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Biomedical subjects

E Durand

Publications and source records attributed to E Durand.

At least 19 recordsLinked to original sources
PubMed2000

Genomewide search for type 2 diabetes-susceptibility genes in French whites: evidence for a novel susceptibility locus for early-onset diabetes on chromosome 3q27-qter and independent replication of a type 2-diabetes locus on chromosome 1q21-q24.

Despite recent advances in the molecular genetics of type 2 diabetes, the majority of susceptibility genes in humans remain to be identified. We therefore conducted a 10-cM genomewide search (401 microsatellite markers) for type 2 diabetes-related traits in 637 members of 143 French pedigrees ascertained through multiple diabetic siblings, to map such genes in the white population. Nonparametric two-point and multipoint linkage analyzes-using the MAPMAKER-SIBS (MLS) and MAXIMUM-BINOMIAL-LIKELIHOOD (MLB) programs for autosomal markers and the ASPEX program for chromosome X markers-were performed with six diabetic phenotypes: diabetes and diabetes or glucose intolerance (GI), as well as with each of the two phenotypes associated with normal body weight (body-mass index<27 kg/m(2)) or early age at diagnosis (<45 years). In a second step, high-resolution genetic mapping ( approximately 2 cM) was performed in regions on chromosomes 1 and 3 loci showing the strongest linkage to diabetic traits. We found evidence for linkage with diabetes or GI diagnosed at age <45 years in 92 affected sib pairs from 55 families at the D3S1580 locus on chromosome 3q27-qter using MAPMAKER-SIBS (MLS = 4.67, P=.000004), supported by the MLB statistic (MLB-LOD=3.43, P=.00003). We also found suggestive linkage between the lean diabetic status and markers APOA2-D1S484 (MLS = 3. 04, P=.00018; MLB-LOD=2.99, P=.00010) on chromosome 1q21-q24. Several other chromosomal regions showed indication of linkage with diabetic traits, including markers on chromosome 2p21-p16, 10q26, 20p, and 20q. These results (a) showed evidence for a novel susceptibility locus for type 2 diabetes in French whites on chromosome 3q27-qter and (b) confirmed the previously reported diabetes-susceptibility locus on chromosome 1q21-q24. Saturation on both chromosomes narrowed the regions of interest down to an interval of <7 cM.

Age of Onset↗
PubMed2000

Multidimensional MR mapping of multiple components of velocity and acceleration by fourier phase encoding with a small number of encoding steps.

Previous studies have shown that the multi-step approach of velocity or acceleration encoding is highly efficient in terms of the signal-to-noise ratio per unit time. This work describes a multidimensional extension of this method for simultaneously measuring multiple components of velocity and acceleration with a few encoding steps. N flow dimensions were encoded with an ND-matrix, obtained by combining the various flow-encoding gradients. The small matrix obtained with as few as two encoding steps can be extended by zero-filling in all N dimensions and using ND-Fourier transformation to obtain the maximum of the resulting peak in the ND-matrix, which gives simultaneously all the components of velocity and/or acceleration. The processing time was shortened by using a method of phase computation that gives the same precision as Fourier transformation, but is much faster. A rotating disk was used to show that the velocity-to-noise ratio increases with the number of dimensions acquired, demonstrating the efficiency of multidimensional flow measurements. The feasibility of the method is illustrated by 3D maps of the myocardium velocity, and 2D measurement of velocity and acceleration in the ascending aorta-both obtained by multidimensional phase encoding in volunteers.

Acceleration↗
PubMed2000

Can dimercaptosuccinic acid renal scintigraphy be used to assess global renal function?

Use of dimercaptosuccinic acid (DMSA) has been proposed for the assessment of both relative and absolute renal function. Our aim was to test whether the renal absolute DMSA uptake (ADU) can reflect the absolute renal function from a theoretical point of view. A simple model was used to compute the ADU in the case of injury to one kidney. It was found that the assumption that ADU correctly reflects the absolute renal function may lead to a more than 50% overestimation of the function of both the normal and the impaired kidney. The later the measurement is made and the more impaired is the kidney, the more important is the error. Although DMSA can reliably quantify the relative renal function, it should not be used to assess absolute renal function lest major overestimation should occur.

