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Biomedical subjects

C M Edwards

Publications and source records attributed to C M Edwards.

72 records · Page 4Linked to original sources
PubMed1993

Lipoprotein-X fails to inhibit hydroxymethylglutaryl coenzyme A reductase in HepG2 cells.

Abnormalities of lipid composition and metabolism are frequently observed in patients with cholestatic liver disease. Both elevated low-density lipoprotein (LDL) levels and the appearance of lipoprotein-X (LP-X) in plasma underlie the high incidence of hypercholesterolemia in this population. We tested the hypothesis that the hypercholesterolemia of cholestasis may reflect a failure of normal feedback regulation of hepatic cholesterogenesis by determining the influence of LP-X on the rate-limiting enzyme of cholesterol synthesis, hydroxymethylglutaryl coenzyme A (HMG CoA) reductase. Cultured human hepatoma (HepG2) cells were incubated in purified lipoprotein for 24 hours, harvested, and then assayed for HMG CoA reductase activity and mass. LDL isolated from either normal controls or patients with cholestasis decreased reductase activity in a dose-dependent fashion (2 to 30 micrograms cholesterol/mL media) to a level approximately 50% of that measured in cells incubated in lipid-deficient serum. LP-X failed to downregulate enzyme activity compared with LDL, with little change in reductase activity at cholesterol concentrations (30 micrograms/mL media) that produced maximal reductase inhibition by LDL. Three distinct LP-X subspecies were purified from the plasma of a patient with primary biliary cirrhosis (PBC) and tested in an analogous manner. All LP-X subspecies were similar in their inability to decrease reductase activity as compared with LDL. HMG CoA reductase mass was increased approximately twofold in cells incubated with LP-X, as estimated by Western blot analysis. These results suggest that LP-X may contribute to hypercholesterolemia in the cholestatic patient by not effectively downregulating hepatic cholesterol synthesis.

Adult↗
PubMed1993

The use of agarose gels for quantitative determination of fluid saturations in porous media.

The use of agarose gel reference standards for quantifying petrophysical properties in porous media is described. The specific interest is to determine the values of fluid saturations and porosity in oil bearing rocks; the MRI methodology for estimating these properties is discussed. It is shown that the relaxation times of the gel reference standard and the relaxation times of the fluid contained in the porous media affect the estimation process. The determination of porosity and fluid saturations can be greatly simplified if the relaxation times of the reference standard and the relaxation times of the fluid are closely matched. Gel concentration of paramagnetic impurities in the form of copper ions is used to control the longitudinal relaxation properties. The relaxation properties of agarose gels, as a function of agarose and paramagnetic impurity concentrations, have been measured at 2.0 T. The data are well fitted by a simple polynomial in agarose concentration and paramagnetic impurity concentration. Finally, a one-dimensional imaging example of use of agarose gels as reference phantoms is discussed.

Engineering↗
PubMed1989

A pharmacokinetic study of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist: correlation with anti-emetic response.

As part of an open dose-ranging study, the pharmacokinetics of granisetron (BRL 43694A), a selective 5-HT3 receptor antagonist given by the i.v. route, was studied in 18 patients receiving highly emetogenic cytotoxic drugs, predominantly cisplatin, either alone or in combination with other cytostatic agents. All patients received 30-min infusions of granisetron at a dose of 40 micrograms/kg. Nine showed complete absence of the gastrointestinal side effects normally associated with cisplatin, and in the majority of the remaining patients, the onset and severity of nausea was significantly modified. No acute side effects were observed at this dose and the drug was well tolerated in all cases. Peak plasma concentrations and area under the curve (AUC) values for granisetron showed considerable inter-patient variation. Higher plasma levels of granisetron were observed at 5 h in responding patients compared with those in whom the drug was ineffective in controlling emesis (P less than 0.05). AUC values were higher in responding patients, but this difference was not statistically significant. There was apparently no defined plasma concentration threshold for the drug's anti-emetic effect in these patients. Granisetron seems to be an effective and safe anti-emetic in patients receiving cytotoxic chemotherapy. Further exploration of its dose scheduling and pharmacokinetic profile is warranted.

Adult↗
PubMed1989

Arginine vasopressin--a mediator of chemotherapy induced emesis?

Concentrations of plasma arginine vasopressin (AVP) were studied in patients receiving chemotherapy. Of the 18 patients studied, nine experienced nausea and vomiting and the remaining nine were nonvomiters who suffered at worst mild nausea. Plasma AVP in the non-vomiting group remained within the normal range (0.5-1.5 pmol 1(-1] throughout the sampling period. However, patients who vomited showed (with one exception) substantial rises in AVP ranging from 4 to 129-fold. Plasma AVP concentrations were outside the normal range in vomiters and were higher than in non-vomiting patients at 3 h (P less than 0.05) and 5h (P less than 0.01) after chemotherapy. One patient was sampled during consecutive treatment courses, once as a vomiter and once as a non-vomiter; results demonstrated a 16-fold rise in AVP as a vomiter and no rise as a non-vomiter. Significant changes in plasma AVP levels were also observed in patients who suffered moderate or severe nausea compared to those who had mild or no nausea (P less than 0.05). Plasma AVP may prove to be a good objective marker for nausea in future anti-emetic trials.

Adult↗
PubMed1989

Experience in diagnosis and treatment of impotence caused by cavernosal leak syndrome.

