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Biomedical subjects

J L Barnes

Publications and source records attributed to J L Barnes.

At least 37 records · Page 2Linked to original sources
PubMed1993

Synthesis and evaluation of 2-pyridinone derivatives as HIV-1-specific reverse transcriptase inhibitors. 4. 3-[2-(Benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one and analogues.

A new series of potent specific 2-pyridinone reverse transcriptase (RT) inhibitors was developed based on the preliminary development lead 3-[(phthalmido)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (3), a non-nucleoside derivative which exhibited weak antiviral activity in cell culture against HIV-1 strain IIIB. One compound, 3-[(benzoxazol-2-yl)ethyl]-5-ethyl-6-methylpyridin-2(1H)-one (9,L-696,229), which was a highly selective antagonist of the RT enzyme (IC50 = 23 nM) and which inhibited the spread of HIV-1 IIIB infection by > 95% in MT4 human T-lymphoid cell culture (CIC95 = 50-100 nM), was selected for clinical evaluation as an antiviral agent.

Antiviral Agents↗
PubMed1993

Temporal expression of autocrine growth factors corresponds to morphological features of mesangial proliferation in Habu snake venom-induced glomerulonephritis.

Habu snake venom induces an accelerated mesangial proliferative glomerulonephritis that follows a predictable course from early capillary aneurysms to micronodules comprised of confluent mesangial cells within 72 hours. We examined morphologically the course of mesangial cell proliferation and correlated it with the expression of messenger (m) RNA encoding two peptide growth factors, platelet-derived growth factor (PDGF) A and B chains and transforming growth factor-beta (TGF-beta). Rats were uninephrectomized and 24 hours later injected with Habu snake venom or saline. Kidney cortex and isolated glomeruli were obtained 24, 48, and 72 hours later for histological assessment, preparation and Northern analysis of mRNA, and immunohistochemical localization of PDGF using a polyclonal antibody that recognizes A and B chains. Maximal expression of PDGF B chain mRNA occurred at 24 hours and before the onset of mesangial cell proliferation; whereas maximal expression of PDGF A chain and TGF-beta mRNA occurred at 48 hours and during active mesangial cell proliferation. Expression of TGF-beta mRNA persisted at 72 hours at a time when PDGF A chain declined and PDGF B chain was not expressed compared to uninephrectomy and saline controls and at a time when mesangial cells within lesions reached confluence and proliferation subsided. PDGF protein localized in glomerular lesions associated with platelets at 24 and 48 hours and within mesangial cells at 48 and 72 hours. These results agree with the known roles of PDGF and TGF-beta as positive and negative modulators, respectively, of mesangial cell growth in vitro and suggest that a relative balance of the expression of these factors may operate in glomerular disease in vivo.

Animals↗
PubMed1992

Nonsurgical closure of femoral pseudoaneurysms complicating cardiac catheterization and percutaneous transluminal coronary angioplasty.

OBJECTIVES: This study was performed to describe the initial experience and follow-up of ultrasound-guided compression of pseudoaneurysms in patients receiving systemic anticoagulant or antiplatelet therapy, or both, after recent cardiac catheterization or percutaneous transluminal coronary angioplasty. BACKGROUND: Femoral artery pseudoaneurysm formation after an interventional procedure is becoming more common as larger caliber catheters and prolonged anticoagulant and antiplatelet therapy are being used. Traditional treatment of this complication has been surgical repair. This study describes a new method of closing femoral pseudoaneurysms by using external compression guided by Doppler color flow imaging. METHODS: Fifteen patients, 3 undergoing cardiac catheterization and 12 undergoing coronary angioplasty, developed an expansile groin mass at the vascular access site diagnosed as a femoral artery pseudoaneurysm by Doppler ultrasound. Seven of the patients had undergone coronary stenting and were receiving postprocedural anticoagulant therapy. These patients underwent progressive graded mechanical (C-clamp) external compression guided by ultrasound. The mechanical compression was titrated to obliterate the vascular tracts to these aneurysms and maintain adequate flow in the femoral artery. RESULTS: After an average compression time of 30 min (range 10 to 120), these tracts remained closed. Follow-up ultrasound examination at 24 h or later confirmed continued closure in all. CONCLUSIONS: This study suggests that nonsurgical closure of femoral pseudoaneurysms is feasible. This technique may be valuable in managing vascular access-related complications after diagnostic and interventional procedures, even in patients requiring prolonged anticoagulant therapy.

