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Biomedical subjects

J Letarte

Publications and source records attributed to J Letarte.

At least 19 recordsLinked to original sources
PubMed1991

Differential synthesis of 5-lipoxygenase in peripheral blood and synovial fluid neutrophils in rheumatoid arthritis.

In order to investigate 5-lipoxygenase enzyme regulation in neutrophils during an inflammatory reaction, we studied 5-lipoxygenase mRNA levels, as well as de novo enzyme synthesis, in resting and activated neutrophils isolated from normal individuals and patients with rheumatoid arthritis. The approach used was to analyze these activities in resting peripheral blood neutrophils of normal individuals on the one hand and in peripheral blood and matched synovial fluid neutrophils isolated from patients with rheumatoid arthritis on the other hand. Our first observation was that resting peripheral blood neutrophils of either normal individuals or patients show detectable levels of 5-lipoxygenase mRNA and are able to synthesize the enzyme de novo. Our second observation was that inflammatory activated neutrophils from synovial fluid reveal lower 5-lipoxygenase mRNA levels and enzyme synthesis than do the patient-matched peripheral blood cells. This is in spite of the fact that, for other proteins, synovial fluid neutrophils are equally or more active than their peripheral blood counterparts. We conclude that peripheral blood neutrophils are capable of synthesizing the enzyme, thus ensuring the turnover of the protein. Furthermore, complex regulatory mechanisms appear to take place in response to inflammation as it occurs in synovial fluids of patients with rheumatoid arthritis, leading to decreased mRNA levels and enzyme synthesis. Possible mechanisms of regulation are discussed and are presently under investigation.

Arachidonate 5-Lipoxygenase↗
PubMed1990

Mechanisms of hypercholesterolaemia in glycogen storage disease type I: defective metabolism of low density lipoprotein in cultured skin fibroblasts.

Hyperlipidaemia is a feature of glycogen storage disease type I (GSD-I) (Levy et al.). High levels of LDL cholesterol (200 +/- 25 mg dl-1) and apo B (387 +/- 44 mg dl-1) were found in association with hypercholesterolaemia in GSD-I. Related causative factors might be attributed to overproduction and/or delayed removal of LDL. In this study, a possible alteration in the clearance of LDL was examined. Using cultured fibroblasts for LDL receptor activity, the following observations were made: 1. GSD-I fibroblasts revealed only a slight decrease in LDL binding (65 +/- 7) when compared with controls (74 +/- 4 ng mg-1 protein), however, LDL internalization (382 +/- 24 vs. 570 +/- 52 ng mg-1 protein) and proteolytic degradation (2082 +/- 280 vs. 2916 +/- 12.5 ng mg-1 protein) were significantly affected (P less than 0.01). 2. Binding, internalization and proteolytic degradation of LDL from GSD-I were compared with that of controls, and were found to be significantly lower (P less than 0.01). 3. Substitution of control lipoprotein-deficient serum (LPDS) by GSD-I LPDS further diminished the above processes (P less than 0.05). Our results demonstrate that increased plasma cholesterol in GSD-I is due to a decreased catabolism of LDL. The data suggest that the problem may well be multifactorial, due to diminished receptor expression, abnormal LDL composition and impaired LDL receptor interaction due to a circulating inhibitory factor.

Adolescent↗
PubMed1989

Detection of beta-1,3-glucanase activity after native polyacrylamide gel electrophoresis: application to tobacco pathogenesis-related proteins.

Beta-1,3-Glucanase (laminarinase) activity was detected after polyacrylamide gel electrophoresis under native conditions by using laminarin as substrate. Following incubation of gels, laminarin was stained with Aniline Blue. Under UV illumination, lysis zones appeared as dark bands against a fluorescent background. As low as 0.001 unit of commercial Penicillium laminarinase could be observed after incubating the polyacrylamide gel for 45 min at pH 5.0. Extracts of commercial Penicillium laminarinase exhibited four bands with lytic activity towards laminarin. Analysis of intercellular fluid extracts of tobacco mosaic virus-infected tobacco leaves revealed four beta-1,3-glucanases corresponding to three acidic pathogenesis-related proteins, b4 (2), b5 (N) and b6b (0), and one basic protein. The presence of laminarin in gels retarded the migration of some proteins with beta 1,3-glucanase activity. This change in electrophoretic mobility could be used as a complementary affinity test for identifying proteins with beta-1,3-glucanase activity.

