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Biomedical subjects

A Cohen

Publications and source records attributed to A Cohen.

At least 541 records · Page 30Linked to original sources
PubMed1990

Long-term verapamil treatment increases [3H]imipramine binding in human platelets.

The effect of long-term verapamil treatment on [3H]imipramine binding to the serotonin transporter in human platelets was studied. A significant increase (24%, P less than 0.05) in the density of high-affinity imipramine binding sites was observed in platelets of cardiac patients maintained exclusively on verapamil. The up-regulation of the serotonin transporter may be relevant to the previously reported beneficial effect of verapamil in affective disorders.

Blood Platelets↗
PubMed1990

Continuous intrahepatic infusion of floxuridine and leucovorin through an implantable pump for the treatment of hepatic metastases from colorectal carcinoma.

Based on laboratory studies showing enhanced cytotoxicity of floxuridine (FUDR) when used with high doses of leucovorin (LV), a pilot study of FUDR and LV through an implantable pump was initiated for the treatment of hepatic metastases from colorectal cancer. The highest dose of LV that could be administered, taking into account the constraints of the capacity of the pump and the solubility of LV, was 120 mg/m2/d. Due to the possibility of added toxicity, 25% of this dose was initially used. Twenty-four patients were treated at three dose levels. Eight patients were treated with the combination of LV (30 mg/m2/d) and FUDR (0.3 mg/kg/d) for a 14-day infusion through the pump, alternating with 2 weeks of saline. All eight patients had a greater than 50% decrease in measurable disease (PR) and a greater than 50% decrease in carcinoembryonic antigen (CEA) value; however, sclerosing cholangitis developed in two of these patients within 4 months. The next seven patients were treated with a lower dose of FUDR (0.2 mg/kg/d) and the same dose of LV, both for 14 days. Four of seven patients had a PR, and toxicity was decreased with no biliary sclerosis. A third regimen explored the combination of FUDR (0.3 mg/kg/d) and LV (30 mg/m2/d) for 7 days, alternating with 1 week of saline, to evaluate a shorter interval of treatment with the same overall dose intensity. Six of nine patients had a PR and all patients had a greater than 50% decrease in CEA value; sclerosing cholangitis developed in three of these patients. The overall response rate was 72%, with 18 of 25 patients alive after 1 year. The median survival time has not been determined, but it is greater than 27 months. FUDR with LV appeared to be effective in the treatment of hepatic metastases from colorectal carcinoma, but hepatic toxicity appeared to be greater than that previously reported with FUDR alone.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Phorbol esters induce changes in adenosine deaminase, purine nucleoside phosphorylase, and terminal deoxynucleotidyl transferase messenger RNA levels in human leukemic cell lines.

We have studied the expression of mRNA encoding adenosine deaminase (ADA; EC 3.5.4.4), purine nucleoside phosphorylase (PNP; EC 2.4.2.1), and terminal deoxynucleotidyltransferase (TdT; EC 2.7.7.31) in different leukemic cell lines of B- and T-cell lineage. Incubation of leukemic cells in the presence of the phorbol esters, 12-O-tetradecanoyl-phorbol-13-acetate or phorbol 12,13-dibutyrate, resulted in reduction of ADA and TdT mRNA levels, while PNP mRNA levels increased under the same treatment. The effect of TPA on the activity of these enzymes correlated well with its effects on their mRNA levels. TPA caused a 40% decrease in ADA and a 60% decrease in TdT enzyme activity, after 6 h of treatment. In contrast, PNP activity increased up to 200% after 12 h of incubation with the phorbol ester. The changes induced by the phorbol esters in the levels of mRNA of ADA, PNP, and TdT, and their enzyme activities in human leukemic cell lines mimic the changes in the activities of these enzymes in developing T-lymphocytes during differentiation in vivo, suggesting a role for protein kinase C in the regulation of ADA, PNP, and TdT gene expression during lymphoid cell differentiation.

Adenosine Deaminase↗
PubMed1990

Radioimmunodetection of hepatic metastases from human colon cancer in nude mice with a gamma-detecting probe.

