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Biomedical subjects

A Evans

Publications and source records attributed to A Evans.

At least 235 records · Page 13Linked to original sources
PubMed1997

Alterations in ornithine decarboxylase characteristics account for tolerance of Trypanosoma brucei rhodesiense to D,L-alpha-difluoromethylornithine.

Ornithine decarboxylase (ODC), the target enzyme of D,L-alpha-difluoromethylornithine (DFMO), was investigated in four DFMO-tolerant Trypanosoma brucei rhodesiense isolates from East Africa and two DFMO-susceptible T. b. gambiense isolates from West Africa. Neither drug uptake nor inhibition of ODC activity by DFMO in cellular extracts differed in the two trypanosome subspecies. However, the specific ODC activity of the cellular extracts was three times as high in T. b. rhodesiense isolates as in T. b. gambiense isolates. Furthermore, a significant difference in the turnover rate of ODC was observed. The time required to induce a 50% reduction of T. b. rhodesiense ODC activity under cycloheximide pressure (tentative half-life) was about 4.3 h, whereas that required for T. b. gambiense ODC was longer than 18 h. We concluded that the higher specific ODC activity and faster enzyme turnover contributed to a substantial degree to the DFMO tolerance observed in the East African T. b. rhodesiense isolates.

Animals↗
PubMed1997

Abnormalities of skeletal muscle metabolism in patients with chronic heart failure: evidence that they are present at rest.

OBJECTIVE: To investigate abnormalities of skeletal muscle metabolism in patients with congestive heart failure. SETTING: A university teaching hospital. METHODS: 43 patients (22 New York Heart Association (NYHA) grade II, 21 grade III) and 10 controls were studied. A forearm model of muscle metabolism was used, with a cannula inserted retrogradely into an antecubital vein of the dominant forearm. Maximum voluntary contraction (MVC) was measured using handgrip dynamometry. Subjects performed handgrip exercise, 5 s contraction followed by 5 s rest for 5 min at 25%, 50%, and 75% of MVC or until exhaustion. Blood was taken at rest and 0 and 2 min after exercise for measurement of lactate and ammonia. After 30 min the procedure was repeated with fixed workloads of 7 kg, 14 kg, and 21 kg. RESULTS: MVC (kg, mean (SEM)) was lower in patients than in controls (control 42.45 (2.3); NYHA II 34.13 (1.3), P = 0.003; NYHA III 33.13 (1.94), P = 0.008). Resting lactate (mmol/l) was higher in patients than controls (control 0.65 (0.06); NYHA II 0.84 (0.08), P = 0.13; NYHA III 1.18 (0.1), P = 0.002). Resting ammonia (mumol/l) was higher in NYHA III (65.7 (6.0)) than in NYHA II (48.0 (3.7), P = 0.016); no difference was found between controls (48.0 (7.1)) and patients. The overall lactate and ammonia response to exercise was greater in NYHA III than in NYHA II and controls (P < 0.05). At volitional exhaustion, peak lactate (mmol/l: NYHA III 3.31 (0.26); NYHA II 2.56 (0.16); controls 2.71 (0.22); P = 0.022 NYHA III v NYHA II) and ammonia (mumol/l: NYHA III) 126.4 (8.97); NYHA II 92.9 (7.23); controls 109 (16.3); P = 0.006 NYHA III v NYHA II) were higher in severe congestive heart failure. CONCLUSIONS: Skeletal muscle metabolism is abnormal at rest in congestive heart failure. During exercise, the degree of metabolic abnormality is related to the symptomatic status of the patient.

Adult↗
PubMed1997

The role of a triplet repeat sequence of the very low density lipoprotein receptor gene in plasma lipid and lipoprotein level variability in humans.

