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Biomedical subjects

R Clarke

Publications and source records attributed to R Clarke.

At least 181 records · Page 10Linked to original sources
PubMed1991

Hyperhomocysteinemia: an independent risk factor for vascular disease.

BACKGROUND: Hyperhomocysteinemia arising from impaired methionine metabolism, probably usually due to a deficiency of cystathionine beta-synthase, is associated with premature cerebral, peripheral, and possibly coronary vascular disease. Both the strength of this association and its independence of other risk factors for cardiovascular disease are uncertain. We studied the extent to which the association could be explained by heterozygous cystathionine beta-synthase deficiency. METHODS: We first established a diagnostic criterion for hyperhomocysteinemia by comparing peak serum levels of homocysteine after a standard methionine-loading test in 25 obligate heterozygotes with respect to cystathionine beta-synthase deficiency (whose children were known to be homozygous for homocystinuria due to this enzyme defect) with the levels in 27 unrelated age- and sex-matched normal subjects. A level of 24.0 mumol per liter or more was 92 percent sensitive and 100 percent specific in distinguishing the two groups. The peak serum homocysteine levels in these normal subjects were then compared with those in 123 patients whose vascular disease had been diagnosed before they were 55 years of age. RESULTS: Hyperhomocysteinemia was detected in 16 of 38 patients with cerebrovascular disease (42 percent), 7 of 25 with peripheral vascular disease (28 percent), and 18 of 60 with coronary vascular disease (30 percent), but in none of the 27 normal subjects. After adjustment for the effects of conventional risk factors, the lower 95 percent confidence limit for the odds ratio for vascular disease among the patients with hyperhomocysteinemia, as compared with the normal subjects, was 3.2. The geometric-mean peak serum homocysteine level was 1.33 times higher in the patients with vascular disease than in the normal subjects (P = 0.002). The presence of cystathionine beta-synthase deficiency was confirmed in 18 of 23 patients with vascular disease who had hyperhomocysteinemia. CONCLUSIONS: Hyperhomocysteinemia is an independent risk factor for vascular disease, including coronary disease, and in most instances is probably due to cystathionine beta-synthase deficiency.

Cerebrovascular Disorders↗
PubMed1991

The multidrug resistance phenotype: 31P nuclear magnetic resonance characterization and 2-deoxyglucose toxicity.

In order to identify changes in 31P nuclear magnetic resonance (NMR) spectra associated with multiple drug resistance (MDR), a number of wild type and drug-resistant cancer cell lines were studied. The resistant cells included cells selected with various drugs, mainly Adriamycin, as well as cells transfected with the human multidrug resistance gene (MDR1 gene), which encodes P-glycoprotein. In most cases, 31P NMR spectra were significantly different from those of parental, drug-sensitive lines. The spectra of resistant cells generally indicated increased levels of ATP and phosphocreatine in the cytoplasm. These changes are compatible with the increased glucose utilization rate previously described for resistant cells. Major changes were also observed in the levels of glycerophosphocholine and glycerophosphoethanolamine. Changes in cellular metabolism reflected by 31P NMR spectra depend on the drug used to select the cells for MDR. The direction of these changes was not consistent for all cell lines studied and could not be directly attributed to expression of P-glycoprotein, suggesting that the changes may be related to alterations in metabolism and membrane function associated with other mechanisms of MDR. The results demonstrate the suitability of 31P NMR for studies of biochemical changes associated with MDR. The toxicity of 2-deoxyglucose, a glucose antimetabolite, was investigated in addition to the NMR studies and was found to be consistently higher in multidrug-resistant cells than in the parental drug-sensitive lines. For MCF-7 breast cancer cells, where several sublines with different levels of resistance were available, the toxicity was highest for the most resistant lines.

Adenosine Triphosphate↗
PubMed1991

Nutritional rehabilitation increases resting energy expenditure without affecting protein turnover in patients with cystic fibrosis.

The effect of nutritional rehabilitation on several nutritional parameters was studied in eight malnourished patients with cystic fibrosis during the first year after gastrostomy tube insertion. Body composition was studied by fat skinfold measurements and by total body potassium count, resting energy expenditure (REE) by indirect calorimeter, and protein turnover by a single dose administration of [15N]glycine. Weight gain was accompanied by a significant increase in the various body compartments: weight 41.4 +/- 7.5 to 46.1 +/- 8.4 kg (p less than 0.0002), fat body mass 5.6 +/- 2.8 to 7.7 +/- 3.4 kg (p less than 0.005) and fat-free body mass (FFBM) 35.7 +/- 6.3 to 38.3 +/- 6.9 kg (p less than 0.0003). REE increased significantly per kg of body weight as well as per kg of FFBM. No significant differences were found in protein turnover during refeeding nor in pulmonary function. We conclude that nutritional support restores body composition, but is accompanied by an increase in energy expenditure. This increase could not be attributed to increased protein turnover.