Electrophoresis, Polyacrylamide Gel↗
PubMed1989

The importance of glyoxylate and other glycine precursors in the hepatic and renal conjugation of benzoate in normal and hyperammonemic mice.

Benzoate conjugation, represented by hippurate synthesis, was measured in hepatocytes isolated from normal and sparse-fur (spf) mutant mice, with X-linked ornithine transcarbamylase deficiency, to compare the effects of glyoxylate and piridoxylate (a hemiacetal of glyoxylate and pyridoxine), substituted for glycine. Various amino acid precursors of glycine described in the literature, including serine, threonine, glutamine, and glutamate, were studied in a similar manner. The role of glyoxylate and piridoxylate was also assessed in the renal cortex, in comparison with liver homogenates from normal and hyperammonemic mice. The results indicate the importance of glyoxylate and piridoxylate to completely substitute for glycine (96-115%) in isolated hepatocytes of spf/Y mice, as compared with 53-69% (p less than 0.05) in normal +/Y controls. The mean value of amino acid precursors to substitute for glycine in spf mice was serine 51%, threonine 29% (p less than 0.05), and glutamine 9%. In normal mice, only serine (21%) (p less than 0.01) partly substituted for glycine, whereas threonine, glutamine and glutamate gave negative values of net hippurate synthesis. The specific activity of renal cortex for hippurate synthesis from glycine, glyoxylate and piridoxylate was 3-4 times that of liver homogenates (p less than 0.01 - less than 0.001). A scheme for the transamination of glyoxylate by alanine is presented. Besides alanine, the excess of glycine, serine, and threonine is readily deaminated in the body to take part in gluconeogenic reactions, thus contributing to hyperammonemia. The cumulative effect of benzoate conjugation to drain these ammoniagenic precursors through glycine may be the basis of its therapeutic effect in hyperammonemia.

Ammonia↗
PubMed1989

Development and inducibility of the hepatic and renal hippurate-synthesizing system in sparse-fur (spf) mutant mice with ornithine transcarbamylase deficiency.

The development of the hepatic and renal hippurate-synthesizing system, as represented by the overall reaction of the benzoyl CoA: glycine N-acyltransferase (EC 2.3.1.13) was studied in 0, 4, 8, 13, 17, 21-day and 8-week old sparse-fur (spf) mutant mice with X-linked ornithine transcarbamylase (OTC) deficiency. The enzyme system in mutant males (spf/Y) showed a retarded development in both liver and kidney cortex, which was statistically significant between 13 and 21 days of age, as compared to normal males (+/Y). Hippurate synthesis in preparations from adult (8-week old) spf/Y mice was not significantly different than the normal. Daily intraperitoneal injections of sodium benzoate in increasing concentrations (125-375 mg/kg), given between 17 and 21 days, did not cause any induction in spf/Y or +/Y mice. However, intraperitoneal sodium phenobarbital (80 mg/kg) increased the specific and total activities of the hepatic enzyme system in normal +/Y mice significantly. spf/Y tolerated a dose of 40 mg/kg only, which resulted in no significant increase of hepatic enzyme activity. The results indicate that barbiturates may induce the hippurate-synthesizing system, whereas benzoate treatment has no effect on changing its developmental profile.

Acyltransferases↗
PubMed1988

A twenty-year experience with thyroid carcinoma in children.

During the past 20 years, 23 patients (7 males, 16 females) were operated on for thyroid carcinoma in our institution. The average age was 13.6 years (range, 22 months to 27 years). Our series includes papillary carcinoma in 11, follicular carcinoma in four, and medullary thyroid carcinoma in eight patients. Follow-up ranged from 8 months to 20.3 years, with an average of 7.5 years for well-differentiated carcinomas and 4.3 years for medullary thyroid carcinomas. All patients are presently alive with no evidence of progressive disease. Patients with papillary and follicular carcinomas underwent partial thyroidectomy; those with medullary carcinoma underwent total thyroidectomy. Serious complications included three permanent hypoparathyroidism and two tracheostomies, all after secondary neck explorations. The overall results observed in our series of patients seem to support the current conservative approach to well-differentiated thyroid carcinoma, reserving total thyroidectomy for medullary cancer of the thyroid. A more aggressive search for familial medullary carcinoma through use of pentagastrin stimulation leads to early detection and more effective therapy.

Adenocarcinoma↗
PubMed1988

Useful parameters to predict the eventual mental outcome of hypothyroid children.

