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Biomedical subjects

J Butler

Publications and source records attributed to J Butler.

At least 91 records · Page 5Linked to original sources
PubMed1987

The effect of the anthrapyrazole antitumour agent CI941 on rat liver microsome and cytochrome P-450 reductase mediated free radical processes. Inhibition of doxorubicin activation in vitro.

The anthrapyrazole CI941 is one of a new series of DNA complexing drugs which displays high level broad spectrum antitumour activity in mice. In view of the proposed role of drug free radical formation, superoxide generation and lipid peroxidation in anthracycline and anthraquinone induced toxicities, the redox biochemistry of CI941 has been investigated. Studies have been performed in vitro using rat liver microsomes and purified cytochrome P-450 reductase. In addition, the ability of CI941 to undergo chemical reduction has been examined. Pulse radiolysis of CI941 demonstrated that the drug can undergo chemical reduction with a one electron reduction potential of E1(7) = -538 +/- 10 mV. However, electron spin resonance (ESR) spectroscopy studies using either NADPH fortified microsomes or cytochrome P-450 reductase, failed to detect a drug free radical signal. Unlike doxorubicin, CI941 (150 microM) inhibited basal rate microsomal NADPH consumption by 45%. Furthermore, CI941 (50-200 microM) antagonised doxorubicin stimulated (1.8-fold) NADPH oxidation by over 50%. CI941 also antagonised the formation of a doxorubicin free radical ESR signal in a concentration dependent manner. CI941 induced minimal superoxide generation in the presence of either microsomes or cytochrome P-450 reductase and inhibited doxorubicin induced (50 microM) superoxide formation by up to 80% (50-200 microM CI941). Importantly, CI941 inhibits both basal rate and doxorubicin (100 microM) stimulated lipid peroxidation (52% inhibition at 5 microM CI941). These data suggest that CI941 is unlikely to induce free radical mediated tissue damage in vivo. On the contrary, CI941 may have a protective role if used in combination with doxorubicin.

Animals↗
PubMed1987

The reduction of anti-tumour diaziridinyl benzoquinones.

The properties of the semiquinone radicals produced for 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone (AZQ) and 2,5-bis(2-hydroxyethylamino)-3,6-diaziridinyl-1,4-benzoquinone (BZQ), have been investigated. AZQ semiquinone radicals can be produced from the reduction of AZQ by superoxide radicals, whereas BZQ semiquinone radicals are unstable in the presence of oxygen. The one-electron reduction potentials of the couples Q/Q-. at pH 7.0 were determined as -70 +/- 10 mV for AZQ and -376 +/- 15 mV for BZQ. The difference in these potentials is explained. As a consequence of ESR studies on the enzymatically produced radicals, we have considered the factors which determine the detection of ESR signals for reduced quinones produced in a biological system.

Antineoplastic Agents↗
PubMed1987

Monoclonal antibody staining and impact of surgical technique on the identification and quantitation of steroid receptors in human breast cancer.

In this prospective study of 31 patients, paired receptor levels from biopsy and mastectomy specimens were found to be significantly correlated on biochemical assay. Despite this fact, 6 of 20 tumors that were estrogen receptor-positive on biopsy, had a negative assay from the mastectomy specimen, indicating the need for a fresh tumor specimen. Immunocytochemical staining with monoclonal antibody H222 Spy, an antibody specific for the estrogen receptor, was evaluated in 34 biopsy and mastectomy specimens. With a sensitivity of 85 percent and specificity of 93 percent, this technique compares favorably with the standard biochemical assay.

Adult↗
PubMed1987

Syndrome of periodic fever, pharyngitis, and aphthous stomatitis.

A syndrome of periodic fever that resembles human cyclic neutropenia in its clinical presentation has been identified in 12 children observed at two major referral centers. Attacks characterized by abrupt onset of fever, malaise, chills, aphthous stomatitis, pharyngitis, headache, and tender cervical adenopathy occur at 4- to 6-week intervals over periods of years. These episodes of illness resolve spontaneously in 4 to 5 days. Mild leukocytosis and elevation of the erythrocyte sedimentation rate during attacks are the only laboratory abnormalities. Affected children grow normally, are not unusually susceptible to infection, and exhibit no long-term sequelae. Attacks may be aborted by short courses of prednisone but do not respond to nonsteroidal anti-inflammatory agents. This syndrome is sporadic and appears to be much more common than cyclic neutropenia.

Blood Sedimentation↗
PubMed1987

Group C Niemann-Pick disease: faulty regulation of low-density lipoprotein uptake and cholesterol storage in cultured fibroblasts.

