infection. The analysis included published studies that evaluated these markers for the diagnosis of bacterial infections in hospitalized patients. PCT level was more sensitive (88% [95% confidence interval [CI], 80%-93%] vs. 75% [95% CI, 62%-84%]) and more specific (81% [95% CI, 67%-90%] vs. 67% [95% CI, 56%-77%]) than CRP level for differentiating bacterial from noninfective causes of inflammation. The Q value for PCT markers was higher (0.82 vs. 0.73). The sensitivity for differentiating bacterial from viral infections was also higher for PCT markers (92% [95% CI, 86%-95%] vs. 86% [95% CI, 65%-95%]); the specificities were comparable (73% [95% CI, 42%-91%] vs. 70% [95% CI, 19%-96%]). The Q value was higher for PCT markers (0.89 vs. 0.83). PCT markers also had a higher positive likelihood ratio and lower negative likelihood ratio than did CRP markers in both groups. On the basis of this analysis, the diagnostic accuracy of PCT markers was higher than that of CRP markers among patients hospitalized for suspected bacterial infections.

Glutaraldehyde: behavior in aqueous solution, reaction with proteins, and application to enzyme crosslinking.

Abstract: Glutaraldehyde possesses unique characteristics that render it one of the most effective protein crosslinking reagents. It can be present in at least 13 different forms depending on solution conditions such as pH, concentration, temperature, etc. Substantial literature is found concerning the use of glutaraldehyde for protein immobilization, yet there is no agreement about the main reactive species that participates in the crosslinking process because monomeric and polymeric forms are in equilibrium. Glutaraldehyde may react with proteins by several means such as aldol condensation or Michael-type addition, and we show here 8 different reactions for various aqueous forms of this reagent. As a result of these discrepancies and the unique characteristics of each enzyme, crosslinking procedures using glutaraldehyde are largely developed through empirical observation. The choice of the enzyme-glutaraldehyde ratio, as well as their final concentration, is critical because insolubilization of the enzyme must result in minimal distortion of its structure in order to retain catalytic activity. The purpose of this paper is to give an overview of glutaraldehyde as a crosslinking reagent by describing its structure and chemical properties in aqueous solution in an attempt to explain its high reactivity toward proteins, particularly as applied to the production of insoluble enzymes.

Cutting Edge: 1,25-dihydroxyvitamin D3 Is a Direct Inducer of Antimicrobial Peptide Gene Expression

Abstract: The hormonal form of vitamin D3, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), is an immune system modulator and induces expression of the TLR coreceptor CD14. 1,25(OH)2D3 signals through the vitamin D receptor, a ligand-stimulated transcription factor that recognizes specific DNA sequences called vitamin D response elements. In this study, we show that 1,25(OH)2D3 is a direct regulator of antimicrobial innate immune responses. The promoters of the human cathelicidin antimicrobial peptide (camp) and defensin β2 (defB2) genes contain consensus vitamin D response elements that mediate 1,25(OH)2D3-dependent gene expression. 1,25(OH)2D3 induces antimicrobial peptide gene expression in isolated human keratinocytes, monocytes and neutrophils, and human cell lines, and 1,25(OH)2D3 along with LPS synergistically induce camp expression in neutrophils. Moreover, 1,25(OH)2D3 induces corresponding increases in antimicrobial proteins and secretion of antimicrobial activity against pathogens including Pseudomonas aeruginosa. 1,25(OH)2D3 thus directly regulates antimicrobial peptide gene expression, revealing the potential of its analogues in treatment of opportunistic infections.

Long-Term Efficacy of Zoledronic Acid for the Prevention of Skeletal Complications in Patients With Metastatic Hormone-Refractory Prostate Cancer

Abstract: In a placebo-controlled randomized clinical trial, zoledronic acid (4 mg via a 15-minute infusion every 3 weeks for 15 months) reduced the incidence of skeletal-related events (SREs) in men with hormone-refractory metastatic prostate cancer. Among 122 patients who completed a total of 24 months on study, fewer patients in the 4-mg zoledronic acid group than in the placebo group had at least one SRE (38% versus 49%, difference = -11.0%, 95% confidence interval [CI] = -20.2% to -1.3%; P =.028), and the annual incidence of SREs was 0.77 for the 4-mg zoledronic acid group versus 1.47 for the placebo group (P=.005). The median time to the first SRE was 488 days for the 4-mg zoledronic acid group versus 321 days for the placebo group (P =.009). Compared with placebo, 4 mg of zoledronic acid reduced the ongoing risk of SREs by 36% (risk ratio = 0.64, 95% CI = 0.485 to 0.845; P =.002). Patients in the 4-mg zoledronic acid group had a lower incidence of SREs than did patients in the placebo group, regardless of whether they had an SRE prior to entry in the study. Long-term treatment with 4 mg of zoledronic acid is safe and provides sustained clinical benefits for men with metastatic hormone-refractory prostate cancer.

