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L Carrier

Publications and source records attributed to L Carrier.

At least 55 records · Page 3Linked to original sources
PubMed1993

Mapping of a novel gene for familial hypertrophic cardiomyopathy to chromosome 11.

Familial hypertrophic cardiomyopathy (FHC) is a cardiac disorder transmitted as an autosomal dominant trait. FHC has been shown to be genetically heterogeneous with less than 50% of published pedigrees being associated with mutations in the beta myosin heavy chain (beta-MHC) gene on chromosome 14q11-q12. A second locus has recently been reported on chromosome 1. We examined the segregation of microsatellite markers in a French pedigree for which the disease is not linked to beta-MHC gene. We found significant linkage of the disease locus to several (CA)n repeats located on chromosome 11 (lod scores between +3.3 and +4.98). The data suggest the localization of the novel FHC gene in a region spanning 17 centiMorgans.

Cardiomyopathy, Hypertrophic↗
PubMed1993

Familial hypertrophic cardiomyopathy. Microsatellite haplotyping and identification of a hot spot for mutations in the beta-myosin heavy chain gene.

Familial hypertrophic cardiomyopathy (FHC) is a clinically and genetically heterogeneous disease. The first identified disease gene, located on chromosome 14q11-q12, encodes the beta-myosin heavy chain. We have performed linkage analysis of two French FHC pedigrees, 720 and 730, with two microsatellite markers located in the beta-myosin heavy chain gene (MYO I and MYO II) and with four highly informative markers, recently mapped to chromosome 14q11-q12. Significant linkage was found with MYO I and MYO II in pedigree 720, but results were not conclusive for pedigree 730. Haplotype analysis of the six markers allowed identification of affected individuals and of some unaffected subjects carrying the disease gene. Two novel missense mutations were identified in exon 13 by direct sequencing, 403Arg-->Leu and 403Arg-->Trp in families 720 and 730, respectively. The 403Arg-->Leu mutation was associated with incomplete penetrance, a high incidence of sudden deaths and severe cardiac events, whereas the consequences of the 403Arg-->Trp mutation appeared less severe. Haplotyping of polymorphic markers in close linkage to the beta-myosin heavy chain gene can, thus, provide rapid analysis of non informative pedigrees and rapid detection of carrier status. Our results also indicate that codon 403 of the beta-myosin heavy chain gene is a hot spot for mutations causing FHC.

Adolescent↗
PubMed1993

[Left ventricular hypertrophy: molecular aspects].

The expression of genes changes during left ventricular hypertrophy. These changes are known as mechanogenic transduction. With respect to the two main contractile proteins, myosin and actin, this is due to a differential expression of their respective multigenic families. Changes of isoform are uncoordinated in time and space. It is important to recognise that the genes themselves are normal and that it is their regulation which is disturbed. Recent data shows that, under normal conditions, the regulation occurs at the transcription stage. A fuller understanding of these mechanisms is necessary if we are to comprehend the pathogenesis of cardiac hypertrophy and failure.

Actins↗
PubMed1993

Exclusion of genes coding for proteins of the cytoskeleton and the extracellular matrix in familial hypertrophic cardiomyopathy using a candidate gene approach.

Familial hypertrophic cardiomyopathy (FHC), a primary cardiac pathology, is a genetically heterogeneous disease, with autosomal dominant inheritance. The first gene identified as responsible for FHC codes for beta-myosin heavy chain (beta-MHC). To find a second locus, a candidate gene approach was applied on two families for which the beta-MHC locus was excluded. Selection of candidate genes is based on the observation of tissular and cellular disorganisation in FHC, and included genes coding for proteins involved in human myocardium architecture: the extracellular matrix components and cytoskeleton proteins. Chromosomal areas containing the candidate genes were examined by linkage analysis with microsatellite markers. The genes coding for different types of collagens, laminins, fibronectin, fibrillins, desmin, titin, alpha-actinin, vinculin, cardiac and skeletal alpha-actins, ankyrin and spectrin were excluded as responsible for FHC.

Cardiomyopathy, Hypertrophic↗
PubMed1992

[Molecular bases of cardiac aging].

The total volume occupied by myocytes in the heart decreases with age, and this is accompanied by a loss of myocytes, by hypertrophy and, to a lesser extent, by hyperplasia of the remaining myocytes. There are differences between ventricles: the right ventricular myocytes have a greater capacity for replication than those of the left ventricle. The expression of genes coding for the 2 principal contractile proteins (myosin and actin) is modified, and there are strong resemblances between the phenotype of the aged heart and that of an adult heart with haemodynamic overload.

