Biomedical subjects

P Richard

Publications and source records attributed to P Richard.

At least 73 records · Page 4Linked to original sources

PubMed2000

[Anomalous origin of coronary arteries from three separate ostia in the right sinus of valsalva. A case port and review of the literature].

The authors report the case of a patient undergoing coronary angiography for a lateral myocardial infarction related with atherosclerosic lesions but associated with a rare anomalous origin of all three coronary arteries from separate ostia in the right sinus of Valsalva. Anomalous origin of coronary arteries from the opposite sinus are potentially serious especially among young subjects and when a vessel runs between the aorta and pulmonary artery. Clinical presentation, angiographic diagnostic and treatment strategies are discussed.

Adult↗

PubMed1999

Splicing mutations in KCNQ1: a mutation hot spot at codon 344 that produces in frame transcripts.

BACKGROUND: Long-QT syndrome is a monogenic disorder that produces cardiac arrhythmias and can lead to sudden death. At least 5 loci and 4 known genes exist in which mutations have been shown to be responsible for the disease. The potassium channel gene KCNQ1, previously named KVLQT1, on chromosome 11p15.5 is one of these. METHODS AND RESULTS: We initially analyzed one family using microsatellite markers and found linkage to KCNQ1. Mutation detection showed a G to C change in the last base of exon 6 (1032 G-->C) that does not alter the coded alanine. Restriction digest analysis in the family showed that only affected individuals carried the mutation. A previous report suggested that a G to A substitution at the same position may act as a splice mutation in KCNQ1, but no data was given to support this hypothesis nor was the transcription product identified. We have shown by reverse-transcription polymerase chain reaction that 2 smaller bands were produced for the KCNQ1 gene transcripts in addition to the normal-sized transcripts when lymphocytes of affected individuals were analyzed. Sequencing these transcripts showed a loss of exon 7 in one and exons 6 and 7 in the other, but an in-frame transcript was left in each instance. We examined other families in whom long-QT syndrome was diagnosed and found another unreported splice-site mutation, 922-1 G-->C, in the acceptor site of intron 5, and 2 of the previously reported 1032 G-->A mutations. All these showed a loss of exons 6 and 7 in the mutant transcripts, validating the proposal that a consensus sequence is affected in the exonic mutations and that the integrity of the base at position 1032 is essential for correct processing of the transcript. CONCLUSIONS: The 6 cases already reported in the literature with the 1032 G-->A transition, the novel 1032 G-->C transversion, and a recent G-->T transversion at the same base show that codon 344 is the second most frequently mutated after codon 341, suggesting at least two hotspots for mutations in KCNQ1.

Child, Preschool↗

PubMed1999

Evidence that the gene YLR070c of Saccharomyces cerevisiae encodes a xylitol dehydrogenase.

The open reading frame YLR070c of Saccharomyces cerevisiae has high sequence similarity to S. cerevisiae sorbitol dehydrogenase and to xylitol dehydrogenase of Pichia stipitis. Overexpression of this open reading frame in S. cerevisiae resulted in xylitol dehydrogenase activity. The enzyme is specific for NADH. The following Michaelis constants were estimated: D-xylulose, 1.1 mM; NADH, 240 microM (at pH 7.0); xylitol, 25 mM; NAD, 100 microM (at pH 9.0). Xylitol dehydrogenase activity with the same kinetic properties can also be induced by xylose in wild type S. cerevisiae cells.

Cloning, Molecular↗

PubMed1999

Intrathoracic gossypiboma: magnetic resonance features.

Gossypiboma, a term used to describe a mass within the body composed of a cotton matrix which usually refers to a retained surgical sponge, is a rare complication of cardiac surgery. We report one case revealed by the recurrence of the anginal symptoms after successful myocardial revascularisation surgery. The preoperative diagnosis was suspected by a combination of imaging techniques and subsequently confirmed by surgical removal. We review the literature to summarise the diagnostic and therapeutic features of gossypibomas.

Foreign Bodies↗

PubMed1999

Identification and quantitation of phosphorus metabolites in yeast neutral pH extracts by nuclear magnetic resonance spectroscopy.

