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J Dupuis

Publications and source records attributed to J Dupuis.

At least 19 recordsLinked to original sources
PubMed2006

Proximal hip geometry is linked to several chromosomal regions: genome-wide linkage results from the Framingham Osteoporosis Study.

INTRODUCTION: Femoral geometry contributes to bone strength and predicts hip fracture risk. The purpose of this study was to evaluate heritability (h(2)) of geometric indices of the proximal hip and to perform whole-genome linkage analyses of these traits, adjusted for body size. METHODS: DXA scans of the proximal femur from 1473 members of 323 pedigrees (age range 31-96 years) from the population-based Framingham Osteoporosis Study were obtained. Using the hip structural analysis program, we measured femoral neck length (FNL, cm) and neck-shaft angle (NSA); subperiosteal width (WID, cm), cross-sectional area (CSA, cm(2)); and section modulus (Z, cm(3)) at the narrowest section of the neck (NN), intertrochanteric (IT) and femoral shaft (S) regions. Linkage analyses were performed for the above indices with a set of 636 markers using variance components maximum likelihood method. RESULTS: Substantial genetic influences were found for all geometric phenotypes, with h(2) values between 0.28 (NSA) and 0.70 (IT_WID). Adjustment for height and BMI did not alter h(2) of NSA and FNL but decreased h(2) of the cross-sectional indices. We obtained substantial linkage (multipoint LOD >3.0) for S_Z at 2p21 and 21q11 and S_WID at Xq25-q26. Inclusion of height and BMI as covariates resulted in much lower LOD scores for S_Z, whereas linkage signals for S_Z at 4q25, S_CSA at 4q32 and S_CSA and S_Z at 15q21 increased after the adjustment. Linkage of FNL at 1q and 13q, NSA at 2q and NN_WID at 16q did not change after the adjustment. CONCLUSION: Suggestive linkages of bone geometric indices were found at 1q, 2p, 4q, 13q, 15q and Xq. The identification of significant linkage regions after adjustment for BMI and height may point to QTLs influencing femoral bone geometry independent of body size.

Absorptiometry, Photon↗
PubMed2003

Clinical evaluation of a nutraceutical, carprofen and meloxicam for the treatment of dogs with osteoarthritis.

The efficacy, tolerance and ease of administration of a nutraceutical, carprofen or meloxicam were evaluated in a prospective, double-blind study on 71 dogs with osteoarthritis. The client-owned dogs were randomly assigned to one of the three treatments or to a placebo control group. The influence of osteoarthritis on the dogs' gait was described by comparing the ground reaction forces of the arthritic dogs and 10 normal dogs. Before the treatments began, and 30 and 60 days later, measurements were made of haematological and biochemical variables and of the ground reaction forces of the arthritic limb, and subjective assessments were made by the owners and by the orthopaedic surgeons. Changes in the ground reaction forces were specific to the arthritic joint, and were significantly improved by carprofen and meloxicam but not by the nutraceutical; the values returned to normal only with meloxicam. The orthopaedic surgeons assessed that there had been an improvement with carprofen and meloxicam, but the owners considered that there had been an improvement only with meloxicam. The blood and faecal analyses did not reveal any changes. The treatments were well tolerated, except for a case of hepatopathy in a dog treated with carprofen.

Administration, Oral↗
PubMed2001

Upstream use of tirofiban in patients admitted for an acute coronary syndrome in hospitals with or without facilities for invasive management. PRISM-PLUS Investigators.

Management and prognosis of acute coronary syndromes may be influenced by the availability of catheterization facilities at admitting hospitals. Treatment effects of tirofiban were examined in a Canadian cohort of 834 patients enrolled in the Canadian Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial according to admission into hospitals without (n = 322) or with catheterization facilities (n = 512). Hospital transfers for cardiac catheterization were facilitated using preexisting networks accelerated for the purposes of the protocol. In hospitals without facilities, the relative risks for occurrence of death, infarction, or refractory ischemia among patients receiving tirofiban plus heparin compared with heparin alone were 0.52 at 7 days (p = 0.02), 0.59 at 30 days (p = 0.03), and 0.70 at 180 days (p = 0.09); and for death or infarction, 0.32 (p = 0.02), 0.46 (p = 0.04,) and 0.51 (p = 0.03), respectively. Benefit was seen regardless of transfer status, with no statistically significant interaction between treatment, hospital type, and catheterization for any end point at any time point. The incidence of Thrombolysis In Infarction defined major bleeding with respect to therapy was not significantly different between hospital types. Thus, upstream treatment with tirofiban plus heparin confers clinical benefits in unstable angina and/or non-ST-segment elevation infarction patients regardless of whether initial presentation is to a hospital without catheterization facilities or to a hospital with such facilities.

