Biomedical subjects
Publications and source records attributed to J Joven.
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Epidemiological and experimental studies suggest that circulating erythrocytes play a role in the incidence of coronary heart disease. We investigated the influence of phenylhydrazine (PHZ)-induced anemia on the formation of atherosclerotic lesions in apo E-deficient mice on regular chow and on a high-fat, high-cholesterol diet during 10 weeks. The repeated doses of PHZ caused sustained anemia throughout the study, changes in the physical characteristics of erythrocytes and increased reticulocyte count. The lesions of the anemic animals were smaller than in the controls and this was even more evident in mice fed with the atherogenic diet. A positive correlation was found between circulating red blood cells at the end of the experiment and the area of aortic lesion. There was also a negative association between the lesion and the reticulocyte count. This reduced progression of atherosclerotic lesions is independent of nutritional status or the lipoprotein cholesterol distribution. The results suggest that mechanisms related to the number of circulating red blood cells may have a significant influence on the development of atherosclerosis.
Disturbances in methyl-carbon metabolism, which result in hyperhomocysteinemia, have been associated with schizophrenia. Homozygosity for the T677 allele of the methylenetetrahydrofolate reductase (MTHFR) gene, which encodes for a thermolabile enzyme associated with hyperhomocysteinemia, has been found to be increased in schizophrenic patients. We have investigated whether plasma homocysteine concentration and the frequency of C677T MTHFR variant were increased in schizophrenic inpatients of a psychiatric hospital (n=210) compared with controls (n=218). There were no significant differences in plasma homocysteine concentrations between the schizophrenia and the control group. The distributions of T allele and TT genotype frequencies were similar in both groups (40% and 15%). These results show that impaired homocysteine metabolism is unlikely in schizophrenia.
With the rationale that a disease that presents with anticipation could be associated with expansion of trinucleotide repeats, we selected parent-offspring pairs of schizophrenia patients with earlier age at onset in the filial generation to measure the expansion of CAG repeats using the repeat expansion detection (RED) method. Intergenerational comparisons were made for age at onset, length of CAG repeats, and clinical variables. Although the patients from the filial generation became affected 13 years earlier than the parents (P < 0.0005), we did not find larger CAG repeats in the offspring. No association was found between size of CAG repeat and age at onset or with any other clinical variable. Overall, the frequency of patients with CAG repeats longer than 40 was 32%, which was similar to that observed in control subjects (27%). It is particularly noteworthy that in 86% of the pairs, the mother was the affected parent. In this Spanish sample with parent-offspring pairs presenting schizophrenia with clinical anticipation and apparent female bias of transmission, neither the phenomenon of anticipation nor disease status was associated with the expansion of CAG repeats.
BACKGROUND/AIMS: The aims of this study were to ascertain: 1) whether hepatic cell DNA fragmentation is increased in rats with early stages of liver disease induced by carbon tetrachloride; 2) whether the inhibition of DNA cleavage is involved in the hepatoprotective effects of zinc; and 3) if relationships exist between DNA fragmentation and the onset of fibrosis in this experimental model. METHODS: Twenty-one treated rats and 23 controls were divided into two groups to receive either a standard diet or one supplemented with zinc. All the animals were sacrificed 1 week later for histological and biochemical assessments, which included a DNA fragmentation index, hepatic zinc and metallothionein concentrations, fibrosis measured by hepatic hydroxyproline concentration and plasma alanine aminotransferase activity. RESULTS: Hepatic cell DNA fragmentation was increased in rats with early hepatic fibrosis and the increase was independent of hepatocytolysis, as measured by alanine aminotransferase activity. Oral zinc administration inhibited hepatic cell DNA fragmentation in the treated rats and was proportional to the hepatic concentration of the metal. The mechanism of the zinc-mediated decrease in DNA cleavage was related to an increase in the hepatic metallothionein concentration. Hepatic cell DNA fragmentation was related to hydroxyproline concentration. CONCLUSIONS: Our results suggest that apoptosis may be involved in the early transformations occurring in the liver and which can lead to the initiation of cirrhosis. As such, the potential therapeutic use of zinc supplementation would warrant further investigation.