The biological role of the very low density lipoprotein receptor (VLDL-R) in humans is not yet elucidated. This cellular receptor binds apolipoprotein E (apoE)-containing lipoparticles and is mainly expressed in peripheral tissues. The VLDL-R gene contains a polymorphic triplet (CGG) repeat located 19 bp upstream of the initiation codon. We explored the allelic distribution of this repeat in 1384 subjects of European Caucasian origin, 609 of them surviving a myocardial infarction. Six alleles corresponding to 5, 6, 7, 8, 9, and 11 repeats were detected in this population. The alleles 5, 8, and 9 were the most frequent, with frequencies of 0.413, 0.275, and 0.292, respectively. No association was found between the VLDL-R polymorphism and myocardial infarction. In controls without lipid lowering treatment, a statistically significant interaction between VLDL-R genotype and apoE phenotype was found for plasma triglycerides (P < .04), suggesting a gene-gene interaction. There was also a main effect of the VLDL-R polymorphism on LpE:B and LpA-I. The VLDL-R 9 allele was associated with lower levels of plasma LpE:B (P < .05) and higher concentrations of plasma LpA-I (P < .01) than the other alleles. These results suggest that VLDL-R has a modest influence on circulating lipoproteins in humans.

Adult↗
PubMed1997

Five frequent polymorphisms of the PAI-1 gene: lack of association between genotypes, PAI activity, and triglyceride levels in a healthy population.

The main function of plasminogen activator inhibitor type 1 (PAI-1) is to decrease fibrinolysis, which leads to fibrin accumulation. An elevated plasma PAI-1 concentration has been identified as a risk factor for the development of myocardial infarction, and an association between 1 polymorphism of the PAI-1 promoter and plasma PAI-1 levels has been described. Our aim was to identify new polymorphisms in the PAI-1 gene and to further examine the relationship between PAI-1 genotypes and circulating PAI-1 levels. We report the presence of 4 new polymorphisms that were identified by non-isotopic single-strand conformational polymorphism analysis followed by sequencing. These polymorphisms were investigated in relation to PAI-1 levels in a sample of 256 healthy men, aged 50-59 years, from France and Northern Ireland. Two G/A substitutions were detected at positions -844 and +9785. The former is in strong positive linkage disequilibrium with the previously described 4G/5G polymorphism at position -675. Two polymorphisms in the 3' untranslated region were identified. One corresponds to a T/G substitution at position +11,053 and is in negative linkage disequilibrium with the G/A substitution (+9785). The other is a 9-nucleotide insertion/deletion located between nucleotides +11,320 and +11,345 in a threefold-repeated sequence. This polymorphism is in strong positive linkage disequilibrium with the G/A substitution (+9785). The overall heterozygosity provided by the 5 PAI-1 polymorphisms (including the 4 new variants and the 4G/5G polymorphism) was .77. No significant association was found between PAI activity and genotypes; furthermore, the well known associations between PAI activity and body mass index, serum triglycerides, or insulin were homogeneous according to PAI-1 genotypes.

France↗
PubMed1997

The Leu33/Pro polymorphism (PlA1/PlA2) of the glycoprotein IIIa (GPIIIa) receptor is not related to myocardial infarction in the ECTIM Study. Etude Cas-Temoins de l'Infarctus du Myocarde.

The GPIIb/IIIa receptor complex may contribute to acute coronary syndromes by mediating platelet aggregation. The Leu33/Pro polymorphism (PlA1/PlA2) of the GPIIIa has recently been shown to be associated with CHD in a small case-control study. We have investigated this polymorphism in a large multicenter study of patients with myocardial infarction and controls and found no difference in the distribution of allele and genotype frequencies between cases and controls.

Adult↗
PubMed1996

Common mutation in methylenetetrahydrofolate reductase. Correlation with homocysteine metabolism and late-onset vascular disease.