Humans↗
PubMed2000

Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity.

By integrating an agonist satiety signal, provided by alpha-melanocyte-stimulating hormone (alpha-MSH), and an antagonist signal, provided by agouti-related protein (AGRP), the melanocortin-4 receptor (MC4-R) is a key element in the hypothalamic control of food intake. Inactivation of the gene encoding this G protein-coupled receptor causes obesity in mice. In humans, frameshift mutations in MC4-R cause an early-onset dominant form of obesity in two families. In this study we find a high frequency (4%) of rare heterozygous MC4-R mutations in a large population of morbidly obese patients. No such mutations were found in controls. By analyzing the phenotypes of the probands carrying these mutations, we demonstrate that these patients display a common, nonsyndromic form of obesity. Interestingly, functional analysis of the mutant receptors indicates that obesity-associated defects in MC4-R range from loss of function to constitutive activation. Transmission of these mutations in the families of the carriers indicates a variable expressivity that is not related to the functional severity of the mutations. This variable expressivity of MC4-R-associated obesity is not due to variations in genes for alpha-MSH or AGRP. Taken together, these results demonstrate that MC4-R mutations are a frequent but heterogeneous genetic cause of morbid obesity.

Adolescent↗
PubMed1999

Endothelial dysfunction and collagen accumulation: two independent factors for restenosis and constrictive remodeling after experimental angioplasty.

BACKGROUND: Constrictive remodeling plays a prominent role in restenosis after balloon angioplasty, but its regulation remains unclear. Because endothelial dysfunction and changes in extracellular matrix have been reported after angioplasty, this study was designed to simultaneously evaluate endothelial function and collagen and elastin changes after restenosis and arterial remodeling. METHODS AND RESULTS: Atherosclerosis was induced in femoral arteries of 22 New Zealand White rabbits by air-desiccation and a high-cholesterol diet. One month later, angioplasty was performed. Histomorphometry and in vitro assessment of endothelial function were performed 4 weeks after angioplasty. Restenosis correlated with constrictive remodeling (r=0.60, P=0.01) but not with neointimal growth (r=-0.06, P=0.79). Restenosis correlated with an impaired relaxation to acetylcholine (ACh; r=0.61, P=0.02) but not with the response to the endothelium-independent vasodilator sodium nitroprusside (r=-0.25, P=0.40). Restenosis correlated positively with collagen accumulation (r=0.69, P=0.004) and inversely with elastin density (r=-0.48, P=0.05). Relaxations to ACh were significantly more decreased in arteries with constrictive remodeling than in those with enlargement remodeling (3.7+/-7.9% versus 35.5+/-15.0%, P=0.04). Neointimal collagen density was significantly higher in arteries with constrictive remodeling than in those with enlargement remodeling (34.5+/-4.5% versus 18.2+/-4.7%, P=0.03). Endothelial function and collagen and elastin density were independent predictors of restenosis in the study. CONCLUSIONS: These results demonstrate that the severity of restenosis after angioplasty correlated with both defective endothelium-dependent relaxation and increased collagen density.

Angioplasty, Balloon↗
PubMed1999

Defective mutations in the insulin promoter factor-1 (IPF-1) gene in late-onset type 2 diabetes mellitus.

Type 2 diabetes mellitus is a common disabling disease with onset in middle-aged individuals, caused by an imbalance between insulin production and action. Genetic studies point to major genetic components, but, with the exception of maturity-onset diabetes of the young (MODY), specific diabetes susceptibility genes remain to be identified. Recent studies showed that a dominant negative mutation in the insulin promoter factor-1 (IPF-1), a pancreatic beta-cell specific transcription factor, causes pancreatic agenesis and MODY. Thus, we investigated 192 French, non-MODY type 2 diabetic families for mutations in IPF-1. We identified 3 novel IPF-1 mutations, including 2 substitutions (Q59L and D76N) and an in-frame proline insertion (InsCCG243). Functional transactivation assays of these IPF-1 mutant isoforms in a beta-pancreatic tumor cell line transfected with a transcriptional reporter and IPF-1 expression plasmids demonstrate a significant inhibition of basal insulin promoter activity (stronger with the InsCCG243 mutant). We find that the InsCCG243 mutation is linked, in 2 families, to an autosomal dominant-like late-onset form of type 2 diabetes, in which insulin secretion becomes progressively impaired. The lower penetrance D76N and Q59L mutations were more prevalent and were associated with a relative risk of 12.6 for diabetes and with decreased glucose-stimulated insulin-secretion in nondiabetic subjects. We propose that IPF-1 mutations can cause MODY or apparently monogenic late-onset diabetes and that they represent a significant risk factor for type 2 diabetes in humans.