(31)P NMR spectroscopy offers a possibility to obtain a survey of all low-molecular-weight phosphorylated compounds in yeast. The yeast cells have been extracted using chloroform into a neutral aqueous phase. The use of high fields and the neutral pH extracts, which are suitable for NMR analysis, results in well-resolved (31)P NMR spectra. Two-dimensional NMR experiments, such as proton-detected heteronuclear single quantum ((1)H-(31)P HSQC) and (31)P correlation spectroscopy ((31)P COSY), have been used to assign the resonances. In the phosphomonoester region many of the signals could be assigned to known metabolites in the glycolytic and pentose phosphate pathways, although some signals remain unidentified. Accumulation of ribulose 5-phosphate, xylulose 5-phosphate, and ribose 5-phosphate was observed in a strain lacking transketolase activity when grown in synthetic complete medium. No such accumulation occurred when the cells were grown in yeast-peptone-dextrose medium. Trimetaphosphate (intracellular concentration about 0.2 mM) was detected in both cold methanol-chloroform and perchloric acid extracts.

Culture Media↗

PubMed1999

V1a- and V2-type vasopressin receptors mediate vasopressin-induced Ca2+ responses in isolated rat supraoptic neurones.

1. The pharmacological profile of receptors activated by vasopressin (AVP) in freshly dissociated supraoptic magnocellular neurones was investigated using specific V1a- and V2-type AVP receptor agonists and antagonists. 2. In 97 % of AVP-responding neurones (1-3000 nM) V1a or V2 receptor type agonists (F-180 and dDAVP, respectively) elicited dose-dependent [Ca2+]i transients that were suppressed by removal of external Ca2+. 3. The [Ca2+]i response induced by 1 microM F-180 or dDAVP was selectively blocked by 10 nM of V1a and V2 antagonists (SR 49059 and SR 121463A, respectively). The response to V1a agonist was maintained in the presence of the V2 antagonist, and the V2 agonist-induced response persisted in the presence of the V1a antagonist. 4. The [Ca2+]i response induced by 1 microM AVP was partially (61 %) blocked by 10 nM SR 121463A. This blockade was increased by a further 31 % with the addition of 10 nM SR 49059. Similarly, the AVP-induced response was partially (47 %) decreased by SR 49059, and a further inhibition of 33 % was achieved in the presence of SR 121463A. 5. We demonstrate that AVP acts on the magnocellular neurones via two distinct types of AVP receptors that exhibit the pharmacological profiles of V1a and V2 types. However, since V2 receptor mRNA is not expressed in the supraoptic nucleus (SON), and since V1b receptor transcripts are observed in the SON, we propose that the V2 receptor agonist and antagonist act on a 'V2-like' receptor or a new type of AVP receptor that remains to be elucidated. The possibility that V2 ligands act on the V1b receptor cannot be excluded.

Animals↗

PubMed1999

C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence.

BACKGROUND: The long-QT syndrome (LQTS) is a genetically heterogeneous disease in which 4 genes encoding ion-channel subunits have been identified. Most of the mutations have been determined in the transmembrane domains of the cardiac potassium channel genes KCNQ1 and HERG. In this study, we investigated the 3' part of HERG for mutations. METHODS AND RESULTS: New specific primers allowed the amplification of the 3' part of HERG, the identification of 2 missense mutations, S818L and V822 M, in the putative cyclic nucleotide binding domain, and a 1-bp insertion, 3108+1G. Hypokalemia was a triggering factor for torsade de pointes in 2 of the probands of these families. Lastly, in a large family, a maternally inherited G to A transition was found in the splicing donor consensus site of HERG, 2592+1G-A, and a paternally inherited mutation, A341E, was identified in KCNQ1. The 2 more severely affected sisters bore both mutations. CONCLUSIONS: The discovery of mutations in the C-terminal part of HERG emphasizes that this region plays a significant role in cardiac repolarization. Clinical data suggests that these mutations may be less malignant than mutations occurring in the pore region, but they can become clinically significant in cases of hypokalemia. The first description of 2 patients with double heterozygosity associated with a dramatic malignant phenotype implies that genetic analysis of severely affected young patients should include an investigation for >1 mutation in the LQT genes.

Adolescent↗

PubMed1999

Genomic organization of the KCNQ1 K+ channel gene and identification of C-terminal mutations in the long-QT syndrome.

