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Biomedical subjects

D R Bell

Publications and source records attributed to D R Bell.

At least 55 records · Page 3Linked to original sources
PubMed1994

Bone presentation of non-Hodgkin's lymphoma: experience at the Royal North Shore Hospital, Sydney; highlighting primary bone lymphoma.

BACKGROUND: Primary lymphoma of bone (PLB) is a rare form of extranodal lymphoma. Between 1975 and 1992 39 patients with lymphoma presenting in bone were seen at the Royal North Shore Hospital (RNSH), Sydney. Of these, 12 (31%) had truly localised disease (Stage IE). AIMS: Patients were studied retrospectively to determine the prognostic significance of bony involvement per se versus involvement of a single bony site, and to determine the impact of treatment modality on outcome. METHODS: The 39 patients were divided into three groups according to extent of disease; single osseous site (Stage IE), multifocal bone, and bone plus visceral and/or nodal disease. Kaplan-Meier survival curves were constructed, and five year actuarial survival stated. Cox regression analysis was used to determine hazard ratios. Overall survival was used as the end-point. RESULTS: A trend for better survival was noted with Stage IE disease. Multifocal and disseminated disease appeared to have a poorer outcome when assessed by hazard ratio, with a value of 3 (95% CI 0.87-10.4; p = 0.08), compared to unifocal disease. Radiotherapy alone was as effective as combined modality treatment although patient numbers were too small for statistical confirmation. CONCLUSIONS: The stage of lymphoma, rather than bony involvement per se, seems to have more prognostic importance. Radiotherapy alone offered equivalent results to combined modality treatment in this series.

Adult↗
PubMed1994

Specificity and sensitivity of immunocytochemistry for detecting P-glycoprotein in haematological malignancies.

AIMS: To determine the optimal working conditions of the alkaline phosphatase-antialkaline phosphatase (APAAP) method to establish a specific and sensitive assay for the detection of low numbers of MDR positive cells in patients with hematological malignancies. METHODS: Three monoclonal antibodies (C-219, JSB-1, MRK-16) were used for the detection of P-glycoprotein (P-gp) in cell lines and in samples from 43 patients with haematological malignancies. The results of the APAAP method were compared with western blotting for specificity and sensitivity. RESULTS: Excellent correlation was obtained between optimised APAAP and western blotting, except in the case of multiple myeloma. JSB-1 seemed to be the more useful monoclonal antibody for the APAAP which was more sensitive than western blotting in its ability to detect single P-gp positive cells. CONCLUSIONS: Methods for P-gp detection, as defined by multidrug resistant (MDR) cell lines, are not necessarily optimal and specific for clinical samples and may lead to higher false positive and negative results, according to the conditions and the monoclonal antibodies used.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Isoproterenol decreases protein permeability in edematous isolated rabbit lungs: estimation of PS and sigma.

The objective of the present study was to determine whether the ability of the beta-adrenergic agonist isoproterenol to attenuate pulmonary edema occurs via a permeability and/or hemodynamic mechanism. In isolated perfused rabbit lungs, the restrictive property of the vascular barrier to the movement of fluid and protein was assessed by measurements of the capillary filtration coefficient (Kf) and the transvascular clearance of 125I-labeled albumin, respectively. Regression analysis of albumin clearance vs. transvascular fluid flux was performed to estimate the permeability-surface area product (PS) and the reflection coefficient (sigma) by use of the linear or nonlinear flux equation. Arterial, capillary, and venous pressures and resistances, weight gain, and the wet-to-dry weight ratio were also assessed. Isoproterenol (8 ng.ml-1.min-1) attenuated the arachidonic acid (4 mg)-induced increases in fluid flux, wet-to-dry weight ratio, albumin clearance, and PS and the decrease in sigma. Isoproterenol had no effect on the increase in Kf, and there was no correlation between capillary pressure and fluid flux in any of the four groups. Regression analysis revealed that the non-linear flux equation provided estimates of PS and sigma that more accurately described the statistical differences in albumin clearance among the groups studied than the linear flux equation. These findings demonstrate that isoproterenol attenuated the increased transvascular flux of albumin in edematous lungs by modifying the protein permeability of the vascular barrier.