Adult↗
PubMed1991

11-Dehydrocorticosterone, a glucocorticoid metabolite, inhibits aldosterone action in toad bladder.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) metabolizes glucocorticoid hormones and diminishes their ability to induce sodium transport. In these studies, we determined the location of this enzyme in toad bladder and assessed the biological role for its 11-dehydro end product. Employing a polyclonal antibody directed toward 11 beta-OHSD and immunofluorescence techniques, we located the enzyme in the epithelial cell layer of the toad bladder. Although corticosterone (10(-7) M) can partially suppress aldosterone (10(-7) M)-stimulated short-circuit current (SCC), a clear excess of corticosterone (10(-6) M) did not inhibit the aldosterone-induced induced (10(-8) M) rise in SCC (n = 6). The 11-dehydro product of corticosterone, 11-dehydrocorticosterone (compound A) added to the serosal bath suppressed aldosterone (10(-8) M) peak SCC (360 min) in a dose-dependent fashion reaching 46 +/- 5% of control values at 10(-5) M (n = 6; P less than 0.001). Compound A (10(-5) M) in the mucosal bath also was capable of partially inhibiting the peak aldosterone rise in SCC to 63 +/- 7% of control values with aldosterone at 10(-8) M (n = 6; P less than 0.01) and to 64 +/- 10% of control values with aldosterone at 10(-7) M (n = 9; P less than 0.01). Compound A alone at 10(-5) M did not have any effect on SCC. Isolated toad bladders were not able to transform compound A (at 10(-8) and 10(-5) M) back to corticosterone. Thus the 11-dehydro end product of 11 beta-OHSD (compound A) may play a biologic role by regulating a component of mineralocorticoid-induced sodium transport.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1991

Effect of Ringer infusion on ischemic acute renal failure: caution on interpreting the results of short-term studies.

The effect of a 4.5 mL/h Ringer infusion on the recovery from a unilateral 40-min renal artery occlusion was investigated in Sprague-Dawley rats. The inulin clearance measured in the experimental kidney 24 and 48 h after the insult in control animals that did not receive the Ringer infusion was 0.14 +/- 0.10 (mean +/- SE) and 0.11 +/- 0.05 mL/min, respectively. In animals that received 24 h of Ringer infusion begun at the time of the renal artery occlusion the inulin clearance was 0.81 +/- 0.07 mL/min, a value significantly higher than either of the control groups (p less than .05). If, however, the Ringer infusion was stopped at 24 h and the inulin clearance measured at 48 h, it had decreased significantly (0.27 +/- 0.09 mL/min) and was no longer greater than the control groups. Similarly, if the infusion was continued for 48 h there was no longer a significant difference between the inulin clearance (0.37 +/- 0.11), when compared with 48 h of no infusion (0.11 +/- 0.05). The histology of the different groups corresponded with the functional data. We conclude that 24 h of Ringer infusion leads to functional and histological protection when measured at 24 h; however, if measured at 48 h, protection is no longer evident. These studies suggest that caution should be exercised in extrapolating from the results of protective maneuvers in ischemic acute renal failure investigated by short-term studies.

Acute Kidney Injury↗
PubMed1991

Glomerular mesangial cell migration. Response to platelet secretory products.