Rivastigmine for Dementia Associated with Parkinson's Disease

Abstract: background Cholinergic deficits are prominent in patients who have dementia associated with Parkinson’s disease. We investigated the effects of the dual cholinesterase inhibitor rivastigmine in such patients. methods Patients in whom mild-to-moderate dementia developed at least 2 years after they received a clinical diagnosis of Parkinson’s disease were randomly assigned to receive placebo or 3 to 12 mg of rivastigmine per day for 24 weeks. Primary efficacy variables were the scores for the cognitive subscale of the Alzheimer’s Disease Assessment Scale (ADAS-cog) and Alzheimer’s Disease Cooperative Study–Clinician’s Global Impression of Change (ADCS-CGIC). Secondary clinical outcomes were the scores for the Alzheimer’s Disease Cooperative Study–Activities of Daily Living, the 10-item Neuropsychiatric Inventory, the Mini–Mental State Examination, Cognitive Drug Research power of attention tests, the Verbal Fluency test, and the Ten Point Clock-Drawing test. results A total of 541 patients were enrolled, and 410 completed the study. The outcomes were better among patients treated with rivastigmine than among those who received placebo; however, the differences between these two groups were moderate and similar to those reported in trials of rivastigmine for Alzheimer’s disease. Rivastigmine-treated patients had a mean improvement of 2.1 points in the score for the 70-point ADAS-cog, from a baseline score of 23.8, as compared with a 0.7-point worsening in the placebo group, from a baseline score of 24.3 (P<0.001). Clinically meaningful improvements in the scores for the ADCS-CGIC were observed in 19.8 percent of patients in the rivastigmine group and 14.5 percent of those in the placebo group, and clinically meaningful worsening was observed in 13.0 percent and 23.1 percent, respectively (mean score at 24 weeks, 3.8 and 4.3, respectively; P=0.007). Significantly better outcomes were seen with rivastigmine with respect to all secondary efficacy variables. The most frequent adverse events were nausea (affecting 29.0 percent of patients in the rivastigmine group and 11.2 percent of those in the placebo group, P<0.001), vomiting (16.6 and 1.7 percent, P<0.001), and tremor (10.2 and 3.9 percent, P=0.01). conclusions In this placebo-controlled study, rivastigmine was associated with moderate improvements in dementia associated with Parkinson’s disease but also with higher rates of nausea, vomiting, and tremor.

The Collaborative Cross, a community resource for the genetic analysis of complex traits

Abstract: The goal of the Complex Trait Consortium is to promote the development of resources that can be used to understand, treat and ultimately prevent pervasive human diseases. Existing and proposed mouse resources that are optimized to study the actions of isolated genetic loci on a fixed background are less effective for studying intact polygenic networks and interactions among genes, environments, pathogens and other factors. The Collaborative Cross will provide a common reference panel specifically designed for the integrative analysis of complex systems and will change the way we approach human health and disease.