The Quebec Network for Genetic Medicine has followed the development of some 100 hypothyroid children treated by 1 month of age and evaluated at 18 months, 3 and 5 yr and the Griffiths Mental Development Scales, then at 7 and 9 yr with the Wechsler Intelligence Scale for Children Revised. Results show that the children as a group reach scores within the normal range of the tests. However, a few patients have low scores at each evaluation. Previously, we showed a correlation between a low serum thyroxine concentration, or a relatively retarded bone maturation before treatment, and low mental scores. To better characterize the significance of this relationship we correlated these pretreatment factors and the Wechsler Intelligence Scale for Children Revised results of 43 subjects reaching the age of 7 yr. Again, the same correlation was observed. Calculating a predictive factor (low thyroxine, less than 2 micrograms/dl and retarded bone surface, less than 0.05 cm2) from data recorded before therapy initiation, 10 of 13 children were correctly predicted to have I.Q. values less than 90. The use of these parameters might permit early intervention, and allow specific guidance of the more affected subjects.

Bone Development↗
PubMed1988

A study on the inheritance of thyroxine-binding globulin (TBG) deficiency from data obtained in 13 families detected by a neonatal screening program.

Thirteen families with thyroxine-binding globulin deficiency, detected through probands screened by the Quebec Network of Genetic Medicine, were investigated. These families were divided into two groups, depending on whether hemizygous males had low or undetectable serum thyroxine-binding globulin levels. Five families belonged to the low (hypo-TBGnemic) type while the remaining 8 families belonged to the absent (a-TBGnemic) type. On pedigree analysis, 10 families satisfied the requirements for an X-linked co-dominant mode of transmission. Three families, 2 a-TBGnemic and 1 hypo-TBGnemic, did not satisfy these requirements and three hypotheses had to be put forward to explain these situations: an autosomal recessive mode of transmission, a spontaneous mutation, or an extreme lyonisation of the defective X. Since the thyroxine-binding globulin gene has been localized to the X-chromosome, the two latter explanations appear to be the most plausible.

Female↗
PubMed1988

Circulating lipids and lipoproteins in glycogen storage disease type I with nocturnal intragastric feeding.

With the advent of nocturnal intragastric feeding which protects against acute metabolic complications and promotes growth, patients with glycogen storage disease type I are attracting less attention. However, several biochemical alterations persist and suggest that the long-term risk of atherosclerotic heart disease remains high. Persisting hypertriglyceridemia and hypercholesterolemia were found in seven glycogen storage disease type I subjects, six of them following 5-6 yr of nocturnal intragastric feeding. When compared to ten age-matched controls, the patients showed significantly (P less than 0.001) higher low density lipoprotein cholesterol (LDL-C) (247.7 +/- 46.8 vs. 115.3 +/- 5.0 mg/dl) and lower high density lipoprotein cholesterol (HDL-C) (26.4 +/- 3.4 vs. 55.8 +/- 2.9 mg/dl). Triglyceride (TG) enrichment with cholesteryl ester depletion characterized the lipoprotein classes. The diameters of very low density lipoproteins (VLDL) and LDL were larger, while that of HDL was smaller and consistent with the predominance of the HDL3 subclass and a lower apoA-I/apoA-II ratio. The raised levels of TG appeared attributable not only to the well-described lipogenesis, but also to impaired catabolism of fat, as evidenced by the significantly (P less than 0.001) decreased activity of both peripheral lipoprotein lipase (3.17 +/- 0.43 vs. 14.15 +/- 0.50 mumol FFA.ml-1.hr-1) and hepatic lipase (1.88 +/- 0.30 vs. 4.83 +/- 0.90). This may well explain the high concentration of intermediate density lipoprotein (IDL) and the impaired conversion of HDL3 to HDL2. Low apoC-II/apoC-III1 could be related to defective lipoprotein lipase activity. These data suggest that glycogen storage disease type I patients on nocturnal intragastric feeding remain at risk for atherosclerosis and its complications.

Adolescent↗
PubMed1987

Plasma and lipoprotein fatty acid composition in glycogen storage disease type I.