Blood Glucose↗
PubMed1998

Thrombus generation after adenovirus-mediated gene transfer into atherosclerotic arteries.

Thrombosis represents a major issue during arterial local delivery. We evaluated the occurrence of thrombosis after adenovirus (Ad)-mediated gene transfer into normal and atherosclerotic arteries. A replication-deficient Ad vector expressing the beta-galactosidase reporter gene (Ad.RSV betagal; 4 x 10(9) PFU) was injected into normal and atherosclerotic arteries (n = 11 in both groups). The contralateral artery received either an Ad vector carrying no transgene (Ad.MLPnull) (n = 7 in both groups, 4 x 10(9) PFU) or vehicle buffer (n = 4 in normal group, n = 8 in atherosclerotic group). Animals were sacrificed 3 days following gene transfer for thrombus detection and assessment of beta-galactosidase activity. Thrombus was absent in normal arteries and in atherosclerotic arteries injected with vehicle buffer only. In contrast, nonocclusive thrombus was present in atherosclerotic arteries injected with either Ad.RSV betagal (5 of 11) or Ad.MLPnull (3 of 7). Beta-galactosidase activity was predominantly found in the endothelial layer of the transfected arteries. Gene transfer and expression occurred despite the presence of the thrombus (4 of 5), and its efficiency did not significantly differ regardless of the thrombus. We conclude that thrombus frequently occurred in atherosclerotic arteries after Ad-mediated gene transfer. Further studies are warranted to identify the mechanisms of thrombus generation after Ad-mediated gene transfer into atherosclerotic arteries.

Adenoviridae↗
PubMed1998

A missense mutation in hepatocyte nuclear factor-4 alpha, resulting in a reduced transactivation activity, in human late-onset non-insulin-dependent diabetes mellitus.

Non-insulin-dependent diabetes mellitus (NIDDM) is a heterogeneous disorder characterized by hyperglycemia resulting from defects in insulin secretion and action. Recent studies have found mutations in the hepatocyte nuclear factor-4 alpha gene (HNF-4alpha) in families with maturity-onset diabetes of the young (MODY), an autosomal dominant form of diabetes characterized by early age at onset and a defect in glucose-stimulated insulin secretion. During the course of our search for susceptibility genes contributing to the more common late-onset NIDDM forms, we observed nominal evidence for linkage between NIDDM and markers in the region of the HNF-4alpha/MODY1 locus in a subset of French families with NIDDM diagnosed before 45 yr of age. Thus, we screened these families for mutations in the HNF-4alpha gene. We found a missense mutation, resulting in a valine-to-isoleucine substitution at codon 393 in a single family. This mutation cosegregated with diabetes and impaired insulin secretion, and was not present in 119 control subjects. Expression studies showed that this conservative substitution is associated with a marked reduction of transactivation activity, a result consistent with this mutation contributing to the insulin secretory defect observed in this family.

Age of Onset↗
PubMed1998

Missense mutations in the pancreatic islet beta cell inwardly rectifying K+ channel gene (KIR6.2/BIR): a meta-analysis suggests a role in the polygenic basis of Type II diabetes mellitus in Caucasians.

