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Biomedical subjects

J F Williams

Publications and source records attributed to J F Williams.

At least 37 records · Page 2Linked to original sources
PubMed1998

Effects of the antiproliferative cyclopentenone prostaglandin A1 on glutathione metabolism in human cancer cells in culture.

Homeostatic mechanisms for the maintenance of glutathione (GSH) are fundamental in the provision of a cellular defense against electrophilic/oxidant challenges. Cyclopentenone prostaglandins (CP-PGs) are powerful antiproliferative endogenous substances that may act as electrophilic regulating compounds, by virtue of the presence of an alpha,beta-unsaturated carbonyl group in the cyclopentane ring. Nevertheless, differential resistance to CP-PG cytotoxic/cytostatic effect has been reported in different cell types. It is reported that the activity/expression of gamma-glutamylcysteine synthetase (gamma-GCS, the rate-limiting enzyme in GSH biosynthesis) can be inducibly activated by electrophiles, including CP-PGs. The response of the human cancer strains HEp-2 (larynx carcinoma) and HL-60 (promyelocytic leukemia) cells to treatment with the CP-PG PGA1 in culture was investigated by evaluating the time-course of GSH synthesis and activity of enzymes of GSH metabolism, other than gamma-GCS, after PGA1 addition. HEp-2 cells, being more resistant to PGA1 cytotoxic and cytostatic effects, have basal GSH levels that were 2.4-fold higher than that of HL-60 cells. The activities of GSH S-transferase (GST), glutathione reductase (GSRd) and glutathione peroxidase (GSPx) are constitutively higher in HL-60 cells than in HEp-2 cells (respectively, 17.0-, 28.5- and 12.3-fold). When challenged with PGA1, both cell types exhibited a dose-dependent rise in GSH content that was maximal 18 h after PGA1 addition and was preceded by a rise in GST and GSRd activities in both cell types (at 12 h). GSPx activity increased only in HEp-2 (PGA1 evoked a 93.4%-inhibition in HL-60 cells). Moreover only HEp-2 cells exhibited early capacity to enhance GSH content (1-2 h just after PGA1 addition). These results and earlier data showing that leukemia cells are sensitive to CP-PG treatment suggest that deficiencies in GSH metabolism may be strategically in therapeutic approaches to the treatment of human leukemias.

Cell Division↗
PubMed1998

Dietary fats alter the activity and expression of glucose-6-phosphate dehydrogenase in rat lymphoid cells and tissues.

The effect of diets enriched with fat containing different fatty acids on the activity and expression of the glucose-6-phosphate dehydrogenase (EC 1.1.1.49) of mesenteric lymph nodes lymphocytes and intraperitoneal macrophages was examined. Measurements of the enzyme were also performed using spleen, thymus and liver for comparison. The following fat rich diets containing a variety of fatty acids were used: 1-standard chow (CC); 2-medium chain saturated fatty acids (MS)-coconut fat-oil; 3-long chain saturated fatty acids (LS)-cocoa butter; 4-monounsaturated fatty acids (MU)-canola oil (n-9); 5-polyunsaturated fatty acids (PU)-soybean oil (n-6). Of the fat-rich diets tested, MS had the least effect. The G6PDH activity of lymphocytes was reduced by all the fat-rich diets; 16% for MS, 38% for LS, and 54% for MU. Similarly, the enzyme activity was reduced in macrophages; 35%, 86%, and 73%, for LS, MU, and PU, respectively. In contrast, the fat-rich diets elevated G6PDH activity in the lymphoid organs; by 42% in the spleen due to LS and by 131%, 35%, and 56% in the thymus due to LS, MU, and PU, respectively. Fat-rich diets decreased the activity of G6PDH in liver; 42%, 68%, and 39% for MS, MU, and PU, respectively. Some of the changes in G6PDH activity induced by the fat-rich diets occur through the mechanisms of mRNA abundance.

Animals↗
PubMed1998

Glutathione metabolism and glutathione S-conjugate export ATPase (MRP1/GS-X pump) activity in cancer. II. Cell-to-cell variability, relation with cellular activation state and functional absence of GS-X pump in lymphocytes.