The aim of this study was to identify apolar aldehydes in liver homogenates from rats with CCl4-induced cirrhosis and, as a corollary, the antioxidant effect of zinc administration. The study was performed in five control rats and in ten cirrhotic rats which were further sub-divided into two groups to receive either a standard diet or one supplemented with zinc. The percentage of hepatic fibrosis, plasma malondialdehyde concentration and alanine aminotransferase activity were measured as well as the following aldehydes: hexanal, octanal, decanal, 2-hexenal, 2-octenal, 2-nonenal, 2,4-heptadienal and 2,4-decadienal. Of the 10 cirrhotic rats, 4 had elevated concentrations of the highly toxic 2,4-dialkenals which coincided with a higher percentage of fibrosis and plasma alanine aminotransferase activity. These aldehydes were not observed in the control group. Zinc administration was associated with a reduction of the hepatic malondialdehyde concentration and an amelioration on the degree of hepatic injury. In conclusion, this study demonstrates the presence of the highly toxic 2,4-dialkenals in hepatic tissue of rats whith CCl4-induced cirrhosis. Results obtained would suggest that these particular aldehydes may be related to the severity of the hepatic injury.
We have investigated the effect of most common oils used in human nutrition on the development of atherosclerosis in apoE-knockout mice. Seven groups of animals, separated according to sex, were fed for 10 weeks either chow diet or the chow diet 10% (wt/wt) enriched with different oils (palm, coconut, 2 types of olive oil, and 2 types of sunflower oil) without addition of cholesterol. At the end of this period, plasma lipid parameters were measured and vascular lesions scored. None of the diets induced changes in plasma cholesterol concentrations, whereas plasma triglycerides were uniformly reduced in all diet groups. Some diets caused significant reductions in the size of atherosclerotic lesions in males and others in females; males responded most to sunflower oils and females to palm oil and one olive oil (II). The lesion reduction in males consuming sunflower oils was associated with the decrease of triglycerides in triglyceride-rich lipoproteins, whereas the decrease in females consuming olive oil II or palm oil was accompanied by an increase in plasma apoA-I. The increase in plasma apoA-I in the latter condition, is mainly due to overexpression of hepatic message elicited by a mechanism independent of apoE ligand. The data suggest that the different diets modulate lesion development in a gender specific manner and by different mechanisms and that the development of atherosclerosis, due to genetic deficiencies, may be modulated by nutritional maneuvers that may be implemented in human nutrition.
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BACKGROUND: The measurement of immunoglobulin E (IgE) in serum is widely used in the diagnosis of allergic reactions and parasitic infections. We describe here a fully automated assay for human IgE suitable for routine application in a general chemistry analyzer. METHODS: We used an ILab 900 analyzer. This instrument automates a particle-enhanced immunoturbidimetric assay with an analysis time of 9 min. RESULTS: The assay was linear in the range 4-1000 kIU/L (r = 0.9998). The intra- and interassay CVs at 57, 235, and 434 kIU/L were <3.5% and <7.4%, respectively. The detection limit was 4 kIU/L. Hemoglobin (</=16 g/L), bilirubin (</=250 micromol/L), and myeloma paraproteins did not interfere with the assay. The assay showed good correlation with a microparticle enzyme immunoassay (r = 0.998) with a mean difference between methods of -6 +/- 26 kIU/L. CONCLUSION: The new automated serum assay for IgE is an attractive alternative that avoids the need for dedicated instrumentation.
Platelet glycoprotein IIb/IIIa may be involved in the pathogenesis of myocardial infarction as the key element in platelet aggregation and as the binding site of lipoprotein(a) to platelets, inhibiting plasminogen binding and activation. Recently, a strong association between the P1A2 polymorphism of the glycoprotein IIIa gene and acute coronary thrombosis has been reported. although this has not been confirmed. In an associated study, we determined plasma lipoprotein levels, the apo E genotype and the P1A genotype in 250 males under 55 years with myocardial infarction and they were compared with 250 age- and sex-matched controls. Patients showed an over-representation of the epsilon3/4 genotype with respect to the control group. We found that there were no differences in the allelic frequency of P1A2 between case patients and age-matched controls (chi2 = 0.05, P = 0.92) and that subjects bearing the P1A2 allele showed higher plasma lipoprotein(a) concentration than p1A1/P1A1 individuals. Therefore, in this population there is no association between carriage of p1A2 allele and increased risk of myocardial infarction but the carriage of P1A2 is associated with higher plasma Lp(a) concentration.