Animals↗
PubMed1993

Species-specific induction of cytochrome P-450 4A RNAs: PCR cloning of partial guinea-pig, human and mouse CYP4A cDNAs.

PCR was used to demonstrate the presence of a conserved region and to clone novel members of the cytochrome P-450 4A gene family from guinea pig, human and mouse cDNAs. This strategy is based on the sequences at nucleotides 925-959 and at the haem binding domain (nucleotides 1381-1410) of the rat CYP4A1 gene. Murine Cyp4a clones showed high sequence identity with members of the rat gene family, but CYP4A clones from human and guinea pig were equally similar to the rat/mouse genes, suggesting that the rat/mouse line had undergone gene duplication events after divergence from human and guinea-pig lines. The mouse Cyp4a-12 clone was localized to chromosome 4 using interspecific backcross mapping, in a region of synteny with human chromosome 1. The assignment of the human CYP4A11 gene to chromosome 1 was confirmed by somatic cell hybridization. An RNAase protection assay was shown to discriminate between the murine Cyp4a-10 and Cyp4a-12 cDNAs. Treatment of mice with the potent peroxisome proliferator methylclofenapate (25 mg/kg) induced Cyp4a-10 RNA in liver, and to a lesser extent in kidney; there was no sex difference in this response. Cyp4a-12 RNA was present at high levels in male control liver and kidney samples, and was not induced by treatment with methylclofenapate. However, Cyp4a-12 RNA was present at low levels in control female liver and kidney RNA, and was greatly induced in both organs by methylclofenapate. Guinea pigs were exposed to methylclofenapate (50 mg/kg), but there was no significant induction of the guinea-pig CYP4A13 RNA. These findings are consistent with a species difference in response to peroxisome proliferators between the rat/mouse and the guinea pig.

Amino Acid Sequence↗
PubMed1993

Induction of cytochrome P450 and peroxisomal enzymes by clofibric acid in vivo and in vitro.

We have analysed the induction of microsomal and peroxisomal proteins and their RNAs after treatment of hepatocytes with the peroxisome proliferator, clofibric acid, in vitro and in vivo. After treatment of hepatocytes with 1 mM clofibric acid for 4 days, P450 4A1 RNA is induced 500-fold, and acyl-CoA oxidase and P450 2B1 280-fold, relative to control cultures. These RNAs are detectably induced after administration of 25 microM clofibric acid, and show a similar induction response with increasing doses of clofibric acid. Western blot analysis of the P450 4A and bifunctional enzyme (BFE) proteins showed that both were induced in parallel with increasing doses of clofibric acid, over a range of 25 microM-1 mM. The distribution of the induced proteins was examined by immunocytochemistry. Increasing doses of clofibric acid led to an increase in the average intensity of staining for both proteins throughout the hepatocyte population. There was, however, a graded variation between hepatocytes in the intensity of staining, both for P450 4A and BFE proteins. The heterogeneity in response of the hepatocyte population in vitro may be related to differential sensitivity of hepatocytes to induction in vivo. Therefore, rats were dosed with 0, 50 or 300 mg/kg of clofibric acid for 4 days by gavage, and the livers were examined by immunocytochemistry. After 50 mg/kg of clofibric acid, both P450 4A and BFE were induced mainly in zones 3 and 2 of the liver acinus. However, after 300 mg/kg of clofibric acid, staining for both proteins was strong and homogenous throughout the liver acinus. Thus, hepatocytes from zones 3 and 2 of the acinus are differentially responsive to induction by clofibric acid.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed1993

Vascular smooth muscle responses to endothelial autacoids in rats with chronic coarctation hypertension.