Glomerular mesangial cells migrate in response to platelet-derived growth factor (PDGF), but to date these cells have not been examined for migratory behavior in response to other platelet secretory products. Because migration might provide an additional mode of cell redistribution and local mesangial hypercellularity in certain forms of glomerular disease, we examined, in vitro, the potential of isolated rat mesangial cells to migrate toward gradients of platelet releasate and selected platelet secretory proteins. Chemotaxis assays were performed in two compartment blind well chambers, each compartment separated by a porous membrane. Releasate of activated platelets was added in incremental concentrations (25, 50, and 100 micrograms/ml) to lower compartments, and mesangial cells were placed in upper compartments. The chambers were then incubated at 37 degrees C for 4 hours. Mesangial cell migration through the membranes was quantitated by scanning electron microscopy. Mesangial cells migrated toward platelet releasate in a linear dose-response, achieving cell numbers of approximately 40 times those of controls. Examination of specific platelet alpha granule secretory proteins disclosed a potent mesangial cell migratory response to platelet-released fibronectin (Fn), but not to transforming growth factor-alpha (TGF-alpha), -beta (TGF-beta), epidermal growth factor (EGF), or platelet factor 4 (PF4). Secretory levels of platelet Fn (1 to 25 micrograms/ml) induced a maximum migratory response of approximately 60-fold over controls. Mesangial cell migration in response to both platelet Fn and platelet releasate was abrogated by blocking the integrin receptor for Fn with RGDS tetrapeptide. Thus, platelet Fn appears to be a prominent component of platelet releasate responsible for mesangial cell migration.

Animals↗
PubMed1990

Human rheumatoid factor cross-idiotypes. III. Bla monoclonal rheumatoid factor, prototype of the BLA cross-idiotype group, has distinct kappa chains related to the V kappa III subgroup and VH4 heavy chains.

The BLA cross-idiotype (XId) is present on a unique subset of rheumatoid factors (RF) that cross-react with DNA-histone. In this study, prototype Bla monoclonal RF was shown from serologic investigations and N-terminal amino acid sequence analysis to have distinct kappa chains related to the V kappa III subgroup and VH4 heavy chains. The amino terminus of the heavy chain was cyclized, rendering the protein resistant to Edman degradation and providing a possible investigator bias to the published Ig sequence data to date. This appears to be the first definitive report of a serum IgM that expresses the VH4 gene. RF with DNA cross-reactivity have been reported to be produced by human and mouse cloned cells that have the VH4 or homologous mouse Vh36-60 gene.

Amino Acid Sequence↗
PubMed1990

Glomerular mesangial cell migration in response to platelet-derived growth factor.

Platelet-derived growth factor (PDGF) is a potent mitogenic and chemotactic protein for a variety of cell types. Glomerular mesangial cells also respond to PDGF in terms of proliferation, but, to date, have not been examined for migratory behavior in response to a specific growth factor. Here, we examine the ability of isolated rat mesangial cells to migrate toward gradients of purified PDGF. Chemotaxis assays were performed in two-compartment blind well chambers, each compartment separated by a 14-microns porous filter membrane. Human PDGF was added to 200 microliters of RPMI 1640 medium in the lower compartment beneath the filters to make incremental concentrations from 2.5 to 50 units/ml. Control compartments received diluent without PDGF. Mesangial cells in RPMI 1640 medium were added to the upper compartments and the chambers were incubated for 8 hours at 37 degrees C. After fixation, the number of cells on the underside of the filter were counted by scanning electron microscopy. A linear dose response of mesangial cell migration toward increasing concentrations of PDGF was observed, achieving cell numbers of 9-fold over controls at 50 units/ml. Migratory cells were verified as mesangial cells by fluorescence expression of actin, myosin, and desmin and absence of expression of leukocyte common antigen and Ia antigen. Addition of equimolar concentrations of PDGF on both sides of the filter or addition of anti-PDGF antibody to the lower chamber containing PDGF negated the chemotactic response. These studies indicate that mesangial cells migrate in response to PDGF. This mechanism may, in part, play a role in some forms of mesangial proliferative glomerular disease.

Animals↗
PubMed1989

Glomerular localization of platelet secretory proteins in mesangial proliferative lesions induced by habu snake venom.