Physical Aggression During Early Childhood: Trajectories and Predictors

Abstract: Objectives. Physical aggression in children is a major public health problem. Not only is childhood physical aggression a precursor of the physical and mental health problems that will be visited on victims, but also aggressive children themselves are at higher risk of alcohol and drug abuse, accidents, violent crimes, depression, suicide attempts, spouse abuse, and neglectful and abusive parenting. Furthermore, violence commonly results in serious injuries to the perpetrators themselves. Although it is unusual for young children to harm seriously the targets of their physical aggression, studies of physical aggression during infancy indicate that by 17 months of age, the large majority of children are physically aggressive toward siblings, peers, and adults. This study aimed, first, to identify the trajectories of physical aggression during early childhood and, second, to identify antecedents of high levels of physical aggression early in life. Such antecedents could help to understand better the developmental origins of violence later in life and to identify targets for preventive interventions. Methods. A random population sample of 572 families with a 5-month-old newborn was recruited. Assessments of physical aggression frequency were obtained from mothers at 17, 30, and 42 months after birth. Using a semiparametric, mixture model, distinct clusters of physical aggression trajectories were identified. Multivariate logit regression analysis was then used to identify which family and child characteristics, before 5 months of age, predict individuals on a high-level physical aggression trajectory from 17 to 42 months after birth. Results. Three trajectories of physical aggression were identified. The first was composed of children who displayed little or no physical aggression. These individuals were estimated to account for ∼28% of the sample. The largest group, estimated at ∼58% of the sample, followed a rising trajectory of modest aggression. Finally, a group, estimated to comprise ∼14% of the sample, followed a rising trajectory of high physical aggression. Best predictors before or at birth of the high physical aggression trajectory group, controlling for the levels of the other risk factors, were having young siblings (odds ratio [OR]: 4.00; confidence interval [CI]: 2.2–7.4), mothers with high levels of antisocial behavior before the end of high school (OR: 3.1; CI: 1.1–8.6), mothers who started having children early (OR: 3.1; CI: 1.4–6.8), families with low income (OR: 2.6; CI: 1.3–5.2), and mothers who smoked during pregnancy (OR: 2.2; CI: 1.1–4.1). Best predictors at 5 months of age were mothers’ coercive parenting behavior (OR: 2.3; CI: 1.1–4.7) and family dysfunction (OR: 2.2; CI: 1.2–4.1). The OR for a high-aggression trajectory was 10.9 for children whose mother reported both high levels of antisocial behavior and early childbearing. Conclusions. Most children have initiated the use of physical aggression during infancy, and most will learn to use alternatives in the following years before they enter primary school. Humans seem to learn to regulate the use of physical aggression during the preschool years. Those who do not, seem to be at highest risk of serious violent behavior during adolescence and adulthood. Results from the present study indicate that children who are at highest risk of not learning to regulate physical aggression in early childhood have mothers with a history of antisocial behavior during their school years, mothers who start childbearing early and who smoke during pregnancy, and parents who have low income and have serious problems living together. All of these variables are relatively easy to measure during pregnancy. Preventive interventions should target families with high-risk profiles on these variables. Experiments with such programs have shown long-term impacts on child abuse and child antisocial behavior. However, these impacts were not observed in families with physical violence. The problem may be that the prevention programs that were provided did not specifically target the parents’ control over their physical aggression and their skills in teaching their infant not to be physically aggressive. Most intervention programs to prevent youth physical aggression have targeted school-age children. If children normally learn not to be physically aggressive during the preschool years, then one would expect that interventions that target infants who are at high risk of chronic physical aggression would have more of an impact than interventions 5 to 10 years later, when physical aggression has become a way of life.

Reactive Oxygen Species, Vascular Oxidative Stress, and Redox Signaling in Hypertension What Is the Clinical Significance?

Abstract: Metabolism of oxygen by cells generates potentially deleterious reactive oxygen species (ROS). Under normal conditions the rate and magnitude of oxidant formation is balanced by the rate of oxidant elimination. However, an imbalance between prooxidants and antioxidants results in oxidative stress, which is the pathogenic outcome of oxidant overproduction that overwhelms the cellular antioxidant capacity. The kidney and vasculature are rich sources of NADPH oxidase-derived ROS, which under pathological conditions play an important role in renal dysfunction and vascular damage. Strong experimental evidence indicates that increased oxidative stress and associated oxidative damage are mediators of renovascular injury in cardiovascular pathologies. Increased production of superoxide anion and hydrogen peroxide, reduced nitric oxide synthesis, and decreased bioavailability of antioxidants have been demonstrated in experimental and human hypertension. These findings have evoked considerable interest because of the possibilities that therapies targeted against free radicals by decreasing ROS generation or by increasing nitric oxide availability and antioxidants may be useful in minimizing vascular injury and renal dysfunction and thereby prevent or regress hypertensive end-organ damage. This article highlights current developments in the field of ROS and hypertension, focusing specifically on the role of oxidative stress in hypertension-associated vascular damage. In addition, recent clinical trials investigating cardiovascular benefits of antioxidants are discussed, and some explanations for the rather disappointing results from these studies are addressed. Finally, important avenues for future research in the field of ROS, oxidative stress, and redox signaling in hypertension are considered.

Dissecting the spatial structure of ecological data at multiple scales

Abstract: Spatial structures may not only result from ecological interactions, they may also play an essential functional role in organizing the interactions. Modeling spatial patterns at multiple spatial and temporal scales is thus a crucial step to understand the functioning of ecological communities. PCNM (principal coordinates of neighbor matrices) analysis achieves a spectral decomposition of the spatial relationships among the sampling sites, creating variables that correspond to all the spatial scales that can be perceived in a given data set. The analysis then finds the scales to which a data table of interest responds. The significant PCNM variables can be directly interpreted in terms of spatial scales, or included in a procedure of variation decomposition with respect to spatial and environmental components. This paper presents four applications of PCNM analysis to ecological data representing combinations of: transect or surface data, regular or irregular sampling schemes, univariate or multivariate data. The data sets include Amazonian ferns, tropical marine zooplankton, chlorophyll in a marine lagoon, and oribatid mites in a peat bog. In each case, new ecological knowledge was obtained through PCNM analysis.