The voltage-gated K+ channel KVLQT1 is essential for the repolarization phase of the cardiac action potential and for K+ homeostasis in the inner ear. Mutations in the human KCNQ1 gene encoding the alpha subunit of the KVLQT1 channel cause the long-QT syndrome (LQTS). The autosomal dominant form of this cardiac disease, the Romano-Ward syndrome, is characterized by a prolongation of the QT interval, ventricular arrhythmias, and sudden death. The autosomal recessive form, the Jervell and Lange-Nielsen syndrome, also includes bilateral deafness. In the present study, we report the entire genomic structure of KCNQ1, which consists of 19 exons spanning 400 kb on chromosome 11p15.5. We describe the sequences of exon-intron boundaries and oligonucleotide primers that allow polymerase chain reaction (PCR) amplification of exons from genomic DNA. Two new (CA)n repeat microsatellites were found in introns 10 and 14. The present study provides helpful tools for the linkage analysis and mutation screening of the complete KCNQ1 gene. By use of these tools, five novel mutations were identified in LQTS patients by PCR-single-strand conformational polymorphism (SSCP) analysis in the C-terminal part of KCNQ1: two missense mutations, a 20-bp and 1-bp deletions, and a 1-bp insertion. Such mutations in the C-terminal domain of the gene may be more frequent than previously expected, because this region has not been analyzed so far. This could explain the low percentage of mutations found in large LQTS cohorts.

Base Sequence↗

PubMed1999

Accelerated telomere shortening and telomerase activation in Fanconi's anaemia.

Fanconi's anaemia (FA) is an autosomal recessive disorder characterized by progressive bone marrow failure that often evolves towards acute leukaemia. FA also belongs to a group of chromosome instability diseases. Because telomeres are directly involved in chromosomal stability and in cell proliferation capacity, we examined telomere metabolism in peripheral blood mononuclear cells (PBMC). Telomere length was significantly shorter in 54 FA patient samples, compared to 51 controls (P<0.0001). In addition, mean telomere terminal restriction fragment lengths (TRF) in nine heterozygous patient samples did not differ from those of controls. In 14 samples from FA patients with severe aplastic anaemia (SFA), telomere length was significantly shorter than in 22 samples of age-matched FA patients with moderate haematological abnormalities (NSFA) (P<0.001). However, no correlation was found between TRF length and the presence of bone marrow clonal abnormalities in 16 additional, separately analysed, patient samples. Sequential measurement of TRF in six FA patients showed an accelerated rate of telomere shortening. Accordingly, telomere shortening rate was inversely correlated with clinical status. Telomerase, the enzyme that counteracts telomere shortening, was 4.8-fold more active in 25 FA patients than in 15 age-matched healthy controls. A model for the FA disease process is proposed.

Adolescent↗

PubMed1999

Genetic epidemiology of host predisposition microfilaraemia in human loiasis.

Evidence is accumulating from experimental and human studies that genetic factors are involved both in the control of infectious diseases and in the regulation of infection levels and clinical presentation. So far few studies have investigated the role of these genetic factors in human infection by the filarial parasite Loa loa. We present a segregation analysis on 74 nuclear families who live in the tropical rainforest of southern Cameroun and are exposed to homogeneous loiasis transmission. The results indicate that there is a genetic predisposition to be microfilaraemic and that predisposed subjects might be genetically unable to mount an efficient immune response against loiasis antigens. This individual susceptibility could explain at least in part why the prevalence of infection (microfilaraemic individuals) does not usually exceed 30% of the exposed population in hyperendemic regions. Further genetic studies, based on linkage analysis using both familial information and genetic markers, will help to identify the nature of the genetic factors predisposing to microfilaraemia.

Adolescent↗

PubMed1999

Suicide in patients hospitalized for schizophrenia: 1913-1940.

From a sample of 1357 schizophrenic patients hospitalized between 1913 and 1940 at the Phipps Clinic, we have follow-up data on 1212 (89%) cases, with a mean length of follow-up of 11 years. Of these 1212 patients, 28 (2%) are known to have committed suicide. Suicide was significantly correlated with 1) previous suicide attempts, 2) depressive symptoms, 3) preoccupation with suicide, 4) affective illness in close relatives, 5) poor premorbid social and work history, 6) sexual worries, and 7) psychomotor agitation. Marital status, gender, age at onset, age at admission, number of previous admissions, condition at discharge from Phipps, length of hospitalization, the presence of any type of delusions or hallucinations, alcohol problems, paranoid or catatonic features, and utilization of shock therapies were not significantly correlated with subsequent suicide. The seven variables significantly correlated with suicide enumerated above were chosen to construct a scale suggesting which patients were at high risk for suicide.

Adolescent↗

PubMed1999

Geometrical characterization of hard-sphere systems.