A severe complication in late-stage cancer patients is host immunosuppression. It is suggested that overproduction of the highly cytostatic and cytotoxic antiproliferative cyclopentenone prostaglandins (CP-PGs) within the plasma of cancer-bearing subjects may contribute to immunosuppression. Lymphoid tissues of Walker 256 tumor-bearing rats accumulate large amounts of CP-PGs while the tumor tissue itself does not. Moreover, tumor cells may present differential sensitivity to CP-PGs due to the expression of the multidrug resistance-associated protein (MRP1) gene product which shows a Mg(2+)-dependent vanadate-sensitive glutathione S-conjugate export ATPase (GS-X pump) activity that extrudes CP-PGs from cells as glutathione S-conjugates. In this study, the possibility that deficient GS-X pump activity in immune cells that may be involved in the accumulation of CP-PGs is investigated. Rat lymph node lymphocytes do not exhibit any notable activity even when mitogen-stimulated. Conversely, although rat peritoneal resident (quiescent) or thioglycollate-stimulated (inflammatory) macrophages exhibit low GS-X pump activity, Bacillus Calmette-Guérin (BCG)-activated macrophages show a notable rise in the activity of the ATPase, suggesting that the cellular activation state may modulate GS-X pump activity/expression and that, under appropriate stimuli (e.g., during immune response) macrophages may provide a self-defense against electrophilic CP-PGs by forming GS-conjugates that can be extruded from cells through the GS-X pump. ras oncogene expression may be linked with MRP1/GS-X pump expression/activity, since C2C12 promyoblasts transformed by v-H-ras transfection doubled GS-X pump activity. These results support the proposition that the accumulation of CP-PGs and the immunosuppression of tumor-bearing subjects may be attributed to a lack of GS-X pump activity/expression in lymphocytes.

Adenosine Triphosphatases↗
PubMed1998

Laparoscopic adrenal cyst resection.

Two patients with left adrenal cysts underwent laparoscopic resection. In one case an adrenal origin of the cyst was suspected. In the other case the cyst was thought to be renal in origin. Both patients were female, ages 16 and 40 years. Operative time was 150 and 160 minutes. Blood loss was 50 and 30 mL. One patient received 14 mg of morphine and 60 mg of ketorolac. The other patient did not require any parenteral analgesics. Hospital stay was 1 day for both patients. Return to normal activity occurred at 15 and 7 days postoperatively, respectively. Histology in both cases revealed benign adrenal cysts. Our experience supports the laparoscopic approach for resection of adrenal cysts.

Adolescent↗
PubMed1997

Evidence for the transfer in culture of [14C]-labelled fatty acids from macrophages to lymphocytes.

[14C]-labelled palmitic acid (PA), oleic acid (OA), linoleic (LA) and arachidonic (AA) acids were transferred from macrophages (M phi) to lymphocytes (LY) when equal numbers of the two cell types were co-cultured. The relative degree and amounts of the fatty acids transferred from M phi to LY are as follow: AA (368.57 +/- 21.62) = OA (274.52 +/- 15.41) > LA (42.11 +/- 8.31) = PA (36.53 +/- 2.45). The transfer units are nmol/10(10) M phi/10(10) LY and the values are mean +/- SEM for 7 experiments. The [14C]-radioactivity transferred was mainly directed to the phospholipid fraction of the lymphocytes (85% by PA, 86% by LA, 83% by OA and 79% by AA). In the same order as above, phosphatidylcholine was the phospholipid moiety most heavily labelled (82% by PA, 71% by LA, 66% by OA and 47% by AA). The amount of [14C]-radioactivity transferred to stimulated lymphocytes of thioglycollate treated animals remained unchanged for LA, PA and AA but reduced for OA (71%). The significance of these observations for the immune functions of the cells and resolution of the question of whether some of the [14C]-isotope transfer involves a component of exchange or is unequivocally net fatty acid mass transfer are still being investigated.

Animals↗
PubMed1997

Dirofilaria immitis: heartworm infection alters pulmonary artery endothelial cell behavior.