Incubation of mutant Niemann-Pick C fibroblasts with low-density lipoprotein (LDL) resulted in excessive internalization of lipoprotein and extensive cellular over-accumulation of unesterified cholesterol. The uptake of LDL by the mutant cells appeared to occur through the classic LDL receptor pathway and internalized lipoprotein was processed in lysosomes. Lipoprotein uptake into mutant cells was associated with delays in the initiation of established cellular cholesterol homeostatic responses. Subcellular fractionation of mutant Niemann-Pick C fibroblasts accumulating LDL-cholesterol showed excess unesterified sterol to be localized in the light lysosome-light membrane region of a Percoll gradient, and revealed that cholesterol storage was associated with a specific alteration in the normal profiles of lysosomal marker enzymes.

Cells, Cultured↗
PubMed1987

Remission of hypoparathyroidism during lactation: evidence for a physiological role for prolactin in the regulation of vitamin D metabolism.

We studied a young woman with surgical hypoparathyroidism who, on her usual maintenance dose of calcitriol, developed hypercalcaemia 9 d postpartum when lactation was established. Serum values of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) values were very high (127 pg/ml). The patient remained without exogenous calcitriol treatment for 40 d, during which time serum 1,25(OH)2D3 levels remained within the normal range and serum calcium fell with a half-time of 27 d. The requirements for calcitriol increased to antepartum levels when lactation had ceased. There was a close negative correlation between requirements for calcitriol and serum PRL values. After weaning, an episode of hypercalcaemia was induced by increasing the dose of calcitriol. On stopping calcitriol the serum 1,25(OH)2D3 fell to low values (4 pg/ml) within 2 d and serum calcium fell with a half-time of 3 d, necessitating the early reintroduction of calcitriol. We conclude that in hypoparathyroidism exogenous vitamin D requirements fall during lactation because of enhanced endogenous production of 1,25(OH)2D3. The lactation-associated increase in circulating 1,25(OH)2D3 concentrations thus results from a parathyroid hormone-independent mechanism, possibly by an effect of PRL on the 1 alpha-hydroxylase.

Adult↗
PubMed1987

Temperature alters bronchial blood flow response to pulmonary arterial obstruction.

Lobar bronchial blood flow has been reported to increase and decrease acutely after pulmonary arterial obstruction (PAO). Because bronchial blood flow (Qbr) to the trachea and bronchi is influenced by inspired air temperature, we investigated whether temperature differences could explain these disparate results. In 10 open-chested dogs the left lower lobe (LLL) was isolated and perfused in situ with autologous blood at a controlled temperature with an independent vascular circuit. The abdomen and the chest of the dog were enclosed in a Plexiglas box in which air was fully humidified and temperature could be regulated. Qbr, determined by the reference flow technique using 16 micron microspheres, was measured before and 30 min after onset of PAO with the air in the box being either at 27 or 39 degrees C and with warmed LLL blood (37 degrees C) in the latter condition. Anastomotic bronchial blood flow [Qbr(s-p), determined as overflow from the closed LLL vascular circuit and measured in ml X min-1 X 100 g dry lung wt-1 X 100 Torr mean systemic pressure-1] was measured continuously at both temperatures. Both before and after PAO, Qbr and Qbr(s-p) were closely correlated: Qbr (ml/min) = 1.12 + 0.978Qbr(s-p); R = 0.912. This was true regardless of the presence or the absence of pulmonary flow, showing that the distribution of bronchial blood flow between the anastomotic and the nonanastomotic portion does not change acutely during PAO. When the air in the box was 27 degrees C, Qbr(s-p) was 19.5 +/- 5.2 (SE) and increased to 38.6 +/- 8.1 with PAO (P less than 0.007).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Acute increases in anastomotic bronchial systemic to pulmonary blood flow due to generalized lung injury.

Since pulmonary blood flow to regions involved in adult respiratory disease syndrome (ARDS) is reduced by hypoxic vasoconstriction, compression by cuffs of edema, and local thromboses, we postulated that the bronchial circulation must enlarge to provide for the inflammatory response. We measured anastomotic bronchial systemic to pulmonary blood flow [QBr(s-p)] serially in a lung lobe in 31 open-chest dogs following a generalized lobar injury simulating ARDS. The pulmonary circulation of the weighed left lower lobe (LLL) was isolated and perfused (zone 2) with autologous blood in anesthetized dogs. QBr(s-p) was measured from the amount of blood which overflowed from this closed vascular circuit corrected by any changes in the lobe weight. The LLL was ventilated with 5% CO2 in air. The systemic blood pressure (volume infusion), gases, and acid-base status (right lung ventilation) were kept constant. We injured the LLL via the airway by instilling either 0.1 N HCl or a mixture of glucose and glucose oxidase or via the pulmonary vessels by injecting either alpha-naphthylthiourea or oleic acid into the LLL pulmonary artery. In both types of injury, there was a prompt rise in QBr(s-p) (mean rise = 247% compared with control), which was sustained for the 2 h of observation. The cause of this increase in flow was studied. Control instillation of normal saline into the airways or into the pulmonary vessels did not change QBr(s-p) nor did a similar increase in lobar fluid (weight) due to hydrostatic edema. Neither cardiac output nor systemic blood pressure increased.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Upstream pressure for systemic to pulmonary flow from bronchial circulation in dogs.

