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Biomedical subjects

J M Cook

Publications and source records attributed to J M Cook.

At least 73 records · Page 4Linked to original sources
PubMed1991

Thrombomodulin activity on human saphenous vein grafts prepared for coronary artery bypass.

Thrombomodulin, a membrane glycoprotein present on normal vascular endothelium, binds circulating thrombin and is important in protein C activation. These functions contribute to the nonthrombogenic nature of endothelium. Damage during harvest and ex vivo storage of vein grafts may result in dysfunction of this endothelial anticoagulant barrier and possibly contribute to early graft thrombosis. We studied the functional activity and antigenic expression of thrombomodulin on saphenous veins before (initial) and after (harvested) harvest and storage for coronary artery bypass grafting in 15 patients. Also, fresh saphenous vein was studied after mechanical endothelial stripping. After storage for 2.7 +/- 0.6 hours at room temperature in heparinized saline, thrombomodulin functional activity in harvested vein segments was 28% less than initial segments (p = 0.08). Endothelial stripping resulted in a 79% reduction in thrombomodulin activity compared with initial segments (p = 0.04). Immunohistochemical staining confirmed thrombomodulin antigen on vein grafts after harvest and storage, but not on segments stripped of endothelium. Thrombomodulin functional activity and antigenic expression on human saphenous vein grafts is not significantly changed by harvest and relatively short periods of storage at room temperature in heparinized saline.

Antigens↗
PubMed1991

Recurrent intracaval renal cell carcinoma: the role of intravascular ultrasonography.

The presence of extension into the vena cava does not preclude curative resection for extensive renal cell carcinomas. However, preoperative assessment of (1) the proximal extent of the tumor and (2) the degree of adherence within the vena cava is necessary to plan operative strategies. The following report describes the successful use of intravascular ultrasonography in the preoperative evaluation of a patient with recurrent renal cell carcinoma with vena caval extension.

Carcinoma, Renal Cell↗
PubMed1990

Affinity immunoblotting detection of serum monoclonal immunoglobulins reactive with glycosphingolipids.

The characterization of serum monoclonal IgM reactive with glycosphingolipid present in the nervous system is of major importance in patients with certain neuropathies. A rapid, sensitive and specific one-step method which permits such a characterization is described. Serum immunoglobulins separated by high resolution agarose electrophoresis are transferred to affinity filters (nitrocellulose sheets coated with glycolipids), and revealed with enzyme-tagged monospecific anti-immunoglobulin antibodies.

Antibodies, Monoclonal↗
PubMed1990

Current status of duplex Doppler ultrasound in the examination of the abdominal vasculature.

Duplex Doppler ultrasound has come to play a central role in the diagnosis of a broad spectrum of vascular diseases such as carotid artery occlusive disease and deep vein thrombosis. The role of duplex Doppler in the evaluation of intra-abdominal vascular disease remains unclear. This article summarizes the current status of duplex scanning in the investigation of the mesenteric arteries, the renal arteries, and the portal venous system. The examination is technically demanding, operator-dependent, time-consuming, and frequently unsatisfactory due to bowel gas, obesity, complex anatomy, or postoperative alterations in the normal anatomic patterns. Its advantages reside primarily in the absence of toxicity and in the generation of physiologic as well as anatomic information. In centers with the proper instrumentation and a skilled technician, duplex examination can be useful in the diagnosis and management of abdominal vascular disease and avoids the inherent dangers of contrast angiography.

Humans↗
PubMed1990

Structural requirements for agonist actions at the benzodiazepine receptor: studies with analogues of 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester.

The analogues 2, 3, 8a-c, 9, 13, and 14 of the beta-carboline 6-(benzyloxy)-4-(methoxymethyl)-beta-carboline-3-carboxylic acid ethyl ester (ZK-93423, 1) were synthesized in order to determine which functional groups are required for agonist activity exhibited by the parent compound 1 at the benzodiazepine receptor (BzR). The potencies of these compounds were evaluated in vitro and in vivo; the beta-carbolines 2, 8a-c, and 13 were found to exhibit high affinity (0.5-22 nM) for BzR, but in vivo studies demonstrated they were not anticonvulsant while analogues 8a and 8b antagonized the effects of diazepam. These results are in agreement with the model proposed for the pharmacophore of the agonist site (domain) of the BzR, which requires the interaction of two sites of electron density [N(2) and C(4)], a third at E+ (electrostatic or steric), and two of lipophilicity [C(3) and C(6)] of the ligand with the BzR protein (see Figure 1). The pharmacophore for the agonist site is derived from the structure-activity relationships of the benzodiazepines, pyrazoloquinolines, and the beta-carboline 1, and compared to interactions required for ligand inverse agonist activity.