The utility of a gamma detecting probe (GDP) in the detection of experimental hepatic metastases in nude mice using radiolabeled monoclonal antibody (mAb) was assessed. Twelve mice with established hepatic metastases from the HT-29 LMM cell line, 5 mice with s.c. tumors in the left flank and 6 non-tumor-bearing control mice were given i.v. injections of 40 microCi/4 micrograms of 125I-labeled mAb HT-29-15. Six tumor-bearing mice were given i.v. injections of an isotype-matched control mAb (BL-3). Using the GDP, measurements were obtained daily over the region of the heart, the region of the liver (i.e., the right flank), and the s.c. tumor when applicable. Intraoperative measurements were obtained at laparotomy on days 5 and 7. Subsequently, the metastases, normal liver, and blood were resected and the radioactivity/g tissue was measured in a gamma well counter. External right flank/heart ratios were significantly higher in the tumor-bearing group than in controls. External measurements allowed detection of small tumors weighing only 161 +/- 87 (SD) mg and occupying 11.5 +/- 4% of the entire liver weight. Metastases counted intraoperatively with the GDP measured 1 to 7 mm in greatest diameter. The mean metastasis/heart GDP ratio was 1.7 +/- 0.4:1. Tumors weighing as little as 51 +/- 42 mg could be identified. These experimental results confirm the usefulness of the GDP for the detection of small hepatic metastases from colon cancer and illustrate important features of probe measurement of radiolabeled mAb uptake.

Animals↗
PubMed1990

Glial response to axonal injury: in vitro manifestation and implication for regeneration.

Crushed fish optic axons readily regenerate, while similarly injured rat optic axons do not; the reasons for the differences in regeneration ability may lie in differences in the environment of the axons. We have cultured glial cells from previously crushed optic nerves of fish and rat to determine whether a relationship exists between the ability to regenerate and the nature of the responses of the associated nonneuronal cells to injury. The glial cells were examined using indirect immunofluorescence with antibodies to known glial markers. In the rat cultures, mature GalC oligodendrocytes, which are known to be nonpermissive for axonal growth, were abundant. In contrast, in the fish cultures mature oligodendrocytes were rare, but A2B5 positive cells were abundant. The high number of A2B5 positive cells in the fish may suggest a high number of immature cells. This interpretation, however, should wait until evidence for glial cell lineage of the fish is available. Additional indication is provided also in the present study that the number of mature oligodendrocytes in the fish is regulated by elements external to the nerve. This study thus demonstrates an important difference between rat and fish optic nerves in the response of glial cells to the optic nerve injury.

Animals↗
PubMed1990

Effects of FUdR on primary-cultured colon carcinomas metastatic to the liver.

Hepatic arterial infusion of fluorodeoxyuridine (FUdR) has demonstrated efficacy in the treatment of metastatic colorectal carcinoma of the liver. In this study, the direct cytotoxic effect of FUdR was measured on ten metastatic and two primary-site colorectal carcinomas in a primary culture assay system. Overall, clinically achievable concentrations of FUdR (0.4 to 4 microM) induced partial cell kill in 75% of tumors, including a greater than 50% reduction in viable tumor cell number in only two tumors and less than 50% in the remaining seven. Total cell kill was not observed in any tumor. Three tumors were resistant to these FUdR concentrations. Tumor sensitivity correlated with the size of the tumor growth fraction. Increasing the exposure time to FUdR from 3 to 7 days approximately doubled the magnitude of the response. 5-Flurouracil and cisplatin, at clinically achievable concentrations, were more toxic to metastatic tumor cells than FUdR. Because of the limited chemosensitivity of metastatic colorectal tumor cells to FUdR in vitro, we postulate that other mechanisms besides direct cytotoxicity contribute to the clinical efficacy of FUdR in vivo.

Cell Line↗
PubMed1990

Lambda Red-mediated synthesis of plasmid linear multimers in Escherichia coli K12.

