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Biomedical subjects

J D Cohen

Publications and source records attributed to J D Cohen.

At least 163 records · Page 9Linked to original sources
PubMed1991

Systolic Hypertension of the Elderly Program (SHEP). Part 10: Analysis.

The SHEP is a randomized, placebo-controlled trial that will follow standard clinical trial principles in analyzing data relating to its proposed hypotheses. The protocol has stated a priori the main objective as well as the secondary subgroup hypotheses. Sample size calculations for SHEP have accounted for dropins to and drop-outs from active therapy as well as for the risk of nonstroke death. The sample size achieved (4,736 participants) should be adequate to address the proposed questions. Monitoring procedures have been described and established. A data and safety monitoring board that uses these procedures is closely following the data from the trial. The board will periodically examine the data to determine whether termination of the study is warranted.

Health Services for the Aged↗
PubMed1991

Facilitation of mechanical ventilation in status asthmaticus with continuous intravenous thiopental.

Mechanical ventilation in status asthmaticus is associated with a significant mortality and morbidity. To facilitate intermittent positive pressure ventilation (IPPV), we have used continuous IV thiopental (thiopentone) together with traditional ventilatory techniques. With this policy, we were able to achieve rapid correction of arterial blood gas tensions in a group of 20 severe asthmatics requiring IPPV. By 1 hour, peak airway pressure (PAP) had fallen from 58.6 +/- 15.7 to 30.2 +/- 10.9 cm H2O (p less than 0.001). During the same period, PaCO2 fell from 51.3 +/- 15.3 to 40.17 +/- 8.2 mm Hg (p less than 0.05) and pH rose from 7.25 +/- 0.1 to 7.33 +/- 0.1 (p less than 0.001). Morbidity was low and in particular, no episode of barotrauma was noted. All patients survived the acute attack and were successfully liberated from the ventilator. We conclude that these results are largely attributable to our use of early and continuous IV anesthesia induced by thiopental.

Adult↗
PubMed1991

Radiosensitization of human T-cell leukemia by thymidine and 41.8 degrees C hyperthermia in vitro.

This study tested whether thymidine, a naturally occurring nucleoside metabolite, could increase the sensitivity of human T-cell neoplasms to ionizing irradiation and whether adding 41.8 degrees C hyperthermia (X 1 h) to the combination of thymidine and irradiation would further enhance killing of cells by radiation. The magnitude of cytotoxicity induced directly by thymidine was also evaluated. Finally, the ability of 2'-deoxycytidine to prevent thymidine-induced cytotoxicity and radiosensitization was studied. Using JM and MOLT3, two human T-cell acute lymphoblastic leukemias, it was found that thymidine itself was cytotoxic and the toxicity appeared rapidly upon exposure to the drug (i.e., at 4 h). Thymidine caused significant radiosensitization, and thymidine plus 1 h of 41.8 degrees C hyperthermia enhanced radiation-induced killing significantly more than did thymidine or hyperthermia separately. The addition of 2'-deoxycytidine only partly reversed thymidine-induced killing and did not prevent thymidine-induced radiosensitization. The applicability of these results to the clinical management of T- and null-cell malignancies is discussed, as is the presumed mechanistic basis for these observations relative to deoxyribonucleoside metabolism, NAD metabolism, and inhibition of poly(ADP-ribose) polymerase.

Cell Survival↗
PubMed1990

Thymidine enhancement of carboplatin cytotoxicity: in vivo studies in normal B6D2 F1 mice.

Our laboratory has previously demonstrated that 4-24-h thymidine exposures (50-1000 micrograms/ml) will enhance carboplatin cytotoxicity 2-3.3-fold in vitro. In order to show that these results are clinically applicable, we performed 24-h thymidine infusions with and without carboplatin in B6D2 F1 mice. The mice were evaluated for myelosuppression, weight loss and development of diarrhea. Results obtained demonstrated that thymidine did not enhance systemic carboplatin toxicity. The clinical relevance of these results is discussed.

Animals↗
PubMed1990

A network model of catecholamine effects: gain, signal-to-noise ratio, and behavior.