Animals↗
PubMed1990

Synthesis of substituted 7,12-dihydropyrido[3,2-b:5,4-b']diindoles: rigid planar benzodiazepine receptor ligands with inverse agonist/antagonist properties.

A series of 1-, 2-, 3-, 4-, 5-, 6-, 7-, 10-, and 12-substituted pyridodiindoles were synthesized and screened in vitro against [3H]diazepam for activity at the benzodiazepine receptor (BzR). In vitro, the 2-substituted pyridodiindoles were found to be the most potent (IC50 less than 10 nM) of this new class of BzR ligands. In vivo, 2-methoxypyridodiindole 19a (IC50 = 8 nM) was found to be the most potent partial inverse agonist (proconvulsant) of the series. The parent compound 2 (IC50 = 4 nM) was only slightly less potent. In addition, 2-hydroxypyridodiindole 21a (IC50 = 6 nM) was found to exhibit potent proconvulsant activity when administered as a prodrug derivative, pivaloyl ester 22. 2-Chloropyridodiindole 16a (IC50 = 10 nM) was devoid of preconvulsant activity; however, 16a was found to be the most potent antagonist of the anticonvulsant effects of diazepam in this class of BzR ligands. From the in vivo data available, substitution on ring E of 2 with electron-withdrawing groups results in antagonists at BzR, while replacement of hydrogen at C-2 with electron-releasing groups provides enhanced inverse agonist activity. The pyridodiindoles were used as "templates" for the formulation of a model of the inverse agonist/antagonist active site of the BzR. The proposed model consists of a hydrogen bond acceptor site (A1) and a hydrogen bond donor site (D2) disposed 6.0-8.5 A from each other on the receptor protein. The hydrogen-bonding sites are believed to be located at the base of a narrow cleft. A large lipophilic pocket at the mouth of the narrow cleft serves to direct molecules into the binding site, while the presence of a small lipophilic pocket permits substitution only at position 2 of the pyridodiindole nucleus for maximum binding potency.

Animals↗
PubMed1990

Traumatic left renal artery stenosis managed with splenorenal bypass: case report.

Splenorenal arterial bypass is a well established technique for the treatment of left renal artery occlusive disease. The following is a case report of the use of splenorenal bypass in the management of concomitant traumatic left renal artery intimal dissection and splenic laceration. Arteriographic and intraoperative findings are presented as well as a review of pertinent literature.

Humans↗
PubMed1990

Is routine duplex examination after carotid endarterectomy justified?

Routine follow-up of patients after carotid endarterectomy with duplex scanning is commonly practiced, yet the clinical significance of identifying those with asymptomatic restenosis is unclear. To address this issue we reviewed 120 consecutive patients who underwent 143 carotid endarterectomies from August 1983 to December 1988. One hundred one patients (118 operations) were available for clinical follow-up, and the overall incidence of recurrent symptoms was 6% (6/101). Sixty-three of these patients (78 carotid endarterectomies) had postoperative duplex examination. Two had evidence of residual disease from the time of surgery and were not included in further analysis. Significant recurrent stenosis (greater than 50% diameter reduction) developed in 14 of the remaining 76 arteries (18.2%). Twelve of 14 stenoses remained asymptomatic during follow-up from 18 to 72 months (mean 47.0 months) and did not undergo reoperation. Recurrent ipsilateral hemispheric symptoms developed in two patients with restenosis (14.3%). Four of the 62 arteries without significant recurrent stenosis developed ipsilateral symptoms (6.5%), but none required reoperation during follow-up from 1 to 71 months (mean 31.6 months). Life-table analysis showed no increased risk of transient ischemic attack, stroke, or death in patients with restenosis. This study supports regular clinical follow-up after carotid endarterectomy with emphasis on patient education in the recognition of symptoms. Although duplex scanning may be useful to follow known contralateral asymptomatic disease or evaluate those with recurrent symptoms, its routine use to identify patients with asymptomatic restenosis after carotid endarterectomy may be unnecessary.

Aged↗
PubMed1989

Low molecular weight B cell growth factor-responsive cloned human B cell lines. I. Phenotypic differences and lack of requirement for CD23 (Fc epsilon RII).

