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Biomedical subjects

B M Elliott

Publications and source records attributed to B M Elliott.

At least 73 records · Page 4Linked to original sources
PubMed1987

Correlation of changes in transglutaminase activity and polyamine content of neoplastic tissue during the metastatic process.

Transglutaminase activity and the levels of the polyamines putrescine, spermidine and spermine were measured in two transplantable rat sarcomata: P8 which metastasises consistently to the lung, and P7 which metastasises infrequently. With the P7 sarcoma no metastases were detected following implantation; similarly, no significant changes occurred in the levels of transglutaminase activity, putrescine, spermidine or spermine during tumour growth. However, with the P8 sarcoma at approx. 30 days after implantation there was a marked decrease in transglutaminase activity, mirrored exactly by a 20-fold increase in the levels of acid-soluble putrescine. Measurement of covalently-bound polyamines in the P8 sarcoma indicated a significant and corresponding decrease in the levels of bound putrescine. The timing of these changes coincided with the time at which the P8 sarcoma was shown to have metastasised, and suggests that the changes observed may be related to this phenomenon.

Animals↗
PubMed1987

Lack of DNA damage or lipid peroxidation measured in vivo in the rat liver following treatment with peroxisomal proliferators.

This study was undertaken to investigate the hypothesis linking peroxisome proliferation with the production of reactive oxygen species and subsequent DNA damage. Hepatic peroxisomal proliferation was induced in male Wistar-derived rats by the administration of clofibrate, methyl clofenapate, di(2-ethylhexyl)phthalate, or its metabolite mono (2-ethylhexyl)phthalate (MEHP) for periods of up to 28 days. Genotoxicity was monitored using an alkaline elution technique to assay for DNA strandbreaks and cytotoxicity was monitored by measuring lipid peroxidation. Both parameters might be expected to be elevated if peroxisome proliferation is accompanied by an elevated level of oxygen free radicals within the cell. Enzyme measurements made on the livers of the treated rats showed that peroxisomal palmitoyl CoA oxidase activity was markedly increased over control whereas peroxisomal catalase activity was not. In addition, both the cytosolic glutathione peroxidase and superoxide dismutase activities were found to be lowered in the treated animals by up to 50 and 20% respectively. Despite such changes in enzyme activity, no evidence for increases in DNA strandbreaks or lipid peroxidation was obtained with any of the chemicals at any of the time points examined. DNA strandbreaks were also assayed on hepatocytes treated in culture with MEHP (0.5 mM) for 3 days and then exposed to inhibitors of DNA repair for 2 h immediately before assay. Again, no significant increase over controls was observed. Our data suggest that any increase in radical production in the livers of rats exposed to peroxisome proliferators is not large enough to give rise to a biologically significant degree of DNA damage and that the mechanism whereby such chemicals produce liver tumours in certain rodent species may be one other than simply DNA damage due to increased production of radical species.

Animals↗
PubMed1987

Inactivity of methylene chloride in the mouse bone marrow micronucleus assay.

Methylene chloride (MC) has been evaluated for its ability to induce micronucleated polychromatic erythrocytes (MPEs) in the bone marrow of treated mice. Groups of five male and five female C57BL/6J/Alpk mice were exposed, by gavage, to doses of 4000, 2500 and 1250 mg/kg MC in corn oil, the highest dose-level being selected to be the maximum tolerated dose. Bone marrow samples were taken 24, 36, 48 and 72 h after dosing. No significant increases in the incidence of MPEs over controls were observed for any of the test groups, and it is concluded that MC is not clastogenic in this assay.

Animals↗
PubMed1987

The malpositioned Greenfield filter: lessons learned.

It is essential that a malpositioned Greenfield filter be recognized as such immediately. Three of the 21 Greenfield filters inserted in the current study were malpositioned. One was placed in the right renal vein, one in the right common iliac vein, and another in the right inferior vena cava in a patient with caval duplication and left ileofemoral thrombosis. A review of the postprocedure radiographs was performed. It was found that two of the three malpositioned filters were at an appropriate vertebral level, and, therefore, this single criteria was inadequate to judge proper filter positioning. A more reliable parameter was the maximal diameter of the open legs of the filter. The mean diameter of the legs in the correctly positioned filters was 29.9 mm compared with 19.0 mm for the malpositioned filters. The authors recommend that the diameter of the filter legs be measured on all postprocedure radiographs. If this diameter is not 30 +/- 4 mm (two standard deviations), then malposition of the filter should be suspected, regardless of the vertebral level at which the filter lies.

Adult↗
PubMed1986

Electrophoretic variants of alpha 2u-globulin in the livers of adult male rats: a possible polymorphism.