Acute Disease↗
PubMed2001

Effectiveness of a nonselective ET(A/B) and a selective ET(A) antagonist in rats with monocrotaline-induced pulmonary hypertension.

BACKGROUND: Both nonselective ET(A/B) receptor and selective ET(A) receptor antagonists can reduce pulmonary hypertension (PH) and right ventricular hypertrophy (RVH) in various animal models. Depending on their net effects after blockade of endothelial and smooth muscle ET(B) receptors, nonselective ET(A/B) antagonists could be more or less effective than selective ET(A) antagonists. METHODS AND RESULTS: Two weeks after injection of saline or 60 mg/kg monocrotaline (MCT), rats received 50 mg x kg(-1) x d(-1) of a selective (LU135252) or nonselective (BSF420627) antagonist for 3 weeks. This resulted in 4 groups: control (n=15), MCT (n=60), MCT+ET(A) (n=39), and MCT+ET(A/B) (n=40). Five-week survival was 35% in the MCT group; this was increased to 56% in the MCT+ET(A) group (P:=0.10) and to 67% in the MCT+ET(A/B) group (P:=0.0015). Drug administration was stopped 48 hours before hemodynamic measurements to evaluate the chronic effects of therapy: PH in the MCT group (RV systolic pressure 87+/-1 mm Hg) was improved similarly in both MCT+ET(A) and MCT+ET(A/B) groups (72+/-3 and 70+/-3 mm Hg, respectively, P:<0.05). Severe RVH in the MCT group (RV/left ventricle+septum weight ratio 73+/-1%) was not affected by the selective antagonist (70+/-2%) but was reduced to 54+/-2% in the MCT+ET(A/B) group (P:<0.01). Pulmonary resistive properties, assessed from isolated lung pressure-flow relationships, were improved similarly in survivors from both treated groups. CONCLUSIONS: Both the nonselective ET(A/B) antagonist BSF420627 and the selective ET(A) antagonist LU135252 are effective in this model of PH. Similar direct comparative studies in other models of PH and with various dosage regimens are warranted to define the optimal pharmacological approach of PH when ET receptor antagonists are used.

Animals↗
PubMed2001

Effect of ET(A) receptor antagonist on pulmonary hypertension and vascular reactivity in rats with congestive heart failure.

BACKGROUND: We evaluated the effects of chronic therapy with the selective ET(A)receptor antagonist LU 135252 (LU) on pulmonary vascular reactivity in congestive heart failure. METHODS AND RESULTS: After myocardial infarction (MI) or sham operation, rats were gavaged with LU or saline for 4 weeks. Studies were performed in isolated lungs and to differentiate acute from chronic effects, some experiments were performed with LU in the perfusate. The MI+saline group developed moderate pulmonary hypertension (PH) and right ventricular hypertrophy (RVH). This was improved by LU therapy despite no change in left ventricular function and a larger scar area. Vasodilation to sodium nitroprusside (SNP) was reduced after MI and modestly improved by LU therapy. Vasodilation to acetylcholine (Ach) was similar among the four groups, but accentuated after acute LU administration in the sham+saline and MI+saline groups. A23187 produced higher vasoconstriction (18+/-4%) in the MI+LU compared to the MI+saline (10+/-3%, P<0.05) and the two control groups (3+/-1% and 4+/-3%, with and without LU, P<0.01): this was reversed to vasodilation following the acute addition of LU. CONCLUSION: ET(A)receptor blockade after MI reduces PH and RVH. LU therapy mildly improves dilation to SNP and favorably modulates pulmonary endothelium-dependent responses. These results support future studies to better define the mechanisms of improvement in pulmonary vascular reactivity after ET receptor antagonist therapy.

Animals↗
PubMed2001

Mechanisms of acute coronary syndromes and the potential role of statins.

The conventional concepts of the pathogenesis of acute coronary syndromes are changing. High-risk lesions are not necessarily the angiographicaly 'tight' stenoses. Rather, vulnerable lesions are those that are unstable, with a large lipid core and a thin fibrous cap. Plaque instability is closely related to the development of inflammation within the intima and acute coronary syndromes result from rupture of a vulnerable atherosclerotic plaque. Stabilization of lesions by modification of structure and content, rather than simple improvement in the luminal diameter, provides a new therapeutic target. Stabilization may be accomplished through lifestyle changes and appropriate pharmacologic therapy. In the past few years, it has become evident that a major beneficial effect of statins is to induce plaque stability and regression. In fact, statins, in addition to lowering low-density lipoprotein cholesterol, have a variety of pleiotropic, or cholesterol-independent, effects that make them a particularly suitable choice in patients with acute coronary syndromes. Among these are improvements in endothelial function, smooth muscle cells, thrombus formation/platelet function, and inflammation.