Platelets have been implicated in mesangial cell proliferation in experimental and clinical glomerular disease. In this study, the temporal relationship between release of platelet secretory cationic proteins (PSCP) and progression of mesangial hyperplasia was examined in a model of mesangial proliferative glomerulonephritis induced by Habu snake venom (HSV). Intravenous injection of HSV (2 mg/kg body wt) led to capillary dilatation and ballooning into cysts filled with prominent platelet aggregates at 8 hr and 24 hr. At 48 hr, lesions were heterogeneous, some exclusively cystic, others exclusively nodular (comprised of confluent proliferative mesangial cells). Most lesions were mixed, showing features of cystic lesions containing clusters of proliferating cells. At 72 hr, all lesions were exclusively nodular. These lesions were associated with persistent localization of PSCP, as demonstrated by immunofluorescence microscopy. At 8 hr, PSCP were restricted primarily to platelets, became more intensified and diffuse at later time intervals, and by 72 hr was demonstrated in a homogeneous pattern interspaced throughout the nodular lesions. Studies utilizing antiserum to a specific platelet secretory protein, platelet factor 4 (PF4), showed an identical pattern of glomerular localization. Thus, before and during the proliferative phase of nodular formation, mesangial cells are exposed to a milieu replete with PSCP, some of which are presumably biologically active, suggesting a potential role for platelet-secreted proteins in mesangial hyperplasia in this model.

Animals↗
PubMed1989

Amelioration of habu venom-induced glomerular lesions: potential role for platelet secretory proteins.

Platelets have been implicated as mediators of mesangial cell proliferation. Of interest is a potential role for platelet secretory proteins (some of which are known to be growth factors) in proliferative glomerular disease. This study examines the effect of sulindac, an inhibitor of platelet thromboxane A2 generation and platelet activation, on the development of glomerular cystic and proliferative lesions after injection of habu snake venom (HSV). To examine the association of platelet secretory proteins with glomerular lesions after HSV, antiserum against a pool of platelet secretory cationic proteins (PSCPs) was used, by immunofluorescence, as a marker of the secretory component of platelet activation in platelet-compromised and normal rats. Uninephrectomized rats received sulindac (60 mg/kg body weight) or vehicle daily before and after HSV (2 mg/kg body weight, IV). Glomerular cysts, proliferative nodules, and mixed lesions (cystic plus proliferative) were quantitated and PSCP localization was examined 48 hours after HSV. Sulindac substantially reduced the total number of glomerular lesions and preferentially reduced proliferative lesions when compared with controls. PSCPs localized in glomerular lesions in both groups and paralleled the severity of disease, but overall intensity of PSCP staining was less in sulindac-treated rats. Sulindac did not alter renal function before HSV, ruling out hemodynamic factors. The concomitant localization of PSCPs in glomerular lesions and amelioration by antiplatelet therapy supports a role for platelet secretory proteins in this model of proliferative glomerular disease.

Animals↗
PubMed1989

Food restriction retards body growth and prevents end-stage renal pathology in remnant kidneys of rats regardless of protein intake.

The objectives of this study were to evaluate the effects of food restriction (without protein or phosphorus restriction) and protein restriction (without the restriction of other nutrients or calories) on the outcome of the remnant kidney model of chronic renal failure in rats. After 5/6 nephrectomy, rats were assigned to one of the following dietary groups: group I (control-ad libitum) consumed a 21% casein diet ad libitum; group II (food restriction with protein restriction) consumed 36% less calories, protein and minerals than group I; group III (food restriction without protein restriction) consumed 36% less calories and minerals than group I, but equivalent amounts of protein; group IV (protein restriction) consumed 38% less protein than group I, but equivalent amounts of calories and minerals; group V (NaCl restriction) consumed 40% less sodium chloride than group I, but equivalent amounts of all other nutrients. All groups consumed equivalent amounts of calcium, phosphorus and vitamins. Groups II and III experienced retardation of growth in comparison to groups I, IV and V. The food-restricted groups II and III, but not groups IV and V, had less proteinuria than group I 20 weeks postablation. By 21 weeks postablation, the kidneys from group I showed severe parenchymal damage, characteristic of end-stage renal pathology. These changes were prevented in the food-restricted groups II and III, but not in groups IV and V. The percentage of glomeruli with severe structural damage was less in groups II (27.3 +/- 8.8) and III (26.9 +/- 7.5) compared with group I (72.4 +/- 7.8). In contrast, the corresponding values in groups IV and V were not significantly different from group I. Interstitial volume (the percentage of tubulointerstitium which is interstitium) which was proportional to the severity of tubular damage was significantly lower in groups II (25.1 +/- 4.5) and III (20.4 +/- 2.8) when compared with groups I (48.1 +/- 3.0), IV (44.4 +/- 6.6), or V (41.9 +/- 4.2). An interstitial volume less than 30 correlated with well preserved renal histology, whereas a value greater than 40 was indicative of end-stage renal pathology. These results indicate that the restriction of carbohydrate, fat, and minerals (except for calcium and phosphorus) retarded growth and prevented the development of end-stage renal pathology in the remnant kidney model of chronic renal failure in rats, regardless of whether protein was restricted or not.(ABSTRACT TRUNCATED AT 400 WORDS)

Animal Feed↗
PubMed1988

Anionization of an antigen promotes glomerular binding and immune complex formation.