By using molecular dynamics simulations on a large number of hard spheres and the Voronoï tessellation we characterize hard-sphere systems geometrically at any packing fraction eta along the different branches of the phase diagram. Crystallization of disordered packings occurs only for a small range of packing fraction. For the other packing fractions the system behaves as either a fluid (stable or metastable) or a glass. We have studied the evolution of the statistics of the Voronoï tessellation during crystallization and characterized the apparition of order by an order parameter (Q(6)) built from spherical harmonics.

Journal Article↗

PubMed1999

[Diabetic coronary disease and risk of myocardial infarction].

The raised incidence of myocardial infarction and sudden death in diabetics was explained over 20 years ago by the increase in prevalence and severity of coronary atherosclerosis. Coronary angiographies of 820 consecutive patients admitted to hospital for coronary artery disease were analysed. One hundred and fifteen of these patients (14%) were diabetic. In 77.4% of diabetics and 72.6% of non-diabetics, coronary angiography showed coronary lesions which were usually distal and three vessel in diabetics. When the three coronary arteries were analysed globally, the percentage of patients with at least one mild stenosis was much higher in diabetics than in non-diabetics (50.6% vs 30.3% respectively, p < 0.001), but there was no statistical difference in the number of severe stenoses or occlusions. The increase in mild stenosis in the diabetic population could indicate an anatomical predisposition to future rupture of a plaque. This result could explain the increased frequency of myocardial infarction and sudden death in diabetes, not necessarily preceded clinically by angina pectoris.

Aged↗

PubMed1999

[Congenital long QT syndrome. The value of genetics in prognostic evaluation].

The congenital long QT syndrome (QTL) is a heterogenic clinical and genetic entity characterised by prolongation of the QT interval which may be complicated by syncope and sudden death. Four genes have been identified for the cardiac potassium (KCNQ1, HERG and KCNE1) and sodium (SCN5A). The aim of this study was to assess the prognosis of the disease by the site of mutation identified on the morbid gene. Thirty-two genotyped families participated to this study. Each subject gave a clinical history, an ECG and a search for genetic mutation. Eighteen mutations in the transmembrane domains of KCNQ1 were identified in 25 families and 2 mutations in the C-terminal part were found in 4 families. The phenotype was less severe in C-terminal part mutations: less syncopes and sudden deaths (22 vs 55%, p < 0.001) and a shorter QTc (458 +/- 31 ms vs 479 +/- 31 ms, p = 0.0003). Three mutations were detected in the C-terminal part of HERG in 3 different families. Their phenotype was less severe with syncoped related to hypokalemia. The authors also report the case of a family in which two subjects who were the most severely affected had two mutations, one in HERG and the other in KCNQ1. This study confirms the value of a genetic research in assessing the severity of the congenital long QT syndrome.

Adolescent↗

PubMed1999

Double heterozygosity for mutations in the beta-myosin heavy chain and in the cardiac myosin binding protein C genes in a family with hypertrophic cardiomyopathy.

Familial hypertrophic cardiomyopathy is a genetically heterogeneous autosomal dominant disease, caused by mutations in several sarcomeric protein genes. So far, seven genes have been shown to be associated with the disease with the beta-myosin heavy chain (MYH7) and the cardiac myosin binding protein C (MYBPC3) genes being the most frequently involved. We performed electrocardiography (ECG) and echocardiography in 15 subjects with hypertrophic cardiomyopathy from a French Caribbean family. Genetic analyses were performed on genomic DNA by haplotype analysis with microsatellite markers at each locus involved and mutation screening by single strand conformation polymorphism analysis. Based on ECG and echocardiography, eight subjects were affected and presented a classical phenotype of hypertrophic cardiomyopathy. Two new mutations cosegregating with the disease were found, one located in the MYH7 gene exon 15 (Glu483Lys) and the other in the MYBPC3 gene exon 30 (Glu1096 termination codon). Four affected subjects carried the MYH7 gene mutation, two the MYBPC3 gene mutation, and two were doubly heterozygous for the two mutations. The doubly heterozygous patients exhibited marked left ventricular hypertrophy, which was significantly greater than in the other affected subjects. We report for the first time the simultaneous presence of two pathological mutations in two different genes in the context of familial hypertrophic cardiomyopathy. This double heterozygosity is not lethal but is associated with a more severe phenotype.

Adult↗

PubMed1999

[Treatment of stable angina. Coronary angioplasty versus medical treatment].