Systemic to pulmonary flow from bronchial circulation, important in perfusing potentially ischemic regions distal to pulmonary vascular obstructions, depends on driving pressure between an upstream site in intrathoracic systemic arterial network and pulmonary vascular bed. The reported increase of pulmonary infarctions in heart failure may be due to a reduction of this driving pressure. We measured upstream element for driving pressure for systemic to pulmonary flow from bronchial circulation by raising pulmonary venous pressure (Ppv) until the systemic to pulmonary flow from bronchial circulation ceased. We assumed that this was the same as upstream pressure when there was flow. Systemic to pulmonary flow from bronchial circulation was measured in left lower lobes (LLL) of 21 anesthetized open-chest dogs from volume of blood that overflowed from pump-perfused (90-110 ml/min) pulmonary vascular circuit of LLL and was corrected by any changes of LLL fluid volume (wt). Systemic to pulmonary flow from bronchial circulation upstream pressure was linearly related to systemic arterial pressure (slope = 0.24, R = 0.845). Increasing Ppv caused a progressive reduction of systemic to pulmonary flow from bronchial circulation, which stopped when Ppv was 44 +/- 6 cmH2O and pulmonary arterial pressure was 46 +/- 7 cmH2O. A further increase in Ppv reversed systemic to pulmonary flow from bronchial circulation with blood flowing back into the dog. When net systemic to pulmonary flow from bronchial circulation by the overflow and weight change technique was zero a small bidirectional flow (3.7 +/- 2.9 ml.min-1 X 100 g dry lobe wt-1) was detected by dispersion of tagged red blood cells that had been injected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Bronchial circulation and cyclooxygenase products in acute lung injury.

The role of cyclooxygenase products in the response of the bronchial circulation to acute lung injury was examined in 30 dogs. By use of an open-chest preparation the left lower lobe (LLL) pulmonary circulation was isolated, continuously weighed, and perfused in situ. The anastomotic bronchial blood flow [Qbr(s-p)] was measured as the rate of increase in the volume of the LLL-perfusion circuit. Four groups of dogs were studied. In group A, six dogs received cyclooxygenase inhibition (COI) with either indomethacin (2 mg/kg) or ibuprofen (10 mg/kg). In group B (n = 10) lung injury caused by airway instillation of glucose (15 mg) with glucose oxidase (500 micrograms/kg) (G/GO) or LLL pulmonary arterial infusion of alpha-napthyl thiourea (ANTU, 2 mg/kg). Group C (n = 10) received COI, and 30 min later injury was induced as above with either ANTU or G/GO. Group D (n = 4) received COI immediately after anesthesia; then, 30 min after completion of the surgical preparation, injury was induced with ANTU or G/GO. After COI, Qbr(s-p) decreased to 35 +/- 9% of the basal values (P less than 0.05). After administration of ANTU or G/GO, Qbr(s-p) increased irrespective of whether COI was present. 6-Ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and thromboxane B2 (TxB2) were measured by radioimmunoassay in the LLL pulmonary artery and systemic venous blood, demonstrating an increase in 6-keto-PGF1 alpha due to surgical preparation and confirming complete COI in those animals receiving COI immediately after anesthesia. These findings demonstrate that 1) the bronchial circulation is capable of a sevenfold increase in flow in response to acute lung injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Evaluation of breathlessness in asbestos workers. Results of exercise testing.

We studied 120 asbestos-exposed workers seeking compensation for asbestos-related ventilatory impairment who were referred to us for evaluation of their complaint of dyspnea. We reviewed history, chest radiographs, pulmonary function studies, and exercise tests. The workers were 59.9 +/- 9.5 (mean +/- SD) yr of age and their first asbestos exposure had been 34.4 +/- 10 yr prior to the study; 63% were smokers, 19% were ex-smokers, and 18% were nonsmokers. Chest radiographs were normal in 4%, showed only pleural disease in 35%, only parenchymal diseases in 5%, and pleuroparenchymal disease in 56%. Restrictive pulmonary function abnormalities were present in 25% of the workers, and obstructive abnormalities were present in 27%. Because the impairment of one of several organ systems (i.e., ventilatory, cardiac, pulmonary vascular, or peripheral circulatory) may limit exercise performance, we designed an exercise test score in an attempt to identify the system causing the limitation. No abnormal limitation was detectable in half (49.2%) of the subjects. Only 26% had a ventilatory limitation, which was much more frequent in smokers (32%) than in nonsmokers (9%) (p less than 0.05). Unexpectedly, rather more (37%) had a cardiac rather than a ventilatory limitation. We conclude that the complaint of dyspnea in these asbestos-exposed workers was usually not caused by a ventilatory dysfunction.