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We evaluated the performance of a homogeneous assay for the automated measurement of high-density lipoprotein cholesterol (HDL-C) and compared it with a conventional precipitation technique in the following groups of people: control subjects (group A), clinically-healthy elderly (group B), myocardial infarction patients (group C), nephrotic syndrome patients (group D), and liver cirrhosis patients (group E). The performance of the technique was acceptable with respect to precision, accuracy, linearity, and detection limit. Triglycerides up to 40 mmol/L and bilirubin up to 150 micromol/L did not cause interferences. Hemoglobin decreased HDL-C measurements. Samples were stable at -20 degrees C for up to four months. Bland-Altman plots showed a good agreement between both techniques in the control group but with a progressive divergence in the patient groups B to E. Results indicate limitations of the technique in certain clinical conditions and, coincidentally, the need for reliable calibration materials.
BACKGROUND: Clinical data suggest that autologous blood donation may prevent postsurgical venous thrombosis. If confirmed, this is probably due to beneficial effects in rheologic and hematologic variables which may be changed in patients as a result of repeated bleeding. STUDY DESIGN AND METHODS: To ascertain this point, we studied variations in hematological, hemorheological, coagulative and fibrinolytic parameters in 30 patients undergoing autologous blood donation. RESULTS: Whole blood viscosity (WBV), plasma viscosity and blood viscosity adjusted to 40% hematocrit, progressively and substantially decreased throughout the successive bleeding at all the shear rates considered. WBV was further reduced by presurgical hemodilution with autologous plasma which decreased the platelet and leukocyte count. The hemostasis and fibrinolysis variables, however, underwent no clinically significative changes. CONCLUSION: Repeated bleedings change most hemorheological variables. By decreasing cytocrit and viscosity, reducing aggregability and increasing blood cell deformability an optimal milieu to help prevent thrombosis is artificially created.
The repeat expansion detection (RED) method was described to detect expansions of trinucleotide repeats of unknown chromosomal location. We have improved the RED method by the use of 8-mer oligonucleotides and assessed its usefulness in 30 samples from patients with spinocerebellar ataxia type 1 (SCA1), Huntington's disease (HD), and Machado Joseph's disease (MJD), for which the number of CAG/CTG repeats was determined by sequencing. There was a good correlation between the number of repeats detected by sequencing and those identified by RED. However, in 17% of samples, the RED gave additional fragments for ligation products of different size than the CAG/CTG repeat expansion detected in the sample by sequencing. The same was observed in a group of control subjects (n = 78) without known clinical abnormalities in which products of more than 40 repeats were detected in 27% of them, indicating that CAG/CTG repeat expansions are common in the general population. Wether this corresponds to unidentified loci with expansions deserves further investigation.
BACKGROUND/AIMS: To investigate whether physicochemical alterations in plasma lipoproteins are associated with changes in plasma oncotic pressure and viscosity in liver cirrhosis. METHODS: The study included 66 patients with cirrhosis (confirmed by liver biopsy) and 58 healthy volunteers. The constituents measured were: the concentration, density and composition of plasma lipoproteins; plasma oncotic pressure and viscosity; and the concentrations of albumin, total protein, haptoglobin, transferrin, immunoglobulin M and alpha2-macroglobulin. RESULTS: Step-wise multiple regression analysis indicated that, in the patients with cirrhosis, plasma oncotic pressure was significantly correlated with plasma albumin+viscosity (r=+0.85; p<0.001) and with plasma total protein+the density of low density lipoprotein (r=+0.74; p<0.001). The inclusion of viscosity and the density of low density lipoprotein in the regression equations significantly improved the observed correlation between albumin and plasma oncotic pressure (r=+0.70; p<0.001). Similarly, plasma viscosity was significantly correlated with the sum of plasma total protein and cholesterol (r=+0.68; p<0.001). The inclusion of cholesterol in the regression equation significantly increased the observed correlation between total protein and plasma viscosity (r=+0.59; p<0.001). CONCLUSIONS: These results suggest that lipoprotein alterations associated with liver cirrhosis may play a role in determining plasma oncotic pressure and viscosity, and thus could influence the progression of the disease.