Anticholesteremic Agents↗
PubMed2001

Pulmonary metabolism of endothelin 1 during on-pump and beating heart coronary artery bypass operations.

BACKGROUND: Coronary artery bypass operations are associated with increased circulating levels of the powerful vasoconstrictor endothelin 1. The pulmonary circulation is an important site for both production and clearance of endothelin 1. Lung endothelial injury resulting from cardiopulmonary bypass could modify pulmonary endothelin 1 metabolism through an increase in production, a reduction in removal, or a combination of both. METHODS: Pulmonary endothelin 1 kinetics were quantified by using the indicator-dilution technique in patients undergoing coronary artery bypass grafting with (n = 11) or without cardiopulmonary bypass (ie, beating heart; n = 10). Mixed venous endothelin 1 levels were also measured in samples from the pulmonary artery, and systemic levels were obtained from the radial artery. RESULTS: Pulmonary artery endothelin 1 levels were similar before and after cardiopulmonary bypass, with means of 1.59 +/- 0.37 pg/mL and 1.33 +/- 0.15 pg/mL (P =.45), respectively. Systemic endothelin 1 levels, however, increased after bypass from 1.64 +/- 0.22 pg/mL to 2.07 +/- 0.16 pg/mL (P =.01). In the beating heart group, endothelin 1 levels before and after the operation were similar in the pulmonary artery (1.25 +/- 0.27 pg/mL and 1.45 +/- 0.31 pg/mL, respectively; P =.38), as well as in the radial artery (1.70 +/- 0.26 pg/mL and 1.73 +/- 0.35 pg/mL, respectively; P =.92). The capacity to clear endothelin 1 from the pulmonary circulation, as computed from the permeability-surface area product for endothelin 1, was not affected by cardiopulmonary bypass before and after the operation (25.19 +/- 2.67 mL/s and 23.12 +/- 4.39 mL/s, respectively; P =.49). It was similar and also unaffected in the beating heart group. CONCLUSION: Coronary artery bypass grafting with cardiopulmonary bypass is associated with an increase in systemic endothelin 1 levels. The mechanism involved is not related to a decreased pulmonary clearance of endothelin 1 from the systemic circulation but rather to an increased endothelin 1 release by the lungs.

Aged↗
PubMed2001

Intravascular ultrasound assessment of pulmonary vascular disease in patients with pulmonary hypertension.

BACKGROUND: Measurements of pulmonary pressure and resistance are still considered to be the "gold standard" in the evaluation of pulmonary hypertension (PH), despite their limitations in predicting irreversible disease. Hemodynamic assessment also only provides a global evaluation of the pulmonary vascular bed, whereas PH is an inhomogeneous disease of the vessel wall. METHODS AND RESULTS: We assessed the value of intravascular ultrasound (IVUS) in 30 patients with suspected PH and correlated the structural changes in distal pulmonary arteries found on IVUS with conventional hemodynamic data. Plasma endothelin (ET)-1 levels and pulmonary ET-1 extraction also were measured as markers of the severity of PH. The anatomic abnormalities revealed by IVUS were more severe in the lower lobes than in the upper lobes, as evidenced by the greater percentage of wall thickness (WT), the smaller lumen diameter/WT and lumen area/total vessel area (p < 0.05 for each). IVUS anatomic indexes correlated directly with hemodynamic data (eg, with pulmonary arterial systolic pressure; r = 0.56; p < 0.001) and ET-1 levels but inversely with pulmonary ET-1 extraction. CONCLUSION: Patients with PH have greater pulmonary arterial WT that is more severe in the lower lobes than in the upper lobes. The severity of structural abnormalities found on IVUS is directly correlated with hemodynamic findings and ET-1 levels. IVUS may provide useful additional information in the assessment of patients with PH.

Adult↗
PubMed2000

Multipoint linkage analysis of the pseudoautosomal regions, using affected sibling pairs.

