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M Powers

Publications and source records attributed to M Powers.

13 recordsLinked to original sources
PubMed1992

Reconstitution, identification, purification, and immunological characterization of the 110-kDa Na+/Ca2+ antiporter from beef heart mitochondria.

The mitochondrial Na+/Ca2+ antiporter plays a key role in the physiological regulation of intramitochondrial Ca2+, which in turn attunes mitochondrial enzymes to the changing demands of the cell for ATP. We have now purified the Na+/Ca2+ antiporter from beef heart mitochondria by assaying detergent-solubilized chromatography fractions for reconstitutive activity. Na+ and Ca2+ transport were assayed using the fluorescent probes, sodium-binding benzofuran isophthalate and Fura-2, respectively. This approach enabled us to identify Na+/Ca2+ exchange activity with a 110-kDa inner membrane protein that catalyzed Na(+)-dependent Ca2+ transport and Ca(2+)-dependent Na+ transport. A new finding was that the Na+/Ca2+ antiporter also catalyzed Na+/Li+ exchange in the absence of Ca2+. All modes of transport were electroneutral and were inhibited by diltiazem and tetraphenylphosphonium cation. Monospecific polyclonal antibodies to the 110-kDa protein inhibited Na+/Ca2+ and Na+/Li+ exchange in the reconstituted system and recognized 110-kDa proteins in mitochondrial membranes isolated from rat heart, liver, and kidney.

Animals↗
PubMed1992

Development of high-affinity 5-HT3 receptor antagonists. 1. Initial structure-activity relationship of novel benzamides.

This report describes the development of novel benzamides which are orally active, highly potent, specific antagonists of 5-HT3 receptors. Described in this first report are the structure-activity relationships that led to novel structures with improved potency and selectivity. From this series of compounds, (S)-28 was identified and selected for further evaluation as a 5-HT3 receptor antagonist. Compared with 5-HT3 antagonists such as GR 38032F, BRL 43694, and metoclopramide, (S)-28 was most active in (a) inhibiting binding to 5-HT3 receptor binding sites in rat entorhinal cortex with an Ki value of 0.19 nM and (b) blocking cisplatin-induced emesis in the ferret with an ED50 value determined to be 9 micrograms/kg po.

Animals↗
PubMed1992

Development of high-affinity 5-HT3 receptor antagonists. 2. Two novel tricyclic benzamides.

Two new classes of potent 5-HT3 agents have been developed and examined as inhibitors of cytotoxic drug induced emesis in the ferret and dog. The absolute configuration of the most active molecules 10 and 18 have been determined by X-ray crystallography. These two compounds are more potent than known 5-HT3 receptor antagonists both in vivo and in vitro in blocking 5-HT3 receptor activation and preventing chemotherapeutic induced emesis. Compared with 5-HT3 antagonists, such as GR 38032F, zacopride, BRL 43694, and ICS 205-930, compound 10 was more potent in (1) inhibiting binding to 5-HT3 receptor binding sites in rat cortex (Ki = 0.17 nM), (2) blocking the von Bezold-Jarisch effect in the rat (lowest effective dose, 1 microgram/kg iv), and (3) inhibiting 5-HT-induced contraction of guinea pig ileum (lowest effective concentration, 10(-9) M). This novel agent was as effective given po as when given iv in reducing cisplatin-induced emetic episodes in the ferret (ED50 = 4 micrograms/kg iv or po). A 1 mg/kg po dose of 10 virtually abolished cisplatin-induced emesis for 10 h in the ferret. However, it was inactive against apomorphine or copper sulfate-induced vomiting. These data, coupled with receptor binding studies of ligands for D2-dopamine, a1, a2, 5-HT1, 5-HT2, and muscarinic receptors demonstrate that 10 is a highly selective 5-HT3 receptor antagonist with remarkable potency in vivo.

Amides↗
PubMed1992

A chimaeric 11 beta-hydroxylase/aldosterone synthase gene causes glucocorticoid-remediable aldosteronism and human hypertension.

Glucocorticoid-remediable aldosteronism (GRA), an autosomal dominant disorder, is characterized by hypertension with variable hyperaldosteronism and by high levels of the abnormal adrenal steroids 18-oxocortisol and 18-hydroxycortisol, which are all under control of adrenocorticotropic hormone and suppressible by glucocorticoids. These abnormalities could result from ectopic expression of aldosterone synthase, which is normally expressed only in adrenal glomerulosa, in the adrenal fasciculata. Genes encoding aldosterone synthase and steroid 11 beta-hydroxylase (expressed in both adrenal fasciculata and glomerulosa), which are 95% identical and lie on chromosome 8q (refs 7, 10), are therefore candidate genes for GRA. Here we demonstrate complete linkage of GRA in a large kindred to a gene duplication arising from unequal crossing over, fusing the 5' regulatory region of 11 beta-hydroxylase to the coding sequences of aldosterone synthase (maximum lod score 5.23 for complete linkage, odds ratio of 170,000:1). This mutation can account for all the physiological abnormalities of GRA. Our result represents the demonstration of a mutation causing hypertension in otherwise phenotypically normal animals or humans.

Base Sequence↗
PubMed1992

Endobronchial interstitial Au-198 implantation in the treatment of recurrent bronchogenic carcinoma.