Actins↗
PubMed1992

Contractile proteins and sarcoplasmic reticulum calcium-ATPase gene expression in the hypertrophied and failing heart.

The physiology of myocardial contractility has been studied for over a century, but only recently has molecular biology provided new insights into the mechanisms responsible for the alterations of contraction and relaxation observed during cardiac hypertrophy and heart failure. Pressure and volume overload produce in the myocyte both qualitative changes characterized by protein isoform switches and quantitative changes characterized by modulation of single genes through a mechanogenic transduction the pathways of which are largely unknown. The qualitative changes involve differential expression of multigene families of contractile proteins, especially myosin heavy chain (MHC) and actin. All situations of pressure overload, or of combined pressure and volume overload activate the beta-MHC gene and deactivate the alpha-MHC one, which leads to a slower, more efficient contraction. In rat, pressure overload transitorily activates the alpha-skeletal actin gene, and both the timing and the distribution of the newly formed beta-MHC and alpha-skeletal actin mRNAs differ. We recently found that the isoactin pattern is the same in patients with end-stage heart failure as that of control human hearts. Moreover, both in rat and human, expression of isomyosins and isoactins are not coordinated, neither during ontogeny nor senescence. All this suggests the existence of several regulatory mechanisms activated during normal cardiac growth or by a mechanical trigger, and preliminary results indicate that it is possible to perform nuclear run-on assays in order to analyze the transcriptional step of these isogenes.(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Physiological↗
PubMed1992

Expression of the sarcomeric actin isogenes in the rat heart with development and senescence.

Sarcomeric actin genes, alpha-cardiac and alpha-skeletal, are coexpressed in neonatal rodent hearts and are regulated in response to hormonal and hemodynamic stimuli; however, their precise developmental pattern of expression has not been determined, and it is unknown whether they are coexpressed during senescence. We have, therefore, investigated the accumulation of sarcomeric actin transcripts in rat heart during fetal and postnatal development and with senescence by two different techniques: primer extension analysis with an oligonucleotide common to both sarcomeric actins and RNA hybridization with specific cardiac alpha-actin cRNA probes. We found that at 17-19 days in utero both isogenes are coexpressed and alpha-skeletal actin mRNAs represent 28.0 +/- 0.8% of the sarcomeric actin mRNA total. Skeletal actin mRNAs increase to 40% of the total 1 week after birth (NS, p = 0.15), remain constant for 3 weeks, and decrease to less than 20% of the total in ventricles and atria of 1-month-old rats. The alpha-skeletal actin transcripts further decline to less than 5% of the total at 2 months of age and do not reaccumulate in senescent animals. There was no significant difference between male and female rat ventricles. By comparison with the known accumulations of alpha- and beta-myosin heavy chain mRNAs, our results demonstrate that whatever the developmental stage the kinetics of expression for the sarcomeric myosin and actin multigene families are independent.

Actins↗
PubMed1992

Exclusion of cardiac myosin heavy chain and actin gene involvement in hypertrophic cardiomyopathy of several French families.

Familial hypertrophic cardiomyopathy (FHC) is characterized by idiopathic myocardial hypertrophy, which often and predominantly involves the interventricular septum. The disease is transmitted as an autosomal dominant trait, and its major risk is sudden death. It was recently demonstrated that this disease is genetically heterogeneous and that in 13 of 18 unrelated families the morbid locus, termed FHC-1, maps to chromosome 14q11-12 in and/or very near the cardiac beta-myosin heavy chain gene. We have performed linkage analysis with five chromosomal markers detecting polymorphisms in either the cardiac beta-myosin heavy chain gene or the cardiac actin gene (located on chromosome 15q) on eight families from different regions of France. We show that 1) it is possible to analyze medium-sized families by using highly informative microsatellite markers located in these genes and 2) the disease is not linked to the two contractile protein genes in any of these families. Moreover, 10-20% of chromosome 14 and 20-40% of chromosome 15 in the vicinity of the respective markers were excluded as possible locations for the morbid locus. These results provide new insights into the identification of the genes responsible for FHC.

Actins↗
PubMed1992

Regulation of myosin heavy chain and actin isogenes during cardiac growth and hypertrophy.