The EBV-transformed B cell line JR-2 proliferates in response to partially purified preparations of low m.w. B cell growth factor (LMW-BCGF). Two clones of JR-2 were generated that retained this LMW-BCGF responsiveness, exhibiting similar dose/response characteristics but differing phenotypically. The B10 clone grows as single, discrete, small round cells, whereas D3 grows in aggregates. The clones also differ in the expression of cell surface Ag, D3 being weakly DR+ and strongly CD23+, whereas B10 lacks these Ag. The CD23 on D3 cells binds IgE. Both clones are T9+, 4F2+, B1-, B2- and CALLA-. D3 expresses surface IgG and differentiates in the presence of LMW-BCGF, to secrete IgG. B10 lacks surface and cytoplasmic Ig and fails to differentiate in response to LMW-BCGF. CD23 cannot be induced on B10 by incubation with either LMW-BCGF or IL-4. B10 does not shed CD23 and shed CD23 is not a growth factor for either cloned line. Expression of CD23 on D3 cells is not affected by preincubation with LMW-BCGF. Neither B10 or D3 cells respond to rIL-1, rIL-2, rIL-4, rIL-6, rTNF-alpha/beta, rIFN-gamma, or to high m.w. BCGF (Namalwa), alone or in combination. Both clones absorb BCGF activity and crossover absorptions indicate that the clones remove growth factors required by each other. D3 and B10 both appear therefore to respond selectively to LMW-BCGF. These data suggest that the loss of CD23 from a cloned derivative of the cell line JR-2, although accompanied by considerable phenotypic change, is not associated with the disappearance of LMW-BCGF responsiveness, indicating that CD23 is not the essential receptor for LMW-BCGF.

Absorption↗
PubMed1989

Behavioral differentiation of benzodiazepine ligands after repeated administration in baboons.

Baboons received repeated daily administration of saline, 5.6 mg/kg midazolam, 5.0 mg/kg flumazenil (Ro15-1788), 3.2 mg/kg 3-carboethoxy-beta-carboline hydrochloride (beta CCE) or 10 mg/kg beta CCE for 5 days. Behavioral signs of sedation and excitation were scored for 1 h after i.m. injections. Daily administration of these benzodiazepine-receptor ligands differentiated their behavioral effects; repeated midazolam resulted in tolerance to the sedative and ataxic effects; repeated beta CCE resulted in sensitization to its convulsant properties; and repeated flumazenil or saline produced no changes in behavior. In a second study, baboons received repeated injections of midazolam (5.6, 11.2 or 20 mg/kg per day) for 6 days. All three groups became tolerant to the sedative and ataxic effects of midazolam. Acute injections of flumazenil (5.0 mg/kg) on day 5 produced a dose-dependent withdrawal syndrome. This flumazenil treatment produced a slight attenuation in the degree of tolerance to midazolam on day 6, suggesting that receptor sensitivity to the benzodiazepine agonist may have partially reset.

Animals↗
PubMed1989

Behavioral effects of benzodiazepine antagonists in chlordiazepoxide tolerant and non-tolerant rats.

Rats were trained to respond under 3-min fixed-interval schedules of food presentation, and effects of the benzodiazepine-receptor ligands, flumazenil, 2-(4-methoxy-phenyl)-pyrazolo[4,3-c]quinolin-3(5H)-one (CGS 9895), 3-carbo-t-butoxy-beta-carboline (beta-CCtB), and beta-carboline-3-carboxylic acid ethyl ester (beta-CCE) were assessed before and after the induction of tolerance to chlordiazepoxide. Before daily administration of chlordiazepoxide, none of the antagonists produced appreciable effects on rates of responding up to doses of 32.0 mg/kg i.p. beta-CCE was the only antagonist studied at a higher dose (100.0 mg/kg i.p.), which decreased response rates. After 23 days of daily chlordiazepoxide administration (oral doses started at 10 and increased to 100 mg/kg/day by the 17th day), dose-effect curves for chlordiazepoxide were shifted to the right by about one-half log unit. Subjects were also more sensitive to the flumazenil, CGS 9895, and beta-CCtB, however, since these drugs produced only small effects in non-tolerant subjects, precise estimates of the degree of the shift in dose-effect curves could not be estimated. However, there were differences in the changes in the dose-effect curves induced by chlordiazepoxide tolerance. These results suggest differences in mechanism of action of antagonists in tolerant and non-tolerant subjects, and further that the sensitivity that is induced to antagonists in tolerant subjects is not conferred equally to all drugs having benzodiazepine antagonist activity.

Animals↗
PubMed1989

Inhibition of sleep and benzodiazepine receptor binding by a beta-carboline derivative.