Expression of the red+ and gam+ genes of bacteriophage lambda in plasmids cloned in Escherichia coli wild-type cells leads to plasmid linear multimer (PLM) formation. In mutants that lack exonuclease I (sbcB sbcC), either of these lambda functions mediates PLM formation. In order to determine whether PLM formation in sbcB sbcC mutants occurs by conservative (break-join) recombination of circular plasmids or by de novo DNA synthesis, thyA sbcB sbcC mutants were transferred from thymine- to 5-bromo-2'-deoxyuridine (BUDR)-supplemented medium, concurrently with induction of red+ or gam+ expression, and the density distribution of plasmid molecular species was analyzed. After a period of less than one generation in the BUDR-supplemented medium, most PLM were of heavy/heavy density. Circular plasmids, as well as chromosomal DNA, were of light/light or light/heavy density. These results indicate that Red or Gam activities mediate de novo synthesis of PLM in sbcB sbcC mutants. Examination of plasmid DNA preparations from sbcB sbcC mutants expressing gam+ or red+ reveals the presence of two molecular species that may represent intermediates in the PLM biosynthesis pathway: single-branched circles (sigma-structures) and PLM with single-stranded DNA tails. While Gam-mediated PLM synthesis in sbcB mutants depends on the activity of the RecF pathway genes, Red-mediated PLM synthesis, like Red-mediated recombination, is independent of recA and recF activities. One of the red+ products, beta protein, suppresses RecA deficiency in plasmid recombination and PLM synthesis in RecBCD- ExoI- cells. The dependence of PLM synthesis on the RecE, RecF or Red recombination pathways and the dependence of plasmid recombination by these pathways on activities that are required for plasmid replication support the proposal that PLM synthesis and recombination by these pathways are mutually dependent. We propose the hypothesis that DNA double-stranded ends, which are produced in the process of PLM synthesis, are involved in plasmid recombination by the RecE, RecF and Red pathways. Conversely, recombination-dependent priming of DNA synthesis at 3' single-stranded DNA ends is hypothesized to initiate PLM synthesis on circular plasmid DNA templates.

Bacteriophage lambda↗
PubMed1990

Analysis and prediction of left ventricular performance under load changes during cardiac catheterization.

The applicability of a computer model, which relates the transmural mechanical distribution in the left ventricle (LV) to its global function at different loading conditions, was evaluated in patients with normal to near normal LV function undergoing cardiac catheterization. Left ventriculography and measurements of aortic and LV pressures were performed at baseline conditions and repeated following rapid volume expansion with intravenous infusion of 250 to 300 ml of physiologic saline and also after sublingual isosorbide-dinitrate (ISDN) administration. Twenty patients (18 men and 2 women, average age = 53 years) underwent coronary angiography and left ventriculography. Sixteen patients had coronary artery disease with one- to three-vessel involvement and 4 had normal coronary arteries. The measured input data into the model included the end-diastolic LV volume and wall thickness, aortic pressure, heart rate, and the peripheral resistance. The model parameters of myocardial contractility and arterial system capacitance for the control baseline conditions were estimated so that an accurate match was obtained between the predicted and the measured end-systolic (ES) volume and pressure. Using these parameters, model predictions for the two load perturbations were compared to the measurements. An excellent correlation was found between the predicted and measured LV ES volumes and peak-systolic pressures (PSP) (R2 greater than 0.994). In four patients, who developed ischemic symptoms during saline injection, the prediction of end-systole volumes were lower than the measured values, suggesting an actual reduction in contractility during acute ischemia. Therefore, the model is sensitive to contractility changes. The model predicts global LV performance, under different loading conditions, including stroke work, peak developed wall stress, velocity of fiber shortening, and myocardial oxygen consumption.

Cardiac Catheterization↗
PubMed1990

Acute withdrawal of short-term or prolonged L-triiodothyronine administration to thyroidectomized rats results in similar rapid increases in TSH beta mRNA.

