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L Cook

Publications and source records attributed to L Cook.

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

DNA ploidy, proliferation, and neu-oncogene protein overexpression in breast carcinoma.

DNA content, proliferative activity (Ki-67 immuno-staining and S-phase fraction by flow cytometry), and neu-oncogene overexpression were studied in 135 patients with invasive breast carcinoma. Image analysis and flow cytometry of fresh tumors showed good correlation between the two methods and yielded 39% diploid tumors and 61% aneuploid tumors. Aneuploidy, including tetraploidy, was significantly related to the loss of estrogen (p = 0.0002) and progesterone (p = 0.03) receptors, high histologic (p = 0.014) and nuclear (p less than 0.0001) grades, and mitotic rate (p = 0.0001). Immunohistochemical evaluation of proliferation by staining with Ki-67 monoclonal antibody and of neu-oncogene protein overexpression was performed in fresh frozen tissue from 83 tumors. The Ki-67 score, quantitated by the CAS-200 image analyzer, correlated only moderately with S-phase fraction obtained by flow cytometry by linear regression analysis (r = 0.39, p less than 0.001). However, both of these proliferation markers correlated strongly with the mitotic rate (p less than 0.0001). Aneuploid and tetraploid tumors demonstrated higher Ki-67 scores and S-phase fractions than diploid tumors. Neu-oncogene protein overexpression was seen in 24 tumors (29%) overall and was much higher in aneuploid tumors (38%) and tetraploid tumors (50%) than in diploid tumors (7%). However, the concentration of neu-oncogene protein positive tumors in the tetraploid region reported by others was not observed. Neu-oncogene protein overexpression was also associated with higher Ki-67 scores (p = 0.016) and S-phase fractions (p = 0.037).(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1992

DuP 734 [1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'- oxoethyl)piperidine HBr], a potential antipsychotic agent: preclinical behavioral effects.

It has been suggested that sigma receptors may be involved in the etiology of psychosis and that 5-hydroxytryptamine2 (5-HT2) antagonists may have utility in treating the negative symptoms of psychosis as well as reducing the side effects associated with the typical antipsychotic haloperidol. We have evaluated the potential antipsychotic effects of 1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'-oxoethyl)piper i din e HBr (DuP 734), a selective and potent sigma and 5-HT2 receptor ligand with weak affinity for D2 receptors, in behavioral animal models that are not necessarily dependent on dopamine antagonism. DuP 734 potently blocked mescaline-induced scratching (ED50 = 0.35 mg/kg, p.o.) and aggressive activity (ED50 = 1.9 mg/kg, p.o.) and was relatively much weaker as an apomorphine antagonist (ED50 = 12 mg/kg, p.o.). This was in contrast to the typical antipsychotic agents such as haloperidol and chlorpromazine, which were very potent in all three tests. In rats, DuP 734 did not antagonize avoidance behavior or induce catalepsy, and, therefore, differed from the potent dopamine receptor antagonist antipsychotics. It did, however, reduce lever response rates in a random interval 60-sec food reward schedule of reinforcement (ED50 = 6.0 mg/kg, p.o.) in rats. The results suggest that DuP 734 may have antipsychotic activity without the liability of motor side effects typical of neuroleptics. Although DuP 734 itself did not antagonize avoidance activity, it significantly enhanced the potency of haloperidol in blocking avoidance behavior by 3-fold (by shifting the ED50 from 0.94 to 0.36 mg/kg, p.o.), whereas the ED50 of haloperidol for blockade of escape behavior and induction of catalepsy was not affected.(ABSTRACT TRUNCATED AT 250 WORDS)

Aggression↗
PubMed1992

DuP 734 [1-(cyclopropylmethyl)-4-(2'(4''-fluorophenyl)-2'-oxoethyl)- piperidine HBr], a sigma and 5-hydroxytryptamine2 receptor antagonist: receptor-binding, electrophysiological and neuropharmacological profiles.