At the level of individual neurons, catecholamine release increases the responsivity of cells to excitatory and inhibitory inputs. A model of catecholamine effects in a network of neural-like elements is presented, which shows that (i) changes in the responsivity of individual elements do not affect their ability to detect a signal and ignore noise but (ii) the same changes in cell responsivity in a network of such elements do improve the signal detection performance of the network as a whole. The second result is used in a computer simulation based on principles of parallel distributed processing to account for the effect of central nervous system stimulants on the signal detection performance of human subjects.

Behavior↗
PubMed1990

Radiant heat systemic hyperthermia clinical trials.

Results of a Phase I study led our group to the conclusion that a radiant heat system provides a safe and effective method of inducing 41.8 degrees C whole body hyperthermia (WBH) which is suitable for combination therapy. The review to follow summarizes our progress in combining WBH with other cancer-treatment modalities, including ionizing irradiation, chemotherapy and immunotherapy.

Clinical Trials as Topic↗
PubMed1990

Whole body hyperthermia and intraperitoneal carboplatin in residual ovarian cancer.

Intraperitoneal (IP) cisplatin-based chemotherapy provides prolonged disease-free survival in some women with residual peritoneal ovarian cancer following systemic chemotherapy. This review presents several considerations which support the combined use of IP carboplatin and whole body hyperthermia in this patient population. This novel treatment approach is predicated on projected advantages which relate to improved therapeutic index.

Carboplatin↗
PubMed1990

Sensitization of C6 glioma to carboplatin cytotoxicity by hyperthermia and thymidine.

Thymidine (a nucleoside metabolite) and 41.8 degrees C hyperthermia were used to sensitize C6 glioma cells to carboplatin cytotoxicity in vitro. Clinically achievable thymidine concentrations (0, 200, 400, or 1000 micrograms/ml X 24 hours) significantly enhanced carboplatin killing. Clinically achievable hyperthermia exposures (40.5 or 41.8 degrees C X 1 hour) also enhanced carboplatin killing; 41.8 degrees C was more effective than was 40.5 degrees C. Thymidine and 41.8 degrees C hyperthermia together enhanced carboplatin killing significantly more than did the thymidine-carboplatin or hyperthermia-carboplatin combinations. These results illustrate the concept of 'combination chemosensitization' for simultaneously addressing the divergent drug resistance mechanisms of malignant gliomas.

Animals↗
PubMed1990

Cytotoxicity of diethyldithiocarbamate in human versus rodent cell lines.

Diethyldithiocarbamate (DDTC) and other dithiocarbamates are currently receiving attention as potential adjuncts to traditional chemotherapy. In vitro studies with rodent cancer cell lines have consistently shown that DDTC concentrations of 0.1-1.0 micrograms/ml are highly cytotoxic. Paradoxically, however, concentrations of 10-100 micrograms/ml have been significantly less toxic. In the present study, such a 'biphasic' pattern was reproduced when 3 rodent cell lines were exposed for 1 hour to 0.001 to 1000 micrograms DDTC/ml. In contrast, in 7 human cell lines survival decreased steadily with increasing DDTC concentration (in the same dose range) without evidence of a biphasic pattern. These data might have implications for studies in which rodent cell lines are used to model the effects of dithiocarbamates in human tissues.

Animals↗
PubMed1990

Adjunctive therapy (whole body hyperthermia versus lonidamine) to total body irradiation for the treatment of favorable B-cell neoplasms: a report of two pilot clinical trials and laboratory investigations.