The behavior of apolipoprotein (apo) A-I in lipoprotein (Lp) AI and LpAI:AII was studied in 11 postmenopausal females and 11 males matched for plasma triglyceride and total cholesterol levels. Subjects consumed a baseline diet [35% fat (14% saturated, 15% monounsaturated, and 7% polyunsaturated), 15% protein, 49% carbohydrate, and 147 mg cholesterol/1000 kcal] for 6 weeks before the start of the kinetic study. At the end of the diet period, using a primed-constant infusion of [5,5,5-2H3]leucine, residence times (RT) and secretion rates (SR) of apoA-I were determined in 2 subpopulations of high-density lipoprotein (HDL) particles, LpAI and LpAI:AII. Plasma total cholesterol, low-density lipoprotein cholesterol, and triglyceride concentrations were similar in males and females. The mean plasma HDL cholesterol concentration in males (1.14 +/- 0.23 mmol/L; mean +/- SD) was lower than in females (1.42 +/- 0.18 mmol/L; P =. 0034). Similarly, the mean plasma concentration of apoA-I in males (130 +/- 21 mg/dL) was lower than that in females (150 +/- 19 mg/dL; P = .0421). The RT of apoA-I in either LpAI or LpAI:AII was similar between men and women. Despite the higher plasma apo A-I levels in female compared with male subjects, total apoA-I and apoA-I in LpAI and LpAI:AII pool sizes were similar between the two groups, attributable to the lower body weight of the female subjects. The mean SR of total apoA-I in males (8.5 +/- 2.7 mg.kg-1.d-1) was 22% lower than in females (10.9 +/- 2.3 mg.kg-1.d-1; P = .0389). The SR of both apoA-I in LpAI and LpAI:AII was lower in males than females, although the differences did not reach statistical significance. These data suggest that the difference observed in HDL cholesterol concentration between males and females is attributable to SR of apoA-I and not the catabolic rate.
The concentrations of 25 plasma proteins were measured in 22 patients with membranous nephropathy. For some large proteins, the plasma concentrations were increased; there were also large proteins with low plasma concentrations, but small or medium-sized proteins showed uniformly lower plasma concentration than the controls. Plasma colloid osmotic pressure (pi) and viscosity (eta) were not interrelated but showed positive and significant correlations with plasma concentrations of small and medium-sized proteins (pi) and plasma concentrations of large proteins (eta), respectively. Nephrotic plasma is not efficient in maintaining plasma pi but highly efficient in maintaining plasma eta. High plasma fibrinogen concentrations and low antithrombin III concentrations may predispose to thrombosis, and low IgG concentrations may account for the higher predisposition to bacterial infection. The relative composition of nephrotic plasma is heavily dependent on the size of the different proteins. Plasma pi and eta are also maintained by the relative preponderance of different plasma proteins.
In the normal population, the usual effect of the epsilon 2 allele is to decrease plasma cholesterol and to increase plasma triglyceride. We report here the association of nephrotic syndrome and the apo epsilon 2 epsilon 2 genotype in which we observed a hyperlipidemia characterized by very low levels of lipoprotein lipase activity, chylomicronemia, high levels of plasma apo B, C III, E and lipoprotein(a), very low levels of high density lipoprotein cholesterol and concentrations of cholesterol and triglyceride that are higher than expected in all the other lipoprotein fractions. When proteinuria was partially resolved and plasma albumin levels returned to normal, a residual type III hyperlipidemia was still present. These findings suggest that the combination of apo epsilon 2 homozygosity and massive proteinuria may cause considerable changes in the clearance of triglyceride rich particles probably mediated by the almost complete absence of lipolytic enzymes and a low interaction of lipoproteins with specific receptors. The apo E genotype should be investigated in nephrotic patients with chylomicronemia.