Two-dimensional polyacrylamide gel electrophoresis has been used to examine the microsomal fractions from the livers of 32 adult male Alpk/AP (Wistar-derived) rats for the presence of alpha 2u-globulin variants of differing isoelectric point. Three major such isoelectric variants are described. Different combinations of these three forms were found in the population examined, with one-half of the animals expressing all three variants in approximately equal proportions and with one variant being present in all the animals examined. An understanding of the relevance of such different alpha 2u-globulin profiles to the individual animal must now await the assignment of a biological role for alpha 2u-globulin.

Alpha-Globulins↗
PubMed1986

Fibromuscular dysplasia of the carotid arteries.

Fibromuscular disease of the carotid artery was identified in 30 patients, which represented 3.2 percent of all patients who had cerebral angiography at Brooke Army Medical Center in the 6 year period from 1978 to 1984. Focal neurologic events were the presenting symptoms in 63 percent of the patients. The majority of the patients were treated with antiplatelet therapy, and eight patients had a total of 10 carotid artery dilatations. The only patients with recurrent symptoms were those who received either no treatment or antiplatelet therapy. There were no recurrent symptoms in the operated patients. This study suggests that surgical treatment for the symptomatic patient may prevent recurrent symptoms with an acceptably low morbidity and mortality. There was, however, no indication that prophylactic dilation of the fibromuscular disease in the asymptomatic patient was beneficial. Fibromuscular dysplasia of the carotid arteries is often associated with intracranial aneurysms, and surgical therapy rather than antiplatelet therapy may be advisable in patients who have intracranial aneurysms. Patients with concomitant atherosclerosis of the carotid artery bifurcation should be treated like any patient with atherosclerotic disease and an endarterectomy should be performed with carotid dilatation when indicated. Fibromuscular disease of the carotid artery is an infrequent angiographic finding that is associated with focal and global neurologic symptoms. Most patients can be effectively treated with antiplatelet drugs with no recurrent symptoms, however, for persistent or progressive symptoms, some patients will require surgical dilatation of the carotid artery. Fibromuscular disease of the carotid artery may lead to catastrophic symptoms of stroke or intracranial hemorrhage if left undiagnosed or untreated.

Adult↗
PubMed1986

Localized intraarterial streptokinase therapy.

In a retrospective study, 26 patients underwent 34 episodes of selective intraarterial streptokinase infusion for peripheral arterial thromboembolic occlusive disease. Thrombolytic therapy was beneficial in 23 instances (67 percent), caused no change in 7 instances, and caused deterioration in 4 instances. Nine patients (26 percent) had a major complication and 15 (44 percent) had a minor complication. Puncture site hematoma, which occurred in 11 cases (32 percent), was the most frequent complication. Local thrombolytic therapy is an effective primary or adjuvant method of treatment for thromboembolic occlusive disease in properly selected patients. Protocols for the safe use of streptokinase therapy are necessary. Enthusiasm for thrombolytic therapy must be tempered by the recognition of its potential for serious complications, the requirement for intensive care monitoring, and the availability of dedicated radiologists and vascular surgeons.

Adult↗
PubMed1986

Intraoperative local anesthetic injection of the carotid sinus nerve. A prospective, randomized study.

One hundred patients undergoing carotid endarterectomy under general anesthesia were prospectively randomized to receive either a local anesthetic injection of their carotid sinus nerve with bupivacaine (Marcaine) or no injection. Systolic blood pressure and pulse rate were recorded before injection and at 5 and 30 minutes after injection. The need for intraoperative and postoperative use of systemic vasopressor and vasodilator medications was recorded for each group as was the incidence of arrhythmias, neurologic complications, and myocardial infarctions. Intraoperative local anesthetic injection of the carotid sinus nerve did not significantly influence the intraoperative pulse rate or incidence of hypotension. It did, however, significantly increase the incidence of intraoperative hypertension and the need for systemic vasodilator medications intraoperatively. The incidence of postoperative hypotension (6 percent of patients), hypertension (34 percent), arrhythmias (6 percent), cerebrovascular accidents (1 percent), transient ischemic attacks (3.1 percent), and myocardial infarctions (2 percent) were not significantly influenced by intraoperative local anesthetic injection of the carotid sinus nerve. Intraoperative and postoperative hypotension did not cause morbidity in this series, however, local anesthetic injection was associated with a significant incidence of perioperative hypertension. Routine prophylactic local anesthetic injection of the carotid sinus nerve cannot be recommended in view of its detrimental effects in relation to the development of hypertension.