Beneficial Cardiovascular Pleiotropic Effects of Statins

Abstract: Pleiotropic effects of a drug are actions other than those for which the agent was specifically developed. These effects may be related or unrelated to the primary mechanism of action of the drug, and they are usually unanticipated. Pleiotropic effects may be undesirable (such as side effects or toxicity), neutral, or, as is especially the case with HMG-CoA reductase inhibitors (statins), beneficial. Pleiotropic effects of statins include improvement of endothelial dysfunction, increased nitric oxide bioavailability, antioxidant properties, inhibition of inflammatory responses, and stabilization of atherosclerotic plaques. These and several other emergent properties could act in concert with the potent low-density lipoprotein cholesterol-lowering effects of statins to exert early as well as lasting cardiovascular protective effects. Understanding the pleiotropic effects of statins is important to optimize their use in treatment and prevention of cardiovascular disease.

Theorizing the Father-Child Relationship: Mechanisms and Developmental Outcomes

Abstract: The aim of this article is to propose a theorization of the father-child relationship based on our current understanding of attachment, interactions between fathers and their young children, and human-specific adaptations. The comparison of mother-child and father-child interactions suggests that fathers play a particularly important role in the development of children’s openness to the world. Men seem to have a tendency to excite, surprise, and momentarily destabilize children; they also tend to encourage children to take risks, while at the same time ensuring the latter’s safety and security, thus permitting children to learn to be braver in unfamiliar situations, as well as to stand up for themselves. But this dynamic can only be effective in the context of an emotional bond between father and child; this relationship is termed the father-child activation relationship, in contrast to the mother-child attachment relationship aimed at calming and comforting children in times of stress. The activation relationship is developed primarily through physical play. It is postulated, in particular, that father-child rough-and-tumble play encourages obedience and the development of competition skills in children.

Metabolic and Body Composition Factors in Subgroups of Obesity: What Do We Know?

Abstract: Obesity is thought to be a heterogeneous disorder with several possible etiologies; therefore, by examining subtypes of obesity we attempt to understand obesity's heterogeneous nature. The purpose of this review was to investigate the roles of metabolic, body composition, and cardiovascular disease risk in subtypes of obesity. We briefly consider two subtypes of obesity that have been identified in the literature. One subset of individuals, termed the metabolically healthy, but obese (MHO), despite having large amounts of fat mass compared with at risk obese individuals shows a normal metabolic profile, but remarkably normal to high levels of insulin sensitivity. Preliminary evidence suggests that this could be due at least in part to lower visceral fat levels and earlier onset of obesity. A second subset, termed the metabolically obese, but normal weight (MONW), present with normal body mass index, but have significant risk factors for diabetes, metabolic syndrome, and cardiovascular disease, which could be due to higher fat mass and plasma triglycerides as well as higher visceral fat and liver content. We also briefly consider the potential role of adipose and gastrointestinal hormonal profiles in MHO and MONW individuals, which could lead to a better understanding of potential factors that may regulate their body composition. This information will eventually be invaluable in helping us understand factors that predispose to or protect obese individuals from metabolic and cardiovascular disease. Collectively, a greater understanding of the MHO and MONW individual has important implications for therapeutic decision making, the characterization of subjects in research protocols, and medical education.

Roles of G-protein-coupled receptor dimerization.

Abstract: The classical idea that G-protein-coupled receptors (GPCRs) function as monomeric entities has been unsettled by the emerging concept of GPCR dimerization. Recent findings have indicated not only that many GPCRs exist as homodimers and heterodimers, but also that their oligomeric assembly could have important functional roles. Several studies have shown that dimerization occurs early after biosynthesis, suggesting that it has a primary role in receptor maturation. G-protein coupling, downstream signalling and regulatory processes such as internalization have also been shown to be influenced by the dimeric nature of the receptors. In addition to raising fundamental questions about GPCR function, the concept of dimerization could be important in the development and screening of drugs that act through this receptor class. In particular, the changes in ligand-binding and signalling properties that accompany heterodimerization could give rise to an unexpected pharmacological diversity that would need to be considered.

Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist.

