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Biomedical subjects

J A Bennett

Publications and source records attributed to J A Bennett.

At least 91 records · Page 5Linked to original sources
PubMed1991

Estrogen-stimulation of postconfluent cell accumulation and foci formation of human MCF-7 breast cancer cells.

Foci, nodules of cellular overgrowth, that appear after confluence are an in vitro characteristic of malignant transformation. A well-studied in vitro model of estrogen-dependent tumors is the MCF-7 cell line, derived from a pleural metastasis of a human breast adenocarcinoma. We report that cultivation of MCF-7 cells, using routine methods, results in extensive estrogen-stimulated postconfluent cell accumulation characterized by discrete three-dimensional arrays. Side view Nomarski optical sections revealed these to be principally multicellular foci with occasional domes and pseudoacinar vacuoles. This effect on MCF-7 cell growth occurs in media containing fetal bovine serum but not with calf serum or charcoal-dextran-treated fetal bovine serum unless supplemented with estrogens. Foci formation starts 5-6 days after confluence, and the number of foci generated is a function of the concentration of added estrogens. Foci formation is suppressed by the antiestrogens Tamoxifen and LY 156758. Addition of progesterone, testosterone, or dexamethasone had little or no effect, while various estrogens (ethinyl estradiol, diethylstilbestrol, and moxestrol) induced foci development. Clones derived from single cells of the initial MCF-7 population revealed a wide variance in estrogen-induced foci formation, demonstrating heterogeneity of this tumor cell line. The postconfluent cell growth of the estrogen receptor-deficient cell line, MDA-MB-231, contrasted with MCF-7 by developing an extensive multilayer morphology devoid of discrete structures. The tumorigenic potential of the MCF-7 cells used in our experiments was confirmed by their estrogen-dependent growth in immunosuppressed male BDF1 mice. These data suggest an estrogen receptor-based mechanism for the development of multicellular foci during postconfluent growth of MCF-7 cells. After confluence, foci, in contrast to the quiescent surrounding monolayer, retain proliferating cells. Focus formation, therefore, reflects the heterogeneous responsiveness of these cells to estrogens and should provide a model permitting in vitro comparisons between the progenitor cells of multicellular foci and the monolayer population.

Adenocarcinoma↗
PubMed1991

Inhibition of neutral endopeptidase (EC 3.4.24.11) leads to an atrial natriuretic factor-mediated natriuretic, diuretic and antihypertensive response in rodents.

1. Atrial natriuretic factor is metabolized by neutral endopeptidase (atriopeptidase; EC 3.4.24.11) in vitro. Inhibitors of this enzyme have been reported to prolong the half-life of atrial natriuretic factor in vivo and to potentiate the renal and haemodynamic effects of exogenous atrial natriuretic factor. 2. (+/-)-Candoxatrilat, a selective neutral endopeptidase inhibitor, potentiated the natriuretic and diuretic response to volume loading in anaesthetized rats. Part of the response to volume loading and the potentiation by (+/-)-candoxatrilat was prevented by a polyclonal atrial natriuretic factor antiserum. The diuretic and natriuretic responses evoked by hydrochlorothiazide were not altered by the antiserum. 3. (+/-)-Candoxatrilat reduced systolic blood pressure of one-kidney deoxycorticosterone acetate-salt hypertensive rats for over 5 h. This response was abolished by pretreatment with atrial natriuretic factor antiserum. 4. These data demonstrate that the neutral endopeptidase inhibitor (+/-)-candoxatrilat has natriuretic/diuretic and antihypertensive effects in rodents, and that these effects are mediated via endogenous atrial natriuretic factor.

Animals↗
PubMed1990

Inhibition of estrogen-dependent breast cancer growth by a reaction product of alpha-fetoprotein and estradiol.