Expression of myosin heavy chain (MHC) and actin multigene families changes in mammals during cardiac growth and hypertrophy, but whether or not there is a common regulatory pathway is unclear. To address this question, we have looked at the alpha- and beta-MHC, and at the alpha-skeletal and alpha-cardiac actin (alpha-skel act and alpha-card act) isomRNA transitions during development and senescence, both in rat and human hearts. Since the precise amounts of each isoactin mRNA were not precisely known in the above situations, we first analyzed the time- course of accumulations of the two sarcomeric transcripts by primer extension assays, which allow an umambiguous quantification of the ratios of the two actin transcripts. In rats, both isogenes are expressed in-utero. alpha-skel act represents 40% of the total one week after birth, remains constant for 3 weeks, decreases to less than 5% at two months and does not re-accumulate thereafter. In humans, in contrast, alpha-skel act represents < 20% in-utero and in neonates, increases to 48% during the first decade after birth and becomes the predominant isoform of adult hearts. In rats beta-MHC mRNAs accumulate at birth, become undetectable at 3 weeks and reaccumulate to as much as 80% during senescence, and in humans beta-MHC mRNAs predominate throughout all developmental stages. These data show that in both species, the multigene families encoding the major contractile proteins are not coordinately regulated during development and aging.(ABSTRACT TRUNCATED AT 250 WORDS)

Actins↗
PubMed1991

Abnormal rapid Ca2+ release from sarcoplasmic reticulum of malignant hyperthermia susceptible pigs.

Using the rapid filtration technique to investigate Ca2+ movements across the sarcoplasmic reticulum (SR) membrane, we compare the initial phases of Ca2+ release and Ca2+ uptake in malignant hyperthermia susceptible (MHS) and normal (N) pig SR vesicles. Ca2+ release is measured from passively loaded SR vesicles. MHS SR vesicles present a 2-fold increase in the initial rate of calcium release induced by 0.3 microM Ca2+ (20.1 +/- 2.1 vs. 6.3 +/- 2.6 nmol mg-1 s-1). Maximal Ca2+ release is obtained with 3 microM Ca2+. At this optimal concentration, rate of Ca2+ efflux in absence of ATP is 55 and 25 nmol mg-1 s-1 for MHS and N SR, respectively. Ca(2+)-induced Ca2+ release is inhibited by Mg2+ in a dose-dependent manner for both MHS and N pig SR vesicles (K1/2 = 0.2 mM). Caffeine (5 mM) and halothane (0.01% v/v) increase the Ca2+ sensitivity of Ca(2+)-induced Ca2+ release. ATP (5 mM) strongly enhances the rate of Ca2+ efflux (to about 20-40-fold in both MHS and N pig SR vesicles). Furthermore, both types of vesicles do not differ in their high-affinity site for ryanodine (Kd = 12 nM and Bmax = 6 pmol/mg), lipid content, ATPase activity and initial rate of Ca2+ uptake (0.948 +/- 0.034 vs. 0.835 +/- 0.130 mumol mg-1 min-1 for MHS and N SR, respectively). Our results show that MH syndrome is associated to a higher rate of Ca2+ release in the earliest phase of the calcium efflux.

Adenosine Triphosphatases↗
PubMed1991

Skeletal actin mRNA increases in the human heart during ontogenic development and is the major isoform of control and failing adult hearts.

Expression of the two sarcomeric actins, alpha-skeletal and alpha-cardiac, is regulated in the rodent heart in response to developmental, hormonal, and hemodynamic stimuli. Little is known in man, except that both isogenes were found to be coexpressed in three adult ventricles. In this report, we investigated the isoactin mRNA composition in ventricles from 21 control patients (4 fetal, 5 juvenile, 12 adult) and from 15 patients undergoing cardiac transplantation (5 idiopathic dilated cardiomyopathies, 5 ischemic myopathies with myocardial infarcts, 5 diverse etiologies) by two different and complementary techniques: RNA dot blot analysis with specific cDNA probes, and primer extensions with an oligonucleotide common to alpha-cardiac and alpha-skeletal actins. In the case of dot blot analysis, quantification of each isoform was performed by using as standards RNA transcripts obtained from cloned human alpha-actin sequences, and the total amount of sarcomeric actin mRNA was evaluated as a function of total poly(A+)RNA. We found that both isogenes are always coexpressed, and that the isoactin pattern changes during development. In utero and in neonatal hearts, alpha-skeletal actin mRNA represents less than or equal to 20% of sarcomeric actins, it increases to 48 +/- 6% during the first decade after birth and becomes the predominant isoform of adult hearts (60.4 +/- 8.5%). The 15 adult failing hearts exhibited the same isoactin pattern as the control ones (62.84 +/- 11.06%), and there was no difference in expression between patients with dilated cardiomyopathy or ischemic heart disease. These observations demonstrate that cardiac development in man, in contrast to rodent heart, is characterized by an up-regulation of the skeletal actin gene, the expression of which does not change in hypertrophied and failing hearts, and suggest that the actin and myosin heavy chain families are independently regulated in human heart.