In man, following the treatment of hyperthyroidism, or the withdrawal of prolonged suppressive thyroid hormone therapy, recovery from thyrotrope suppression may not occur until thyroid hormone concentrations have been subnormal for several weeks. Short-term studies in rodents have demonstrated a rapid increase in TSH synthesis after the acute withdrawal of thyroid hormones. We treated thyroidectomized rats with supraphysiologic doses of 1-triiodothyronine (T3) for 67 days, then abruptly withdrew treatment and compared the time course of thyrotrope recovery to that in animals given T3 for only 10 days. Increases in TSH beta mRNA after abruptly stopping T3 were qualitatively similar in both groups. After short-term T3 administration, TSH beta mRNA was detectable on the second day after stopping T3 administration and rose an additional 10-fold by day 5. After prolonged T3 administration, TSH beta mRNA was barely detectable on the second day after stopping T3 administration, clearly detectable on the third day, and increased an additional 20-fold by day 7. Compared to animals who received T3 for only 10 days, suppression of the thyrotrope by T3 administration for 67 days resulted in a nonsignificant delay in TSH beta mRNA synthesis of 24 h or less following the abrupt withdrawal of thyroid hormone. It is possible that differences in rat and human thyrotrope responsiveness account for the apparently different biologic behavior.

Animals↗
PubMed1990

True emergency coronary artery bypass surgery.

Previous reports of emergency coronary artery bypass grafting often included cases that were not true surgical emergencies, thereby creating inappropriately favorable results. To accurately investigate this important subgroup of patients, we analyzed our recent experience with truly emergent coronary artery bypass grafting. From January 1984 to January 1989, 117 patients underwent true emergency bypass grafting for acute refractory coronary artery ischemia. Clinical deterioration was associated with failure of percutaneous angioplasty in 37 patients and instability during diagnostic catheterization in 13 patients. Refractory ischemia developed in the remaining patients while on the ward or in the intensive care unit. All operations were performed within four hours of surgical consultation, most within one hour. Overall in-hospital operative mortality was 14.5% (17/117), and 76.5% of deaths (13/17) were due to cardiac-related causes. Major morbidity occurred in 35.9% (42/117). Univariate analysis isolated ejection fraction, extent of coronary artery disease, previous myocardial infarction, hypertension, need for inotropic support, use of an intraaortic balloon pump, and cardiopulmonary resuscitation as risk factors for operative mortality. Stepwise multivariate analysis confirmed that previous myocardial infarction, hypertension, cardiopulmonary resuscitation, and reoperation were independently significant risk factors. Age, sex, diabetes, left main disease, and peripheral vascular disease had no significant impact on the prognosis. The 4% operative mortality (2/50) for patients taken directly to the operating room from the catheterization suite was significantly lower than the 22.4% mortality (15/67) associated with emergencies arising on the ward or intensive care unit (p less than 0.01). A logistic risk equation developed from this population accurately modeled operative mortality.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1990

Effects of different exercise training intensities on lipoprotein cholesterol fractions in healthy middle-aged men.

Exercise training has been associated with decreases in total cholesterol and increases in high-density lipoprotein (HDL) cholesterol. The effect of the intensity of the exercise on alterations in cholesterol and lipoprotein fractions has not been defined and is the subject of this study. We divided 49 healthy men (aged 44 +/- 8 years) into four groups and evaluated them before and after 12 weeks of cycle ergometer exercise training at (1) an intensity of 65% of maximal achieved heart rate, (2) 75% maximal heart rate, (3) 85% maximal heart rate, and (4) a 12-week nonexercise control period. Pre- and post-training evaluations included maximal ergometer exercise ECG examinations with measurement of maximal minute oxygen consumption and serum total cholesterol, HDL cholesterol, and triglyceride levels. Low-density (LDL) and very low-density lipoprotein (VLDL) cholesterol levels were calculated. Dietary histories were obtained before and after the training period, and body weight and percentage of body fat were measured. Post-training oxygen uptake was significantly increased (training effect) in the groups exercising to 65%, 75%, and 85% maximal heart rate. Results of within-group analysis showed significant increases in the HDL cholesterol fractions in the 75% and 85% groups but not in the 65% group or the control group. Significant decreases in calculated LDL fractions occurred only in the 75% exercise-trained group with maximal heart rate. Aerobic exercise training favorably alters plasma lipoprotein profiles. A minimum training intensity equal to 75% maximal heart rate is required to the increase HDL cholesterol level.