BACKGROUND: Increased homocysteine levels are a risk factor for atherosclerosis and its sequelae. A common genetic mutation in methylenetetrahydrofolate reductase (MTHFR), an enzyme required for efficient homocysteine metabolism, creates a thermolabile enzyme with reduced activity. We determined the prevalence of this mutation in many subjects with and without vascular disease and related it to homocysteine and folate levels. METHODS AND RESULTS: DNA from 247 older subjects with vascular disease and 594 healthy subjects without vascular disease (in three different control groups) was screened for the MTHFR 677 C-to-T mutation. Within each group, 9% to 17% of the subjects were homozygous for this mutation, and the mutant allele frequency was 31% to 39%. The genotype distributions, homozygote frequencies, and allele frequencies did not differ significantly between the study groups. In the vascular disease subjects, despite significantly lower folate levels in MTHFR homozygotes, there was no significant difference in homocysteine levels among the MTHFR genotype groups. The negative slope of the regression line relating homocysteine and folate was significantly steeper for those with a homozygous MTHFR mutation compared with those without this mutation. CONCLUSIONS: Although the thermolabile MTHFR mutation is very common, it does not appear to be a significant genetic risk factor for typical late-onset vascular disease. Because MTHFR homozygotes have increased homocysteine with low folate levels, this mutation may contribute to early-onset or familial vascular disease. The genotype dependence of the folate-homocysteine correlation further suggests that homozygotes for this mutation may have both an exaggerated hyperhomocysteinemic response to folic acid depletion and a better response to folic acid therapy.

Adult↗
PubMed1996

Functional imaging of an illusion of pain.

Touching warm and cool bars that are spatially interlaced produces a painful burning sensation resembling that caused by intense, noxious cold. We demonstrated previously that this thermal grill illusion can be explained as an unmasking phenomenon that reveals the central inhibition of pain by thermosensory integration. In order to localize this unmasking in the human brain, we have used positron emission tomography (PET) to compare the cortical activation patterns evoked by the thermal grill and by cool, warm, noxious cold and noxious heat stimuli. The thermal grill illusion produces activation in the anterior cingulate cortex, whereas its component warm and cool stimuli do not. This area is also activated by noxious heat or cold. Thus, increased activity in the anterior cingulate cortex appears to be selectively associated with the perception of thermal pain. Disruption of thermosensory and pain integration may account for the central pain syndrome that can occur after stroke damage.

Adult↗
PubMed1996

Homocysteine and risk of premature coronary heart disease. Evidence for a common gene mutation.

BACKGROUND: Plasma homocysteine levels are modulated by nutritional and genetic factors, among which is the enzyme methylenetetrahydrofolate reductase (MTHFR). A common defective (thermolabile) variant of this enzyme is causally associated with elevated plasma homocysteine, itself an independent risk factor for coronary heart disease. METHODS AND RESULTS: To examine the hypothesis that the allele (T) that codes for the thermolabile defect increases the risk of coronary heart disease, we studied 111 patients with clinical and objective investigational evidence of coronary heart disease and 105 control subjects. The frequencies of the thermolabile defect (T) in patients and control subjects were measured, and the prevalence of elevated plasma total homocysteine according to genotype was assessed. The frequency of the defective allele was higher in patients than in control subjects with an OR of 1.6 (95% CI, 1.1 to 2.4; P = .02). The OR in the coronary heart disease group for the homozygous TT genotype was 2.9 (95% CI, 1.2 to 7.2; P = .02); 17% of patients and 7% of control subjects had the TT genotype. Plasma total homocysteine levels were significantly associated with disease status, a relationship that matched the strength of the association between disease and homozygous inheritance of the defective enzyme. CONCLUSIONS: Homozygotes for the defective allele (T) are at increased risk of premature coronary heart disease. MTHFR, which modulates basal plasma homocysteine concentration, is folate dependent, and dietary supplementation or fortification with folic acid may reduce plasma homocysteine levels and consequent coronary risk in a significant proportion of the general population.

Alanine↗
PubMed1996

The Gln/Arg polymorphism of human paraoxonase (PON 192) is not related to myocardial infarction in the ECTIM Study.