Nineteen patients with non-small-cell bronchogenic carcinoma, recurrent following initial conventional external beam radiotherapy, were treated with endobronchial implantation of Au-198 seeds. Seventeen patients were symptomatic with primary symptoms of persistent hemoptysis (9), bronchial obstruction (2), or worsening dyspnea (6). Two patients were asymptomatic and implanted for bronchoscopic evidence of tumor recurrence. The dose delivered was described by three dosimetric parameters: 1) the total activity implanted (m Ci); 2) the midbronchial dose point; and 3) the volume of tissue that received greater than 20 Gy. Response was determined based on a system reflecting the primary indication for the implant. Seven of nine (78%) presenting with hemoptysis, four of six (67%) with increasing dyspnea, and one of two with bronchial obstruction responded. The overall median survival was 5.25 months (2.5-10 months 95% confidence interval). There was no clear correlation between any of the dosimetric parameters evaluated and a clinical response to therapy. Technical complications related to the inability to penetrate the scirrhous tumor surface adequately often led to less than optimal dose distribution. Endobronchial Au-198 implantation is associated with a poor calculated dose distribution but is, nonetheless, a relatively simple and comparatively inexpensive technique that often produces a clinical response and can be a useful option in the management of patients with recurrent bronchogenic carcinoma.

Adult↗
PubMed1992

Hereditary hypertension caused by chimaeric gene duplications and ectopic expression of aldosterone synthase.

Patients with glucocorticoid-remediable aldosteronism (GRA) from 12 kindreds possess chimaeric gene duplications arising from unequal crossing-over, fusing regulatory sequences of steroid 11 beta-hydroxylase to coding sequences of aldosterone synthase. These chimaeric genes are specific for GRA and explain the biochemistry, physiology and genetics of this form of hypertension. Sites of crossing over range from intron 2 to intron 4. Most mutations have arisen independently from either sister or non-sister chromatid exchange between these genes, which are only 45 kilobases apart. The possibility of a susceptibility allele for GRA of Irish origin is suggested. These findings indicate the utility of a direct genetic test for this disorder.

Alleles↗
PubMed1992

Effects of insulin-like growth factors (IGFs) and IGF receptor antibodies on the proliferation of human breast cancer cells.

It has been shown previously that MCF-7 cells proliferate in response to nanomolar concentrations of IGF-I and IGF-II. It has also been reported that the actions of both peptides are mediated through the IGF-I receptor. To further characterize these observations, we used MCF-7 and Hs578T cell lines in the serum-free/phenol red-free system developed by Ogasawara and Sibarsku, 1988. Cell proliferation was studied in the presence of insulin, IGF-I and -II and a series of growth factor receptor antibodies. No effect was observed on Hs578T cell proliferation with any of the growth factors. However, MCF-7 cells were stimulated 4-5 fold with IGF-I and insulin, while IGF-II was only slightly less potent. alpha IR3, a monoclonal antibody directed against the IGF-I receptor, was stimulatory when added alone. However, alpha IR3 blocked approximately 50% of the IGF-I response, only 5% of the insulin response, and did not block the IGF-II effect on cell proliferation. These data suggest that alpha IR3 and IGF-I are acting as agonists through the IGF-I receptor, but that insulin and IGF-II are acting through other receptors. Two different IGF-II/M-6-P receptor antibodies and an insulin receptor antibody failed to significantly block IGF-II actions. All three antibodies were stimulatory when added alone. beta-gal inhibited 27% of the IGF-II response and had no effect when added alone. Since beta-gal decreases the binding affinity of the IGF-II/M-6-P receptor for IGF-II and does not bind to the IGF-I or insulin receptor, these data suggest the possibility that IGF-II mitogenic action is mediated through the IGF-II/M-6-P receptor. In summary, these data indicate that nanomolar concentration of insulin, IGF-I and IGF-II are potent mitogens in MCF-7 cells and can potentially stimulate cell proliferation through all three receptors.

Analysis of Variance↗
PubMed1978

Somatosensory-evoked potentials elecited by bilateral stimulation of the median nerve and its clinical application.

Somatosensory evoked potentials (SEPs) elicited by bilaterally simultaneous median nerve stimulation (BS) were studied in 28 normal subjects and in 20 patients with various cerebral lesions. In normals, SEP'S evoked by BS were symmetric between the homologous areas of the two hemispheres and resembled the response contralateral to unilateral stimulation (US). In patients with a cerebral lesion, BS responses were not only asymmetric but often differed in wave form from the response of the affected hemisphere to contralateral US. These alterations were attributed to the cumulative interactions of the anomalous contralateral and ipsilateral components. The additional use of BS made it possible to demonstrate SEP abnormalities that might have been regarded as normal or equivocal if only the US method had been used. The neurophysiologic mechanisms of the origin of SEP are discussed.

Adult↗
PubMed1977

Which patients respond to a mental health consumer survey.

Characteristics of patients at the Los Angeles County - University of Southern California Medical Center, Adult Psychiatric Outpatient Clinic who responded to a Los Angeles County voluntary "Client Satisfaction Survey" were compared with those who did not. Three significant differences consistently emerged. If an individual was a member of a minority group (black of Spanish surname), had less than a high school education, and was taking antispsychotic medication, his chance of returning a questionnaire to a waiting-room collection box was 79% as compared to the 30% chance of returning if he had none of these three characteristics. Younger patients had "Anglos" more often used the U.S. mail than the collection box to return the questionnaires. It is important that both methods be used to minimize bias. Most of the many patient-characteristics studied did not influence return rate. These findings are discussed in relation to the return method, ethnicity, medication, chronic mental illness, diminished freedom, and consumer voice in voluntary questionnaires.

Adult↗