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Biomedical subjects

D R Bell

Publications and source records attributed to D R Bell.

At least 73 records · Page 4Linked to original sources
PubMed1992

Influence of saline infusions on transvascular protein transport.

Anesthetized rabbits were given an intravenous infusion of saline over a 1-h period to increase transvascular protein transport in skin and skeletal muscle. The infusion rate was adjusted to rapidly decrease the plasma concentration of total protein without increasing mean arterial blood pressure or the venous pressure in the leg. The 1-h clearance for radiolabeled albumin and a set of charge-modified albumins was measured in the heel skin and the gastrocnemius muscle. For both skin and skeletal muscle, the clearance for native albumin during the saline infusion was twice the value for control. The increase in clearance for the most neutral protein was greater than that for native albumin, suggesting that transvascular fluid movement was through a pathway which excludes native albumin. The clearance for cationic albumin increased slightly in skin and did not change in skeletal muscle, indicating that transport of the cationic protein through this pathway is predominantly diffusion. The data were consistent with a two-pore model for transvascular transport of water and proteins and with the increase in water transport through the small pores during the saline infusion.

Animals↗
PubMed1992

Importance of charge on transvascular albumin transport in skin and skeletal muscle.

To test the hypothesis that charge affects the transvascular transport of albumin, the tracer clearance for albumin and a set of charge-modified albumins was measured in heel skin and gastrocnemius muscle from anesthetized rabbits. The charge on albumin was made less negative by modifying the carboxyl groups of aspartic and glutamic acids to alcohol groups. Four preparations of modified albumin having isoelectric points of 5.1 +/- 0.4, 5.8 +/- 0.4, 7.1 +/- 0.5, and 8.1 +/- 0.7 were studied. In skin, the clearances for the most neutral modified albumin and cationic albumin were 20 and 80% greater than that for native albumin, respectively. In skeletal muscle, the clearances for the most neutral modified albumin and cationic albumin were 50% and 1.5 times greater than that for native albumin, respectively. Calculation of the reflection coefficient for native albumin from the change in clearance with increased venous pressure resulted in estimates greater than 0.95 in both tissues. The change in clearance for the modified albumins during increased venous pressure was not different from that for native albumin. Charge appears to effect transvascular diffusion of proteins more than convective transport.

Animals↗
PubMed1992

Comparison of protein lymph flux and extravascular uptake in skin during increased venous pressure.

The hypothesis that the albumin reflection coefficient is underestimated from measurements of lymph protein flux because of a prolonged interstitial washout was tested in the hindleg of anesthetized rabbits. In heel skin, the initial extravascular uptake for labeled albumin and immunoglobulin G (IgG) was compared with prenodal lymph flux for native albumin and IgG. Venous pressure was increased in one leg for 4 h, while the contralateral leg was the control. The extravascular uptake for labeled albumin was 67% greater than control during the fourth hour of increased venous pressure. Lymph albumin flux was 2.3 times control, indicating a small but significant washout of interstitial albumin. The magnitude of the interstitial washout for IgG was less than that for albumin. Using the relationship between the change in extravascular uptake and the change in lymph flow, the reflection coefficients for albumin and IgG were both 0.91. The reflection coefficient for albumin using lymph protein flux was lower because of a continued interstitial washout.

Animals↗
PubMed1992

Transvascular albumin and IgG flux in skin after a continuous 3-h bradykinin infusion.

Bradykinin (1 microgram/min) was infused into the femoral artery of one hindleg of anesthetized rabbits for 3 h. Measurements of the initial extravascular uptake for labeled albumin and immunoglobulin (Ig) G were compared with measurements of the lymph protein flux for endogenous albumin and IgG. With bradykinin, the initial extravascular uptake for both albumin and IgG, calculated as the 1-h extravascular distribution space at plasma concentration divided by time and expressed as a plasma clearance, was 12 times the control values. For both proteins, the lymph fluxes were not significantly greater than the values for extravascular uptake, indicating that the sustained increase in lymph protein flux was not due to washout of interstitial protein. The extravascular uptake for IgG was approximately 80% of that for albumin in both control and bradykinin animals, suggesting that the sustained response did not change the selectivity between the two proteins. Changes in the extravascular masses of endogenous albumin and IgG suggest that the initial response to bradykinin was a transient formation of endothelial gaps that did not restrict transvascular IgG transport more than albumin.

Animals↗
PubMed1992

Simultaneous measurement of fluid and protein permeability in isolated rabbit lungs during edema.