Reaction of picomolar quantities of human or rodent alpha-fetoprotein (AFP) with nanomolar quantities of 17 beta-estradiol (E2) generates a product of unknown structure, designated AFP/E2, that inhibits estrogen-stimulated growth of mouse uterus. We describe herein the effect of rodent AFP/E2 on the in vivo growth of two estrogen-dependent breast cancers, the MCF-7 human breast cancer and the MTW9A rat mammary cancer. Both cancers were grown as xenografts under the kidney capsule of cyclosporine-immunosuppressed male BDF1 mice. In addition, the MTW9A tumor was grown as a homograft in syngeneic ovariectomized Wistar-Furth female rats. Estrogen support was provided by s.c. Silastic E2 implants. Injecting AFP/E2 that was generated by incubating 1.0 microgram of AFP with 0.5 microgram of E2 for 1 h at room temperature resulted in cessation of growth and, in most cases, regression of MCF-7 tumor xenografts. It also produced regression of MTW9A tumor homografts and significantly inhibited growth of MTW9A xenografts. Treatment with AFP alone or E2 alone did not inhibit growth of these tumors. The data suggest that AFP/E2 has a unique property which causes attenuation or shut-down of the biochemical reactions through which estrogen-dependent tumor growth is mediated.

Animals↗
PubMed1990

Anticholinergic serum levels and cognitive performance.

Integrity of central cholinergic neurotransmission is essential for adequate cognitive functioning. Many psychotherapeutic medications have anticholinergic side-effects. In order to determine the impact of circulating anticholinergic activity on cognitive performance, 28 geropsychiatric inpatients underwent cognitive testing at different levels of anticholinergic serum activity. In 10 subjects with a diagnosis of probable Alzheimer's disease, significant deterioration of selected cognitive functions was observed at anticholinergic serum levels that caused no dysfunction in the 18 non-demented subjects. The data suggest that non-demented elderly patients with psychiatric problems tolerate psychotropic pharmacotherapy without significant negative impact on their cognitive competency. By contrast, patients with Alzheimer's disease are at risk of additional impairment. The introduction of anticholinergic serum activity as a monitoring technique for safe psychopharmacotherapy in geriatric patients is discussed.

Aged↗
PubMed1990

Neurones in the dorsal motor vagal nucleus of the cat with non-myelinated axons projecting to the heart and lungs.

Extracellular recordings were made from ninety-four single motoneurones in the dorsal motor vagal nucleus of chloralose-anaesthetized or decerebrate cats. Fifty-five neurones had axons in cardiac vagal branches and thirty-nine had axons in pulmonary vagal branches; the conduction velocities of the axons were in the C fibre range, i.e. the axons were non-myelinated. The neurons exhibited little or no spontaneous activity. Excitatory and inhibitory synaptic inputs were demonstrated by electrical stimulation of the vagus nerve or its branches. Twenty-four neurones were tested by carotid sinus distension but only one was excited. Iontophoretic excitation of neurones projecting to cardiac vagal branches had no effect on heart rate. The properties of these neurones and their possible functions are discussed and contrasted with those of cardiac and pulmonary vagal motoneurones in the nucleus ambiguus.

Action Potentials↗
PubMed1990

A study of the clinical efficacy of maintenance ECT.

Six cases of maintenance electroconvulsive treatment (ECT) in elderly patients with major mood disorders were followed for 1 to 6 years. Documented duration of illness before instituting maintenance ECT ranged from 6 to 53 years (mean +/- SD = 22 +/- 18 years). Measures of effectiveness and safety of maintenance treatment and measures of functional status were prospectively obtained during periods of outpatient ECT administration, and functional status measures were retrospectively obtained for equivalent pre-ECT periods. Such measures included mean frequency of annual hospital admissions and average annual length of inpatient stay, mean scores on standard rating instruments of global functioning and cognitive performance, the average number of prescribed psychotropic medications, and ratings of affect. Some of the authors' findings support the contention that maintenance ECT may help sustain remission in the course of affective illness.

Aged↗
PubMed1989

Accuracy of the subrenal capsule xenograft assay in predicting the clinical growth and chemosensitivity of human squamous head and neck carcinomas.