The K+ inwardly rectifier channel (KIR) is one of the two sub-units of the pancreatic islet ATP-sensitive potassium channel complex (I(KATP)), which has a key role in glucose-stimulated insulin secretion and thus is a potential candidate for a genetic defect in Type II (non-insulin-dependent) diabetes mellitus. We did a molecular screening of the KIR6.2 gene by single strand conformational polymorphism (SSCP) and direct sequencing in 72 French Caucasian Type II diabetic families. We identified three nucleotide substitutions resulting in three amino acid changes (E23K, L270V and 1337V), that have also been identified in other Caucasian Type II diabetic subjects. These variants were genotyped in French cohorts of 191 unrelated Type II diabetic probands and 119 normoglycaemic control subjects and association studies were done. The genotype frequencies of the L270V and 1337V variants were not very different between Type II diabetic subjects and control groups. In contrast, analysis of the E23K variant showed that the KK homozygocity was more frequent in Type II diabetic than in control subjects (27 vs 14%, p = 0.015). Analyses in a recessive model (KK vs EK/EE) tended to show a stronger association of the K allele with diabetes (p = 0.0097, corrected p-value for multiple testing < 0.02). The data for the E23K variant obtained here and those obtained from three other Caucasian groups studied so far were combined and investigated by meta-analysis. Overall, the E23K variant was found to be significantly associated with Type II diabetes (0.001 < or = p < or = .00106, corrected p-values for multiple testing p < or = 0.01). This study shows that KIR6.2 polymorphisms are frequently associated with Type II diabetes in French Caucasians. Furthermore, a meta-analysis combining different Caucasian groups suggests an significant role of KIR6.2 in the polygenic context of Type II diabetes.

Aged↗
PubMed1998

A recurrent left atrium leiomyosarcoma.

Cardiac leiomyosarcoma is a rare tumour which can grow either intramurally or extramurally. Its prognosis is dismal. Surgery lengthens survival, but recurrences usually occur in the short term. Gated MRI is useful for the assessment of cardiac masses since it provides fine spatial and contrast resolution. We present the case of a left atrial leiomyosarcoma whose recurrence was diagnosed by gated MRI. Our patient underwent a second resection but died soon after.

Echocardiography, Transesophageal↗
PubMed1998

[Study of the general and topical tolerance of Trinipatch and its clinical efficacy in the therapy of chronic stable angina in 5078 coronary disease patients].

Nitrates still play an important role in the treatment of coronary heart disease after more than hundred years of use in this indication. Following oral administration, they undergo intense gastric hydrolysis, and are largery destroyed by the first-pass effect. The development of an attenuation phenomenon of the therapeutic effect has been frequently reported during continuous treatments at fixed doses. Percutaneous administration of nitroglycerin due to the development of transdermal devices palliates these various obstacles. Trinipatch is a small, transparent, matricial, monolayer patch with an absorption promoter, marketed in two dose-strengths (5 mg/24 h and 10 mg/24 h) by Laboratoires Synthelabo. Its systemic and local safety and clinical efficacy were studied by 383 private cardiologists and 2,294 general practitioners in 5,079 coronary patients, between the ages of 19 and 91 years, in two open, multicentre trials lasting 3 months. The systemic safety, assessed by adverse event reporting, was good. 2.7% of patients experienced adverse events, but only 0.3% of patients presented a serious adverse event. The effects most frequently encountered were vasodilator effects. A very good stability of cardiovascular parameters was observed, with no reflex tachycardia. The local safety, evaluated by the Draize scale, was also satisfactory; after 1 month and 3 months of treatment, 6.6% and 5.7% of patients presented erythema, usually isolated and moderate. The clinical efficacy was evaluated by subjective criteria in the 740 patients included by cardiologists. A significant reduction of the number of angina attacks and the numbers of doses of nitroglycerin was observed. The percentage of pain-free patients increased from 18.2% at the start of the study to 76% at the end of the trial. These two trials confirmed the good systemic and local safety and clinical efficacy of Trinipatch.

Adult↗
PubMed1997

[Compensatory enlargement versus chronic constriction. The two features of vascular remodelling after experimental angioplasty].

Considerable efforts have been made to prevent post-angioplasty restenosis targeted mainly against a pathogenesis suggesting a dominant role of hyperplasia. We and others have already shown that constrictive remodelling plays a major role in restenosis. This article evaluates not only the constrictive remodeling theory but also compensatory enlargement associated with prevention of restenosis. The present study on 33 rabbits used the following protocol. Four weeks after inducing an atherosclerotic lesion by air-dessication of a femoral artery segment and a high cholesterol diet, angioplasty was performed. The angiographic minimal luminal diameter significantly increased after angioplasty. Three to four weeks later, initial gain was significantly lost. Restenosis was quantified histologically as well as a remodelling index and a hyperplasia index. No correlations were observed between degree of stenosis and hyperplasia present at the same degree in animals with and without restenosis. On the other hand, there was a strong correlation between restenosis and constrictive remodelling, and with absence of restenosis and compensatory enlargement. Moreover, there was significant a correlation between the degree of hyperplasia and the compensatory remodelling. These data point to the double nature of remodelling: compensatory enlargement observed in animals without restenosis, and constrictive remodelling, the principal mechanism observed in animals with restenosis.