The pathogenesis of filariasis has generally been attributed to either physical presence of the adult parasites or the host's immune response to the parasites. However, the spectrum of filariasis cannot be entirely explained by these causes, and other mechanisms must be operative. It is now evident that factors released by filarial parasites likely contribute to the pathogenesis of filarial diseases. Adult heartworms (Dirofilaria immitis) reside in the right heart and pulmonary artery, so the pulmonary artery should be exposed to the highest concentration of filarial factors. We tested the hypothesis that endothelium-dependent relaxation is altered in the in vitro pulmonary artery from heartworm-infected dogs. Relaxation responses to endothelium-dependent vasodilators (methacholine, bradykinin, substance P, and A-23187) and the nonendothelium-dependent vasodilator nitroglycerin and contractile responses were measured in rings of pulmonary artery from control and heartworm-infected dogs. Endothelium-dependent relaxation was assessed in the presence and absence of inhibitors of nitric oxide synthase, cyclooxygenase, and guanylate cyclase. Responses to methacholine, substance P, and A-23187, but not to bradykinin, nitroglycerin, norepinephrine, or KCl, were depressed in pulmonary artery from heartworm-infected dogs when compared with control, suggesting that changes in endothelial cell and not vascular smooth muscle behavior are involved in altered relaxation. The mechanism of endothelium-dependent relaxation in control pulmonary artery appears to involve nitric oxide in the case of methacholine and both nitric oxide and a cyclooxygenase product in the case of bradykinin and A-23187. The mechanism of endothelium-dependent relaxation in pulmonary artery from heartworm-infected dogs was not clearly elucidated. These data provide no evidence that heartworm infection globally influences either endothelial cell receptor function or the vascular smooth muscle guanylate cyclase guanosine 3',5'-cyclic monophosphate system, making it likely that changes in intracellular signaling are primarily responsible for the observed alteration of endothelium-mediated relaxation. Alteration of endothelial cell function by filarial parasites may be an important component in the pathology associated with filariasis.

Animals↗
PubMed1997

Effect of arsenical drugs on in vitro vascular responses of pulmonary artery from heartworm-infected dogs.

OBJECTIVE: To test the effect of thiacetarsamide and melarsomine on vascular responses in isolated rings of pulmonary artery from heartworm-infected dogs. ANIMALS: 18 heartworm-infected dogs. PROCEDURE: Isolated rings of pulmonary artery from heartworm-infected dogs were randomly treated with thiacetarsamide (30 micrograms/ml) or melarsomine dihydrochloride (30 micrograms/ml) for 30 minutes; untreated rings from the same dog served as control. Cumulative dose-response relations to norepinephrine, nitroglycerin, and methacholine were determined. RESULTS: Norepinephrine-induced constriction was not altered by treatment with either thiacetarsamide or melarsomine. Treatment with thiacetarsamide depressed nitroglycerin-induced relaxation, compared with values for untreated control rings and rings treated with melarsomine. Treatment of rings with thiacetarsamide or melarsomine depressed methacholine-induced relaxation, compared with values for untreated rings. Histologic examination of rings indicated that treatment with thiacetarsamide or melarsomine resulted in loss of endothelial cells. CONCLUSION: Endothelial cell loss as a direct drug effect may be responsible for impaired endothelium-dependent relaxation in pulmonary artery from heartworm-infected dogs. Thiacetarsamide appears to have additional effects on vascular smooth muscle, which may explain why fewer complications are observed in dogs treated with melarsomine. CLINICAL RELEVANCE: Melarsomine may be a safer drug than thiacetarsamide and could be a better treatment for dogs with heartworm infection.

Animals↗
PubMed1997

Effect of heartworm infection on in vitro contractile responses of canine pulmonary artery and vein.

OBJECTIVE: To test the effect of heartworm infection on agonist-induced constriction of canine pulmonary artery and vein in vitro. PROCEDURE: Cumulative concentration-response relations to norepinephrine, serotonin, histamine, prostaglandin F2 alpha, and the thromboxane A2 analog U-44069 were determined, using isolated rings of pulmonary artery and vein from control and heartworm-infected dogs. To determine the role of endothelial cells in histamine constriction, some rings were denuded of endothelial cells in both artery and vein. ANIMALS: Noninfected control and heartworm-infected dogs. RESULTS: There was no difference in constriction response to norepinephrine, serotonin, prostaglandin F2 alpha, or U44069 of pulmonary artery or vein from control or heartworm-infected dogs. Histamine-induced constriction of pulmonary artery from heartworm-infected dogs was not different from control values, however, when endothelial cells were removed from control, but not heartworm-infected pulmonary artery, histamine-induced constriction was enhanced. Histamine-induced constriction of pulmonary vein from heartworm-infected dogs was significantly depressed, compared with that of control pulmonary vein. However, removal of endothelial cells in pulmonary vein from heartworm-infected, but not control dogs significantly increased constriction. CONCLUSION: Heartworm infection alters histamine-induced constriction responses of pulmonary artery and vein. These changes may reflect high circulating histamine concentrations in heartworm-infected dogs, compared with that in controls. Increased circulating histamine concentrations in vivo could bring about decreased sensitivity of histamine receptors o decreases in the number of receptors expressed. CLINICAL RELEVANCE: Mast cells and histamine may be important factors in altered endothelium-mediated responses associated with heartworm disease.