Fluid conductance and protein permeability have been studied in isolated perfused lung models of pulmonary edema. However, previous studies have not investigated changes of both fluid conductance and protein permeability in the same isolated lung preparation after injury. Arachidonic acid (AA) metabolites are involved in the inflammatory processes that lead to the development of pulmonary edema. The hemodynamic effects of AA have been well established; however, controversy exists concerning the ability of AA to alter the permeability of the pulmonary microvasculature to fluid and protein. The purpose of this study was to simultaneously determine whether transvascular fluid conductance and protein permeability are increased in isolated perfused rabbit lungs with pulmonary edema induced by AA. Indomethacin (80 microM) was added to the perfusate to inhibit the hemodynamic effects of AA and produce a pressure-independent model of pulmonary edema. Fluid conductance was assessed by determination of the capillary filtration coefficient (Kf), and protein permeability was evaluated by measurement of 125I-albumin clearance. The injection of AA (3 mg/200 ml of perfusate) into the pulmonary arterial catheter resulted in an increase in lung weight over the remaining 30-min experimental period. Kf (microliter.s-1 x cmH2O-1 x g dry lung-1) was increased (P < 0.05) in AA-treated lungs at 10 and 30 min post-AA injection when compared with control lungs and baseline values (determined 10 min before AA injection). Albumin clearance was also greater (P < 0.05) in lungs that received AA. 125I-albumin clearance was measured at different rates of fluid flux produced by elevation of venous pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗
PubMed1991

Induction of acyl-CoA oxidase and cytochrome P450IVA1 RNA in rat primary hepatocyte culture by peroxisome proliferators.

We have characterized the induction of acyl-CoA oxidase and cytochrome P450IVA1 RNAs in a primary hepatocyte culture system in vitro, using a sensitive and specific RNAse protection assay. Hepatocytes were cultured with a maximal inducing dose of the peroxisome proliferator clofibric acid (1 mM), or vehicle control, for 4 days, and the level of RNAs compared with the level in rats which had been treated with corn oil or clofibric acid (300 mg/kg) for 4 days. The level of acyl-CoA oxidase and P450IVA1 RNAs in 4-day-old control hepatocytes was less than 2% of that in control liver. However, the level of these RNAs in RNA from treated hepatocytes was 61% of that in liver RNA from treated rats. Hepatocytes were treated with the potent peroxisome proliferator methylclofenapate (100 microM), and the induction of RNAs determined at various times after exposure. P450IVA1 RNA was significantly induced 1 h after dosing, rising to 34-fold above control after 8 h, whereas acyl-CoA oxidase RNA was not significantly induced until 4 h, increasing to 5.2-fold above control after 8 h. A similar time course of induction was seen after treatment of hepatocytes with 100 microM-nafenopin, 100 microM-methylclofenapate, 1 mM-clofibric acid or 1 mM-mono(ethylhexyl) phthalate, suggesting that the differential time course of induction of P450IVA1 and acyl-CoA oxidase RNAs is not related to the esterification, structure or potency of the peroxisome proliferator, but is intrinsic to the process of peroxisome proliferation. Hepatocytes were treated with methylclofenapate in the presence and absence of cycloheximide. P450IVA1 RNA was significantly induced by methylclofenapate in the presence of cycloheximide, rising to 17-fold above control after 8 h. However, no induction of acyl-CoA oxidase RNA was detected in the presence of cycloheximide. Therefore we characterize the induction of acyl-CoA oxidase and P450IVA1 RNAs in primary hepatocyte culture in vitro as a faithful model of the induction response in rat liver, and suggest that induction of P450IVA1 RNA is a primary event in the process of peroxisome proliferation.

Acyl-CoA Oxidase↗
PubMed1991

Regulation of differentially spliced transcripts of acyl-CoA oxidase in the rat.

RNAse protection assay was used to distinguish between and to quantify alternatively spliced transcripts of acyl-CoA oxidase in liver, kidney and testis of control and methylclofenapate treated rats. The ratio of spliced transcripts (type I to II) was 1.18:1 in control liver RNA, with 130 and 110 molecules/cell, respectively, and 3.1:1 in treated liver RNA, with 2800 and 900 molecules/cell. The ratios were 1.6 and 2:1 in control and treated kidney, and 0.31:1 in testis. This is likely to be due to differential splicing, which is, therefore, regulated during peroxisome proliferation, and also in a tissue specific fashion.

Acyl-CoA Oxidase↗
PubMed1991

Localization and differential induction of cytochrome P450IVA and acyl-CoA oxidase in rat liver.

