Electrically induced arrhythmias in the rat.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
M J Walker
Publications and source records attributed to M J Walker.
Soft tissue sarcomas of the adult thoracic wall.
Forty-nine adult patients with soft tissue sarcomas of the thoracic wall have been treated by the Division of Surgical Oncology at the University of Illinois. Fibrosarcoma was the most common histologic type (20%). Patients with dermatofibrosarcoma protuberans had the longest mean overall survival time (150.8 months). The mean overall survival time for all patients was 98.2 months, and the disease-free 2-, 5-, and 10-year survival rates were 68%, 51%, and 34%, respectively. Wide excision was the treatment of choice; selected patients also received adjuvant radiotherapy, chemotherapy, or both. In all 10-year survivors, the sarcomas were low grade and well differentiated, or were less than or equal to 5.0 cm in diameter. Aggressive treatment afforded these patients good long-term results.
Adult↗
Cutaneous thick melanoma. Prognosis and treatment.
Among proponents of elective lymph node dissection (ELND) for clinical stage I melanoma, controversy exists as to whether there is an upper limit of tumor thickness beyond which ELND should not be considered. We reviewed 169 patients with clinical stage I and II melanoma that was greater than or equal to 3.0 mm thick and who were treated at the University of Illinois Hospital, Chicago. Of 139 patients with clinical stage I disease, 117 underwent ELND. Five- and ten-year survival rates were 55.7% and 48.9%, respectively. Multifactorial analysis demonstrated that anatomical location, level, pathologic stage, and ulceration were the best predictors of survival. Thickness did not emerge as a significant variable. Our findings do not support basing treatment decisions, eg, ELND in this group of patients, solely on the thickness of the primary tumor. We continue to recommend ELND in patients with either intermediate or thick melanomas.
Adult↗
Aversive property of opioid receptor blockade in drug-naive mice.
The motivational effect of naloxone administration in the non-dependent laboratory mouse was examined with taste and place conditioning procedures. Thus, male CD1 mice without any history of drug exposure avoided a cue paired with three SC injections of as little as 0.1 mg/kg naloxone HCl. The aversive effect of naloxone was also seen in DBA/2 and C57BL/6 mice. In addition, it only occurred with the minus isomer and not the plus isomer, and it was potentiated by implantation, 3 days prior to training, of a morphine-containing (37.5 mg) but not a placebo pellet. Naloxone injection, therefore, acts as an aversive stimulus in naive mice and this is probably produced by decreases in activity of endogenous opioid peptide systems. Together with other data, the present results support the conclusion that the aversive effect of opioid receptor blockade in the opiate non-dependent organism may be general to a wide range of species including primates. The importance of training and testing variables for observing the naloxone aversive effect is discussed. Advantages of studying preference conditioning with mice are also given.
Animals↗
Construction of a transposon containing a gene for polygalacturonate trans-eliminase from Klebsiella oxytoca.
A DNA fragment containing a Klebsiella oxytoca gene for polygalacturonate trans-eliminase was cloned into the kanamycin resistance transposon Tn5. This new transposon, designated Tn5-Pga+, had a transposition frequency of 1 X 10(-6). The broad host range plasmid pR751::Tn5-Pga+ was conjugally transferred to a variety of genetic backgrounds. The ability to degrade polygalacturonate was expressed in Aeromonas hydrophila, Alcaligenes eutrophus, Azotomonas insolita, Escherichia coli, Pseudomonas putida and Rhodopseudomonas sphaeroides, but not in Zymomonas mobilis.
Cloning, Molecular↗
Models for the study of arrhythmias in myocardial ischaemia and infarction: the use of the rat.
Explore the source record for details and available documents.
Animals↗
Effects of (-), (+/- ), and (+) verapamil on coronary occlusion-induced mortality and infarct size.
In a blind and randomised study, (-), (+/- ), and (+) verapamil were compared for their abilities to reduce mortality induced by occlusion of the left anterior descending coronary artery in conscious rats. In addition, effects on infarct size were also measured. In a separate experiment, the ability of an observer to detect ventricular fibrillation (VF) on the basis of changes in behaviour alone was established; (+/- ) verapamil statistically significantly reduced total mortality compared with controls, while (-) verapamil produced a similar, but non-statistically significant reduction. Both (+/- ) and (-) verapamil reduced mortality caused by VF; (-) verapamil was more effective than (+/- ) verapamil. Neither (-), (+/- ), nor (+) verapamil reduced infarct size in 24-h survivors; (-) verapamil produced the highest incidence of morbidity and associated cardiovascular depression (hypotension, bradycardia, and P-R interval prolongation), whereas (+) verapamil produced the least. Since (-) verapamil is a more potent calcium antagonist than (+) verapamil, the results of this study support the hypothesis that calcium antagonism was responsible for the observed antiarrhythmic actions.