Animals↗
PubMed1996

Thiacetarsamide depresses relaxation of canine pulmonary artery in vitro.

Little information is available on the primary pharmacological effects of thiacetarsamide on mammalian systems, particularly on blood vessels. The effects of thiacetarsamide on arterial responses was studied in isolated rings from canine pulmonary artery. Vessels were exposed to thiacetarsamide and dose-response relationships were applied to methacholine and nitroglycerin. To rule out non-specific effects of antihelmintics, the effects of two other antifilarial drugs, diethylcarbamazine and ivermectin, were also tested. Thiacetarsamide significantly depressed relaxation of canine pulmonary artery to both methacholine and nitroglycerin, and significantly enhanced constriction to norepinephrine. Neither diethylcarbamazine nor ivermectin altered vascular response. These direct effects of thiacetarsamide on arterial responsiveness may be responsible, in part, for acute pulmonary complications observed in dogs infected with Dirofilaria immitis after adulticide treatment.

Animals↗
PubMed1996

Effects of phenobarbital and interleukin-6 on cytochrome P4502B1 and 2B2 in cultured rat hepatocytes.

The objectives of this study were to characterize further the effects of phenobarbital (PB) on cytochrome P4502B1 and 2B2 (P4502B1/2) enzyme activity and immunoreactivity in rat hepatocytes and to investigate the mechanism(s) mediating the ability of interleukin-6 (IL-6) to inhibit this induction. PB caused a concentration-dependent increase in benzyloxyresorufin O-deethylase (BROD) activity with maximal effects (a 25-fold increase) at concentrations of 0.3 to 1 mM. The induction of BROD activity was linear over 24 hr of exposure. Immunoblot profiles of P4502B1/2 agreed with measurements of enzyme activity. In addition to inducing P4502B1/2, PB (0.75 mM) also increased the levels of P450 reductase by approximately 2-fold following a 24-hr exposure to PB. When IL-6 was added concomitantly with or up to 12 hr after the addition of PB, the PB induction of BROD activity and immunoreactivity was inhibited significantly. When 18 hr elapsed between the time of addition of PB and IL-6, the inhibitory effects of IL-6 were no longer apparent, suggesting that the actions of IL-6 were mediated by early events in the induction process. IL-6 did not affect the PB induction of P450 reductase. To determine whether IL-6 altered the degradation of P4502B1/2, hepatocytes were exposed to PB for 24 hr, then washed, and the loss of BROD activity and immunoreactivity following incubation with a protein synthesis inhibitor was measured. IL-6 did not alter the rate of loss of either enzyme activity or immunoreactivity, indicating that the effects of IL-6 could not be attributed to the enhanced degradation of P4502B1/2. Results suggest that the inhibition of PB-induced BROD activity by IL-6 is due to an action on early cellular and molecular events in the induction process.

Animals↗
PubMed1996

Ivermectin distribution in the plasma and tissues of patients infected with Onchocerca volvulus.

OBJECTIVE: To determine the distribution of ivermectin in plasma and tissues of onchocerciasis patients following a single oral dose of 150 micrograms kg-1. SETTING: Medical Department at Soba University Hospital, Khartoum. PATIENTS: Twenty five patients and fourteen healthy volunteers. METHODS: Serial blood samples were obtained from both groups. Tissue samples were removed from various patients as full thickness skin punch biopsies or during nodulectomy. Ivermectin concentration was determined by radioimmunoassay. RESULTS: The plasma pharmacokinetic variables for patients were; maximum plasma concentration 52.0 ng ml-1; time to achieve maximum concentration, 5.2 h.; elimination half life, 35.0 h; and the area under the plasma concentration curve versus time, 2852 ng.h.ml-1. In healthy volunteers, the plasma ivermectin distribution was similar to that in patients, and both groups showed a tendency for a second rise in plasma concentration of the drug suggestive of enterohepatic recirculation. Ivermectin was detected in tissues obtained from patients. Fat showed the highest and most persistent levels, whilst values for skin, nodular tissues, and worms were comparable. Subcutaneous fascia contained the lowest concentrations. CONCLUSIONS: Infection with O. volvulus does not affect the pharmacokinetics of ivermectin, and filarial infected tissues and parasites themselves do take up the drug. There may be prolonged retention of ivermectin because of depot formation in fat tissue.