Based on earlier clinical and preclinical investigations, we designed two different pilot trials for patients with nodular lymphoma or chronic lymphocytic leukemia. These studies evaluated the use of either 41.8 degrees C whole body hyperthermia (WBH), or the nonmyelosuppressive chemotherapeutic drug, lonidamine (LON), as an adjunct to total body irradiation (TBI) (12.5 cGy twice a week, every other week for a planned total dose of 150 cGy). Whole body hyperthermia was initiated approximately 10 min after total body irradiation; lonidamine was administered orally (420 mg/m2) on a daily basis. Although entry to the studies was nonrandomized, the two patient populations were accrued during the same time frame and were comparable in terms of histology, stage of disease, performance status, and prior therapy. Of 8 patients entered on the TBI/WBH study, we observed 3 complete responses (CR), 4 partial responses (PR), and 1 improvement (i.e., a 48% decrease in tumor burden). Of 10 patients entered in the TBI/LON study, there was 1 CR and 4 PR. For the TBI/WBH study, myelosuppression was not treatment-limiting; there were no instances of infection or bleeding and platelet support was never required. The median survival time for the TBI/WBH study is 52.5 months based on Kaplan Meir estimates. Two patients remain in a CR. The median time to treatment failure (MTTF) is 9.4 months (90% confidence interval = 7-15.4 months). In the TBI/LON study, 50% of patients receiving TBI required treatment modification due to platelet-count depression during therapy, but there were no instances of infection or bleeding. Frequently observed LON-related toxicities included myalgias, testicular pain, photophobia and ototoxicity. For the TBI/LON study, median survival is 7.6 months; MTTF was 2.4 months. In analyzing the results of these pilot studies, our subjective clinical impressions lead to the hypothesis that WBH protected against TBI-induced thrombocytopenia during therapy, whereas LON had no effect on TBI-induced myelosuppression. This speculation was tested and confirmed in a series of in vitro and in vivo experiments.

Adult↗
PubMed1990

On the control of automatic processes: a parallel distributed processing account of the Stroop effect.

Traditional views of automaticity are in need of revision. For example, automaticity often has been treated as an all-or-none phenomenon, and traditional theories have held that automatic processes are independent of attention. Yet recent empirical data suggest that automatic processes are continuous, and furthermore are subject to attentional control. A model of attention is presented to address these issues. Within a parallel distributed processing framework, it is proposed that the attributes of automaticity depend on the strength of a processing pathway and that strength increases with training. With the Stroop effect as an example, automatic processes are shown to be continuous and to emerge gradually with practice. Specifically, a computational model of the Stroop task simulates the time course of processing as well as the effects of learning. This was accomplished by combining the cascade mechanism described by McClelland (1979) with the backpropagation learning algorithm (Rumelhart, Hinton, & Williams, 1986). The model can simulate performance in the standard Stroop task, as well as aspects of performance in variants of this task that manipulate stimulus-onset asynchrony, response set, and degree of practice. The model presented is contrasted against other models, and its relation to many of the central issues in the literature on attention, automaticity, and interference is discussed.

Attention↗
PubMed1990

Radiosensitization of C6 glioma by thymidine and 41.8 degrees C hyperthermia.

The cytotoxic, antiproliferative, and radiosensitizing effects of thymidine (a nucleoside metabolite) were studied using the C6 glioma cell line in vitro. Radiosensitization by a combination of thymidine and 41.8 degrees C hyperthermia was also evaluated. Thymidine concentrations above 100 micrograms/ml completely inhibited C6 proliferation while concentrations of 100 to 1000 micrograms/ml (for up to 24 hours) decreased C6 cell survival to as little as 7.4% compared to untreated control cells. Radiosensitivity was enhanced by the administration of thymidine alone (400 micrograms/ml x 24 hours before irradiation); sensitization by 41.8 degrees C hyperthermia alone (1 hour ending immediately before irradiation) was less pronounced. Thymidine and hyperthermia together produced greater radiosensitization than did heat alone or thymidine alone. These data support the further investigation of thymidine as a neuro-oncology radiosensitizer.

Animals↗
PubMed1990

Risk factors for cardiovascular disease in U.S. medical students: the Preventive Cardiology Academic Award Collaborative Data Project.