Adult↗
PubMed1990

Vision and hearing during deferoxamine therapy.

To determine the frequency of eye and auditory complications and their relationship to drug dosage and iron stores in patients receiving deferoxamine, we studied 52 regularly transfused patients who received deferoxamine by subcutaneous or intravenous infusion in doses from 26 to 136 mg/kg/day, and whose serum ferritin levels of 185 to 17,775 micrograms/L reflected a wide range of iron stores. Forty-nine patients (94%) had no evidence of drug-induced visual or auditory abnormalities. Symptomatic loss of vision and hearing developed in one patient; both problems improved when chelation therapy was stopped. Of the 51 symptom-free patients, one had a mild degree of macular stippling and one had a mild, bilateral, high-frequency sensorineural hearing loss. Eye and ear abnormalities in the symptom-free patients did not progress despite continuation or resumption of chelation therapy at the same dosage. Patients with ophthalmologic and audiologic abnormalities did not receive higher doses of deferoxamine and did not have lower serum ferritin levels than patients without such abnormalities. These findings demonstrate that eye and ear abnormalities during chelation therapy with deferoxamine may not occur uniformly at as high a frequency as previously reported, even in patients who receive large doses of the chelating agent or who have only modest amounts of excessive iron.

Adolescent↗
PubMed1990

Dissociation of short- and long-range apparent motion in visual search.

The visual search paradigm was used in four experiments to investigate apparent motion perception. The addition of distractor items led to a linear increase in reaction time under long-range (LR) conditions (greater than 35 min of arc displacement), whereas reaction time was independent of displays size under short-range (SR) conditions (less than 18 min of arc). Although clear performance differences were obtained, Ss had difficulty in distinguishing between the two types of apparent motion displays when asked to make such judgments (Experiment 2). Experiments 3 and 4 explored some variables that may constrain the search process. Search times under LR conditions were reduced when some of the distractors were stationary or the motion of the distractors was homogeneous. Form and motion were found to be separable, whereas color and motion were not. Varying the color (and brightness) interfered with the processing of motion information.

Adult↗
PubMed1990

Genes for tryptophan biosynthesis in the archaebacterium Haloferax volcanii.

Recent technical advances permit direct genetic approaches for isolating genes and mapping auxotrophic mutations in the halophilic archaebacterium (Archaea) Haloferax volcanii. Twenty-nine mutations in tryptophan biosynthesis mapped to two separate chromosomal locations. DNA sequencing of one gene cluster shows a unique gene order (trpCBA) and unusual potential secondary structures in the 5'-flanking region.

Alkadienes↗
PubMed1990

Induction of verotoxin sensitivity in receptor-deficient cell lines using the receptor glycolipid globotriosylceramide.

Verotoxin 1 is an Escherichia coli-derived subunit toxin that specifically binds to the glycolipid globotriosylceramide and is cytotoxic for cells that contain this plasma membrane glycolipid. Glycolipid incorporation experiments have now been performed using human lymphoid cells of the B lineage that lack this receptor, to conclusively demonstrate that globotriosylceramide alone is a functional receptor for this toxin. Globotriosylceramide incorporated into the membrane of toxin-resistant cells provides intracellular access to verotoxin by receptor-mediated endocytosis. Protein synthesis is then inhibited and globotriosylceramide-containing cells are killed.

Bacterial Toxins↗
PubMed1990

Is pulsed Doppler echocardiography an adequate method to evaluate left ventricular function during filling in hypertensive patients?

Pulsed Doppler tracings of the mitral inflow are often proposed to describe left ventricular function during filling in hypertensive patients. The tracings are determined by the complex interaction of left atrial pressure and left ventricular relaxation, diastolic compliance and contractility of the left atrium. They strongly depend on preload and, thus, do not allow precise characterization of the left ventricle. In addition, they vary with age, heart rate and the site of measurement. The modifications caused by the presence of hypertensive hypertrophy are not specific: similar changes are seen for example, in the presence of hypertrophic cardiomyopathy or coronary heart disease, but are absent in highly trained athletes in spite of very significant physiologic hypertrophy.

Aging↗