Animals↗
Potentiation of cardiac electrophysiologic effects of verapamil after autonomic blockade or cardiac transplantation.
Cardiac electrophysiologic effects of verapamil in vivo are the result of both direct and indirect actions on the heart (the latter due to augmentation of sympathetic neural tone, diminution of parasympathetic neural tone, and increased circulating catecholamines). In this study we assessed the interaction of verapamil's direct and indirect actions on electrophysiologic properties of the heart in awake, previously instrumented, unsedated dogs. After administration of intravenous verapamil (0.2 mg/kg), electrophysiologic effects were assessed serially over a 1 hr period in 10 awake dogs before (group 1 studies) and during pharmacologic autonomic blockade (group 2 studies), and in a subset of these dogs (n = 5) after orthotopic cardiac transplantation (group 3 studies). In group 1 dogs, sinus cycle length (SCL) initially shortened after verapamil (postverapamil 379 +/- 50 msec vs baseline of 494 +/- 72 msec, p less than .001) and subsequently gradually prolonged. In groups 2 and 3, transient SCL shortening was absent. SCL prolonged promptly after verapamil, and sinus arrest developed in two of 10 group 2 and two of five group 3 animals. Verapamil exerted a negative dromotropic effect on atrioventricular node conduction in all three experimental groups, as assessed by drug-induced changes in minimum cycle length with sustained 1:1 atrioventricular conduction and measurements of atrioventricular node effective and functional refractory period. However, compared with findings in group 1, this negative dromotropic effect occurred more rapidly and was markedly potentiated in groups 2 and 3.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Estrogen receptor in malignant melanoma.
The significance of an estrogen binding protein (ER) in malignant melanoma remains controversial. We have prospectively assayed for ER on 141 patients with malignant melanoma and correlated the presence of the ER with known prognostic variables. The overall incidence of ER was 43%. The incidence of ER in males was 38.7% and 50% in females (not significant). There is an increased incidence of ER+ melanoma in women with extremity lesions (P = .08). The disease-free interval (DFI), survival, and recurrent interval were 42.0 +/- 4.0, 52.3 +/- 4.3, 13.7 +/- 1.7 months in ER- patients; 63.7 +/- 11.6, 76.1 +/- 11.4, 26.5 +/- 7.3 months in ER+ patients (1 to 10 fmol/mg cytosol protein), and 69.8 +/- 17.9, 102.7 +/- 27.9, 29.4 +/- 9.9 months in ER+ patients (greater than 10 fmol/mg cytosol); respectively. When ER+ groups were combined, the DFI in women with ER+ lesions was significantly longer than those with ER- tumors (P less than .05). Cox multivariate analysis demonstrated that ER status is a significant variable of survival along with thickness level and nodal status. These observations suggest that ER may be a marker for a more biologically indolent melanoma.
Female↗
Actions of cardiotoxins from the southern Chinese cobra (Naja naja atra) on rat cardiac tissue.
The cardiotoxic actions of southern Chinese cobra (Naja naja atra) venom have been investigated. Cardiotoxicity accounted for lethality of crude venom in anaesthetized rats and cardiotoxic polypeptides constituted the bulk of the venom when it was fractionated by CM-Sephadex chromatography. The cardiotoxic actions of these polypeptides were investigated in isolated cardiac tissue. Actions of cardiotoxins on rate, force and intracellular potentials occurred more readily in ventricular tissue and were reversible in all cardiac tissues. Bolus injections of cardiotoxins to perfused rat hearts produced profound changes in intracellular potentials, but such changes were reversed by 10 min after toxin wash-out. The changes included depolarization and loss of the fast phase (0) of the action potential. The loss of beating and contracture produced by cardiotoxins in isolated atria and ventricles showed such marked tachyphylaxis that toxicity was lost after 2-5 exposures. Both calcium and heparin ameliorated the cardiotoxic actions of cardiotoxins. Since the actions of cardiotoxin were partially selective for ventricular tissue, reversible, demonstrated tachyphylaxis and could be prevented, it is suggested that a specific molecular mechanism may be involved, rather than a non-specific action such as cell membrane destruction.
Animals↗
An improved perfusion apparatus for small animal hearts.