The effects of systemic injections of beta-carboline-3-carboxylate-t-butyl ester (beta-CCtB) were investigated with regard to normally occurring sleep and several measures of benzodiazepine receptor occupancy in rats. A dose of 30 mg/kg of beta-CCtB was found to have a long time-course of action as measured by an in vivo assay for benzodiazepine binding, with an 84% depletion of [3H]diazepam binding at one hour after the intraperitoneal injection. This dose of beta-CCtB was shown to delay sleep onset, decrease non-REM and total sleep in the first two hours after the injection, and to delay the appearance of REM sleep after the sleep onset. The dose- and time-dependence of the effects on sleep approximated the dose- and time-dependence of inhibitory effects of an IP injection of beta-CCtB on in vitro measures of benzodiazepine receptor affinity and number.

Animals↗
PubMed1989

Effect of arachidonic acid metabolites on CR1 expression by B-lymphocytes.

The effect of arachidonic acid metabolites on the expression of the receptor for the C3b/C4b fragment of complement (CR1) by human B-lymphocytes was investigated. Kinetic experiments to determine CR1 expression over time indicated that the maximal receptor number occurred at 2 h, followed by a return to baseline values. Addition of 10(-4) M puromycin to the cells suggested that the increase was due to the expression of an intracellular pool and not de novo synthesis of new receptor molecules. B-lymphocytes were incubated with arachidonic acid, 15-hydroxyeicosatetraenoic acid, leukotrienes B4 or C4 or prostaglandin E2 (PGE2). The quantity of membrane antigenic binding sites was determined before and after incubation. The lipoxygenase metabolites did not alter CR1 numbers. In contrast, PGE2 significantly decreased (P less than 0.05) the quantity of CR1 expressed. In kinetic experiments, PGE2 blocked the maximal expression of CR1 seen at 2 h, indicating that it prevents the appearance of an intracellular pool of receptor. These results show that CR1 number on B-lymphocytes can be altered by at least one arachidonic acid metabolite. This may offer a partial explanation for the inhibitory effects of PGE2 on B-cell proliferation and immunoglobulin secretion since CR1 is implicated in B-lymphocyte differentiation and specific antibody response.

Arachidonic Acids↗
PubMed1989

Etoposide (VP-16) uptake by tumour spheroids and activity in the presence of Brij 30, formulation additives and sodium salicylate.

A number of additives typically used in the formulation of poorly soluble drugs can be shown to influence drug transport across various physiological barriers. Multicellular spheroids from a human neuroblastoma cell line (NB1-G) were used to investigate the effect of etoposide in solution, as its commercial formulation, Vepesid, in the presence of a nonionic surfactant, Brij 30, and a hydrotropic agent, sodium salicylate. Enhanced growth delay, apparently related to increased drug uptake, was observed both with the Vepesid and the sodium salicylate formulations. Brij 30, however, showed no enhancement of growth delay or drug uptake at a concentration at which it was not in itself cytotoxic. Significant morphological changes in the spheroid were observed at higher concentrations of additives, particularly with Brij 30, emphasizing the fact that many formulation additives cannot be used with impunity in tissue culture systems. The enhanced uptake of drug into tumour cells and potential synergy between additive and drug is worthy of further investigation.

Adjuvants, Pharmaceutic↗
PubMed1988

3-Ethoxy-beta-carboline: a high affinity benzodiazepine receptor ligand with partial inverse agonist properties.

3-Ethoxy-beta-carboline binds with high affinity to benzodiazepine receptors in the central nervous system (Ki approximately equal to 10.1, 15.3, and 25.3 nM in rat cerebellum, cerebral cortex, and hippocampus, respectively). This compound has pharmacological actions reminiscent of benzodiazepine receptor partial inverse agonists such as FG 7142 and 3-carboethoxy-beta-carboline. Thus, while not a convulsant, 3-ethoxy-beta-carboline potentiated the convulsant actions of pentylenetetrazole in mice. Furthermore, this compound reduced both the time spent and the total entries in the open arms of an elevated plus maze and also inhibited stress-induced ulcer formation, effects that are also observed with benzodiazepine receptor inverse agonists. These findings suggest that 3-ethoxy-beta-carboline is a partial inverse agonist at benzodiazepine receptors which may prove useful for in vivo studies since it has a higher affinity for benzodiazepine receptors and better solubility than the commonly used partial inverse agonist FG 7142. Furthermore, 3-ethoxy-beta-carboline appears to be less vulnerable to metabolic degradation than ester analogs with a similar pharmacological profile such as 3-carboethoxy-beta-carboline.

Animals↗