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Biomedical subjects

S Jackson

Publications and source records attributed to S Jackson.

At least 253 records · Page 14Linked to original sources
PubMed1991

Metabolic consequences of methylenecyclopropylglycine poisoning in rats.

We describe the effects of methylenecyclopropylglycine in fasted rats. A 75% decrease in the blood glucose concentration and an increase of lactate and pyruvate were observed 6 h after administration of 100 mg of this amino acid/kg. By contrast with the effects reported for hypoglycin [Williamson & Wilson (1965) Biochem. J. 94, 19c-21c], the plasma concentrations of ketone bodies decreased after administration of methylenecyclopropylglycine and the concentrations of branched-chain amino acids in the plasma were increased 6-fold. The oxidation of decanoylcarnitine or of palmitate was nearly completely inhibited in rat liver mitochondria from methylenecyclopropylglycine-poisoned rats. The activities of acetoacetyl-CoA and of 3-oxoacyl-CoA thiolase were decreased to 25% and less than 10% of the controls. There was a pronounced aciduria, due to the excretion of dicarboxylic acids and of oxidation products of branched-chain amino acids. The accumulation of the toxic metabolite methylenecyclopropylformyl-CoA in the mitochondrial matrix was detected after administration of methylenecyclopropylglycine. Similarly we confirmed experimentally that methylenecyclopropylacetyl-CoA accumulates in mitochondria incubated with methylenecyclopropylpyruvate.

Acyl Coenzyme A↗
PubMed1991

Immunoreactive enzyme protein in medium-chain acyl-CoA dehydrogenase deficiency.

Medium-chain acyl-CoA dehydrogenase (MCAD) deficiency is a common inborn error of mitochondrial fatty acid oxidation. To determine if immunoreactive enzyme protein is present in patients with MCAD deficiency, we studied cultured skin fibroblasts from patients with the 985 point mutation, present in about 85% of cases, and cell lines from patients in which the point mutation is not present or only involves one allele. Immunoblotting studies, using a polyclonal antibody to the purified protein, showed an absence of immunoreactive protein in mitochondrial fractions prepared from fibroblasts from MCAD-deficient patients. To determine whether MCAD protein accumulated in the cytosol because of impaired transport into the mitochondria, we immunoprecipitated MCAD protein from the fibroblast homogenate. MCAD protein was detected in the immunoprecipitates from controls, but not in those from the MCAD-deficient patients. These results suggest that either the MCAD protein is not synthesised or, if produced, it is rapidly degraded.

Acyl-CoA Dehydrogenase↗
PubMed1991

IGF1 and 2 in two models of adrenal growth.

Insulin-like growth factors (IGFs) 1 and 2 were measured in the adrenal glands of rats undergoing either compensatory growth following left unilateral adrenalectomy or adrenal regeneration following bilateral adrenal enucleation. In normal rat adrenal gland, the tissue concentration of IGF2 (7.45 +/- 0.99 pg/micrograms protein) wa higher than IGF1 (1.26 +/- 0.23 pg/micrograms protein), both peptides being more abundant in the inner zones of the adrenal gland compared to the capsule-glomerulosa. During compensatory growth of the right adrenal gland, IGF1 and 2 increased significantly compared with control right adrenal glands at 24 h following left unilateral adrenalectomy (P less than 0.001). At 68 h, the increase remained significant for IGF1 (P = 0.012). The two peptides were measured in the regenerating adrenal gland at 7, 14 and 21 days following bilateral enucleation. Whilst there was a trend towards an increase in the IGF1 and 2 content of regenerating adrenal glands, the increase was significant only for IGF2 in the left adrenal gland at 21 days following enucleation. Plasma IGF1 and 2 did not increase compared to controls during the experiments (110.97 +/- 1.95 and 46.33 ng/ml, respectively), suggesting that the changes in tissue IGF reflect increased local production during rapid growth of the adrenal gland.

Adrenal Glands↗
PubMed1991

Selective elevation of monomeric IgA1 in IgA nephropathy patients with normal renal function.

The molecular form of the pathognomonic IgA in IgA nephropathy (IgAN) remains controversial. Because characterization of the molecular form of IgA molecules can lend insight into their origin (systemic v mucosal), we developed immunoassays to measure both total and J chain-containing (polymeric) IgA1 and IgA2. These assays were used to measure IgA in sera from two groups of IgAN patients (with normal or decreased renal function), as well as from a group of normal individuals. IgA1 levels were higher in both groups of patients with IgAN when compared with the controls. The elevation appeared to be restricted to non-J chain-containing (monomeric) IgA1 in patients with normal renal function, whereas polymeric IgA1 was also slightly elevated in patients whose renal function was diminished. While there were no significant differences between the groups in terms of the levels of total IgA2, the patient group with normal kidney function appeared to have lower levels of polymeric IgA2. The observation that the elevation in serum IgA appears to be restricted to the monomeric form of IgA1, at least when renal function is normal, implies a systemic origin of the pathognomonic IgA in IgAN and further suggests an abnormality in the regulation of IgA secretion by immunoglobulin-producing cells in bone marrow, the site of systemic IgA synthesis.