A perfusion apparatus for mechanical and electrophysiological studies in small animal (e.g., rat, guinea pig) hearts is described. The apparatus consists of a number of individual perfusion chambers connected to the aortic perfusion cannula of a Langendorff perfused heart. The aortic root perfusion pressure is controlled by the oxygenating gas (usually 5% CO2 in O2) at a range of 0-200 mmHg. Different solutions can be placed in different individual chambers. Pressure in the left ventricle is monitored by means of a special compliant, but nonelastic, balloon while special atraumatic electrodes allow high-voltage, noise-free ECG recordings to be made from all parts of the epicardium. The apparatus keeps hearts beating for hours while the multichamber allows multiple drug applications to be made rapidly. Thus, the apparatus can be used for all types of pharmacodynamic analysis.
Animals↗
Estrogen and antiestrogen binding sites in desmoid tumors.
Clinical and experimental evidence suggests a role for estrogen in the natural history of desmoid tumors (DT). Antiestrogen (tamoxifen) has been used empirically in some patients with significant tumor regression. To further investigate the mechanism of hormonal influence on desmoid tumors we initially characterized the cytosol estrogen receptor (ER) and antiestrogen binding sites (AEBS) in microsomal fractions of 15 cases of DT. Biopsy specimens were obtained from nine female and six male patients. ER assay was determined in cytosol (105,000 g) and the AEBS was detected in the microsomal fraction (7000 g for 20 min) by a DCC assay technique. ER was present in 33% of DT assayed (5/15), with equal incidence in males and females. Receptor content in female patients was higher than in male patients (26.52 +/- 16 vs 10.82 +/- 8.32 fmol/mg protein). Dissociation constant (Kd) range (0.44-3.97 nM) was well within the values seen in other estrogen target tissues. The AEBS were detected in 79% of the cases. The mean binding value was 236.7 +/- 170.2 fmol/mg protein. Kd values were between 0.39 and 5.97 nM. ER settled predominantly in the 4S region and AEBS settled in the 5-5.5S region in a 5-20% sucrose gradient. AEBS was detected in seven patients with negative ER. No correlation between ER and AEBS contents was observed. Competition studies revealed minimal binding with either DEX, DHT, R5020, and R1881, but partial binding with tamoxifen in cytosol and estradiol in microsomal fractions. ER and AEBS assays may be of prognostic significance in the natural history of these tumors.
Adult↗
Primary lymphoma of the liver.
We report a case of primary lymphoma of the liver, diffuse large cell type, which was treated by lobectomy. A review of the literature shows nine other similar cases of which six were also of the diffuse large cell type. Diffuse large cell lymphomas of the liver tend to form one or two large masses that can often be resected in toto. We suggest that lobectomy should be considered as a mode of treatment of primary diffuse large cell lymphoma of the liver.
Adult↗
Actions of the verapamil analogues, anipamil and ronipamil, against ischaemia-induced arrhythmias in conscious rats.
Two analogues of verapamil, ronipamil and anipamil, were tested for their ability to reduce arrhythmias induced by occlusion of the left anterior descending coronary artery in conscious rats. Only anipamil (50 and 150 mg kg-1 orally) produced a statistically significant reduction in arrhythmias; it was most effective against ventricular fibrillation. Ronipamil at the same doses had limited antiarrhythmic actions. Only anipamil delayed the development of ECG signs of ischaemia, while both drugs reduced the magnitude of such changes. Anipamil has a more favourable ratio of antiarrhythmic to hypotensive effects when compared with verapamil.
Animals↗
The mechanism of action of the optical enantiomers of verapamil against ischaemia-induced arrhythmias in the conscious rat.
The actions of (-)-verapamil (0.2-6 mg kg-1) and (+)-verapamil (0.4-12 mg kg-1) against arrhythmias induced by coronary artery occlusion were studied in conscious rats. Intravenously administered (-)- and (+)-verapamil dose-dependently reduced ventricular arrhythmias. (-)-Verapamil was consistently 4 times more potent than (+)-verapamil. In the same animals, (-)-verapamil was approximately 4 times more potent than (+)-verapamil for effects on heart rate and blood pressure. Both enantiomers prolonged P-R interval, but had no effect on QRS interval. In separate groups of conscious rats, neither enantiomer influenced the threshold voltage and pulse width required to elicit fibrillo-flutter, or altered the maximum following frequency, during electrical stimulation of the left ventricle. In isolated, paced, Langendorff-perfused ventricles of the rat, both enantiomers dose-dependently reduced contractility, (-)-verapamil being 8-21 times more potent than (+)-verapamil; both absolute and relative potencies were dependent on potassium concentration. These results are compatible with the hypothesis that calcium antagonism in the ischaemic ventricular myocardium is antiarrhythmic during acute myocardial ischaemia.