Adipose Tissue↗
PubMed1996

Studies on the lipid metabolism of Walker 256 tumour-bearing rats during the development of cancer cachexia.

Aspects of the lipid metabolism of Walker 256 carcinosarcoma-bearing cachectic rats (TB) were investigated during a 14 day interval of tumour growth. Food intake and body weight of the TB rats were reduced by 18% and 13%, respectively, on day 14, as compared with non-tumour-bearing animals. The tumour burden then, corresponded to 19% of total body weight. The total fat content was not different in the liver, heart, carcass, epididymal (EAT) and retroperitoneal (RPAT) adipose tissues of the two groups. The brown adipose tissue (BAT) and skeletal muscle (gastrocnemius-SM) of the TB rats had increased levels of fat (23% and 200%, respectively). Enteral absorption of 14C-triolein was decreased in the TB rats, but the liver, heart, and SM of these animals incorporated more radiolabelled lipid than the control animals, while the adipose tissues exhibited a decreased incorporation of radioactivity in relation to controls. More lipid was incorporated into the VLDL fraction secreted by the liver of TB rats, which exhibited a different distribution of the incorporated 14C-oleate in the various lipid subfractions. Ultrastructural studies showed that the hepatocytes of the TB rats had a greater incidence of lipid droplets in the cytoplasm.

Adipose Tissue↗
PubMed1996

A prospective study of the impact of patient preferences on life-sustaining treatment and hospital cost.

OBJECTIVES: Ethicists advise that life-sustaining treatment decisions should be made in keeping with patient preferences. Until recently, there has been little systematic study of the impact of patient preferences on the use of various life-sustaining treatments or the consequent cost of hospital care. This prospective study was designed to answer the following questions: a) Do patient treatment preferences about the use of life-sustaining treatment influence the treatments they receive? and b) Do patient treatment preferences influence the total cost of their hospitalization? DESIGN: A prospective, cohort study. SETTING: A university teaching hospital. PATIENTS: Hospitalized patients, at least 50 yrs of age, with short life expectancy due to end-stage heart, lung, or liver disease, metastatic cancer, or lymphoma. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Patients were interviewed to determine their desire for life-sustaining treatment and other characteristics and then were followed for 6 months to determine life-sustaining treatment use and costs during hospitalization. Two hundred forty-four patients were interviewed. Fifty-eight percent of patients expressed a desire for life-sustaining treatments to prolong life for 1 wk. During 245 subsequent hospitalizations, there were 20 episodes of mechanical ventilation, 63 episodes of intensive care, and 66 cancer treatments given. Bivariate and multivariate analyses showed no significant association between patient desire to receive treatment to prolong life and either life-sustaining treatment use (p = .59) or hospital costs (p = .20). CONCLUSION: In a university teaching hospital setting, there is no systematic evidence that patient preferences determine life-sustaining treatment use or hospital costs.

Aged↗
PubMed1996

Legionella contamination of dental-unit waters.

Volume 61, no. 4, p. 1211, column 2, line 40: this sentence should read as follows. "The viable-culture methods for Legionella sp. detection, however, often fail, and the Centers for Disease Control and Prevention has turned, when necessary, to PCR for epidemiological investigations of Legionnaires' disease and Pontiac fever (19)." Line 46: "(6)" should read "(11)." [This corrects the article on p. 1208 in vol. 61.].

Journal Article↗
PubMed1996

Gender differences in medical presentation and detection of patients with a history of alcohol abuse or dependence.

Women and men with alcohol use disorders differ in many respects. A retrospective medical record review of 132 patients was performed to determine outpatient clinic utilization, presentation patterns and physician actions related to patient gender and lifetime DIS-status. Women, irrespective of DIS-status, utilized out-patient health care services more often than did DIS-positive or negative men. Of 16 specific alcohol-related complaints, gender differences were only detected for trauma. DIS-positive men were more likely to have had an alcohol history taken during the preceding 12 months than were DIS-positive women. Sedatives/minor tranquilizers were most often prescribed to DIS-positive women. This study supports the need in primary care settings for more screening to detect and diagnose alcohol-abusing patients, particularly women. Physicians should routinely screen for alcohol abuse before prescribing sedatives or minor tranquilizers.

Adult↗