Bovine serum albumin (BSA, pI 4.9) was maleylated to yield highly anionic MBSA (pI 3.0). Maleylation of BSA lead to an expansion of molecular size of native BSA from an effective molecular radius (EMR) of 37 A to 57 A for MBSA as assessed by gel filtration chromatography. MBSA, but not BSA, bound to the peripheral capillary wall (PCW) and mesangium in vitro in frozen sections, and in vivo following i.v. injection (0.006 mg/g body wt), examined by immunofluorescence. When similarly injected rats or controls were given antibodies to either MBSA or BSA following injection of antigen, immune complexes were observed in glomeruli by immunofluorescence and EM only in MBSA injected rats. Deposits occurred in the mesangium and subendothelium in the PCW. In frozen sections, bound MBSA could be partially removed from tissue sections by high ionic strength buffer. Also, binding of MBSA was diminished by prior treatment of sections with synthetic polyanions. Maleylated bovine gamma-globulin and succinylated BSA showed identical binding patterns as described for MBSA, indicating that binding was not unique to the modified BSA molecule nor to the form of anionization. These results indicate that charge interactions between circulating highly anionic macromolecules and cationic domains within glomerular structures are responsible, in part, for MBSA binding and subsequent localization of immune complexes. Furthermore, it is inferred that the selective binding of MBSA to glomeruli and formation of immune complexes occurred by a mechanism not related to difference in size between MBSA and BSA. These findings are different from conventionally understood charge interactions in glomerular immune complex formation.

Albumins↗
PubMed1987

Human rheumatoid factor crossidiotypes. II. Primary structure-dependent crossreactive idiotype, PSL2-CRI, present on Wa monoclonal rheumatoid factors is present on Bla and other IgM kappa monoclonal autoantibodies.

The amino acid sequence of the L-CDR2 (complementarity-determining region) of Bla mRF (monoclonal rheumatoid factor) is identical to that of the Wa mRFs. The PSL2-CRI (crossreactive idiotype), as determined by anti-PSL2, which has been shown to be present on all Wa mRFs, is also present on the Bla mRF and other monoclonal autoantibodies. PSL2-CRI is, therefore, not unique to Wa mRFs and may be present on most IgM kappa monoclonal autoantibodies. Whether PSL2-CRI is a crossidiotype (XId) that is selectively present on autoantibodies or represents an allotypic marker for a V kappa III gene is undetermined.

Amino Acid Sequence↗
PubMed1987

Hypercalcemia can potentiate the nephrotoxicity of Bence Jones proteins.

Hypercalcemia is frequently observed in patients with multiple myeloma and renal failure. Whether Bence Jones protein (BJP) is directly nephrotoxic and how and whether hypercalcemia might contribute to this putative nephrotoxicity is currently unclear. To examine this issue, we studied the effect of modest hypercalcemia on the glomerular filtration rate (GFR) of rats exposed to a BJP that by itself had been found to be nonnephrotoxic. Three groups of rats were studied. All were anesthetized and underwent a baseline measurement of inulin clearance (Cin). After this, group 1 (n = 13) rats were given 2 ml of vehicle (phosphate-buffered saline solution [PBS]) and were then made hypercalcemic with an infusion containing 0.048 mol/L CaCl2. At the end of 2 hours a second Cin was measured. Group 2 rats (n = 8) were given 100 mg BJP in 2 ml PBS and a non-calcium-containing infusate. Group 3 (n = 11) rats were given 100 mg of the BJP in 2 ml PBS and then the calcium-containing infusate used in group 1 rats. Rats in groups 2 and 3 also had a second Cin measured at the end of 2 hours. Renal blood flow was measured with an electromagnetic flow probe. At the completion of the second clearance, kidneys were processed for renal histologic assessment. The serum calcium level measured during the second Cin period was 13.5 mg/dl for group 1, 7.9 mg/dl for group 2, and 13.7 mg/dl for group 3. No significant decrement in GFR was observed in group 1 or 2 rats. In contrast, group 3 rats had a 46% fall in GFR.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Human rheumatoid factor crossidiotypes. I. WA and BLA are heat-labile conformational antigens requiring both heavy and light chains.