Adolescent↗
PubMed1991

Epstein-Barr virus transformation of B lymphocytes from IgA nephropathy patients and first-degree relatives results in increased immunoglobulin synthesis not restricted to IgA.

In order to study B-cell activation patterns independent of T-cell regulation in patients with IgA nephropathy (IgAN), peripheral blood mononuclear cells from 67 patients with IgAN, 15 first-degree relatives of patients with familial disease, and 13 normal controls were transformed with Epstein-Barr virus (EBV). Culture supernatants of these transformed cells were assayed for levels of IgG, IgA, and IgM, and results obtained on the three populations were compared. EBV-transformed cells of IgAN patients, as well as the population of first-degree relatives, secreted significantly elevated levels of all three isotypes as compared with the normal controls. However, in comparing ratios of secreted isotypes, it was determined that more IgA relative to IgG and IgM was synthesized by cells of these two populations as compared with the normal controls. Our results imply that (1) the population of B cells susceptible to EBV activation is increased in IgAN patients; (2) this population of "activatable" B lymphocytes is polyclonal and not restricted to the IgA class; and (3) even though there may be a primary B-cell abnormality in IgAN, an additional defect(s) is probably operative in the pathogenesis, since cells of clinically unaffected relatives behaved in a pattern similar to that of patients.

B-Lymphocytes↗
PubMed1991

IgA nephropathy in blacks: studies of IgA2 allotypes and clinical course.

The prevalence of IgA nephropathy (IgAN) varies among racial groups, being most common among Caucasians and Orientals and rare in Blacks. Other investigators have hypothesized that the risk for IgAN may be influenced by the IgA2 allotype. It has been suggested that the rare Black patients with IgAN may be homozygous for the A2m(1) allele which predominates in Whites, but is less common in Blacks. In a multicenter study, 27 Black IgAN patients were enrolled to investigate this hypothesis and analyze the clinical course of disease in Blacks. The IgA2 allotypes of 18 Black patients and 14 controls were determined using restriction fragment length polymorphism analysis. Three patients were homozygous for the A2m(1) allele, four were homozygous for A2m(2) and 11 were heterozygous. The respective allelic frequencies of A2m(1) and A2m(2) were 0.47 and 0.53 and did not differ significantly from Black controls. Most clinical manifestations of disease did not significantly differ with respect to distribution of the two alleles, although the gender ratio differed between the homozygous A2m(1) and heterozygous patients. The presence of the A2m(1) allele did not increase the risk for IgAN, and the presence of the A2m(2) allele or homozygosity for this allele did not protect Blacks from the development of IgAN.

Adult↗
PubMed1991

DNA looping between sites for transcriptional activation: self-association of DNA-bound Sp1.

The Sp1 protein activates transcription from many eukaryotic promoters. Sp1 can act in vivo from enhancer sites that are distal to the promoter and exhibit synergistic interaction with promoter-proximal binding sites. To investigate possible protein-protein interactions between DNA-bound Sp1 molecules, we have used electron microscopy to visualize the DNA-protein complexes. At the SV40 promoter, we observed the expected localized interaction at the Sp1 sites; in addition, we found that DNA-bound Sp1 served to associate two or more DNA molecules. At a modified thymidine kinase promoter, we observed a localized interaction at each of two binding locations that were separated by 1.8 kbp; in addition, we noted a substantial fraction of DNA molecules in which the distant binding regions were joined by a DNA loop. As judged by studies with mutant Sp1 proteins, the distant interactions depended on the glutamine-rich regions of Sp1 required for transcriptional activation. We conclude that DNA-bound Sp1 can self-associate, bringing together distant DNA segments. From the correlation between DNA looping in vitro and synergistic activation of the modified thymidine kinase promoter shown previously in vivo, we suggest that Sp1 exerts its transcriptional synergism by a direct protein-protein association that loops the intervening DNA. Our experiments support the DNA-looping model for the function of transcriptional enhancers.

Base Sequence↗
PubMed1991

Long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency.

We describe the clinical features and biochemical findings of two patients with long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Both children presented with an acute metabolic crisis. Both had hypoglycemia and excreted even-chain unsubstituted dicarboxylic and 3-hydroxy-dicarboxylic acids in the urine. Measurement of the enzymes of fatty acid oxidation in cultured skin fibroblasts showed low activity of long-chain 3-hydroxyacyl-CoA dehydrogenase, but normal activity of short-chain 3-hydroxyacyl-CoA dehydrogenase. The defect was further characterized by immunoprecipitating the short-chain enzyme using monospecific antibodies. It is probably inherited as an autosomal recessive trait, inasmuch as intermediate enzyme activity was found in the fibroblasts from the parents of one child.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1991

Deficiency of the pyruvate dehydrogenase complex and of mitochondrial fatty acid oxidation.