Thirty-seven of 54 human squamous head and neck carcinomas were successfully grown as first transplant generation xenografts under the kidney capsule of conventional mice immunosuppressed by daily treatment with 60 mg/kg of cyclosporine. Of the 18 different tumors evaluated for chemosensitivity, 39% responded to cis-platinum, 19% to 5-fluorouracil, 33% to methotrexate, and 40% to Cis-Pt/5Fu. In comparing the assay results in nine patients who received the same chemotherapeutic drugs, two of three patients responded to their drug with xenograft shrinkage noted, whereas four of six patients who did not respond had tumor growth in the mouse. It is hoped that this model will become useful for new drug testing and, in certain cases, for selection of chemotherapy for patients with refractory tumors.

Animals↗
PubMed1989

Cleft palate lateral synechia syndrome. Review of the literature and case report.

Cleft palate lateral synechiae syndrome is a rare syndrome consisting of cord-like interalveolar adhesions and concomitant hypoplasia of the mandible. We have presented an infant with CPLS syndrome and coincident hydrocephalus. Surgical division of the adhesions is necessary to allow normal feeding, avoid upper airway obstruction, and allow normal mandibular function and growth.

Abnormalities, Multiple↗
PubMed1989

Growth and chemosensitivity of human head and neck cancers implanted under the kidney capsule of cyclosporine-immunosuppressed mice.

Thirty-seven of 54 human squamous cell head and neck carcinomas were grown successfully at first transplant generation xenografts under the kidney capsule of conventional mice immunosuppressed by daily treatment with 60 mg/kg of cyclosporine. Eighteen different tumors were evaluated for chemosensitivity to cis-diamminedichloroplatinum (cisplatin), 5-fluorouracil, and methotrexate. Thirty-nine percent of the tumors responded to cisplatin, 19% to 5-fluorouracil, and 33% to methotrexate. This assay response is consistent with the clinical response of human squamous head and neck carcinoma to these drugs used as single agents. It is hoped that this model will become useful for new drug testing and, in certain cases, for selection of chemotherapy for patients with refractory tumors.

Animals↗
PubMed1988

Persistent sensitization of dopamine neurotransmission in ventral striatum (nucleus accumbens) produced by prior experience with (+)-amphetamine: a microdialysis study in freely moving rats.

In humans the repeated use of amphetamine (AMPH) produces a hypersensitivity to the psychotogenic effects of AMPH that persists for months to years after the cessation of drug use. To explore the neurobiological basis of this phenomenon the long-term effects of dextroamphetamine [+)-AMPH) on brain monoamines and behavior were studied in an animal model of AMPH psychosis. An escalating dose pretreatment regimen (from 1 to 10 mg/kg over 5 weeks) was used to mimic the pattern of drug use associated with the development of addiction and AMPH psychosis. The effect of pretreatment with AMPH on dopamine (DA) release in the ventral striatum (nucleus accumbens) was determined by measuring the extracellular concentrations of DA and DA metabolites using in vivo microdialysis, both before and after an AMPH challenge. The postmortem tissue concentrations of DA, serotonin and their metabolites were measured to determine if this treatment was neurotoxic. Escalating doses of (+)-AMPH were not neurotoxic, and 25-30 days after the cessation of drug treatment animals showed relatively normal levels of spontaneous motor activity across the day-night cycle. However, AMPH pretreatment produced robust behavioral sensitization. Animals showed a marked hypersensitivity to the motor stimulant effects of an AMPH challenge, even after 15-20 days of withdrawal. Most importantly, this hyperdopaminergic behavioral syndrome was accompanied by significantly elevated DA release in the ventral striatum. In contrast, AMPH pretreatment had no effect on the basal extracellular concentrations of DA.(ABSTRACT TRUNCATED AT 250 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed1988

Inhibition of brain stem neuronal activity by cardiac and pulmonary vagal afferent fibres in the cat.