It has been suggested that sigma receptor antagonists may be useful as antipsychotic drugs and that 5-hydroxytryptamine (5-HT2) receptor antagonists produce improvements of the negative symptoms of schizophrenia. [1-(Cyclopropylmethyl)-4-(2'-(4''-fluorophenyl)-2'- oxoethyl)-piperidine HBr] (DuP 734) is a novel compound with high affinity for the sigma (Ki = 10 nM) and 5-HT2 (Ki = 15 nM) receptors, but low affinity for dopamine receptors (Ki > 1000 nM) as well as 33 other receptors, ion channels and second messenger systems in vitro. DuP 734 did not inhibit the synaptosomal uptake of dopamine, 5-HT or norepinephrine. Oral administration of DuP 734 potently blocked 5-hydroxy-L-trytophan (5-HTP)-induced head twitch in the rat (ED50 = 6.5 mumol/kg), indicating 5-HT2 antagonist activity. Extracellular single-unit recording studies demonstrated that DuP 734 antagonized the effect of the selective sigma ligand (+)-3-(3-hydroxyphenyl-N-(1-propyl) piperidine [(+)-3-PPP] on dopamine neuronal activity in the substantia nigra of the rat with an ED90 of 3.6 mumol/kg i.v. The sigma receptor agonists (+)-SKF 10,047 and phencyclidine both elicited rotational behavior in rats with unilateral lesion of the substantia nigra. The rotational behavior induced by either (+)-SKF 10,047 or phencyclidine was dose-dependently antagonized by DuP 734 with oral ED50 of 8.7 and 19.6 mumol/kg, respectively. The 5-HT2 receptor antagonist ICI 169,369, even at high doses (up to 33 mumol/kg, s.c.), did not antagonize the rotational behavior induced by (+)-SKF 10,047.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Discriminative stimulus effects of spiradoline, a kappa-opioid agonist.

This study represents the initial step in assessing the discriminative effects of spiradoline (U62,066), a potent congener of the selective kappa-opioid agonist, U50,488. Separate groups of rats were trained to discriminate between SC injections of saline and either 3.0 mg/kg spiradoline or 3.0 mg/kg morphine in a discrete-trial shock-avoidance/escape procedure. Spiradoline-trained rats generalized completely to U50,488 (ED50S for spiradoline and U50,488 were 0.66 and 8.71 mg/kg, respectively), but selected the choice lever appropriate for saline in generalization tests with graded doses of morphine, phencyclidine, and agonist-antagonist opioids with varying degrees of kappa activity, ethylketocyclazocine, nalorphine, and butorphanol. Morphine-trained rats did not generalize to spiradoline. Naltrexone (0.01 or 0.1 mg/kg) blocked surmountably the discriminative effects of both spiradoline and morphine, but was approximately 10-fold less potent against spiradoline. These results indicate that the discriminative effects of spiradoline are mediated by kappa-opioid receptors; meaningful mu-opioid and PCP/sigma components of action were not in evidence. The potency and apparent pharmacological selectivity of spiradoline suggest the potential value of this drug for studying kappa-opioid-mediated stimulus control of behavior.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1991

Do rat kidney cortex microsomes possess the enzymatic machinery to desaturate and chain elongate fatty acyl-CoA derivatives?

Rat kidney cortex microsomal preparations were unable to catalyze delta 9, delta 6 and delta 5 desaturation of stearoyl-coenzyme A (CoA), linoleoyl-CoA and dihomo-gamma-linolenoyl-CoA, respectively. The kidney cortex microsomal fraction, however, did catalyze the malonyl-CoA dependent fatty acyl-CoA elongation. The biochemical properties of palmitoyl-CoA elongation were studied as a function of protein concentration, time, reduced nicotinamide adenine dinucleotide phosphate (NADPH), malonyl-CoA and substrate concentrations; of the substrates investigated, delta 6,9,12-18:3 was the most active. Unlike what was observed in the hepatic system, a high-carbohydrate, fat-free diet did not induce kidney fatty acid chain elongation. All intermediate kidney cortex microsomal reactions, i.e., beta-ketoacyl-CoA reductase, beta-hydroxyacyl-CoA dehydrase and trans-2-enoyl-CoA reductase activities, were significantly higher (greater than one order of magnitude) than the condensing enzyme activity, suggesting that the rate-limiting step in total elongation is the initial condensation reaction. Contrary to other reports, the results suggest that the kidney cannot synthesize arachidonic acid needed for eicosanoid production.