Affected sibling pairs are often the design of choice in linkage-analysis studies with the goal of identifying the genes that increase susceptibility to complex diseases. Methods for multipoint analysis based on sibling amount of sharing that is identical by descent are widely available, for both autosomal and X-linked markers. Such methods have the advantage of making few assumptions about the mode of inheritance of the disease. However, with this approach, data from the pseudoautosomal regions on the X chromosome pose special challenges. Same-sex sibling pairs will share, in that region of the genome, more genetic material identical by descent, with and without the presence of a disease-susceptibility gene. This increased sharing will be more pronounced for markers closely linked to the sex-specific region. For the same reason, opposite-sex sibling pairs will share fewer alleles identical by descent. Failure to take this inequality in sharing into account may result in a false declaration of linkage if the study sample contains an excess of sex-concordant pairs, or a linkage may be missed when an excess of sex-discordant pairs is present. We propose a method to take into account this expected increase/decrease in sharing when markers in the pseudoautosomal region are analyzed. For quantitative traits, we demonstrate, using the Haseman-Elston method, (1) the same inflation in type I error, in the absence of an appropriate correction, and (2) the inadequacy of permutation tests to estimate levels of significance when all phenotypic values are permuted, irrespective of gender. The proposed method is illustrated with a genome screen on 350 sibling pairs affected with type I diabetes.

Alleles↗
PubMed2000

Randomized trial comparing intravenous nitroglycerin and heparin for treatment of unstable angina secondary to restenosis after coronary artery angioplasty.

BACKGROUND: The treatment of unstable angina targets the specific pathophysiological thrombotic process at the site of the active culprit lesion. In unstable angina due to a restenotic lesion, smooth muscle cell proliferation and increased vasoreactivity may play a more important role than thrombus formation. Therefore, the relative benefits of nitroglycerin and heparin might differ in unstable angina associated with restenosis compared with classic unstable angina. METHODS AND RESULTS: We randomized 200 patients hospitalized for unstable angina within 6 months after angioplasty (excluding those with intracoronary stents) to double-blind administration of intravenous nitroglycerin, heparin, their combination, or placebo for 63+/-30 hours. Recurrent angina occurred in 75% of patients in the placebo and heparin-alone groups, compared with 42.6% of patients in the nitroglycerin-alone group and 41.7% of patients in the nitroglycerin-plus-heparin group (P<0.003). Refractory angina requiring angiography occurred in 22.9%, 29.2%, 4. 3%, and 4.2% of patients, respectively (P<0.002). The odds ratios for being event free were 0.24 (95% CI, -0.13 to 0.45, P=0.0001) for nitroglycerin versus no nitroglycerin and 0.98 (95% CI, -0.55 to 1. 73, P=NS) for heparin versus no heparin. No patient died or suffered myocardial infarction. CONCLUSIONS: Intravenous nitroglycerin is highly effective in preventing adverse ischemic events (recurrent or refractory angina) in patients with unstable angina secondary to restenosis, whereas heparin has no effect.

Aged↗
PubMed2000

Importance of local production of endothelin-1 and of the ET(B)Receptor in the regulation of pulmonary vascular tone.

Interaction between locally released endothelin-1 (ET-1) and the endothelial ET(B)receptor could modulate pulmonary vascular tone. We evaluated pulmonary ET-1 clearance and ET-1-ET(B)receptor interaction in the modulation of pulmonary vascular tone. Controls and rats with Monocrotaline (MCT)-induced pulmonary hypertension (PH) were studied. Lungs were isolated and perfused under constant pressure. The effect of the selective ET(B)antagonist BQ-788 (10(-12)-10(-8)mole) on perfusion flow rate and(125)I-ET-1 extraction was determined. Baseline(125)I-ET-1 extraction was reduced from 62+/-5% in controls to 49+/-10% in PH (P=0.012). BQ-788 inhibited extraction with a higher half-inhibitory dose in the MCT group (-Log ID(50)= 8.9+/-0.4 vs. 9.5+/-0.1, P=0.03). BQ-788 induced a mild reduction in perfusion flow rate of 0.7+/-0.3 ml/min in controls. In the MCT group, this occurred at a lower dose and was more pronounced with a maximal reduction of 3.3+/-0.7 ml/min (P<0.01 vs. control). ET-1 was undetectable in the effluent at baseline but was present in similar concentrations in both groups after ET(B)blockade. Addition of 2 pg/ml ET-1 to lung perfusate did not modify pulmonary ET-1 clearance or the effect of BQ788 on perfusion flow rate in control lungs. In normal rat lungs, the ET(B)receptor plays a minor regulatory role on vascular tone. In MCT hypertension however, despite a reduction in ET(B)mediated extraction, luminal production of ET-1 attenuates the increase in pulmonary vascular tone.

Animals↗
PubMed2000

LU135252, an endothelin(A) receptor antagonist did not prevent pulmonary vascular remodelling or lung fibrosis in a rat model of myocardial infarction.