Animals↗
Effects of naltrexone on intravenous cocaine self-administration in rats during food satiation and deprivation.
Rats self-administered i.v. delivered cocaine (0.1 mg/kg) under conditions of continuous access (session length 24 hr). Each lever press resulted in an infusion according to a fixed-ratio 1 schedule. Food was continuously available except for every third session, when the rats were food deprived, i.e., provided with only 8 g at the start of the session. After behavior stabilized, the rats were given naltrexone (N), saline (V) or no injections (O) on successive days according to the following sequence: N, V, O, V, N, O. . . . This sequence began on a food deprivation session and repeated until four naltrexone and four saline injections had been given during both food satiation and deprivation sessions, although data were reported from only the last three sessions under each condition. Injections were given at the start of the session and after 7 hr of the session had elapsed. Cocaine was then replaced by saline for approximately half the rats, and the entire injection sequence was repeated until three naltrexone and three saline pretreatment sessions were completed during both food satiation and deprivation. Three separate groups of 9 or 10 rats each received a different dose of naltrexone (0.5, 1 or 2 mg/kg i.v.). As reported earlier, cocaine- and saline-reinforced responding increased more than 2-fold during food deprivation. During food satiation, naltrexone pretreatment nearly doubled cocaine self-administration, with the greatest increase at the 1-mg/kg naltrexone dose. Naltrexone had no systematic effect on cocaine-reinforced responding during food deprivation, and it had no effect on saline-maintained responding during food satiation or deprivation.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of glucocorticoids on the growth of human fibrosarcoma cell line HT-1080.
The human fibrosarcoma cell line HT-1080 exhibits rapid growth following s.c. inoculation in 4-6-week-old male athymic mice. Cytosols from tumors carried in athymic mice bind glucocorticoid (Kd, 1.8 +/- 0.48 X 10(-8) M; Bmax, 240.5 +/- 35.3 fmol/mg cytosol protein, mean +/- SEM). Receptor sediments primarily in the 8-9S region on 5-20% sucrose gradients and is specific for the glucocorticoids. HT-1080 growth in vitro (as measured by cell count) was inhibited over a range of 10(-6)-10(-8) M after 7 days of incubation with dexamethasone and triamcinolone acetonide. Progesterone, estradiol, and dihydrotestosterone had no effect on HT-1080 growth in vitro. Preincubation with a 100-fold excess of progesterone reversed the growth inhibition observed with triamcinolone acetonide but not dexamethasone acetate. HT-1080 tumor cell growth responded biphasically to dexamethasone in vivo. Athymic mice given s.c. injections every other day with 5 or 25 micrograms dexamethasone showed an increase in tumor size inversely proportional to dose. In contrast, 200 micrograms of dexamethasone significantly inhibited tumor growth. Adrenalectomy did not significantly alter HT-1080 growth or glucocorticoid binding to tumor cytosols (Kd, 3.4 X 10(-8) +/- 1.1, Bmax, 236.9 +/- 9.9 fmol/mg cytosol protein, mean +/- SEM) although tumor incidence was decreased in sham adrenalectomized mice. Glucocorticoid binding in tumors grown in vivo was decreased by increasing amounts of dexamethasone. High pharmacological doses of glucocorticoids inhibit the growth of human fibrosarcomas in vivo and in vitro.
Adrenalectomy↗
Soft tissue sarcomas of the distal extremities.
Multimodality therapy and limb salvage procedures constitute a significant advance in the treatment of soft tissue sarcoma of the extremity. The applicability of these procedures to soft tissue sarcoma of the distal extremities was evaluated in a retrospective study of 159 such cases treated during a 10-year period. Thirty-seven patients were treated by operation alone, 57 had operation and adjuvant chemotherapy, and 65 had multimodal therapy. The distal extremities are unusual sites for soft tissue sarcomas and accounted for only 20% of our patients with sarcoma. The majority of patients were younger than 50 years and the sex distribution was approximately equal. The major histologic types were synovial cell sarcoma (18.2%), fibrosarcoma (15%), liposarcoma (13.8%), and rhabdomyosarcoma (13.8%). The 5-year survival rate was 72% with multimodality therapy, 72% for operation and chemotherapy, and 51% for operation alone. The local recurrence rate was 13% with operation alone, 9% with operation and adjuvant chemotherapy, and 12% with multimodality therapy. Based on our review, wide local excision and adjuvant chemotherapy proved to be as effective as multimodal therapy.
Adult↗