Paraoxonase is a high-density-lipoprotein associated enzyme capable of hydrolyzing lipid peroxides, which has been suggested to contribute to atherosclerosis and coronary heart disease (CHD). We studied the Gln/Arg polymorphism affecting codon 192 of human paraoxonase (PON 192) to determine whether this polymorphism, which is associated with serum paraoxonase (PON) activity, represents a risk factor for myocardial infarction (MI). The PON 192 polymorphism was analysed in 642 male patients with myocardial infarction and 701 age-matched controls participating in the ECTIM Study (Etude Cas-Témoins de l'Infarctus du Myocarde). The frequency of the Gln allele was 0.69 in cases and 0.70 in controls (ns). The frequency of the PON 192/Arg allele in 405 MI patients who underwent coronary angiography was 0.295, 0.323 and 0.331, respectively in those with 1, 2 or 3 stenosed arteries (stenosis > 50%) (ns). The mean levels of several plasma lipids, lipoproteins and apolipoproteins were compared between the 3 PON genotypes and no difference was observed. The PON 192 polymorphism was unrelated to MI, the severity of coronary atherosclerosis and to plasma levels of several lipid variables.

Adult↗
PubMed1996

Functional imaging of cerebral arteriovenous malformations with a comment on cortical reorganization.

Functional brain imaging is poised to become a standard diagnostic tool. The authors review their experience using functional positron emission tomography (fPET) in patients with cerebral arteriovenous malformations (AVMs). Twelve patients, three males and nine females aged 16 to 30 years, 11 with a cerebral AVM and one with a cavernous angioma, of which five were located in the central area and seven in a speech region, underwent fPET and three-dimensional magnetic resonance imaging. These studies were coregistered in stereotactic space and correlated to Brodmann's areas that were identified from the atlas of Talairach and Tournoux. Vibrotactile and/or motor stimulation of the contralateral hand were used to identify the central region in patients whose AVM resided within, or close to, the motor strip, and language tasks specifically designed to activate visual, auditory, expressive, or semantic language were used in patients whose AVM resided within, or close to, Broca's or Wernicke's areas. Somatosensory and motor activation reliably identified the central region in all cases as validated by identification of Brodmann's areas and by intraoperative cortical mapping, which was performed with the patient under local anesthesia. Similarly, language tasks accurately lateralized major language function to one hemisphere concordantly with neuropsychological assessment, including dichotic listening and intracarotid Amytal tests, and localized language areas appropriately as verified by stereotactic coordinates. Functional cerebral imaging is feasible in patients with structural brain lesions. It is a reliable method to identify the relationship of a cerebral AVM to the central region. The determination of a similar relationship to language areas is dependent on the development and further validation of language-based tasks designed to activate visual, auditory, expressive, and semantic aspects of language specific to particular sites within the anterior and posterior speech regions.

Journal Article↗
PubMed1996

Molecular cloning of a human melanoma-associated chondroitin sulfate proteoglycan.

A human melanoma-associated chondroitin sulfate proteoglycan (MCSP), recognized by mAb 9.2.27, plays a role in stabilizing cell-substratum interactions during early events of melanoma cell spreading on endothelial basement membranes. We report here the molecular cloning and nucleotide sequencing of cDNA encoding the entire core protein of human MCSP and provide its deduced amino acid sequence. This core protein contains an open reading frame of 2322 aa, encompassing a large extracellular domain, a hydrophobic transmembrane region, and a relatively short cytoplasmic tail. Northern blot analysis indicated that MCSP cDNA probes detect a single 8.0-kb RNA species expressed in human melanoma cell lines. In situ hybridization experiments with a segment of the MCSP coding sequence localized MCSP mRNA in biopsies prepared from melanoma skin metastases. Multiple human Northern blots with an MCSP-specific probe revealed a strong hybridization signal only with melanoma cells and not with other human cancer cells or a variety of human fetal and adult tissues. These data indicate that MCSP represents an integral membrane chondroitin sulfate proteoglycan expressed by human malignant melanoma cells. The availability of cDNAs encoding MCSP should facilitate studies designed to establish correlations between structure and function of this molecule and help to establish its role in the progression of human malignant melanoma.

Adult↗
PubMed1996

Alcohol consumption and myocardial infarction: a case-control study in France and Northern Ireland.

