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Biomedical subjects

L A Price

Publications and source records attributed to L A Price.

At least 19 recordsLinked to original sources
PubMed1998

A linear hexapeptide somatostatin antagonist blocks somatostatin activity in vitro and influences growth hormone release in rats.

Somatostatin (SRIF) is the main inhibitory peptide regulating growth hormone (GH) secretion. It has been difficult to establish the role of endogenous SRIF release in the absence of pure SRIF antagonists. Although several SRIF antagonists have recently been described, none have been shown to possess in vivo activity in the absence of added SRIF. Here, an SRIF antagonist with no detectable agonist activity has been identified from a synthetic combinatorial hexapeptide library containing 6.4 x 10(7) unique peptides. Each peptide in the library is amino-terminally acetylated and carboxyl-terminally amidated and consists entirely of D-amino acids. A SRIF-responsive yeast growth assay was used as a primary screening tool, and cAMP accumulation, competitive binding, and microphysiometry also were used to confirm and further characterize SRIF antagonist activity. The hexapeptide library was screened in stepwise iterative fashion to identify AC-178,335, a pure SRIF antagonist of the sequence Ac-hfirwf-NH2. This D-hexapeptide bound SRIF receptor type 2 with an affinity constant (Ki) of 172 +/- 12 nM, blocked SRIF inhibition of adenylate cyclase in vitro (IC50 = 5.1 +/- 1.4 microM), and induced GH release when given alone (50 micrograms intravenously) to anesthetized rats with or without pretreatment with a long-acting SRIF agonist.

Animals↗
PubMed1996

ORK1, a potassium-selective leak channel with two pore domains cloned from Drosophila melanogaster by expression in Saccharomyces cerevisiae.

A K+ channel gene has been cloned from Drosophila melanogaster by complementation in Saccharomyces cerevisiae cells defective for K+ uptake. Naturally expressed in the neuromuscular tissues of adult flies, this gene confers K+ transport capacity on yeast cells when heterologously expressed. In Xenopus laevis oocytes, expression yields an ungated K(+)-selective current whose attributes resemble the "leak" conductance thought to mediate the resting potential of vertebrate myelinated neurons but whose molecular nature has long remained elusive. The predicted protein has two pore (P) domains and four membrane-spanning helices and is a member of a newly recognized K+ channel family. Expression of the channel in flies and yeast cells makes feasible studies of structure and in vivo function using genetic approaches that are not possible in higher animals.

Amino Acid Sequence↗
PubMed1996

Chronic copper toxicosis presenting as liver failure in an Australian child.

A 20 month old Caucasian male child, after a five week illness, developed liver failure which was successfully treated by liver transplantation. The explanted liver had a histology identical to that seen in Indian childhood cirrhosis and its copper content was increased tenfold. Water used to prepare the child's milk feeds came from a bore via copper conduits and at times contained 120 mumol/l of copper, eight times the recommended maximum for human consumption. Because non-Indian cases of Indian childhood cirrhosis associated with excess copper ingestion are increasingly being recognised, and as early treatment can restore normal liver morphology, we support the use of the previously suggested alternative term for this condition, ie; 'copper-associated liver disease in childhood'. Measurement of hepatic copper concentrations in all children less than six years of age who develop hepatic failure of unknown cause will increase its recognition. On diagnosis sources of increased dietary copper should be investigated to ensure that younger siblings are not similarly exposed.

Australia↗
PubMed1996

Identification and characterization of novel somatostatin antagonists.

The study of the five somatostatin receptor subtypes (SSTx, where x is the subtype number) has been hampered by the lack of high affinity antagonists. Potent and selective antagonists would increase our understanding of SST structure, function, and regulation. In this study, the identification of novel disulfide-linked cyclic octapeptide antagonists of somatostatin is described. The antagonists contain a core structure of a DL-cysteine pair at positions 2 and 7 of the peptides. Substitution of a D-cysteine at position 2 with an L-cysteine converts the full antagonist into a full agonist. All somatostatin receptor subtypes are coupled to inhibition of adenylate cyclase. The functional properties of these peptides have been determined in radioligand binding assays, in functional coupling of the SST2 subtype to yeast pheromone response pathway, and in cAMP accumulations. One peptide antagonist [Ac-4-NO2-Phe-c(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)-D-Tyr-NH2] displays a binding affinity to SST2 comparable with that observed for the native hormone (Ki = 0.2 nM) and reverses somatostatin-mediated inhibition of cAMP accumulation in rat somatomammotroph GH4C1 cells, cells transfected with the SST2 and SST5 subtypes, as well as somatostatin-stimulated growth of yeast cells expressing the SST2 subtype. This class of somatostatin antagonists, which are the first to be described, should be useful for determination of somatostatin's diverse functions in vivo and in vitro.

Amino Acid Sequence↗
PubMed1996

Pharmacological characterization of the rat A2a adenosine receptor functionally coupled to the yeast pheromone response pathway.