Nocturnal intragastric feeding has been shown to be an effective means to improve clinical and biochemical features in glycogen storage disease type I (GSD-I). In this study, we investigated the fatty acid patterns in a whole plasma and in circulating lipoproteins in patients on this therapy. The results demonstrated massive concentration of total fatty acids coupled with higher levels of triglycerides, free cholesterol, cholesterol ester and phospholipids. This hyperlipidemia involved all fatty acids without distinction of carbon or bond numbers. However, the increase was more pronounced for saturated than polyunsaturated fatty acids, as was demonstrated by the ratios of both oleic acid to linoleic acid (1.91 +/- 0.40 vs 0.80 +/- 0.09 in controls) and of omega 3 + omega 6 to omega 9 fatty acid families (0.92 +/- 0.11 vs 1.66 +/- 0.08 in controls). The fatty acid patterns in very low (VLDL), low (LDL) and high (HDL) density lipoprotein showed substantial differences in composition, reflecting an association between an abnormal lipoprotein pattern and essential fatty acid deficiency. Furthermore, GSD-I patients exhibited a significant increase in VLDL (17 +/- 2 vs 47 +/- 7 mg/dl) and LDL cholesterol (124 +/- 7 vs 206 +/- 24 mg/dl), coupled with a decrease in HDL cholesterol (49 +/- 4 vs 28 +/- 3 mg/dl). These data documenting high LDL cholesterol and low HDL cholesterol associated with an increased concentration and proportion of saturated fatty acids suggest that GSD-I patients on nocturnal intragastric feeding are at high risk for atherosclerosis and its complications.

Adolescent↗
PubMed1987

Somatosensory evoked potentials and auditory brain-stem responses in congenital hypothyroidism. II. A cross-sectional study in childhood. Correlations with hormonal levels and developmental quotients.

We report the results of somatosensory evoked potentials (SEPs) and auditory brain-stem responses (ABRs) done in 48 congenital hypothyroid (CH) treated children, early detected and aged 18 months, 3 and 5-9 years of age. We report also the results of SEP and ABR done in 9 3-year-old CH children, before and after a 1 month therapy interruption to reassess the thyroid status. The more frequent abnormalities were increased wave I latencies for 18 month and 3-year-old CH children. In some children, these increases were not associated with signs of otitis media. No significant difference was seen between CH children and controls for SEP latencies and ABR and SEP interpeak latencies (IPLs). Similarly, no significant difference was seen between the two recording sessions in the 9 3-year-old CH children for ABR and SEP. On an individual basis, we observed abnormalities of central conduction time for ABR and SEP in several CH children. Moreover, significant partial correlations were found between ABR and SEP IPLs and thyroxine (T4) serum levels at diagnosis and thyrotropin (TSH) serum levels at the time of recording. There was also a significant partial correlation between N19-P22 IPLs and the practical reasoning scale of the Griffiths test considering the whole group of CH children. These results indicate that SEP might eventually be used to detect CH children at risk of presenting developmental abnormalities.

Brain Stem↗
PubMed1987

Malabsorption, hypocholesterolemia, and fat-filled enterocytes with increased intestinal apoprotein B. Chylomicron retention disease.

Eight infants presented with a malabsorption syndrome, normal fasting triglycerides, hypocholesterolemia (64.3 +/- 10.0 mg/dl), and deficiency of vitamins A and E. Plasma low-density lipoprotein, apolipoprotein B, and apolipoprotein A-I were decreased. After a fatty meal, plasma triglycerides did not increase and chylomicrons could not be identified. Lipoprotein composition was characterized by normal apoproteins, high phospholipids, and low cholesterol. Increased triglycerides were present in low-density lipoproteins. Immunoperoxidase localization of apolipoprotein B on fasting biopsy specimens showed increased staining of the lipid-laden intestinal epithelial cells compared to normals. On electron microscopy after a fat load, the enterocytes contained large numbers of fat particles vesiculating the endoplasmic reticulum. These particles, morphologically similar to chylomicrons, were also present as aggregates of well-individualized lipid droplets within dilated vesicles in the Golgi zone, but were not seen in the intercellular spaces and lacteals. This recessively transmitted condition differs from abetalipoproteinemia and from the homozygous form of hypobetalipoproteinemia and may be caused by a defect in the final assembly of chylomicrons or in the mechanism of their exocytosis.

Apolipoproteins B↗
PubMed1986

Kinetic abnormalities of carbamyl phosphate synthetase-I in a case of congenital hyperammonaemia.