The effect of alcohol consumption was assessed in 561 men with myocardial infarction and 643 healthy controls recruited from France and Northern Ireland between 1988 and 1991 in the ECTIM Study (Enquête Cas-Témoins de I'Infarctus du Myocarde). In total, patients consumed less wine than did controls, while non-wine-derived alcohol consumption did not differ significantly. After adjustment for cardiovascular risk factors and country of recruitment by logistic regression, alcohol consumption displayed a protective effect against myocardial infarction, the magnitude of which was comparable in both countries. This effect, which was essentially due to wine consumption in France and to nonwine consumption in Northern Ireland, was largely attenuated by the introduction of high density lipoprotein cholesterol into the model. Thus, both wine and nonwine consumption appear to exert a protective effect against myocardial infarction which is partly mediated through an increase in high density lipoprotein cholesterol.

Adult↗
PubMed1996

Specific involvement of human parietal systems and the amygdala in the perception of biological motion.

To explore the extent to which functional systems within the human posterior parietal cortex and the superior temporal sulcus are involved in the perception of action, we measured cerebral metabolic activity in human subjects by positron emission tomography during the perception of simulations of biological motion with point-light displays. The experimental design involved comparisons of activity during the perception of goal-directed hand action, whole body motion, object motion, and random motion. The results demonstrated that the perception of scripts of goal-directed hand action implicates the cortex in the intraparietal sulcus and the caudal part of the superior temporal sulcus, both in the left hemisphere. By contrast, the rostrocaudal part of the right superior temporal sulcus and adjacent temporal cortex, and limbic structures such as the amygdala, are involved in the perception of signs conveyed by expressive body movements.

Adult↗
PubMed1996

Dopamine transporters are markedly reduced in Lesch-Nyhan disease in vivo.

Dopamine (DA) deficiency has been implicated in Lesch-Nyhan disease (LND), a genetic disorder that is characterized by hyperuricemia, choreoathetosis, dystonia, and compulsive self-injury. To establish that DA deficiency is present in LND, the ligand WIN-35,428, which binds to DA transporters, was used to estimate the density of DA-containing neurons in the caudate and putamen of six patients with classic LND. Comparisons were made with 10 control subjects and 3 patients with Rett syndrome. Three methods were used to quantify the binding of the DA transporter so that its density could be estimated by a single dynamic positron emission tomography study. These approaches included the caudate- or putamen-to-cerebellum ratio of ligand at 80-90 min postinjection, kinetic analysis of the binding potential [Bmax/(Kd x Vd)] using the assumption of equal partition coefficients in the striatum and the cerebellum, and graphical analysis of the binding potential. Depending on the method of analysis, a 50-63% reduction of the binding to DA transporters in the caudate, and a 64-75% reduction in the putamen of the LND patients was observed compared to the normal control group. When LND patients were compared to Rett syndrome patients, similar reductions were found in the caudate (53-61%) and putamen (67-72%) in LND patients. Transporter binding in Rett syndrome patients was not significantly different from the normal controls. Finally, volumetric magnetic resonance imaging studies detected a 30% reduction in the caudate volume of LND patients. To ensure that a reduction in the caudate volume would not confound the results, a rigorous partial volume correction of the caudate time activity curve was performed. This correction resulted in an even greater decrease in the caudate-cerebellar ratio in LND patients when contrasted to controls. To our knowledge, these findings provide the first in vivo documentation of a dopaminergic reduction in LND and illustrate the role of positron emission tomography imaging in investigating neurodevelopmental disorders.

Adolescent↗
PubMed1996

Beta fibrinogen gene polymorphisms are associated with plasma fibrinogen and coronary artery disease in patients with myocardial infarction. The ECTIM Study. Etude Cas-Temoins sur l'Infarctus du Myocarde.