The rat A2a adenosine receptor, a G protein-coupled receptor, was functionally expressed in the yeast Saccharomyces cerevisiae. High affinity binding sites for A2a adenosine agonists were detected in yeast membranes containing the endogenous Grx protein Gpa1. Agonist saturation binding isotherms using [3H]5'-N-ethylcarboxamidoadenosine indicated that the A2a adenosine receptor expressed in yeast cell membranes displays pharmacological properties equivalent to those observed when the receptor is expressed in human embryonic kidney 293 cell membranes. The rank order of potency of various agonists in [3H]5'-N-ethylcarboxamidoadenosine competition binding assays performed with yeast cell membranes was comparable to that seen for the receptor expressed in mammalian cell membranes. Adenosine agonist-dependent growth response of yeast strains expressing the A2a adenosine receptor was elicited via activation of the yeast pheromone-response pathway. Induction of a pheromone-responsive FUS1-HIS3 reporter gene in far1 his3 cells permits cell growth in medium lacking histidine. The sensitivity of the bioassay was increased by deletion of the STE2 gene, which encodes the yeast alpha-mating pheromone receptor. The growth response was dose dependent, and agonists of varying affinities displayed a rank order of potency comparable to that observed in competition binding assays. Agonist-activated growth assays performed in liquid culture gave ED50 values for various adenosine agonists consistent with reported Kd alpha values. Yeast strains expressing a single receptor/G protein complex will be useful as a model system for the study of receptor/G protein interactions in vivo.

Adenosine↗
PubMed1995

Paraquat and diquat interference in the analysis of creatinine by the Jaffé reaction.

Paraquat and diquat were shown to interfere significantly in the measurement of plasma creatinine by the alkaline picrate (Jaffé) reaction in a young man who ingested a massive dose of a mixture of the 2 herbicides. It is likely that these bipyridylium compounds react in a manner similar but at different rates compared with creatinine in the Jaffé reaction.

Adult↗
PubMed1995

Functional coupling of a mammalian somatostatin receptor to the yeast pheromone response pathway.

A detailed analysis of structural and functional aspects of G-protein-coupled receptors, as well as discovery of novel pharmacophores that exert their effects on members of this class of receptors, will be facilitated by development of a yeast-based bioassay. To that end, yeast strains that functionally express the rat somatostatin receptor subtype 2 (SSTR2) were constructed. High-affinity binding sites for somatostatin ([125I-Tyr-11]S-14) comparable to those in native tissues were detected in yeast membrane extracts at levels equivalent to the alpha-mating pheromone receptor (Ste2p). Somatostatin-dependent growth of strains modified by deletion of genes encoding components of the pheromone response pathway was detected through induction of a pheromone-responsive HIS3 reporter gene, enabling cells to grow on medium lacking histidine. Dose-dependent growth responses to S-14 and related SSTR2 subtype-selective agonists that were proportional to the affinity of the ligands for SSTR2 were observed. The growth response required SSTR2, G alpha proteins, and an intact signal transduction pathway. The sensitivity of the bioassay was affected by intracellular levels of the G alpha protein. A mutation in the SST2 gene, which confers supersensitivity to pheromone, was found to significantly enhance the growth response to S-14. In sst2 delta cells, SSTR2 functionally interacted with both a chimeric yeast/mammalian G alpha protein and the yeast G alpha protein, Gpa1p; to promote growth. These yeast strains should serve as a useful in vivo reconstitution system for examination of molecular interactions of the G-protein-coupled receptors and G proteins.

Animals↗
PubMed1994

Causes of higher in-hospital mortality in women than in men after acute myocardial infarction.

Clinical, laboratory and cardiac catheterization parameters were reviewed in 355 men and 155 women hospitalized at a tertiary care referral center between February 1987 and December 1991 to analyze why women have a higher in-hospital mortality rate than do men after acute myocardial infarction. Hospital mortality was 21.4% in women and 12.1% in men (p = 0.007). In comparison with men, women were older (63.3 +/- 11.9 vs 60.5 +/- 12.6 years; p = 0.023), had more systemic hypertension (46.5 vs 34.4%; p = 0.001) and higher serum total cholesterol levels (211 +/- 51 vs 197 +/- 49 mg/dl; p = 0.0015), sought medical care later (8.9 vs 5.3 hours; p = 0.026), were referred later (47.7 vs 43.7 hours; p = 0.063) and had more shock (34.8 vs 24.2%; p = 0.013). Logistic regression analysis revealed 5 variables predictive of hospital mortality; age > 65 years, diabetes, shock, non-Q-wave infarction, and not undergoing cardiac catheterization. Gender was of borderline significance in predicting hospital mortality. Cardiac catheterization, performed in 88% of women and 87% of men, showed similar rates of 1-, 2- and 3-vessel disease, and similar characteristics of the infarction-related artery. The differences in hospital mortality between men and women are due to a combination of pre- and in-hospitalization factors in women. The excess mortality is not due to differences in disease severity as evaluated by cardiac catheterization information.

Age Factors↗
PubMed1994

Lack of survival advantage in patients with advanced squamous cell carcinomas of the oral cavity receiving neoadjuvant chemotherapy prior to local therapy, despite achieving an initial high clinical complete remission rate.