Acyl Coenzyme A↗
PubMed1991

Phenobarbital increases rat hepatic prostaglandin F2 alpha, glutathione S-transferase activity and oxidative stress.

Eight-week-old female F344/N rats were fed 3.0 or 6.0% of calories (kcal%) as linoleate with or without 0.05% phenobarbital (PB) for 35 days. PB treatment increased glutathione S-transferase (GST) activity by 80% and prostaglandin (PG) F2 alpha levels 4-fold (p less than 0.05). PB decreased hepatic alpha-tocopherol significantly. Hepatic linoleate was decreased by PB in rats fed 6 kcal% but not 3 kcal% linoleate. Increased dietary linoleate had no significant effect on hepatic PGF2 alpha or alpha-tocopherol levels or GST activity. This study suggests that PB hepatotoxicity and tumor-promoting ability may be mediated, at least in part, by PGF2 alpha. PB's effect on PGF2 alpha could be a result of both GST-mediated prostaglandin synthesis and oxidative stress. The removal of significant amounts of hepatic alpha-tocopherol during oxidative stress induced by PB might diminish endogenous inhibition of hepatic PG synthesis by a-tocopherol.

Animals↗
PubMed1991

Hypertonic citrate solution as an alternative to modified Euro-Collins' solution for lung preservation.

In a canine model of acute ischemic lung injury, a hypertonic citrate solution (HTC) widely used for renal preservation in the United Kingdom, was compared with modified Euro-Collins' solution (ECS) currently the most widely clinically used pulmonary perfusate. Ten beagle dogs underwent left thoracotomy and exclusion of the left lung in situ. The lung was flushed with 30 ml/kg of either HTC or ECS and subjected to 60 min of warm ischemia. The circulation to the lung was then restored, the contralateral lung excluded, and the animal ventilated at a fixed FiO2 of 0.4 for 4 hr. Lung function was assessed by arterial oxygenation and hemodynamic measurements and, following sacrifice, by lung weight gain, bronchoalveolar lavage, and ultrastructural studies. Flush perfusion with HTC was associated with significantly less severe reperfusion injury, as determined by superior arterial oxygenation (PaO2 at 1 hr: HTC--152 mmHg [(95% confidence interval) CI] [122-182], ECS--59 [47-70]; PaO2 at 4 hr: HTC--124 [100-149], ECS--51 [42-61]), lower pulmonary vascular resistance index (PVRI at 4 hrs: HTC--838 dynes sec cm-5m-2 [651-1075], ECS--1233 [963-1588]); and lower lung weight (HTC--85 g [66-107], ECS--146 [114-184]). Bronchoalveolar lavage studies demonstrated an influx of neutrophils following reperfusion that was significantly less marked in the HTC group (increase in % neutrophils: HTC 24 [19-29], ECS 77 [72-82]). Lung injury assessed by electron microscopy tended to be less severe in the HTC animals. We conclude that HTC may offer an alternative superior to ECS for lung preservation.

Animals↗
PubMed1991

Decreased long-chain fatty acyl CoA elongation activity in quaking and jimpy mouse brain: deficiency in one enzyme or multiple enzyme activities?