OBJECTIVE: To examine whether elevated intravascular pressure in chronic hypertension alters responses of vascular smooth muscle to agents of endothelial origin. METHODS: Coarctation hypertensive, sham normotensive control, and one-kidney, one clip hypertensive (1K1C) rats were used. Tail systolic, carotid and femoral arterial pressures were measured. Responses to histamine, endothelin-1 and the prostacyclin analog iloprost were evaluated in isolated helically cut strips of thoracic and abdominal aortas, with and without endothelium, from all groups. Responses to nitroglycerin were also evaluated in strips of abdominal aortas. RESULTS: Thoracic aortas from 1K1C and coarctation hypertensive rats, as well as abdominal aortas from 1K1C rats, but not abdominal aortas from coarctation hypertensive rats were exposed chronically to elevated arterial pressure. Endothelium-dependent maximal relaxation by histamine was significantly depressed in thoracic aortas from both groups of rats, as well as in abdominal aortas from 1K1C rats. Maximal relaxation and sensitivity to histamine were normal in abdominal aortas from coarctation hypertensive rats. Sensitivity to nitroglycerin was impaired in abdominal aortas from 1K1C rats but not in those from coarctation hypertensive rats; maximal relaxation to nitroglycerin was similar in all groups. Relaxation to iloprost was independent of the endothelium, observed only in thoracic aortas and impaired in hypertensive rats. Responses to endothelin-1 were similar in the groups. CONCLUSION: Vasorelaxation by histamine, iloprost and nitroglycerin are impaired in hypertension. The impaired relaxation by histamine results from exposure of the vascular endothelium to chronically elevated pressure. This impairment may be related to effects of high pressure in reducing the ability of the endothelium to produce endothelium-derived relaxing factor and inhibit cyclic GMP-dilator mechanisms.

Acetylcholine↗
PubMed1993

Transvascular albumin flux in rabbit hindlimb after tourniquet ischemia.

Transvascular clearance of labeled rabbit albumin was measured in gastrocnemius muscle and heel skin from anesthetized rabbits after 1 or 2 h of tourniquet ischemia. Albumin clearance, calculated as a 1-h extravascular uptake, was 4.7 +/- 0.4 and 29 +/- 1 microliter.h-1 x g dry wt-1 for control gastrocnemius muscle and heel skin, respectively. During the first hour of reperfusion, the clearance was 101 +/- 23 and 56 +/- 6 microliters.h-1 x g dry wt-1 in the muscle and skin, respectively. The clearance in skin during the second and third hour of reperfusion was not different from control. The increased clearance in muscle persisted during 2 h of reperfusion but returned to control levels during the third hour of reperfusion. The solvent drag reflection coefficient was measured by increasing venous pressure during reperfusion in one leg after bilateral ischemia. In skin, the reflection coefficient, calculated as 1 minus the change in clearance divided by the change in water weight, was 0.94 +/- 0.05 and did not change with tourniquet ischemia. The reflection coefficient in muscle was 0.98 +/- 0.01 for control animals and decreased to 0.66 +/- 0.11 during the first hour of reperfusion. The reflection coefficient was not different from control during the third hour of reperfusion. The transitory increase in microvascular permeability to albumin in skeletal muscle is more indicative of an acute inflammatory response than of endothelial injury.

Animals↗
PubMed1993

Selective antagonism of native and cloned kainate and NMDA receptors by polyamine-containing toxins.