The peroxisome proliferators are structurally diverse chemicals which induce hyperplasia, hypertrophy and the proliferation of peroxisomes in the rodent liver. Cytochrome P450IVA1 and peroxisomal enzymes, such as acyl-CoA oxidase, are induced and are early markers of treatment with peroxisome proliferators. In this study, rats were dosed intraperitoneally with the potent peroxisome proliferator methylclofenapate and the hepatic induction response was studied. There was no significant change in the enzyme activities of laurate hydroxylase (cytochrome P450IVA1) or acyl-CoA oxidase in the first 8 h after treatment, but the activities had doubled at 24 h, suggesting that these enzymes are not involved in the mediation of early events in peroxisome proliferation. Hepatic cytochrome P450IVA1 mRNA was significantly increased at 6 and 8 h after treatment, rising to 15-fold above control values at 30 h. In contrast, acyl-CoA oxidase mRNA showed no significant change in the first 8 h, but increased to 13-fold above control values at 24 and 30 h, thereby demonstrating different kinetics of induction of the two mRNAs. In order to determine whether cytochrome P450IVA1 and peroxisomal enzymes were included in the same cells, rats were treated daily with sub-maximal (2 or 5 mg/kg) and maximal (25 mg/kg) inducing doses of methylclofenapate for 4 days. The lobular distribution of induced proteins was determined immunocytochemically with antibodies raised against P450IVA1 and acyl-CoA oxidase. Livers from control animals showed minimal staining for both proteins. However, in the livers of animals treated with 2 or 5 mg of methylclofenapate/kg, both acyl-CoA and P450IVA immunostaining was increased, mainly in the centrilobular area. Immunostaining of serial sections revealed that these proteins were induced in the same region of the lobule. A maximal inducing dose of methylclofenapate (25 mg/kg) caused panlobular induction of both proteins. The results demonstrate that these proteins are induced in a dose-dependent manner in the same, spatially distinct, sensitive region of the liver lobule.

Acyl-CoA Oxidase↗
PubMed1991

Horizontal transmission of hepatitis B virus amongst British 2nd World War soldiers in South-East Asia.

Infection with hepatitis B virus (HBV) is much more common in tropical than in temperate countries. Visitors to the tropics are thus at risk from HBV, though the degree of risk, and the routes of infection involved are uncertain. We report serological markers of HBV in two groups of 2nd World War soldiers, who served in the Thai/Burma jungles. The groups comprised 100 ex-prisoners of the Japanese (POW), and 100 Burma Campaign Veterans (BCV). Surface antigen to HBV (HbsAg) was positive in 0% of POW and 2% of BCV (P = not significant). Surface antibody (anti-HBs) and core antibody (anti-HBc) were both positive in 40% POW and 13% BCV (P less than 0.001). Quoted UK prevalence rates for these markers are 0.1% for HBsAg, 1.5% for anti-HBs and 0.7% for anti-HBc. Both groups thus show very high rates of past HBV infection. For the POW there were many possible reasons, including contaminated surgical instruments and needles, blood transfusions, and multiple beatings with common weapons. None of these factors operated significantly for BCV. Malarial transmission was, however, intense in both groups, though more so in POW. The data thus again raise the possibility of horizontal transmission of HBV by biting insects in tropical countries.

Hepatitis B↗
PubMed1991

Endothelium in functional aortic changes of coarctation hypertension.

Eleven coarctation hypertensive (CH), twelve sham control (C), and seven one-kidney, one-clip (1K,1C) rats were used to examine the role of pressure and the endothelium in vascular sensitivity changes to acetylcholine (ACh), serotonin (5-HT), and norepinephrine (NE) in chronic arterial hypertension. Terminal mean carotid artery pressures were CH = 156 +/- 5 mmHg, C = 99 +/- 3 mmHg, and 1K,1C = 159 +/- 5 mmHg. Femoral artery pressures were CH = 100 +/- 3 mmHg, C = 98 +/- 4 mmHg, and 1K,1C = 154 +/- 4 mmHg, respectively. Isometric tension recordings were made from helically cut strips of thoracic and abdominal aortas, with and without functional endothelium, from the three groups of rats. Sensitivity to relaxation by acetylcholine, expressed as -log of 50% effective dose, was significantly depressed in thoracic aortas from CH and 1K,1C rats and abdominal aortas from 1K,1C rats but not from abdominal aortas of CH rats. A similar relationship between the groups was seen for 5-HT contractions. Sensitivity to NE was enhanced in thoracic and abdominal aortas of hypertensive rats. Inactivation of aortic endothelia abolished ACh responses, did not alter 5-HT relationships between the three groups, and abolished the differences in sensitivity to NE in thoracic aortas. The data suggest that pressure and the endothelium may play a role in vascular sensitivity changes in hypertension.