Using long-chain fatty acyl CoAs (arachidoyl CoA and behenoyl CoA), a decrease in overall fatty acid chain elongation activity was observed in the quaking and jimpy mouse brain microsomes relative to controls. Arachidoyl CoA (20:0) and behenoyl CoA (22:0) elongation activities were depressed to about 50% and 80% of control values in quaking and jimpy mice, respectively. Measurement of the individual enzymatic activities of the elongation system revealed a single deficiency in enzyme activity; only the condensation activity was reduced to the same extent as total elongation in both quaking and jimpy mice. The activities of the other three enzymes, beta-ketoacyl CoA reductase, beta-hydroxyacyl CoA dehydrase, and trans-2-enoyl CoA reductase, in both mutants were similar to the activities present in the control mouse. In addition, the activities of these three enzymes were more than two to three orders of magnitude greater than the condensing enzyme activity in all three groups, establishing that the condensing enzyme catalyzes the rate-limiting reaction step of total elongation. When the elongation of palmitoyl CoA was measured, only a 25% decrease in total elongation occurred in both mutants; a similar percent decrease in the condensation of palmitoyl CoA also was observed. The activities of the other three enzymes were unaffected. These results support the concept of either multiple elongation pathways or multiple condensing enzymes.

Acetyltransferases↗
PubMed1991

Overwhelming fatal infection in a young woman after intravenous cyclophosphamide therapy for lupus nephritis.

We describe the case of a 19-year-old woman who died of overwhelming aspergillosis 3 months after receiving intravenous (IV) cyclophosphamide for progressive lupus nephritis. Her history is instructive because it illustrates the wisdom of strict adherence to the National Institutes of Health protocol for this treatment, specifically, the contraindication to use of IV cyclophosphamide when other immunosuppressive therapy has recently been employed.

Adult↗
PubMed1991

Quantitative DNA analysis in breast carcinomas: a comparison between image analysis and flow cytometry.

We compared the results of quantitative DNA analysis of fresh tumor tissue from 50 invasive breast carcinomas by image analysis and flow cytometry. For image analysis, Feulgen-stained slides of tumor imprints and of disaggregated tumor cytospin preparations were evaluated with the CAS-200 image analyzer. For flow cytometry, propidium iodide-stained disaggregated tumor cells were analyzed with the Coulter EPICS-C flow cytometer. The two methods yielded comparable results. The DNA indices obtained by the two methods showed close correlation by linear regression analysis (r = 0.86, P less than 0.001). There were 26 diploid (52%) and 24 nondiploid (48%) carcinomas. The ploidy pattern between the two methods showed agreement in 41 carcinomas (82%) and discordance in two (4%). Three tumors (6%) were equivocal by flow cytometry and four (8%) by image analysis. The equivocal cases presented potential sources of error in the evaluation of histograms in the near-tetraploid region by flow cytometry and in the near-diploid region by image analysis. Image analysis required smaller tissue samples and permitted direct visualization and selection of tumor cells. It also detected more tetraploid carcinomas. In contrast, flow cytometry analyzed larger cell samples and provided histograms with better resolution. It more readily detected the presence of multiple aneuploid peaks and also the presence of aneuploid peaks in the near-diploid range. The presence of aneuploidy was significantly related to the loss of hormone receptor expression, high mitotic rate, and high histologic and nuclear grades. Our study indicates that image analysis and flow cytometry provide comparable results in a majority of breast carcinomas.(ABSTRACT TRUNCATED AT 250 WORDS)

Breast Neoplasms↗
PubMed1990

Enzyme site-specific changes in hepatic microsomal fatty acid chain elongation in streptozotocin-induced diabetic rats.

The hepatic microsomal fatty acid chain elongation of palmitoyl-CoA and gamma-linolenoyl-CoA was diminished by 40-50% in male Sprague-Dawley rats made diabetic for 2 and 4 weeks following the intravenous administration of a single dose (65 mg/kg) of streptozotocin. Analysis of the activities of the four enzymatic components showed that only one enzyme, the condensing enzyme, which catalyzes the initial and rate-limiting step in chain elongation, was altered by the diabetic state. Both chain elongation and condensation activities were depressed to the same extent, whereas beta-ketoacyl-CoA reductase, beta-hydroxyacyl-CoA dehydrase and trans-2-enoyl-CoA reductase activities were the same as the values obtained with non-diabetic controls. 2 week administration of 10 units of insulin per day to rats which were diabetic for a 2-week period resulted in the reversal of the reduced palmitoyl-CoA elongation and condensation activities to control values. However, neither the condensation nor the elongation of gamma-linolenoyl was reversed by the insulin treatment. These results support the notion of multiple condensing enzymes or chain elongation systems.