Anesthesia, Local↗
PubMed1986

The noninvasive diagnosis of vasculogenic impotence.

One hundred eleven impotent men and 25 potent men were prospectively evaluated with a standardized exercise treadmill test (SETT) used to noninvasively define their pelvic hemodynamics. Fifty-six men had vasculogenic impotence, whereas the remaining 55 had erectile dysfunction resulting from undetermined causes (31), psychogenic factors (10), or other identifiable reasons (14). Arteriography was performed on 40 (71%) of the patients with vasculogenic impotence without false positive results, as well as in 11 (44%) of the potent control patients and in six (11%) of the patients with nonvasculogenic impotence without false negative results, confirming the validity of the SETT. The distinction between vasculogenic and nonvasculogenic impotence can be accurately made with the SETT. Patients with vasculogenic impotence had a resting penile-brachial index (PBI) equal to 0.60 +/- 0.022 (mean +/- SEM) and a PBI after exercise equal to 0.45 +/- 0.019 with a fall in the mean PBI of -0.15 (p less than 0.001). Patients with nonvasculogenic impotence had a resting PBI equal to 0.80 +/- 0.024 and a PBI after exercise equal to 0.88 +/- 0.019 with a rise in mean PBI of 0.08 (p less than 0.001). This response was not significantly different between the control group and the nonvasculogenic impotence patients. The addition of PBI determinations after treadmill exercise revealed that 18% of the patients with vasculogenic impotence would have been incorrectly diagnosed, because their resting PBI was greater than the traditional standard of 0.70. Furthermore, 18% of the patients with nonvasculogenic impotence would have been incorrectly diagnosed as having vasculogenic impotence because their resting PBI was less than 0.70.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiography↗
PubMed1986

Increased hydroxyl radical production in liver peroxisomal fractions from rats treated with peroxisome proliferators.

Electron spin resonance (e.s.r.), using the spin trap 5,5-dimethyl-1-pyrroline-N-oxide (DMPO), has been employed to measure hydroxyl radical production in liver peroxisome-enriched fractions isolated from male Alpk/Ap rats administered chemicals known to cause peroxisome proliferation. The DMPO-OH adduct was found to decay to an e.s.r. silent species so rapidly in the presence of the native peroxisome-enriched fraction as to preclude any measurements in this system. All of the experiments were therefore carried out in the presence of cyanide in order to visualise the DMPO-OH adducts, although a consequence of this was the inhibition of the peroxisomal catalase activity. The DMPO-OH adduct was identified in fractions from both control and treated animals in the presence of palmitoyl CoA as substrate and was found to be present at 3-4 times the control value in animals orally administered di(2-ethylhexyl)phthalate (2000 mg/kg), clofibrate (200 mg/kg) or methyl clofenapate (25 mg/kg) for 9 days. The rate of production of hydroxyl radicals was also greater in fractions from treated animals. The fatty acyl CoA oxidase system of liver peroxisome-enriched fractions has now been shown to produce increased levels of hydrogen peroxide and hydroxyl radicals in the presence of a suitable substrate. Despite such evidence from in vitro enzyme systems, evidence of genotoxicity in vivo is still required to confirm the hypothesis linking such reactive oxygen species to the carcinogenicity observed in rodents with certain peroxisome proliferators.

Animals↗
PubMed1985

Activation of transglutaminase at calcium levels consistent with a role for this enzyme as a calcium receptor protein.

The sensitivity of tissue transglutaminase to activation by Ca2+ and other cellular factors was investigated using the enzyme purified from rat liver. The inclusion of Mg2+ in the assay system appeared to reduce the Ca2+-requirement of the enzyme when native N,N'-dimethylcasein was used as the protein acceptor substrate. However, when this protein was dephosphorylated, the Ca2+-requirement was unaffected by Mg2+. In addition, using this modified assay, a Km for Ca2+ was calculated to be in the range of 3-4 microM, at least an order of magnitude lower than that obtained with native acceptor substrate. Membrane phospholipids, 1,2-diolein and calmodulin were found not to affect the activation of transglutaminase by Ca2+. The sensitivity of transglutaminase to Ca2+ which we have now demonstrated suggests that this enzyme may directly act as a receptor protein for Ca2+ during stimulus-response coupling mediated by this cation.

Animals↗
PubMed1985

Studies in vivo to investigate the status of 4-N-pyrrolidinylazobenzene as a pure cancer initiating agent to the rat liver.