Adolescent↗
PubMed1991

Development of verotoxin 2- and verotoxin 2 variant (VT2v)-specific oligonucleotide probes on the basis of the nucleotide sequence of the B cistron of VT2v from Escherichia coli E32511 and B2F1.

We and others have noted that there are serological differences between verotoxin 2 (VT2) (also known as Shiga-like toxin II) produced by Escherichia coli C600(933W) and the VT2 variant (VT2v) produced by strain E32511. Recent reports have described nucleotide sequence differences between the VT2v B subunit cistron of E32511 and B2F1 and that of VT2. We have confirmed the sequence differences and have used them to design oligonucleotide probes which differentiate the B subunit cistron of VT2v from that of VT2. Isolates of VT-producing E. coli obtained from human as well as food and veterinary sources were classified according to the toxin phenotype by using a toxin neutralization assay with VT2-specific monoclonal antibody and VT2v-specific polyclonal antisera. Using the oligonucleotide probes in colony hybridization, we detected 35 of 35 VT2 producers and 16 of 16 VT2v producers. One VT2 producer was falsely identified as containing the VT2v gene. The E32511 strain in our collection hybridized only with the VT2-specific probe. Southern hybridization of radiolabeled oligonucleotide probes showed that strains carried zero to one copy of the VT2 gene and zero to two copies of the VT2v gene. We conclude that colony hybridization with the VT2- and VT2-specific probes is highly predictive of the toxin phenotypes in the clinical isolates described in this study.

Amino Acid Sequence↗
PubMed1991

Hyperhomocysteinaemia and multiple aneurysms.

Homozygous homocystinuria, the most common genetic disorder of transulphuration, is associated with elevated plasma concentrations of homocystine, homocysteine, multiple clinical abnormalities and life-threatening thromboembolism. Several instances of vascular aneurysms have also been documented. More recently, an association between premature occlusive vascular disease and the heterozygous state has been proposed. We now report an unusual case in whom multiple aneurysms were associated with heterozygous homocystinuria.

Amino Acid Metabolism, Inborn Errors↗
PubMed1991

Factors driving costs must figure into reform.

Employers and employees seeing their health plan premium costs rise faster than physician and hospital costs is one indication that the U.S. healthcare system is in a state of crisis. Examining factors behind providers' and health plans' costs--demographics, increased hospital expenses, insurance overhead, fragmentation among managed care plans, and failure of some cost-containment initiatives--indicates the shape healthcare reform must take if it is to succeed. Reform proposals in the 1990s likely will entail simplification and consolidation, such as providing universal access, consolidating managed care, and establishing a single-payer system.

Canada↗
PubMed1991

Effect of refeeding on the energy metabolism of adolescent girls who have anorexia nervosa.

The effect of refeeding on resting energy expenditure (REE) and substrate utilization was studied in 18 hospitalized adolescent girls (aged 12.9-19.1 years) suffering from anorexia nervosa. Changes in body composition were monitored weekly and included weight, fat body mass (FBM), lean body mass (LBM) and total body potassium (TBK). REE was studied weekly by open-circuit calorimetry. Weight gain was noted in all patients (38.2 +/- 5.6 to 44.5 +/- 5.3 kg), involving increased FBM and LBM. REE increased per kg of weight (91.6 +/- 15.1 to 101.7 +/- 18.0 kJ kg-1 d-1) and LBM over the first weeks of refeeding (P less than 0.025) and then stabilized. Substrate utilization showed an increase in carbohydrate and protein utilization (P less than 0.001) during the first few weeks of refeeding. We also studied the thermic effect of food (TEF) in 14 of the 18 subjects. Upon admission the subjects had a reduced TEF (36.4 +/- 24.3 kJ 2 h-1) (P less than 0.001). With refeeding TEF rose to a peak or plateau, then decreased to normal levels (61.9 +/- 36.0 kJ 2 h-1) before discharge from hospital. We conclude that the energy metabolism of adolescent girls adapts to semi-starvation by a reduction in both REE and TEF; with refeeding there is reversal of this adaptive function.

Adolescent↗
PubMed1991

Inhibition of cholesterol side-chain cleavage. Part 5. Synthesis of 22-(p-chlorophenyl) cholesterol analogues.