To delineate neural, arterial, and venous components contributing to impotence, we used a previously described noninvasive screening sequence combined with stimulation of artificial erection with papaverine injection, selective pudendal arteriography (SPA), and dynamic cavernosography (DC). Among 572 men with impotence, age range 17 to 78 years (average age 54.8 years), 26 men with potential cavernosal leaks in absence of other factors were identified; 16 underwent DC; among these five had normal cavernous venous drainage. Eight men with abnormal cavernosal venous drainage required cavernous infusion flow rates higher than 120 ml/min to obtain erection and higher than 40 ml/min to maintain erection. Radiographic studies showed cavernosal leakage in all eight patients. Eight men, ages 39 to 61 years, underwent surgical ablation of abnormal cavernosal venous drainage. Among these, five men have had excellent results for up to 3 years. One failure was related to unrecognized penile arterial disease later shown by SPA. In two men small doses of papaverine now induce erection. We now recommend SPA before DC to rule out an arterial abnormality. Accurate identification of factors contributing to erectile failure is critical for successful treatment; in this experience candidates for correction of cavernosal leak syndrome were uncommon.

Adolescent↗
PubMed1988

Cross-reacting bacterial determinants in ankylosing spondylitis.

The importance of the association between the human histocompatibility antigen human leukocyte antigen-B27 and ankylosing spondylitis is undisputed, but its biologic significance remains unresolved. We have demonstrated specific cross reactivity between a range of enteric bacteria and a specific determinant found only on the surfaces of cells from human leukocyte antigen-B27-positive persons with ankylosing spondylitis. We have proposed that the genetic element coding for this cross-reactive determinant is mobile and that its acquisition by B27-positive cells in vivo represents an important step in the eventual development of ankylosing spondylitis.

Antigens, Bacterial↗
PubMed1987

Etoposide-induced DNA cleavage in human leukemia cells.

The nuclear enzyme, topoisomerase II, is the major site of action for cancer chemotherapy agents such as etoposide, teniposide, and a variety of intercalating agents. These compounds cause the enzyme to cleave DNA, forming a DNA-protein complex that may be a key step leading to cell death. It is apparently unique as a chemotherapy target, since drug potency diminishes with decreasing enzyme activity. It was thus of interest to examine the topoisomerase content and drug-induced DNA cleavage in freshly obtained human leukemia cells and to compare the obtained data with the results of similar studies performed in well-characterized human leukemia cell lines. The human T-lymphoblast line, CCRF-CEM, was more than 100-fold more sensitive to the DNA-cleavage effect of etoposide than the cells of the 13 leukemic patients examined. One of the leukemia lines (HL-60) and a lymphoblastoid line (RPMI-7666) were somewhat less sensitive than cells of the CCRF-CEM cells, but were still 10-fold more sensitive than the patients studied. The relative insensitivity of the freshly obtained cells could not be accounted for by differences with respect to drug uptake but were associated with markedly reduced topoisomerase-II content as assayed by immunoblotting using a mouse polyclonal serum against topoisomerase II. Heterogeneity was observed in the sensitivities of patients' cells with respect to both drug-induced DNA cleavage and enzyme content. The observed differences between cultured cell lines and patients' cells may have been related to their proliferative status. Etoposide potency in normal resting lymphocytes resembles that observed in circulating leukemia cells. However, following mitogenesis with phytohemagglutinin and interleukin-2, proliferating lymphocytes become as sensitive to etoposide as cultured cell lines with regard to DNA cleavage. This effect was accompanied by an increase in topoisomerase-II content. Our data thus support the hypothesis that topoisomerase-II content may be an important determinant of cell sensitivity to certain classes of chemotherapy agents. Efforts to stimulate topoisomerase-II content may improve the therapeutic efficacy of these drugs.

Cell Division↗
PubMed1987

A screening sequence for vasculogenic impotence.

Delineation of neural, arterial, and venous components contributing to penile erectile failure is critical to proper patient selection for surgical interventions, particularly for a subset of men with impotence as the sole manifestation of pelvic arterial disease. In addition to obtaining a history and physical examination specific for disordered erectile function and vascular risk factors, we developed a sequence of testing to include noninvasive estimates of penile perfusion, pulse volume recording (PVR), and penile/brachial blood pressure indices (PBPI); somatosensory evoked potentials from dorsal penile (PEP) and posterior tibial nerve stimulation (SEP) and bulbocavernosus reflex time (BCR); stimulation of artificial erection with injection of papaverine (AE); and selective hypogastric-pudendal arteriography with patients under epidural anesthesia, and corpus cavernosography with AE. Three hundred fifty-three men complaining of impotence were screened by PVR and PBPI; among these 42 impotent men and 20 additional concurrent potent control subjects had evoked potentials and BCR measurements, and 55 men received one or more AE injections. On the basis of these results, angiographic investigation was recommended. Age and risk factors were similar in the two groups. Abnormal penile blood perfusion was associated significantly only with cigarette smoking (p less than 0.0001) or overt large vessel disease. Impotent men with (138) or without perfusion abnormalities (215) averaged 54 and 56 years of age, respectively; impotent men with normal flow patterns most commonly had treated hypertension or diabetes (79 of 215 men). Covert neurologic abnormalities were detected in 28 of 42 impotent men. Abnormal penile perfusion plus failure of AE predicted isolated ischiopudendal trunk or pudendal artery disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