The early intervention with endothelin(A) (ET(A)) receptor antagonists following coronary artery ligation has been shown to reduce the development of pulmonary hypertension, despite a lack of improvement in left ventricular function. The present study examined the contribution of pulmonary vascular remodelling and the progression of lung fibrosis in the development of pulmonary hypertension and the subsequent role of endothelin-1 in these processes in a rat model of myocardial infarction (MI). The administration of 60 mg kg(-1) per day of the specific ET(A) receptor antagonist LU135253 ((+)-(S)-2-(4, 6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphenyl-propionic acid) 24 h following coronary artery ligation, failed to improve left ventricular contractile indices, but reduced the extent of pulmonary hypertension, as reflected by the significant decrease in right ventricular systolic pressure. The medial wall thickness of small pulmonary arteries (50 - 200 microm) was significantly increased 4 weeks following MI, albeit LU135253 treatment did not ameliorate this pattern of vascular remodelling. The steady-state mRNA levels of collagen, fibronectin, transforming growth factor-beta(1), and -beta(3) were significantly increased in the lungs of MI rats. The treatment with LU135252 did not alter this pattern of gene expression. Thus, these data demonstrate pulmonary vascular remodelling and the increased expression of extracellular matrix proteins represent underlying mechanisms implicated in the development of pulmonary hypertension in the MI rat. Despite the amelioration of the pulmonary hypertensive state, ET(A) receptor blockade was insufficient to reverse pulmonary vascular remodelling, or the development of lung fibrosis in the MI rat.

Animals↗
PubMed2000

Role of ET(A) receptors in the regulation of vascular reactivity in rats with congestive heart failure.

Endothelium-derived nitric oxide (NO) and endothelin (ET)-1 interact to regulate vascular tone. In congestive heart failure (CHF), the release and/or the activity of both factors is affected. We hypothesized that the increased ET-1 production associated with CHF may result in a reduced smooth muscle sensitivity to NO. The aim of this study was to evaluate the effects of a chronic treatment with the ET(A)-receptor (ET receptor A) antagonist LU-135252 (LU) on cerebrovascular reactivity to sodium nitroprusside (SNP) in the rat infarct model of CHF. Rats were subjected to coronary artery ligation and were treated for 4 wk with placebo (n = 24) or LU (50 mg. kg(-1). day(-1), n = 29). CHF was associated with a decreased (P < 0.05) efficacy of SNP to induce relaxation of isolated middle cerebral arteries. Furthermore, neither NO synthase inhibition with N(omega)-nitro-L-arginine (L-NNA) nor endothelial denudation affected the efficacy of SNP. Thus the endothelium no longer influences smooth muscle sensitivity to SNP. LU treatment, however, normalized (P < 0.05) smooth muscle sensitivity to SNP. Sensitivity of ET-1-induced contraction was increased in CHF only in the presence of L-NNA, whereas contraction induced by ET(B) receptor (receptor B) stimulation was increased (P < 0.05) in endothelium-denuded vessels. LU treatment restored these changes in reactivity and revealed a significant endothelium-dependent ET(B)-mediated relaxation after NO synthase inhibition. In conclusion, CHF decreases and uncouples cerebrovascular smooth muscle sensitivity to SNP from endothelial regulation. The observation that chronic ET(A) blockade restored most of the changes associated with CHF suggests that activation of the ET-1 system importantly contributes to the alteration in vascular reactivity observed in experimental CHF.

Animals↗
PubMed2000

Novel mutations in the gene encoding ATP-binding cassette 1 in four tangier disease kindreds.

Tangier disease (TD) is an autosomal co-dominant disorder in which homozygotes have a marked deficiency of high density lipoprotein (HDL) cholesterol and, in some cases, peripheral neuropathy and premature coronary heart disease (CHD). Homozygotes are further characterized by cholesteryl ester deposition in various tissues throughout the body, most notably in those of the reticuloendothelial system. Several studies have demonstrated that the excess lipid deposition in TD is due to defective apolipoprotein-mediated efflux of cellular cholesterol and phospholipids. Although much progress has been made in our understanding of the metabolic basis of TD, the precise molecular defect had remained elusive until very recently. By positional cloning methods, we: 1) confirm the assignment of TD to chromosome 9q31, 2) provide evidence that human ATP-binding cassette-1 (hABC-1) maps to a 250 kb region on 9q31, and 3) describe novel deletion, insertion, and missense mutations in the gene encoding hABC-1 in four unrelated TD kindreds. These results establish a causal role for mutations in hABC-1 in TD and indicate that this transporter has a critical function in the regulation of intracellular lipid trafficking that dramatically affects plasma HDL cholesterol levels.

ATP-Binding Cassette Transporters↗