4-N-Pyrrolidinylazobenzene (4N) has been described sequentially as a potential rat hepatocarcinogen, a non-hepatocarcinogen to the rat, a possible pure initiating agent to the rat liver and as unlikely to be either a rat hepatocarcinogen or a cancer initiating agent. Given the importance of defining a pure initiating agent to the rodent liver we have conducted experiments to evaluate the status of 4N in this respect. By histopathological criteria 4N is non-hepatotoxic to the rat liver following daily oral gavage for 6 weeks, but it can be detected unbound in the rat liver following a single exposure via oral gavage and methaemoglobin is evident in peripheral blood. In addition, it fails to bind covalently to hepato-proteins or to initiate unscheduled DNA synthesis in the rat liver following oral dosing. Under similar conditions of bioassay, the rat liver carcinogen 3'-methyl-4-dimethylaminoazobenzene (3'M) gave a positive response on each count. Further, no evidence of histopathological change was observed in the rat liver following daily intraperitoneal injection of 4N for 2 weeks. It is concluded that 4N is both non-toxic and non-genotoxic to the rodent liver in vivo in all respects studied, and that it is therefore very unlikely to possess cancer initiating activity in this tissue.

Animals↗
PubMed1985

Irreversible depression in the ratio of tetraploid:diploid liver nuclei in rats treated with 3'-methyl-4-dimethylaminoazobenzene (3'M).

A reduction in the ratio of tetraploid to diploid liver nuclei has been investigated as an early indicator of hepatocarcinogenesis in the rat using the liver carcinogen 3'-methyl-4-dimethylaminoazobenzene (3'M). In a dose ranging study 3'M was administered by gavage to rats at 5, 12.5 and 25 mg/kg for up to 10 weeks and the following parameters studied: bodyweight gain, dye binding to hepatic protein, nuclear ploidy in liver and histopathology. Significant reduction in bodyweight occurred only with 25 mg/kg; dye binding to protein occurred in a dose-related manner; depression of the percentage of tetraploid nuclei compared with diploids was dose-related and effects were detected even at the lowest dose. These observations were consistent with those from previous studies by other investigators. In a separate experiment 3'M was administered at the maximum tolerated dose (MTD) of 25 mg/kg for 3 weeks, during which time there was a significant reduction in bodyweight gain and a reduction in the ratio of tetraploid:diploid liver nuclei. After cessation of dosing the rate of bodyweight gain returned to normal but there was no corresponding recovery of the ratio of tetraploid:diploid nuclei in the liver. A long-term continuous gavage study at 2.5 mg/kg revealed a time dependent reduction in the ratio of tetraploid:diploid liver hepatocyte nuclei and histopathological changes that included hepatocarcinoma were also observed. There was no correlation between the severity of pathological changes and the change in nuclear ploidy ratio in this experiment and it is concluded that the changes in ploidy ratio are related to the carcinogenic effect of 3'M and are independent of its gross toxicity.

Animals↗
PubMed1985

Alterations in the distribution and activity of transglutaminase during tumour growth and metastasis.

Transglutaminase activity and subcellular distribution have been examined in both normal and tumour tissue. Subcellular fractionation of rat liver demonstrated a bimodial distribution for transglutaminase between the particulate (approximately 40%) and cytosol (approximately 60%) fractions. Isolation of enriched plasma membrane fractions indicated the presence of membrane associated transglutaminase activity which co-distributed with that of 5'-nucleotidase and Na+/K+-ATPase. Induction of hepatocellular carcinomas in rats by treatment with either diethylnitrosamine or 6-p-dimethylaminophenylazobenzothiazole resulted in a reduction in transglutaminase activity which was accompanied by redistribution of the enzyme to the particulate fraction of the cell. The tumour bearing liver appeared to represent an intermediate stage between the hepatocellular carcinoma and control liver when assayed for content and distribution of transglutaminase activity. The transglutaminase activity of four transplantable rat sarcomas (P7, P8, MC3 and CC5) was found to be greatly reduced when compared with the normal tissues of rat liver, lung and spleen. A further reduction in this activity occurred in the primary growths of the sarcomas P7 and P8 following detection of metastases. Our data suggest that such changes in the distribution and content of transglutaminase may be a feature of tumour tissue and may be of value in both monitoring and investigating the carcinogenic process.

Acyltransferases↗
PubMed1984

Azoreductase activity of Sprague Dawley and Wistar-derived rats towards both carcinogenic and non-carcinogenic analogues of 4-dimethylaminophenylazobenzene (DAB).