Subset analyses have been performed on 50 patients with squamous cell carcinomas of the oral cavity from our earlier series of 208 patients with advanced, previously untreated head and neck tumors (J Clin Oncol 1986;4:1340-7). Forty patients (80%) responded to two initial courses of Schedule A chemotherapy. Side effects were minimal. After definitive local therapy the final complete remission (CR) rate was 76%. Neither chemotherapy response, nor achievement of final CR was significantly affected by stage, T or N status, sex, or histologic grade. With a median follow-up of 11.6 years, the overall 10-year survival rate was 25%. Multivariate analysis indicated that both age, i.e., < 50 years (p = .004) and achievement of a final CR (p = .002) were significant factors for improved survival. Median survival for all patients was only 21 months and for those in final CR 30 months. These survival figures were all significantly lower than those of similarly treated patients with laryngeal or nasopharyngeal tumors, illustrating that all patients with head and neck tumors achieving a final clinical CR do not automatically have improved survival. These results emphasize the need for randomized trials, with sufficient numbers to identify optimal treatment strategies for tumors at specific sites within the head and neck region.

Adult↗
PubMed1994

When academic assistance is not enough: addressing the mental health issues of adolescents and adults with learning disabilities.

This article focuses on an answer to a critical question for adolescents and adults with learning disabilities: How can professionals assist students with learning disabilities who have psychosocial issues that appear to be affecting their academic progress and life adjustment? Inherent in this inquiry are other, equally important issues, such as: How do learning disabilities service providers know when to involve other service providers? What are the steps in referring a student for further assistance with different mental health issues? When are team interventions necessary? How are team interventions conducted in either secondary or postsecondary settings? How should learning disabilities service providers establish the boundaries of their professional expertise and/or responsibilities to adequately meet the needs of individuals with learning disabilities? This article illustrates answers to these questions by providing examples of interventions and case studies from two federally funded research/demonstration projects at the University of Minnesota: the Learning Disabilities Transition Project and Project Extra. The authors describe theoretical models for mental health services that address the psychosocial issues frequently encountered in academic or vocational settings. Recommendations are also included that discuss how the models can be personalized to fit the reader's home institution or agency.

Adolescent↗
PubMed1990

The role of adjuvant chemotherapy in the treatment of advanced head and neck cancer.

The role of chemotherapy in the multidisciplinary treatment of advanced squamous cell carcinoma of the head and neck remains to be defined. Uncontrolled adjuvant studies integrating chemotherapy with local therapies utilizing a 'sequential' or 'simultaneous' strategy have indicated that high response rates to initial chemotherapy and high complete remission rates are achievable. Both these factors appear to predict for improved survival. Unfortunately results of randomized, controlled studies generally have not confirmed any major overall survival advantage. However, these trials clearly failed to utilize optimal therapies: suboptimal trials yield suboptimal results. Encouraging data from large uncontrolled studies have now provided critical information regarding optimal trial design; a) Since primary tumor site has proved a significant predictive factor for response to treatment and survival, future trials must include sufficient numbers of patients for detailed site-by-site analyses, and b) radical surgery may be omitted without compromising survival by using initial chemotherapy followed by radiotherapy for advanced laryngeal cancer.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1989

Biomimetic oxidation of nonphenolic lignin models by Mn(III): new observations on the oxidizability of guaiacyl and syringyl substructures.

Mn(III) is a one-electron oxidant, produced in vivo by the Mn peroxidases of white-rot fungi, and thought to be involved in lignin degradation by these organisms. However, Mn(III) has not been shown to oxidize the major nonphenolic substructures of lignin under mild conditions. We have used Mn(III) acetate as a biomimetic model for enzymatically generated Mn(III), and report that low concentrations of this oxidant suffice to oxidize nonphenolic lignin models at physiological temperatures and pH values. Under these conditions, the monomeric lignin model veratryl alcohol was oxidized to veratraldehyde, and the diarylpropane model 1-(3,4-dimethoxyphenyl)-2-phenylpropanol was oxidatively cleaved to veratraldehyde, 1-phenylethanol, and acetophenone. In an attempt to identify other lignin models that might be oxidized by Mn(III) more rapidly, we compared the rates at which Mn(III) was reduced by two guaiacyl models, veratryl alcohol and 1-(3-methoxy-4-isopropoxyphenyl)ethanol, vs two syringyl models, 3,4,5-trimethoxybenzyl alcohol and 1-(3,5-dimethoxy-4-isopropoxyphenyl)ethanol. The results were the opposite of those predicted: the syringyl models were oxidized slower than the guaiacyl models by Mn(III). To investigate the basis for this unexpected result, we recorded the visible absorption spectra of charge-transfer complexes prepared between each of the lignin models and an electron acceptor, tetracyanoethylene or p-chloranil. The results, in general agreement with the kinetic findings, showed that the nonphenolic syringyl lignin models had higher ionization potentials than the guaiacyl models.

Biodegradation, Environmental↗
PubMed1988

ICRF appeals.

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