Defects of the pyruvate dehydrogenase complex and of mitochondrial fatty acid oxidation are important causes of disease. Defects of pyruvate dehydrogenase may present in early childhood with severe CNS changes or, as lactic acidosis or later with ataxia. Defects of fatty acid oxidation may present with hypoglycaemic coma, myopathy, liver disease with encephalopathy, cardiomyopathy or sudden infant death. The investigation of both these groups of disorders is difficult and depends upon a combination of biochemical and molecular biology techniques.

Fatty Acids↗
PubMed1990

Liposomes containing anti-idiotypic antibodies: an oral vaccine to induce protective secretory immune responses specific for pathogens of mucosal surfaces.

By using a gnotobiotic rat model system to study the induction of protective immune responses by anti-idiotype (anti-id) vaccines specific for antibodies directed at the cariogenic microorganism Streptococcus mutans, it was shown that administration of such an anti-id vaccine provided partial protection against dental caries after challenge with virulent microorganisms. Protective effects were first demonstrated by direct parenteral administration of the anti-id vaccine into salivary gland regions, as determined by reductions in microbial colonization and caries scores. Subsequently, the anti-id was incorporated into liposomes and administered by gastric intubation. Immunization by this regimen also resulted in a significant reduction in caries as well as S. mutans colonization of the oral cavity, with concomitant increases in salivary immunoglobulin A anti-S. mutans antibodies. These data provide evidence that anti-id vaccines specifically targeted at the secretory immune system can induce protective immune responses to pathogens of mucosal surfaces.

Administration, Oral↗
PubMed1990

Impaired mitochondrial beta-oxidation in a patient with an abnormality of the respiratory chain. Studies in skeletal muscle mitochondria.

Defects of complex I of the mitochondrial respiratory chain are important causes of neurological disease. We report studies that demonstrate a severe deficiency of complex I activity with less severe abnormalities of complexes III and IV (less than 5, 63, and 30% of control values, respectively) in a skeletal muscle mitochondrial fraction from a 22-yr-old female with weakness, lactic acidemia, and the deposition of intramuscular neutral lipid. The observation that lipid accumulates in this and other patients with complex I deficiency suggests impaired mitochondrial fatty acid oxidation. To investigate this mechanism we have shown impaired flux through beta-oxidation [( U-14C]hexadecanoate oxidation was 66% of control rate) and accumulation of specific acyl-CoA ester intermediates. The changes in fatty acid metabolism in complex I deficiency are secondary to the reduced state within the mitochondrial matrix with low NAD+/NADH ratios.

Adult↗
PubMed1990

Plasma N-POMC, ACTH and cortisol concentrations in a psychogeriatric population.

Elderly patients with depression and Alzheimer-type dementia (ATD) were compared with age-matched control subjects using a protocol which measured cortisol, adrenocorticotrophic hormone (ACTH) and N-terminal pro-opiomelanocortin (N-POMC) to determine diurnal variation and the effect of dexamethasone administration. Depressed patients had significantly elevated cortisol concentrations both before and after dexamethasone administration. Basal ACTH and N-POMC concentrations were normal in depressed patients but were both elevated, compared with controls, after dexamethasone. By contrast, in ATD patients, cortisol was elevated only after dexamethasone, as was ACTH, but not N-POMC. This may imply that the pattern of secretion of POMC-derived peptides underlying increased cortisol secretion is different in ATD from that in depression.

Adrenocorticotropic Hormone↗
PubMed1989

Homoeopathy.

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Animals↗
PubMed1989

Enhancing health--a new agenda for Ontario.

Recognizing that changes in demography, the social environment, economics, technology and political trends are underlying factors affecting health, Paradigm Health in Toronto examined these considerations to assess change to achieve a positive vision of health. Phase I of the study looked at opportunities and threats from the broad external environment affecting health, examined the internal strengths and weaknesses of the present Ontario health system, and analyzed the participants in the system. Phase II identified the important strategic issues gathered from the environmental study, and the strategies which could deal with these issues.

Evaluation Studies as Topic↗
PubMed1989

Effect of procarbazine on sperm morphology in Syrian hamsters.

The effect of procarbazine, an antineoplastic drug, on the reproductive system of male Syrian hamsters was studied. Exposure to procarbazine (5 daily doses ranging from 20 to 500 mg/kg body weight) resulted in 5- to 7.5-fold increase in sperm abnormalities, diminished sperm counts, and smaller testes within 4 wk. Transmission electron micrographs showed severe damage to the acrosomal plasma membrane and nucleus of the sperm head in treated hamsters. These findings corroborate the detrimental effect of procarbazine on the germinal tissue and strengthen the basis for using the sperm morphology assay for the detection of mutagens and possibly other germ-cell toxicants in an in vivo mammalian system.

Animals↗