Acyl Coenzyme A↗
PubMed1990

Comparison of DuP 996, with physostigmine, THA and 3,4-DAP on hypoxia-induced amnesia in rats.

DuP 996, 3,3-bis(4-pyrindinylmethyl)-1-phenylindolin-2-one, physostigmine (PH), tetrahydroaminoacridine (THA) and 3,4-diaminopyridine (3,4-DAP) were compared for their ability to protect against hypoxia-induced performance deficits in a passive avoidance (PA) task. The ability to retain PA response was found to decrease as the oxygen concentration decreased with the largest retention deficit occurring at 6.5% oxygen. DuP 996 (0.01-0.1 mg/kg SC), 3,4-DAP (0.1-10.0 mg/kg SC), THA (0.3-5.0 mg/kg SC) and PH (0.001-0.1 mg/kg SC) administered one minute after PA training produced dose-dependent increases in retention latencies following exposure to 6.5% oxygen. In comparing each compound for side effects, DuP 996 induced tremor and mortality at 10 and 40 mg/kg SC, respectively, and PH at 0.3 and 0.8 mg/kg SC, respectively. With PH the 0.3 mg/kg SC dose also produced hypersalivation and a decrease in lift strength. THA produced tremor and mortality at 6.0 and 40 mg/kg SC, respectively, and 3,4-DAP at 50 and 200 mg/kg SC, respectively. 3,4-DAP also produced chromodacryorrhea and hypersalivation at 50 mg/kg SC. Dividing the dose necessary to produce mortality by the highest effective dose active in the hypoxia test yielded a safety ratio for DuP 996 of 400, for 3,4-DAP 20, for PH 8, and for THA 8, showing a greater safety margin for DuP 996 than the other cholinergic agents. These results suggest that DuP 996 may be of use in the treatment of diseases associated with cognitive impairment and may have a greater safety margin than other cholinergic agents.

4-Aminopyridine↗
PubMed1990

Amelioration of lung ischemic injury with prostacyclin.

The single-flush technique of lung preservation is thought to be enhanced by prostaglandin treatment. In order to test this hypothesis, ten beagle dogs underwent thoracotomy and in situ flush perfusion of the excluded left lung with 30 ml/kg of cold, modified Euro-Collins' solution. Group 1 (n = 5) received pretreatment with 30 ng/kg/min of PGI2 by infusion and as an additive to the flush (20 micrograms/L). Group 2 (n = 5) received no PGI2 and served as controls. Following 60 min of warm ischemia, the left lung was reperfused, the contralateral lung excluded, and the animal ventilated at a fixed FiO2 of 0.4 for 4 hr. The severity of reperfusion injury was assessed by arterial oxygenation and hemodynamic measurements and, following sacrifice, by lung weight gain and bronchoalveolar lavage and ultrastructural studies. PGI2 therapy resulted in significant amelioration of reperfusion injury, with superior oxygenation at both 1 and 4 hr (PaO2 at 1 and 4 hr, respectively; PGI2: 145 mmHg +/- 17.0 and 114 +/- 11.2; no PGI2: 59 mmHg +/- 5.8 and 51 +/- 4.5; P less than 0.01 at both times), lower pulmonary vascular resistance index at 4 hr (PVRI; PGI2: 913 dynes sec cm-5m-2 +/- 91; no PGI2: 1239 +/- 68; P less than 0.05) and lower lung weight (PGI2: 76 g +/- 4; no PGI2: 146 +/- 10; P less than 0.001). Bronchoalveolar lavage studies revealed an influx of neutrophils following reperfusion that was less marked in the PGI2 group (increase in % neutrophils; PGI2: 50.4 +/- 6.7; no PGI2: 76.9 +/- 6.0; P less than 0.05). Lung injury score assessed by electron microscopy was lower in the PGI2 group (PGI2: 5.2 +/- 1.1; no PGI2; 8.1 +/- 0.5; P less than 0.05). It is concluded that PGI2 treatment is protective against ischemic lung injury in this model.

Animals↗