Acetylcholine↗
PubMed1991

Effect of fluid resuscitation from endotoxin shock on lung transvascular fluid and protein exchange.

The hypothesis that volume expansion during septic shock produces a greater transvascular protein flux than volume expansion alone was tested in anesthetized sheep by giving a high dose of endotoxin (40 micrograms/kg) intravenously. After 0.5 h of systemic hypotension, Ringer lactate, equivalent to 8% body wt, was infused followed by an additional 4 h of lymph collection. The results were compared with those from control animals receiving only Ringer lactate. The changes in plasma total protein with time were similar between groups. The increases in lymph flow and lymph protein flux were greater in the endotoxin-challenged group compared with the control group receiving Ringer lactate during the first 2 h but were similar thereafter. The interstitial volume was greater in the endotoxin-challenged animals compared with controls. The extravascular masses or apparent tissue concentrations for albumin or immunoglobulin G did not change in either group receiving Ringer lactate. The pulmonary edema following resuscitation from septic shock with Ringer lactate could be accounted for by either the pulmonary hypertensive effects of endotoxin or an initial, transient increase in microvascular protein permeability but not a sustained increase in microvascular permeability.

Animals↗
PubMed1991

Podiatry.

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Education, Medical, Graduate↗
PubMed1990

Combined use of cyclosporin A and verapamil in modulating multidrug resistance in human leukemia cell lines.

This study describes the synergistic interaction of two biochemical modulators, cyclosporin A (CyA) and verapamil (Vp), in multidrug-resistant cells, the highly resistant and moderately resistant variants (CEM/VLB 1000 and CEM/VLB 100) of the parental drug-sensitive T-cell leukemia cell line CEM/CCRF. In the absence of either modulator, the 50% inhibitory concentration for Adriamycin in these cell lines was 270 +/- 10.6 (SD) micrograms/ml, 96 +/- 8.5 micrograms/ml, and 1.5 +/- 0.1 micrograms/ml, respectively. CyA and Vp dramatically reduced multidrug resistance in CEM/VLB 100 and CEM/VLB 1000 in a dose-dependent manner but had no effect on the sensitivity of the parental line to Adriamycin. At a CyA concentration of 8.3 mumol (10 micrograms/ml), the 50% inhibitory concentration of Adriamycin of CEM/VLB 1000 and CEM/VLB 100 fell to 5.9 +/- 0.9 micrograms/ml and 3.3 +/- 0.6 micrograms/ml, respectively. Similarly at a Vp concentration of 10 mumol the 50% inhibitory concentration of Adriamycin of CEM/VLB 1000 and CEM/VLB 100 fell to 23.7 +/- 3.7 micrograms/ml and 5.7 +/- 0.2 micrograms/ml, respectively. More importantly, CyA and Vp showed significant synergism when tested in combination in the moderately resistant line at concentrations normally seen after the clinical administration of these modulators. Synergy was also present when both drugs were tested in the highly resistant variant. These data indicate the need for in vivo studies, given the potential clinical importance of these observations.

Cyclosporins↗
PubMed1990

Initial equilibration of albumin and IgG in rabbit hind paw skin and lymph.

To determine if the interstitial distribution of plasma proteins influences transport from plasma to lymph, the initial plasma-to-extravascular and plasma-to-lymph equilibrations for 131I-labeled rabbit albumin and 125I-labeled rabbit IgG were compared in hind paw heel skin of anesthetized New Zealand White rabbits. Plasma specific activities were maintained constant with time using continuous infusions. The plasma space in skin samples taken at the end of the experiment was estimated by a 3-min accumulation of 59Fe-labeled bovine transferrin. Albumin and IgG concentrations in plasma, lymph, and skin were determined by rocket electroimmunoassay. The lymph specific activity relative to that of plasma for the larger sized IgG was significantly greater (P less than 0.01) than that for albumin during the initial 8 hr of equilibration. The tissue specific activity relative to that of plasma for IgG was significantly less (P less than 0.01) than that for albumin. The distribution space at lymph concentration for both proteins was 1 ml/g dry skin wt, indicating similar excluded volumes. These data are consistent with the hypothesis that convective movement of plasma proteins through the interstitium affects lymph equilibration while diffusion affects tissue equilibration.

Albumins↗
PubMed1990

Fatty streak development in the vicinity of aortic coarctations in hypercholesterolemic rabbits.