A sensitive direct colourimetric method has been employed to measure kinetic parameters and pH dependence of carbamyl phosphate synthetase-I, in a liver sample from a 2 1/2-month-old girl, who died from complications of a late-developing congenital hyperammonaemia. The residual activity of carbamyl phosphate synthetase-I was 25%, whereas other urea cycle enzymes were within normal range. Apparent Km for ammonium ion (0.73 mmol/L) was significantly increased (normal range 0.24-0.51). Km for bicarbonate ion was normal, while Km for NAG showed a slight variation from normal. The pH dependence curve of the patient's enzyme was flat, as compared to two controls showing pH optima at 7.8. Radial immunodiffusion (Mancini) of the abnormal enzyme against human enzyme antiserum gave a cross-reacting material of 10-20%. The methodological approach presented can be used to characterize abnormal enzymes in cases of partial deficiency with only 100-200 mg of liver tissue.

Amino Acid Metabolism, Inborn Errors↗
PubMed1986

Somatosensory evoked potentials and auditory brain-stem responses in congenital hypothyroidism. I. A longitudinal study before and after treatment in six infants detected in the neonatal period.

We report the results of a longitudinal study of auditory brain-stem responses (ABRs) and somatosensory evoked potentials (SEPs) performed in 6 children with congenital hypothyroidism. These infants were detected by the Quebec Network for Genetic Medicine and treated early. ABRs and SEPs were recorded both before and 2 weeks after the initiation of therapy and at 6 months of age. Before treatment, for SEP, we found increased wave N19, P22 latencies and N13-N19, N19-P22 interpeak latencies (IPLs) in congenital hypothyroid (CH) children. For ABR, there were increased wave I latencies with normal I-V IPLs. Substitutive therapy improved these abnormalities although this improvement was more evident after a shorter period of time for ABRs than for SEPs. Even at 6 months, 2 CH children still showed increased N13-N19 IPLs. Both had very low serum T4 levels at the time of diagnosis and one had also a very small knee surface area, both criteria indicating a severe hypothyroidism. It will be interesting to verify if initial and persisting increase of N13-N19 IPL is associated with later neuropsychological problems.

Congenital Hypothyroidism↗
PubMed1986

The role of hepatic ornithine transcarbamylase deficiency in the orotic aciduria of pregnant mice.

Groups of normal and heterozygote sparse-fur (spf) mutant mice were studied at various stages of gestation, to assess the effects of normal pregnancy on orotate excretion, hepatic mitochondrial urea cycle enzymes and any predisposition to the development of fatty liver. Results show a higher total daily excretion of urinary orotate by normal pregnant mice on the 8th and 15th days of gestation, which came to within the usual basal range of excretion of non-pregnant mutant heterozygotes with hereditary ornithine transcarbamylase deficiency. Liver ornithine transcarbamylase and carbamyl phosphate synthetase-I activities were reduced in pregnant mice on the 16th day of gestation (P less than 0.05). No fatty change, bile stasis or glycogen depletion was discernible on optical microscopy in normal or mutant mice. Nonspecific changes were seen on ultrastructural examination. Orotic aciduria seen in pregnant mice may be directly related to a physiological deficiency of liver ornithine transcarbamylase. However, the depletion of both the mitochondrial urea cycle enzymes, seen on the 16th day of pregnancy, may be indicative of a metabolic stress at the mitochondrial level.

Animals↗
PubMed1986

Postnatal maturation of enterocytes in sparse-fur mutant mice.

In adult sparse-fur mutant mice, ornithine transcarbamylase (OTC) activity represents only 14% of the normal values. We studied the development of this activity from birth to adult period and demonstrated that the enzyme deficiency is already fully expressed at birth, in both the liver and the small intestine of mutants. Since OTC catalyzes the conversion of ornithine to citrulline, in the presence of carbamoyl-phosphate, the effect of a disturbed ornithine metabolism on the postnatal development of the small intestine has been evaluated. The normal appearance of sucrase as well as the normal increase of glucoamylase, trehalase, and alkaline phosphatase activities are delayed in sparse-fur mice compared with controls. Moreover, normal adult values are never attained. In contrast, the normal decline of lactase activity is impaired while leucylnaphthylamidase activity is unaffected. Cell proliferation, as evaluated by [3H]thymidine incorporation into DNA and mitotic index, is less active during the 3rd wk of life in mutants. These phenomena are closely associated with a transient weak arginase and ornithine decarboxylase activity in the small intestine. Since arginase catalyzes the conversion of arginine to orthithine, thus ensuring the availability of this substrate for ornithine decarboxylase activity, these results indicate a disturbance of polyamine metabolism in mutant enterocytes with a consequent delay in postnatal differentiation and proliferation. Sparse-fur mutant mouse may therefore represent a useful animal model for evaluating the role of ornithine metabolism in the maturation process of the small intestine.

Animals↗