BACKGROUND: Polymorphisms of the beta fibrinogen gene have been shown to affect plasma fibrinogen levels and the risk of peripheral arterial disease. We now present the results of a detailed analysis of the beta fibrinogen gene in relation to plasma fibrinogen and to the severity of coronary artery disease (CAD) in patients with myocardial infarction (MI) in the ECTIM Study. METHODS AND RESULTS: Ten polymorphisms of the beta fibrinogen gene, including five new polymorphisms identified by single-strand conformation polymorphism analysis, and one polymorphism in the 3' flanking region of the alpha fibrinogen gene were investigated in 565 patients with MI and 668 control subjects. The polymorphisms were in tight linkage disequilibrium and the genotype frequencies were similar in patients with MI and control subjects. In the multivariate analysis, only two polymorphisms, beta Hae III (P < .0003) and beta-854 (P < .01), were independently associated with plasma fibrinogen. The significant association between beta fibrinogen polymorphisms and plasma fibrinogen was present in smokers but not in nonsmokers. In French MI patients, the number of coronary arteries with > 50% stenosis was estimated by angiography and used as a criterion for severity of CAD. Presence of the less frequent allele of the beta Bcl I (P < .0003) and of other polymorphisms was positively associated with the severity of CAD. CONCLUSIONS: Genetic variants of the beta fibrinogen gene are associated with an increased plasma level of fibrinogen, especially in smokers. The association with CAD appears to be the consequence of an increased risk of MI in subjects with severe CAD who carry the predisposing beta fibrinogen genotypes.

Adult↗
PubMed1996

Factor VII Arg/Gln353 polymorphism determines factor VII coagulant activity in patients with myocardial infarction (MI) and control subjects in Belfast and in France but is not a strong indicator of MI risk in the ECTIM study.

This paper describes the relationship of factor VII coagulant activity (FVIIc), FVII Arg/Gln353 genotype and risk of myocardial infarction (MI) in the ECTIM (Etude Cas Témoin sur l'Infarctus du Myocarde) study, a multi-centre case-control study on MI. FVIIc was significantly higher in controls from all four centres: Belfast, Lille, Strasbourg and Toulouse, perhaps because elevated FVIIc may predispose to fatal rather than non-fatal MI. Major influences on FVIIc were FVII Arg/Gln353 genotype, triglyceride and cholesterol levels. There was no significant effect of genotype on MI risk however there was a non-significant trend towards increased MI risk in FVII Arg353 homozygotes. Confirming previous observations, FVIIc was highest in FVII Arg353 homozygotes, intermediate in heterozygotes and lowest in FVII Gln353 homozygotes (except Toulouse cases) these differences being highly statistically significant (except Strasbourg cases P = 0.1). In Belfast, consistent with previous findings, there was significant interaction between FVII Arg/Gln353 genotype and triglyceride level in determining FVIIc, whilst this was absent in the French centres. In conclusion, FVII Arg/Gln353 genotype strongly determines FVIIc although neither factor has a strong impact on MI risk in the ECTIM study.

Adult↗
PubMed1996

Imaging motor-to-sensory discharges in the human brain: an experimental tool for the assessment of functional connectivity.

We present a new approach to studying functional connectivity in the human brain. This approach is based on the observation that when we engage in motor activity, a discharge corollary to the motor command is sent from motor to sensory structures. Thus, as long as movement-related sensory input is either prevented or masked, modulation of neuronal activity in sensory structures would indicate the presence of functional connectivity between the motor and the sensory regions. Using positron emission tomography, such a central interaction between motor and sensory regions can be assessed by measuring regional changes in cerebral blood flow (CBF) in sensory regions. In this paper, we describe the experimental design and the results of two studies of corollary discharges, namely those generated during eye movements and speech. In these studies, a graded approach was used to establish the relationship between the number of eye movements or utterances and CBF in visual or auditory regions, respectively. Significant covariations between the number of movements and CBF in sensory regions were found, thus indicating the presence of functional connectivity between motor and sensory regions. In addition, interregional CBF covariations were computed and the effect of removing the intersubject variance on these covariations was evaluated. The corollary-discharge-based approach to studying functional connectivity is discussed in the context of more traditional computational approaches to network analysis in functional brain imaging.

Brain↗