The influence of altered local hemodynamics on fatty streak development in rabbits fed high cholesterol diets was investigated. An aortic coarctation was created in the abdominal aorta of nine rabbits by placing a partially constricting gold or silver band (1.7 mm x 10 mm) around the aorta between the renal arteries and aortic bifurcation. Controls were 20 rabbits; seven sham operated and 13 unoperated rabbits. The abdominal aorta 1-2 cm proximal to the coarctation showed lipid deposition involving 45 +/- 8% (mean +/- SEM) of the luminal surface which was more than occurred within or distal to the obstruction (p less than 0.05) and also more than in controls (p less than 0.05). Within the coarctation, 4 +/- 2% of the luminal surface showed lipid deposition which was less than either proximally or distally (p less than 0.01) and also less than in comparable regions in controls (p less than 0.05). The aorta 1-2 cm distal to the coarctation showed lipid deposition involving 18 +/- 4% of the surface which was similar to control rabbits. Lipid deposition in corresponding regions of the control rabbits was involved in 17 +/- 4%, 19 +/- 5% and 19 +/- 4% of the luminal surface, respectively. Fatty streak development, therefore, appeared to be inhibited within the coarctation and enhanced proximal to it. The results suggest that some early step in the process of lipid accumulation may be affected by local fluid dynamics or modification of the wall of the vessel.

Animals↗
PubMed1989

Individualities in post-serotonin attenuation and Na+/K+ pump activity in vascular smooth muscle.

Prior treatment with serotonin (10(-8)-10(-7) M for 6 min) attenuated responses of rabbit mesenteric arteries to norepinephrine (NE) by 18-62%, but was without effect on the responses of the rabbit aorta. K+ relaxation responses in the mesenteric arteries were enhanced by serotonin, but in the aortic strips K+ relaxation occurred either before or after treatment with serotonin. Maximum relaxation to monensin was similar in the two tissues. Post-serotonin attenuation and K+ and monensin relaxation were blocked by ouabain, indicating that they depended on Na+/K+ pump stimulation. Intracellular Na+ contents (Nai) were determined in the vessels by the Li substitution method. Nai was greater, and was increased to a greater extent by serotonin and K(+)-free physiological salt solution in the mesenteric artery compared to the aorta, suggesting that the cell membrane of the mesenteric artery is leakier to Na+ than is that of the aorta. We conclude that the absence of post-serotonin attenuation in the aorta results from the failure of serotonin to increase Nai and thereby to stimulate the Na+/K+ pump in this tissue. This study demonstrates that important individualities in vascular smooth muscle reactivity even in the same animal may result from differences in membrane permeability to sodium.

Animals↗
PubMed1989

Atypical multidrug resistance in a therapy-induced drug-resistant human leukemia cell line (LALW-2): resistance to Vinca alkaloids independent of P-glycoprotein.

Near diploid leukemic T-cells (LALW-2), exposed to cytotoxic drugs only as a consequence of therapy administered to the donor patient, have been maintained by serial xenograft in nude mice. In comparison with the leukemic line CCRF-CEM, using a growth inhibition assay, LALW-2 cells were resistant to Vinca alkaloids and actinomycin D (relative resistance, 200-fold or more), were slightly resistant to Adriamycin (relative resistance, 4-fold), and showed no resistance to daunorubicin or teniposide. By comparison, a vincristine-resistant CEM subline developed in our laboratory (CEM/VCR R) was resistant to all these agents by at least 30-fold. The VCR R subline served as a positive control, confirming the previously reported correlation between multidrug resistance and amplification of the P-glycoprotein gene. Comparison of CEM, CEM/VCR R, and LALW-2 cells establish that the P-glycoprotein gene was not amplified or overexpressed in the LALW-2 cells; neither could the gene product be detected by immunoblotting in extracts from these cells. The LALW-2 cells were further distinguished from CEM/VCR R cells due to the lack of increased vincristine efflux by the xenografted cells, an effect readily demonstrable in the CEM/VCR R cells. However, although LALW-2 cells efflux vincristine at the same rate as CCRF-CEM cells, the xenografted cells exhibited a reduced rate of vincristine accumulation. Uptake of daunorubicin by LALW-2 cells was not distinguished from that by CEM cells, consistent with similar 50% inhibitory dose levels for this drug in both cell populations, and differentiating both from CEM/VCR R cells. Thus, clinical resistance in this case appears to be an "atypical" form of multidrug resistance specifically distinguished by resistance to Vinca alkaloids and actinomycin D occurring in the absence of increased amounts of P-glycoprotein and manifesting decreased drug uptake.

ATP Binding Cassette Transporter, Subfamily B, Mem↗