Stable angina is a common clinical condition in everyday practice. Several studies (ACME, MASS, RITA 2) compared the efficacy of angioplasty with medical management in this context with concordant results: significant reduction in the frequency of angina and improved exercise capacity, without reduction in the number of serious events (death, infarction). Even though developments in the field of angioplasty have provided better clinical results, especially with the use of stents, the indication of dilatation should be clearly defined by a series of clinical and angiographic parameters. Although resistance to well conducted medical treatment is an indication for revascularisation when possible, the indications should be reconsidered if persistent ischaemia with medical therapy has not been proved.

Angina Pectoris↗

PubMed1998

Activation of multiple intracellular transduction signals by vasopressin in vasopressin-sensitive neurones of the rat supraoptic nucleus.

1. The intracellular mechanisms activated by the binding of vasopressin to its receptor(s) and which result in the increase of [Ca2+]i were investigated in freshly dissociated supraoptic nucleus neurones. Various pharmacological agents were used to investigate the possible involvement of phospholipase C (PLC) and adenylate cyclase (AC) intracellular pathways in the transduction of the vasopressin action. 2. Both the PLC inhibitor U-73122 and the protein kinase C (PKC) inhibitor calphostin C, reduced the [Ca2+]i rise elicited by vasopressin. The cAMP analogue, 8-Br-cAMP produced an increase in [Ca2+]i and IBMX, a phosphodiesterase inhibitor, potentiated the response to vasopressin. 3. After pre-incubation with the AC inhibitor SQ-22536, 7 out of 18 vasopressin-sensitive neurones showed no inhibition of the vasopressin response, while the response to vasopressin was reduced by greater than 35 % in each of the other 11 neurones. 4. The activation of protein kinase A (PKA) with Sp-cAMPS caused an increase in [Ca2+]i which was additive to the vasopressin-elicited [Ca2+]i increase. After incubation with the PKA inhibitors Rp-cAMPS or H-89, the [Ca2+]i responses triggered by Sp-cAMPS and vasopressin were, respectively, abolished and greatly reduced. 5. A combined administration of SQ-22536 (AC inhibitor) followed by U-73122 (PLC inhibitor), or U-73122 followed by H-89 (PKA inhibitor), virtually abolished the response to vasopressin. 6. In vasopressin-responsive neurones, the pituitary adenylate cyclase-activating polypeptide (PACAP) induced a [Ca2+]i increase similar to the response to vasopressin and in both cases the increase was inhibited to the same extent by a combination of U-73122 and Rp-cAMPS. 7. In conclusion, we suggest that the autoregulation exerted specifically by vasopressin on vasopressin-sensitive neurones involves the activation of both PLC- and AC-linked pathways.

Adenylyl Cyclase Inhibitors↗

PubMed1998

Familial hypertrophic cardiomyopathy: from mutations to functional defects.

Hypertrophic cardiomyopathy is characterized by left and/or right ventricular hypertrophy, which is usually asymmetric and involves the interventricular septum. Typical morphological changes include myocyte hypertrophy and disarray surrounding the areas of increased loose connective tissue. Arrhythmias and premature sudden deaths are common. Hypertrophic cardiomyopathy is familial in the majority of cases and is transmitted as an autosomal-dominant trait. The results of molecular genetics studies have shown that familial hypertrophic cardiomyopathy is a disease of the sarcomere involving mutations in 7 different genes encoding proteins of the myofibrillar apparatus: ss-myosin heavy chain, ventricular myosin essential light chain, ventricular myosin regulatory light chain, cardiac troponin T, cardiac troponin I, alpha-tropomyosin, and cardiac myosin binding protein C. In addition to this locus heterogeneity, there is a wide allelic heterogeneity, since numerous mutations have been found in all these genes. The recent development of animal models and of in vitro analyses have allowed a better understanding of the pathophysiological mechanisms associated with familial hypertrophic cardiomyopathy. One can thus tentatively draw the following cascade of events: The mutation leads to a poison polypeptide that would be incorporated into the sarcomere. This would alter the sarcomeric function that would result (1) in an altered cardiac function and then (2) in the alteration of the sarcomeric and myocyte structure. Some mutations induce functional impairment and support the pathogenesis hypothesis of a "hypocontractile" state followed by compensatory hypertrophy. Other mutations induce cardiac hyperfunction and determine a "hypercontractile" state that would directly induce cardiac hypertrophy. The development of other animal models and of other mechanistic studies linking the genetic mutation to functional defects are now key issues in understanding how alterations in the basic contractile unit of the cardiomyocyte alter the phenotype and the function of the heart.

Animals↗