Actins↗
PubMed1990

Tetrahydroaminoacridine-lecithin combination treatment in patients with intermediate-stage Alzheimer's disease. Results of a Canadian double-blind, crossover, multicenter study.

We studied the efficacy and safety of oral tetrahydroaminoacridine (THA) combined with lecithin in 52 patients with Alzheimer's disease. The maximal tolerated dose of THA (up to 100 mg per day) was determined during an eight-week titration period, after which the tolerated dose of THA or placebo was given during two sequential randomized periods of treatment lasting eight weeks each. Highly purified lecithin (4.7 g per day) was administered during all phases of the study. Efficacy was expressed in terms of scores on the Mini-Mental State (MMS) test, the modified MMS test, the Hierarchic Dementia Scale, the Rapid Disability Rating Scale-II, and the behavioral scale of Reisberg et al. Safety was assessed by careful clinical monitoring as well as serial measurements of liver aminotransferases. Forty-six patients completed the titration period, and 39 completed the double-blind period, during which only the MMS score showed a small but significant increase (P less than 0.05) after four weeks of treatment with THA. Autonomic side effects of THA were common but mild. Reversible elevations of serum aspartate and alanine aminotransferase levels to three or more times the upper limit of normal occurred in 17 percent of patients; most of the patients affected were women. A liver biopsy performed in one patient showed resolving focal liver-cell necrosis. These studies fail to demonstrate a significant clinical benefit of THA given orally in a maximal dose of 100 mg per day over a period of eight weeks in combination with lecithin.

Administration, Oral↗
PubMed1990

Effects of halothane on calcium release from sarcoplasmic reticulum of rabbit psoas and semitendinosus skinned muscle fibers.

Calcium release from sarcoplasmic reticulum was investigated using skinned fibers isolated from rabbit semitendinosus and psoas muscles, representative of slow and fast fibers, respectively. In both types of fibers, halothane at the concentration of 0.03% (v/v) enhanced the Ca2(+)-induced calcium release. In the absence of cytoplasmic free Ca2+, halothane induced calcium release in a dose-dependent manner, with a similar sensitivity for both semitendinosus and psoas fibers. These results are discussed in connection with muscular diseases such as malignant hyperthermia in which the crisis is triggered during anesthesia by halothane.

Adenosine Triphosphate↗
PubMed1990

Demonstration of abnormal peritoneal communication in patients with ascites.

Patients with ascites are known to have complications such as pleural effusions and hernias. Special diagnostic procedures are occasionally necessary to determine the nature of the abnormality and to determine the corrective medico-surgical approach. The two cases described illustrate the usefulness of intraperitoneal as well as intrapleural injection of a radionuclide in diagnosing the leakage of ascitic fluid.

Adult↗
PubMed1990

Technetium-99m HMPAO imaging in Sturge-Weber syndrome.

The Tc-99m HMPAO brain imaging confirmed marked hypoperfusion secondary to anomalous cerebral venous drainage of the Sturge-Weber syndrome. Until now, this had been a hypothesis suggested by results obtained from conventional brain scans and cerebral arteriography.

Angiomatosis↗
PubMed1990

Extrahepatic uptake of technetium-99m-phytate: a prognostic index in patients with cirrhosis.

We examined the usefulness of technetium-99m-phytate (99mTc-phytate) hepatic scintigraphy in the evaluation of hepatic function, and the assessment of prognosis in patients with cirrhosis. Ninety-four patients with biopsy-documented cirrhosis had, at the time of entry into the study, a scintigraphy with 99mTc-phytate complexed with calcium in vivo. Extrahepatic uptake (EHU) of 99mTc-phytate on scintigraphy was graded from 0 (absent EHU) to 5 (important EHU) according to the relative distribution of the radiotracer between the liver, the spleen and the bone marrow. The severity of liver disease was also assessed according to the index of Child and Turcotte as modified by Pugh et al. Mean follow-up was 2 yr. EHU was correlated to the Pugh score (r = 0.73) and to survival. Survival at 2 yr was 97% for an EHU equal or inferior to 2.5, 62% for grades 3-4.5, and 31% for grade 5. In conclusion, hepatic imaging with 99mTc-phytate, in addition to its diagnostic value, also contains valuable prognostic information in patients with cirrhosis.

Bone Marrow↗