Abstract: Objective Recurrent digital ulcers are a manifestation of vascular disease in patients with systemic sclerosis (SSc; scleroderma) and lead to pain, impaired function, and tissue loss. We investigated whether treatment with the endothelin receptor antagonist, bosentan, decreased the development of new digital ulcers in patients with SSc. Methods This was a randomized, prospective, placebo-controlled, double-blind study of 122 patients at 17 centers in Europe and North America, evaluating the effect of treatment on prevention of digital ulcers. The primary outcome variable was the number of new digital ulcers developing during the 16-week study period. Secondary assessments included healing of existing digital ulcers and evaluation of hand function using the Scleroderma Health Assessment Questionnaire. Results Patients receiving bosentan had a 48% reduction in the mean number of new ulcers during the treatment period (1.4 versus 2.7 new ulcers; P = 0.0083). Patients who had digital ulcers at the time of entry in the study were at higher risk for the development of new ulcers; in this subgroup the mean number of new ulcers was reduced from 3.6 to 1.8 (P = 0.0075). In patients receiving bosentan, a statistically significant improvement in hand function was observed. There was no difference between treatment groups in the healing of existing ulcers. Serum transaminase levels were elevated to >3-fold the upper limit of normal in bosentan-treated patients; this elevation is comparable with that observed in previous studies of this agent. Other side effects were similar in the 2 treatment groups. Conclusion Endothelins may play an important role in the pathogenesis of vascular disease in patients with SSc. Treatment with the endothelin receptor antagonist bosentan may be effective in preventing new digital ulcers and improving hand function in patients with SSc.

Translation techniques revisited. : A dynamic and functionalist approach

Abstract: The aim of this article is to clarify the notion of translation technique, understood as an instrument of textual analysis that, in combination with other instruments, allows us to study how translation equivalence works in relation to the original text. First, existing definitions and classifications of translation techniques are reviewed and terminological, conceptual and classification confusions are pointed out. Secondly, translation techniques are redefined, distinguishing them from translation method and translation strategies. The definition is dynamic and functional. Finally, we present a classification of translation techniques that has been tested in a study of the translation of cultural elements in Arabic translations of A Hundred Years of Solitude by Garcia Marquez.

Reactive oxygen species in vascular biology: implications in hypertension

Abstract: Reactive oxygen species (ROS), including superoxide (*O2-), hydrogen peroxide (H2O2), and hydroxyl anion (OH-), and reactive nitrogen species, such as nitric oxide (NO) and peroxynitrite (ONOO-), are biologically important O2 derivatives that are increasingly recognized to be important in vascular biology through their oxidation/reduction (redox) potential. All vascular cell types (endothelial cells, vascular smooth muscle cells, and adventitial fibroblasts) produce ROS, primarily via cell membrane-associated NAD(P)H oxidase. Reactive oxygen species regulate vascular function by modulating cell growth, apoptosis/anoikis, migration, inflammation, secretion, and extracellular matrix protein production. An imbalance in redox state where pro-oxidants overwhelm anti-oxidant capacity results in oxidative stress. Oxidative stress and associated oxidative damage are mediators of vascular injury and inflammation in many cardiovascular diseases, including hypertension, hyperlipidemia, and diabetes. Increased generation of ROS has been demonstrated in experimental and human hypertension. Anti-oxidants and agents that interrupt NAD(P)H oxidase-driven *O2- production regress vascular remodeling, improve endothelial function, reduce inflammation, and decrease blood pressure in hypertensive models. This experimental evidence has evoked considerable interest because of the possibilities that therapies targeted against reactive oxygen intermediates, by decreasing generation of ROS and/or by increasing availability of antioxidants, may be useful in minimizing vascular injury and hypertensive end organ damage. The present chapter focuses on the importance of ROS in vascular biology and discusses the role of oxidative stress in vascular damage in hypertension.

An exact algorithm for the elementary shortest path problem with resource constraints: Application to some vehicle routing problems

Abstract: In this article, we propose a solution procedure for the Elementary Shortest Path Problem with Resource Constraints (ESPPRC). A relaxed version of this problem in which the path does not have to be elementary has been the backbone of a number of solution procedures based on column generation for several important problems, such as vehicle routing and crew pairing. In many cases relaxing the restriction of an elementary path resulted in optimal solutions in a reasonable computation time. However, for a number of other problems, the elementary path restriction has too much impact on the solution to be relaxed or might even be necessary. We propose an exact solution procedure for the ESPPRC, which extends the classical label correcting algorithm originally developed for the relaxed (nonelementary) path version of this problem. We present computational experiments of this algorithm for our specific problem and embedded in a column generation scheme for the classical Vehicle Routing Problem with Time Windows. © 2004 Wiley Periodicals, Inc. NETWORKS, Vol. 44(3), 216–229 2004