Antagonism of rat excitatory amino acid receptors by a synthetic analog [philanthotoxin-343 (PhTX-343)] of a polyamine amide, wasp toxin (philanthotoxin-433) and a structurally related spider toxin, argiotoxin-636 (ArgTX-636), was examined in Xenopus oocytes injected with rat brain RNA or RNA transcribed from the excitatory amino acid receptor clones GluR1, GluR2 and NMDAR1. Antagonism of both kainate- and N-methyl-D-aspartate (NMDA)-elicited responses by PhTX-343 and ArgTX-636 was reversible, noncompetitive and partly voltage-dependent. Dose-inhibition curves were constructed using EC50 concentrations of kainate (100 microM) and N-methyl-D-aspartate (33 microM) in the presence of variable concentrations of ArgTX-636 and PhTX-343. In oocytes injected with rat brain RNA, IC50s for antagonism of kainate-induced currents were similar, i.e., 0.07 microM and 0.12 microM for ArgTX-636 and PhTX-343, respectively, whereas IC50s for antagonism of NMDA-induced currents were dissimilar, i.e., 0.04 microM for ArgTX-636 and 2.5 microM for PhTX-343. In oocytes expressing NMDAR1, IC50s were similar to those for the antagonism of NMDA-induced currents of oocytes injected with rat brain RNA. PhTX-343 and ArgTX-636 were more or less equally potent (IC50s were 2.8 microM and 3.4 microM, respectively) antagonists of the response of GluR1 to 100 microM kainate. However, GluR1 was approximately 50 times less sensitive to the toxins than non-N-methyl-D-aspartate receptors expressed in oocytes injected with rat brain RNA. Receptors co-expressed from GluR1 + GluR2 were virtually insensitive to PhTX-343 (IC50 = 270 microM) and to ArgTX-343 (IC50 approximately 300 microM).

Animals↗
PubMed1993

Ifosfamide combination regimens for soft-tissue sarcoma.

Two trials using ifosfamide-based combination chemotherapy for advanced soft-tissue sarcoma have been completed. In the first study, 50 evaluable patients received ifosfamide (5 g/m2) with mesna (5 g/m2) and doxorubicin (40 or 60 mg/m2) intravenously (i.v.) every 3 weeks. In all, 11 patients (22%) achieved an objective response [3 complete responses (CRs) and 8 partial responses (PRs)]. Toxicities included leukopenia, febrile neutropenia, nausea and vomiting, and alopecia. The overall median survival was 12 months. In the second study, 51 evaluable patients received ifosfamide (3 g/m2) with mesna (3 g/m2), both being given i.v. on day 1, together with etoposide (100 mg/m2) infused i.v. daily for 3 days. Six patients (12%) achieved objective responses (1 CR, 5 PRs). Toxicities included leukopenia, nausea and vomiting, and alopecia. The overall median survival was 7.4 months. Neither of these combination regimens appears to be more effective in advanced soft-tissue sarcoma than single-agent therapy with either ifosfamide or doxorubicin. If the results of chemotherapy in the management of these tumors are to be improved a new approach to therapy is clearly required.

Adolescent↗
PubMed1993

Albendazole is effective treatment for chronic strongyloidiasis.

A total of 301 British ex-Far East prisoners of war, many of whom worked on the Thai-Burma Railway during World War II, consecutively attended The Liverpool School of Tropical Medicine for clinical review between January 1987 and August 1990. Fifty-two (17%) were found to have chronic strongyloidiasis. Diagnostic criteria included any of the following: characteristic larva currens rash, positive Strongyloides serology, and positive stool examination. Forty-seven were evaluable 6 months, after therapy with albendazole 400 mg twice daily for 3 days, which resulted in a 75% cure rate. Cure was defined as disappearance of the rash, if present, negative serology and negative stool examination. Patients who had more than one positive diagnostic feature were only considered cured if both or all had disappeared or become negative. All 12 of the patients in whom initial treatment failed were given a second course of albendazole: three further cures were obtained in eight evaluable patients. The overall cure rate was 81%. The only side-effects recorded were mild nausea and diarrhoea in one patient. We suggest that albendazole should be the treatment of choice for chronic strongyloidiasis.

Aged↗
PubMed1992

Differential tissue-specific expression and induction of cytochrome P450IVA1 and acyl-CoA oxidase.