Recordings have been made of the activity of 311 neurones in the nucleus tractus solitarius (NTS) and dorsal motor vagal nucleus (DMVN) which responded to stimulation of the cardiac or pulmonary vagal branches in the anaesthetized cat. Eighty-one neurones showed inhibitory effects to vagal branch or vagal trunk stimulation which were exhibited in three different ways. First, the responses of forty neurones evoked by stimulation of one vagal branch were reduced or abolished by stimulation of another vagal branch or the vagal trunk. Second, the spontaneous activity of six neurones, not excited by branch stimulation, was reduced or abolished by vagal branch stimulation, and third, thirty-five neurones showed evidence of reduced excitability to a second stimulus pulse applied to the same branch. The inhibitory effects were characterized by a long time course (mean 932 ms, range 4-10,000 ms), and the latency to onset suggests that both myelinated and non-myelinated afferents are capable of such actions. Inhibitory effects were observed on neuronal elements activated both synaptically, i.e. interneurones, and non-synaptically, i.e. efferent motoneurones or afferent fibres, although no pattern of branches mediating particular effects could be discerned. The possible physiological implications of these observations are discussed.

Action Potentials↗
PubMed1988

Endogenous production of cytotoxic factors in serum of BCG-primed mice by monophosphoryl lipid A, a detoxified form of endotoxin.

Monophosphoryl lipid A (MPL), a detoxified form of endotoxin, was evaluated for its ability to elicit cytotoxic factors in the serum of mice pretreated with BCG. BDF1 mice were given a priming dose of bacillus Calmette-Guerin (BCG) intravenously (i.v.). Two weeks later, these mice were challenged with MPL i.v. and their serum was tested for cytotoxicity against Lewis lung carcinoma cells growing in culture. A well-tolerated dose of MPL induced substantial serum cytotoxic activity comparable to that found after a toxic dose of endotoxin. The effective dose of MPL for eliciting serum cytotoxicity was 20 times less than the toxic dose of MPL in BCG-primed mice. No serum cytotoxicity was induced by MPL without prior treatment with BCG or in mice exposed to BCG for less than 10 days. The i.v. route of administration was superior to intraperitoneal, intrapleural, or subcutaneous routes for both BCG priming and induction of serum activity with MPL. Serum manifested TNF-like activity in that it was heat-stable, not species-specific, more effective against tumor than normal cell lines, and more effective against a TNF-sensitive than a TNF-resistant cell line. We conclude that MPL is an effective, well-tolerated biological response modifier that triggers production of cytotoxic factors in serum of mice with an activated reticuloendothelial system.

Animals↗
PubMed1987

A sputtered gold microelectrode in combination with a multibarrelled micropipette: a low impedance extracellular recording electrode with the facility of iontophoresis.

The manufacture of a metal film electrode on a multibarrelled micropipette is described. Gold film is sputtered onto the external surface of a multibarrelled micropipette and subsequently insulated. Gold film exposed at the tip operates as an extracellular recording microelectrode and the micropipettes may be used for iontophoresis of drugs or marker dyes. This method may be used to produce electrodes with increased numbers of iontophoresis channels at the tip without altering the low impedance and good recording characteristics of the metal film (recording) electrode.

Animals↗
PubMed1987

A gamma-aminobutyric-acid-mediated inhibition of neurones in the nucleus tractus solitarius of the cat.

1. Extracellular recordings were made from 123 synaptically activated neurones in the nucleus tractus solitarius of the chloralose-anaesthetized cat. 2. Ninety-one neurones were activated by electrical stimulation of cardiac or pulmonary vagal branches and thirty-two by stimulation of the aortic nerve. 3. Ionophoretic application of GABA abolished or markedly reduced the evoked or spontaneous activity of each neurone tested. These inhibitory effects were antagonized by the simultaneous ionophoretic application of bicuculline. 4. Glycine inhibited the evoked activity of 60% of neurones tested. This inhibition could be antagonized by the simultaneous application of strychnine. 5. Application of bicuculline alone increased the evoked or spontaneous activity of a large proportion of the neurones; strychnine alone had no significant effect on the evoked or spontaneous activity of the neurones. 6. These results are consistent with the hypothesis that GABA acts as an inhibitory transmitter substance within the nucleus tractus solitarius.

Action Potentials↗