Three 22-(p-chloroaryl) analogues of cholesterol (6a-c) were synthesized and evaluated as potential inhibitors of the adrenal cholesterol side-chain cleavage enzyme, in comparison with the known 20-aryl analogue, 20-(p-chlorophenyl)-5-prenen-3 beta,20-diol (2b). All were potent inhibitors. An oxygen at C-22 (analogues 6a and 6b) enhanced the strong binding to the enzyme. Two compounds (6b and 6c) are potential substrates of the enzyme. Possible pharmaceutical uses for these compounds and their derivatives are discussed.

Adrenal Glands↗
PubMed1990

Reduction of the membrane fluidity of human breast cancer cells by tamoxifen and 17 beta-estradiol.

The intracellular steady-state levels of methotrexate were previously shown to be reduced in estrogen receptor (ER)-negative human breast cancer MDA-MB-436 cells and ER-positive human breast cancer MCF7 cells following treatment with pharmacologically relevant concentrations of 17 beta-estradiol (E2). We now report that both E2 and tamoxifen (TMX) significantly decreased the fluidity of MCF7 and MDA-MB-436 cellular membranes. With E2 or TMX at concentrations greater than 1 microM, perturbations in membrane fluidity were accompanied by apparently non-ER-mediated cytotoxicity. Alterations in membrane structure may have contributed to the cytotoxicity of high-dose endocrine therapy and to the ability of E2 to inhibit methotrexate transport and cytotoxicity in some human breast cancer cells.

Breast Neoplasms↗
PubMed1990

The effects of heparin upon atherogenesis in the Watanabe heritable hyperlipidemic rabbit.

Heparin is routinely added to vascular cell cultures to inhibit smooth muscle cell proliferation. The in vivo effects of heparin upon atherogenesis have remained controversial, however. In this experiment 13 four-month-old, heritably hyperlipidemic, Watanabe rabbits were randomly assigned to three treatment groups: 1500 U heparin, 500 U heparin, or saline. An injection protocol was followed for nine months. The rabbits were bled monthly from their marginal ear veins and plasma from these bleeds was analyzed for cholesterol and triglyceride content. At sacrifice each rabbit's aorta was sampled at 10 specific locations from the arch to the iliac bifurcation. The reduction in the area of the aorta by atherosclerotic plaque at each site was calculated using a video imaging system. Heparin injections significantly reduced mean plasma levels of cholesterol and triglycerides compared to pretreatment levels and saline injected controls. However, the magnitude of the reduction was not dose-related. The aortic luminal area occupied by atherosclerotic plaque in rabbits injected with 1500 U of heparin was significantly less (p less than .05) than in rabbits injected with saline or 500 U of heparin. Plaques from heparin-treated animals contained more fatty deposits and foam cells compared to the plaques from saline-treated rabbits which were more fibromuscular in organization. We conclude that heparin modulates the occurrence and composition of atherosclerotic plaques in this animal model of naturally occurring atherogenesis.

Analysis of Variance↗
PubMed1990

Localized fibrous tumors of the pleura: correlation of histopathological, immunohistochemical and ultrastructural features.

The histogenesis of localized fibrous tumor of the pleura (LFTP) is controversial. We studied 12 LFTP's by light microscopy; by immunohistochemical staining for cytokeratin (CK), vimentin, muscle-specific actin, desmin, S-100 protein, epithelial membrane antigen (EMA) and factor VIII; by electron microscopy in 6 tumors; and by lung digestion for asbestos bodies in 4 cases. Three histologic patterns occurred in combination: 1) collagenous, 2) cellular and 3) hypocellular/myxoid. Hemangiopericytoma-like foci were prominent in the cellular areas of 9 tumors. Unusual features included diffuse small cells in 3 tumors, microcystic foci in 2, macrocystic areas in 5 and tumor giant cells in 4 tumors. Neoplastic cells in all patterns stained positively for vimentin and actin in 9 and 4 tumors, respectively, and were negative for all other markers. CK and EMA were identified in mesothelial and epithelial invaginations only. Ultrastructurally, neoplastic cells demonstrated intercellular junctions, intermediate or thin filaments, dense bodies and rough endoplasmic reticulum. Basal lamina was focally present in 5 tumors, while tonofilaments, desmosomes and short microvilli were observed in one case. Our results support the conclusion that LFTP is a neoplasm of the multipotential subserosal cell, and usually expresses mesenchymal (fibroblastic/myofibroblastic) differentiation. Coexpression of mesothelial features is rare. Lung asbestos body quantitation in 4 patients suggests that there is no association between LFTP and asbestos exposure.

Actins↗