Risk factors for cardiovascular disease are commonly obtained in freshman medical students for the purpose of increasing interest and awareness in preventive cardiology. What would be a normal range of values for this select group? This paper describes the major cardiovascular risk factors for 3,811 male and female freshman medical students from eight U.S. medical schools that were obtained in a standardized fashion as part of the Preventive Cardiology Academic Award (PCAA) programs at these institutions. The distributions of height, weight, Quetelet index, systolic and diastolic blood pressures, total cholesterol, triglycerides, high-density lipoprotein cholesterol, and calculated low-density lipoprotein cholesterol are presented for male and female medical students stratified by race into white, black, Asian, and Hispanic groups. The sex and race distributions of cardiovascular risk factors such as previously diagnosed hypertension, diabetes mellitus, smoking, lack of regular exercise (three times a week or more), oral contraceptive use in women, and family history of coronary heart disease are presented. The cardiovascular risk of freshman medical students is compared to other epidemiologic studies of young adults. The use and limitations of these race- and sex-specific data on cardiovascular risk, including physiologic measurements, are discussed in the context of educational programs for medical students and house staff in preventive cardiology.

Adult↗
PubMed1989

Preferential binding of radiolabeled poly-L-lysines to C6 and U87 MG glioblastomas compared with endothelial cells in vitro.

This report describes the preparation of polylysine-diethylene triamine pentaacetic acid (DTPA)-metal ion complexes and of iodinated polylysine derivatives and the preferential binding of these polymers to glioblastomas in culture. Synthetic polylysines (DP88 and DP299) were modified covalently either with the chelator DTPA or with 125I-Bolton Hunter reagent. The polylysine (DP88) was modified initially with fluorescein to permit fluorescence cytological studies and quantitative measurements of polylysine concentrations. The polylysines contained an average of one DTPA per 16 lysyl moieties. The polylysine-DTPA derivatives were then modified with a mixture of 153Gd and stable Gd. A copolymer (DP120) of lysine and tyrosine (4:1) was modified with 125I using chloramine T as catalyst. C6 (rat) and U87 MG (human) glioblastoma cells, in culture, bound six to seven times more polylysine-DTPA-Gd than endothelial cells from either aorta or brain. Each of the tumor cell types bound 10(8) molecules of the modified polylysine per cell when 2.5 x 10(5) cells were reacted with 50 micrograms or greater of the polylysine-DTPA-nuclide complex. The higher molecular weight polylysines delivered more radionuclide to the cells in culture. Although the tumor cells bound more [125I]polylysine and [125I]poly(lysine HBr,tyrosine) than they bound polylysyl-DTPA-Gd, the endothelial cells and the plastic culture dish also bound more of the iodinated polymers. The stoichiometry of polylysine bound per cell suggests that the sialic acid moieties on the cell surface are the primary binding sites for polylysine derivatives. Fluorescence microscopy studies revealed that the fluorescein polylysine (DP88) and the fluorescein polylysine-DTPA nuclide complex bound the tumor cells primarily at branch points along the neuritic processes, at the edge of the perikaryon and at the terminal regions of the outgrowth process. The polylysyl-DTPA-Gd can be used, with magnetic resonance imaging, to provide measurable contrast of the margin between C6 glioblastomas and normal brain in vivo in Wistar Furth rats.

Animals↗
PubMed1989

Interactions of thymidine, hyperthermia, and cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) in human T-cell leukemia.

Using JM and MOLT3, two human T-cell acute lymphoblastic leukemia cell lines, we investigated the ability of 24-h thymidine exposures to enhance the cytotoxicity of cis-diammine-1,1-cyclobutane dicarboxylate platinum (II) (carboplatin). Clinically achievable thymidine concentrations (for 24 h) significantly enhanced carboplatin killing. Unexpectedly, thymidine-carboplatin enhancement was as great at a relatively low 200-micrograms thymidine/ml as at the clinically much more toxic range of 1000 micrograms/ml. For a constant thymidine concentration (500 micrograms/ml), thymidine-carboplatin interaction increased with longer thymidine exposures until about 16 to 24 h. Thymidine and 41.8 degrees C hyperthermia (for 1 h) together enhanced carboplatin killing significantly more than did hyperthermia-carboplatin or thymidine-carboplatin combinations. These results show that relatively brief, presumptively nonmyelosuppressive thymidine exposures can significantly increase carboplatin killing. Carboplatin-thymidine killing can then be further augmented by 41.8 degrees C hyperthermia.

Antineoplastic Agents↗