Angioplasty, Balloon↗
PubMed1997

Keeping in shape: exercise fundamentals for the midlife patient.

The typical physiologic effects of aging on the musculoskeletal system can be impeded with regular exercise and diet. Common orthopedic problems in sedentary midlife patients are shoulder impingement, low back pain, and plantar fasciitis. Although the responsibility for maintaining an exercise program rests with the individual, the primary care physician can play an important role as coach, cheerleader, and respected advisor. The key is to encourage patients to initiate a program of regular, moderate exercise 30 minutes a day, three times a week, and to eat a balanced, nutritious diet. The best exercise and diet regimen is one that is custom-designed to accommodate the individual patient's needs and objectives.

Age Factors↗
PubMed1997

Lung scintigraphy in postpneumonectomy dyspnea due to a right-to-left shunt.

We report the case of a 50-yr-old man who experienced exertional dyspnea 5 mo after a left pneumonectomy for carcinoma. As the clinical features pointed toward a pulmonary embolism, we performed a ventilation plus perfusion radionuclide lung scan. It showed no evidence of pulmonary embolism, but it did show a systemic uptake of the isotope, suggesting a right-to-left shunt that was confirmed by contrast echocardiography, which revealed an atrial septal defect. Right-to-left shunts after pneumonectomy have already been reported and can be diagnosed by lung scintigraphy. Usually, a patent foramen ovale is encountered, but the underlying physiopathology remains under discussion. Clinically, right-to-left shunts are often related to platypnea-orthodeoxia.

Diagnosis, Differential↗
PubMed1997

Remodelling: therapeutic opportunities.

Restenosis after angioplasty has been recently attributed to a lack of compensatory enlargement and/or chronic constrictive remodelling, rather than neointimal growth. Also, restenosis occurring after stent has been clearly related to neointimal growth. This clarification has dramatically helped in designing strategies targeted against the appropriate mechanisms. The mechanism of stent-related restenosis has been the most studied and several antiproliferative agents including gene therapy and radioactive stents have been successfully tested. Constrictive remodelling has been identified more recently and its pathophysiological mechanism remains poorly understood. Control of extracellular matrix metabolism might be an important pathway. Moreover, detection of the arteries that will 'enlarge' should avoid any preventive strategy including systematic stenting.

Adaptation, Physiological↗
PubMed1995

[Restenosis: physiopathology, treatments and prevention].

Despite fifteen years of extensive research, we still do not know how to predict or prevent restenosis. Angioplasty induces lesions in the intima, media and sometimes adventitia, resulting in a cicatricial process comprising proliferation and migration of smooth muscle cells towards the intima and secretion of extracellular matrix, leading to the formation of a neointima. Since angioplasty is associated with the simultaneous development of neointimal hyperplasia and restenosis, a cause and a effect relationship has therefore been proposed between neointimal hyperplasia and restenosis. All the restenosis prevention strategies based on inhibition of smooth muscle cell proliferation, which successfully limited restenosis in animal models have failed in man, due to the hazardous extrapolations from experimental models which are very different from the atheromatous lesions observed in man, rather than to the use of animal models in general. It is reasonable to wonder whether we have not selected the wrong target: is smooth muscle cell proliferation really responsible for restenosis? Experimental results supported by histological and ultrasonographic data in man, show that the cicatricial process which induces restenosis consists of constrictive remodelling, which decreases the perimeter of the external elastic lamina and the lumen. The use of stents appears to be the primary strategy designed to limit restenosis and prevent constrictive remodelling in man, even if it stimulates neointimal hyperplasia. Progress in the understanding of the mechanisms of postangioplasty remodelling open new perspectives in the prevention of restenosis.

Angioplasty, Balloon, Coronary↗