Azoreductase activity towards the hepatocarcinogen p-dimethylaminophenylazobenzene (DAB) and four analogues has been measured in vitro in the liver and caecum of Sprague Dawley (Alpk/SD) and Alderley Park (Alpk/AP Wistar-derived) rats. Two carcinogenic DAB analogues, 3'-methyl-p-dimethylaminophenylazobenzene (3M) and 6-p-dimethylaminophenylazobenzothiazole (6BT) and two non-carcinogenic analogues, 4-N-pyrrolidinylazobenzene (4N) and 5-p-dimethylaminophenylazoindazole (5I) have been examined. The azoreductase activity towards DAB of a 9000 g supernatant of liver homogenate was greater in the SD than the AP strain between 6 and 13 weeks of age, but comparable to that of AP rats at 4 weeks of age. The activity towards DAB fell in both strains with increasing age. Animals of both strains fed a riboflavin-low diet (2-3 mg kg-1) had reduced azoreductase activity with DAB when compared to a standard diet at all ages studied, although the difference was less marked in the AP rats. 3M and 4N were azoreduced by the livers of both strains of rat fed a standard diet at a rate of approximately 50% of that of DAB, whereas 5I and 6BT were cleaved at a much lower rate (5-20%). All the chemicals were reduced by an oxygen-insensitive enzyme in the liver preparation, as has previously been reported for DAB. DAB, 3M and 6BT were reduced at a similar rate to each other by a fraction containing caecal contents, both in and between the two strains of rat. Similarly, 4N and 5I were reduced by a caecal preparation at a similar rate to each other in and between both strains of rat, but at a rate of only 30-50% that shown by DAB, 3M and 6BT. In contrast to the conditions required by the liver azoreductase enzyme, anaerobic conditions were required for maximal activity of the caecal preparation. Liver azoreductase activity towards all the DAB analogues was reduced in both strains of rat maintained on a riboflavin-low diet, while the caecal azoreductase activity was unaffected. Neither the activity profile observed in vitro in the liver nor the caecum was found to correlate with the relative carcinogenicity reported for these compounds, suggesting that other factors are more important in determining this toxicity for the series of azo chemicals examined in this study.

Age Factors↗
PubMed1983

6-p-Dimethylaminophenylazobenzothiazole: a potent hepatocarcinogen in the rat.

6-p-Dimethylaminophenylazobenzothiazole (6BT) administered at a dose of 10 mg/kg by gavage to Sprague-Dawley and Wistar-derived rats for 2 months produced marked cellular changes in the liver, including proliferation of oval cells and the formation of regenerative/hyperplastic nodules. Cellular change continued after stopping dosing at 2 months such that liver tumours were first observed after only 4 months into the study, and animals examined between 4 months and termination at 6 months showed a 75% and 85% incidence of hepatocellular carcinoma for the Sprague-Dawley and Wistar strains, respectively. This study establishes 6BT as a potent hepatocarcinogen in the rat when administered by gavage, and confirms and extends an initial brief report by Brown and Sanchorawala in 1968 of its carcinogenicity following dietary administration.

Animals↗
PubMed1983

Initiation/promotion versus complete carcinogenicity in the rodent liver.

4-N-Pyrrolidinylazobenzene (4N) is a close structural analog of the rodent liver carcinogen 4-dimethylaminoazobenzene (DAB). This structural similarity led us to evaluate it for genotoxic activity in vitro. We observed activity for 4N and DAB in the BHK cell transformation assay and subsequently in the Salmonella mutation assay of Ames. By a curious chance, Scribner, Miller and Miller, probably prompted by the same structural similarity, had synthesized 4N in the 1960s and found it to be noncarcinogenic to the rodent liver using a bioassay test protocol that detected DAB as carcinogenic. These findings were only described following the publication of our observations made in vitro. The conflict that apparently exists between these data can be interpreted in two separate ways. (a) Scribner et al. have suggested that 4N may be a carcinogenic initiator as opposed to a complete carcinogen like DAB. They also suggested that promotion of 4N-treated rodents with phenobarbitone might lead to the production of liver tumors. (b) We have evaluated the simpler concept that the activities observed for 4N in vitro define a carcinogenic potential that is not realized in vivo due to its rapid detoxification, at least in rodents. The first of these explanations implies that pure carcinogenic initiators may form a separate class of genotoxic agents from complete carcinogens, and perhaps of greater interest, that 4N might provide a valuable model compound for the study of carcinogenic promotion in the rodent liver. The second explanation regards potential carcinogenicity as a single property that can be defined in vitro and which may or may not be expressed in vivo depending on the enzymic environments encountered by the test chemical. It is clearly important to evaluate these different propositions in order to aid progress in the study of carcinogenic promotion, especially in the rodent liver. The presentation will describe our recent studies in vitro and in vivo in this connection.

Animals↗