Evidence was obtained that both the WA and BLA crossidiotype (XId) groups are conformational antigens requiring both L and H chains and that with heat denaturation the antigens that define the XIds and antigen-binding activity are lost in parallel. In contrast, the primary structure-dependent crossreactive idiotype (CRI), PSL2, which is only weakly detected on native Wa and Bla monoclonal rheumatoid factors (mRFs), became prominently detected on the heated Wa and Bla mRFs. Heat denaturation may provide a simple method for distinguishing Ids determined by conformational antigen from primary structure-dependent Ids. In addition to heat denaturation, some acid conditions commonly used for preparation of RFs were also found to cause marked loss of Id antigen. The finding of PSL2-CRI on Bla mRF indicates that this Id is not unique to the WA XId.

Antibodies, Monoclonal↗
PubMed1986

Effect of chronic administration of different Bence Jones proteins on rat kidney.

The role of Bence Jones proteins (BJPs) in the genesis of the renal dysfunction that develops in patients with multiple myeloma is not clearly defined. We previously evaluated renal function and morphology in a unique strain of rats (LOU/m) bearing tumors which synthesized BJPs with isoelectric points of 5.2, 4.3 and 6.7. Myeloma cast nephropathy developed in one tumor bearing group (pI 5.2), tubular necrosis was observed in another (pI 4.3), and renal function and histology remained normal in a third group (pI 6.7). To see if these renal outcomes were a function of the BJP being excreted or other factors which could be present in the tumor bearing animals, we have examined the effect of chronic intravenous administration of these three BJPs on renal function and histology in non-tumor-bearing LOU/m rats. Urine containing the BJP was collected from tumor bearing rats, sterilized by passage through a 0.2 mu millipore filter, concentrated to 50 mg/ml, and dialyzed extensively so as to remove material with a molecular weight less than 3500. Chronic indwelling-venous catheters were placed in non-tumor-bearing LOU/m rats and these rats were given 100 mg/day for five days of one of the three BJPs. Polyfructosan clearance (Cin) was measured prior to and following the five days of BJP administration. Renal histology was examined at the completion of the second Cin. In the pI 5.2 group (N = 6), a severe distal nephron cast nephropathy occurred and Cin fell from 2.88 +/- 0.24 to 0.90 +/- 0.17 ml/min (P less than 0.002).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Role of volume depletion in the glycerol model of acute renal failure.

Previous studies have demonstrated significant volume depletion early in the course of glycerol-induced acute renal failure. In addition, it has been shown that acute volume expansion within 6 h of glycerol administration reverses the fall in inulin clearance but volume expansion 12-24 h after glycerol fails to restore that parameter to normal. The current studies were performed to determine whether chronic volume expansion would prevent the fall in inulin clearance normally observed 18-20 h after the insult. Inulin clearance was therefore compared 18-20 h after glycerol in hydropenic rats and in rats undergoing chronic volume expansion by the constant infusion of Ringer solution at a rate of 5 ml/h initiated at the time of the glycerol injection. Inulin clearance was well maintained in the latter group, averaging 1.77 compared with 0.22 ml/min in the hydropenic group. Renal histology revealed no difference in the degree of tubular necrosis between groups but did show a marked decrease in cast formation in the animals undergoing chronic volume expansion. To determine the possible significance of these casts, micropuncture studies were carried out to measure proximal tubular pressures. Under hydropenic conditions these pressures were not different control animals and rats receiving glycerol when studied 18-20 h after glycerol. Following acute volume expansion, however, glycerol-treated rats demonstrated significantly higher pressures than control rats. On the other hand, proximal tubular pressures were comparable in glycerol-treated and control animals receiving the chronic volume expansion.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