We have examined the tissue-specific expression and inducibility of acyl-CoA oxidase and cytochrome P450IVA1 (P450IVA1) RNA in rats. Groups of three rats were dosed daily by gavage with methylclofenapate at 25 mg/kg in 5 ml/kg corn oil for nine weeks, or were administered a vehicle control. P450IVA1 and acyl-CoA oxidase RNA were detected using an RNase protection assay. Similar levels of acyl-CoA oxidase RNA were present in control liver and kidney, but the level of this RNA in lung, muscle and testis was 6-11%, and in pancreas was 0.13%, of that in liver. Treatment of rats with methylclofenapate led to an 11-fold induction of acyl-CoA oxidase RNA in liver and also produced a significant induction of this RNA in kidney, lung, muscle and testis of 1.7-fold, 1.3-fold, 2-fold and 1.7-fold, respectively. Acyl-CoA oxidase RNA was not induced in pancreas. P450IVA1 RNA was present in control liver and also in kidney of control rats at 28% of the level in liver. In contrast to acyl-CoA oxidase RNA, P450IVA1 RNA was not detected in lung, pancreas or testis. Methylclofenapate treatment of rats led to an 18-fold induction of P450IVA1 RNA in liver, and a sevenfold induction in kidney. Induction of P450IVA1 was not detected in any of the other tissues examined. Quantification of the relative amounts of acyl-CoA oxidase and P450IVA1 RNA in control liver revealed that acyl-CoA oxidase RNA was present in a 17.5-fold molar excess over P450IVA1 RNA. Western blotting with an anti-P450IVA IgG revealed two bands of similar apparent molecular mass in liver and kidney microsomes, but not in microsomes from the testis of control rats. Methylclofenapate treatment of rats caused an increase in the intensity of these bands in microsomes from liver, but no induction was obvious in kidney. Immunocytochemical staining for both the microsomal P450IVA and peroxisomal acyl-CoA oxidase proteins was restricted to the proximal convoluted tubule in the kidney cortex, with staining being most intense in the S3 region.

Acyl-CoA Oxidase↗
PubMed1992

Zone-specific inducibility of cytochrome P450 2B1/2 is retained in isolated perivenous hepatocytes.

The expression and induction of the cytochrome P450 2B1/2 isoenzyme is heterogeneous, exhibiting a regional pattern in the intact liver and a varied response to phenobarbital in isolated cultured hepatocytes. We report that P450 2B1/2 immunostaining of hepatocytes isolated from the perivenous liver region and cultured in the presence of phenobarbital is much stronger than that of cells identically treated but isolated from the periportal region. P450 2B1 mRNA, quantified by a sensitive and specific RNAase protection assay, is also preferentially induced in perivenous hepatocytes, demonstrating that the difference in induced expression is at the pretranslational level. Our results suggest that perivenous and periportal hepatocytes are differentially imprinted to retain regiospecific factors governing their inducibility after isolation.

Animals↗
PubMed1992

Transvascular albumin and IgG flux in skin and skeletal muscle following plasmapheresis.

The extravascular uptake for labeled albumin and IgG and the extravascular masses for endogenous albumin and IgG were measured in skin and skeletal muscle from anesthetized rabbits following 24 hr of intermittent plasmapheresis. An amount of protein equivalent to the total intravascular protein mass was removed. There was a significant reduction in the extravascular mass for albumin in both tissues and for IgG in skin. The shift of albumin out of the extravascular space of skin and skeletal muscle could account for 95% of the vascular replacement of albumin. The extravascular uptake for the labeled proteins was measured as the 1-hr extravascular distribution space at plasma concentration divided by time and expressed as a plasma clearance. The plasma volume in the tissue samples was estimated from the 3-min distribution space for labeled transferrin. Following plasmapheresis the rate of extravascular uptake for both labeled proteins was greater than that for control or sham-operated animals, suggesting an increase in transvascular protein permeability. The transvascular fluxes for native albumin and IgG were not increased due to the decrease in the plasma concentrations. The results were consistent with the major mechanism for a shift of plasma proteins being due to a decrease in plasma protein concentration and a subsequent increase in lymph flow instead of a decrease in transvascular protein permeability.

Albumins↗