Asbestosis↗
PubMed1987

Serum thyrotrophin in patients with destructive pituitary lesions assessed by a sensitive immunoradiometric assay.

Using a sensitive immunoradiometric assay, serum concentrations of thyrotrophin (TSH) were measured both basally and after intravenous thyrotrophin releasing hormone (TRH) in two groups of patients with destructive pituitary lesions. Group A patients, who had more extensive pituitary hormone deficiencies and biochemical evidence of hypothyroidism at the time of study, had significantly lower mean serum TSH concentrations than the group B patients who were biochemically euthyroid. Basal TSH was below the lowest value seen in a control group of normal subjects in 5 of the 8 group A patients. In all patients TSH increased significantly after injection of TRH; the peak values being significantly correlated with the basal. In contrast to recent studies, which have emphasised other mechanisms in the production of secondary hypothyroidism, our data suggest that inadequate production of immunoassayable TSH is a common cause of secondary hypothyroidism in patients with destructive pituitary disease. Little, if any, additional clinical information is to be gained by measurement of TSH after TRH stimulation in this circumstance.

Adolescent↗
PubMed1987

Brachial muscles of dystrophic chick embryos atypically sustain interaction with thoracic nerves.

Previous analyses of experimental chick embryos of normal lineage demonstrate the inability of brachial muscles to sustain a successful union with foreign nerves derived from a thoracic neural tube segment transplanted to the brachial region at day 2 in ovo (day 2E). The present experiments were performed to determine if mutant chick embryos afflicted with hereditary muscular dystrophy would respond similarly to this experimental manipulation. Using the same criteria applied to our analysis of experimental normal embryos, our results demonstrated that dystrophic brachial muscles were capable of maintaining a compatible union with foreign thoracic nerves throughout the experimental period analysed. Significant muscle growth occurred, intramuscular nerve branches were maintained, motor endplates formed and wing motility was equivalent to that of unoperated dystrophic embryos. Thus, foreign nerves rejected by normal brachial muscles were accepted by brachial muscles of the mutant dystrophic embryo.

Animals↗
PubMed1987

Beta-adrenoceptor adaptation to endurance training.

Endurance exercise is associated with various cardiovascular adaptations, and these may include changes in sympathoadrenal activity and end-organ responsiveness to norepinephrine (NE). Because beta-adrenoceptor function is a major determinant of sympathetic responsiveness, we used the lymphocyte beta-adrenoceptor as a model to study the effects of endurance training in 19 male subjects before, during, and after preparation for a marathon race. Before the subjects trained, resting beta-adrenoceptor density was positively correlated to resting heart rate (r = 0.47, p less than 0.05) but this correlation was not evident after training. Eleven of the 19 subjects completed the 3 1/2-month training period, and mean (+/- 1 SD) resting beta-adrenoceptor density fell from 1,593 +/- 333 to 1,197 +/- 332 sites per cell (p less than 0.02) after the training period. Two weeks after cessation of training, receptor density was at pretraining values of 1,547 +/- 209 sites per cell. During training, the subjects ran two 21-km races. Each of these was associated with decreases in beta-adrenoceptor density. Our results demonstrate the episodes of endurance running result in reductions in lymphocyte beta-adrenoceptor density. We conclude that down-regulation of beta-adrenoceptors is an important component of the response to endurance training.

Adult↗
PubMed1987

Are reduced quinones necessarily involved in the antitumour activity of quinone drugs?

Several studies have shown that the antitumour quinones, adriamycin, mitomycin C, mitozantrone and 3,6-diaziridinyl-2,5-bis (carboethoxyamino)-1,4-benzoquinone (AZQ) can form semiquinone radicals in vitro. The biophysical chemistry data for these reactions and the properties of the radical quinones are presented together with the proposed mechanisms for cytotoxicity. An attempt has been made to correlate the available in vitro data for the quinones with each other and with the available in vivo data. As a consequence of these correlations a number of conclusions have been proposed regarding the techniques of investigation and the evidence for the role of reduced quinones in antitumour activity.

Antineoplastic Agents↗
PubMed1987

Cardiac embryogenesis: a three-dimensional approach.

In order to aid students in the understanding of cardiac embryogenesis, seven three-dimensional fiberglass models depicting stages eleven to eighteen of cardiac embryogenesis, and one model of a mature heart were constructed. The details of these models, and a review of cardiac embryogenesis is presented. The results we have had with these models in the teaching of cardiac embryogenesis to medical students, cardiac technologists, and nurses have been encouraging, and this approach to teaching is highly recommended.

Heart↗