PubMed Health⌕ Search

Biomedical subjects

D Kowal

Publications and source records attributed to D Kowal.

9 recordsLinked to original sources
PubMed1999

Design and models for estimating antagonist potency (pA2, Kd and IC50) following the detection of antagonism observed in the presence of intrinsic activity.

The antagonist activity of the metabotropic glutamate receptor ligand (2S,1'S,2'S)-2-methyl-2(carboxycyclopropyl)glycine (MCCG) was examined using the [35S]GTPgammaS binding and forskolin (FSK)-stimulated adenosine 3':5'-cyclic monophosphate (cAMP) assays with recombinant Chinese hamster ovary (CHO) cells expressing the G protein-coupled human subtype 2 metabotropic glutamate (hmGlu2) receptor. Whereas MCCG proved to be a partial agonist in the GTPgammaS binding assay, it not only antagonized the agonist effect of (IS,3R)-ACPD in the cAMP assay but further produced an anomalous increase of the cAMP level relative to baseline. The anomalous MCCG response was also observed following treatment of the cells with MCCG in the absence of added agonist. Determination of the glutamate concentration in the incubate at the start and end of the cAMP reaction revealed the existence of micromolar concentrations of cellularly released glutamate throughout the course of the assay, reaching levels which exceeded its reported affinity for the mGlu2 receptor. Considering MCCG's partial agonist effect in the GTPgammaS binding assay and its pseudo-inverse agonist effect in the cAMP assay, available methods of estimating its antagonist potency were inappropriate since the classical Schild method and the alternative model suggested by Waud both assume the antagonist to lack a concentration-response relationship. We derived an alternate design and models that permit estimation of the pA2 (pAx), Kd and IC50 for antagonists which produce a concentration related effect when applied by themselves. With their use, the data acquired in both assays support the designation of MCCG as a competitive antagonist of the hmGlu2 receptor and provide similar pA2 estimates between assays. In addition, the newly derived models and design permit the determination of antagonist potency for partial and inverse agonists so characterized in studies employing the Schild design.

Amino Acids, Dicarboxylic↗
PubMed1998

A [35S]GTPgammaS binding assessment of metabotropic glutamate receptor standards in Chinese hamster ovary cell lines expressing the human metabotropic receptor subtypes 2 and 4.

The activities of metabotropic glutamate receptor (mGluR) standards were evaluated in the [35S]GTPgammaS binding assay and in the forskolin (FSK)-enhanced cyclic AMP assay using Chinese hamster ovary (CHO) cells or homogenates which expressed the human mGluR (hmGluR) subtypes 2 and 4. Though distinct rank orders of activities were determined for the agonists between the cell lines expressing individual hmGluRs, similar rank orders of agonist activities were determined for the standards between assays. O-phospho-L-serine (L-SOP) and (S)-2-amino-2-methyl-4-phosphonobutanoic acid (MAP4) antagonized agonist EC90 responses in the cell lines expressing the hmGluR 2 and 4 subtypes, respectively. In addition to its antagonist effect, L-SOP increased the baseline level of cAMP when tested in the absence of agonist. In spite of this anomalous effect, L-SOP was found to be a competitive antagonist in the cAMP assay as well as in the [35S]GTPgammaS binding assay with a pA2 value of 5.2 in both assays. MAP4 was a competitive antagonist of L(+)-2-amino-4-phosphonobutyric acid (L-AP4)-induced responses in the CHO cell line expressing hmGluR4 with pA2 values of 4.4 and 4.5 determined in the [35S]GTPgammaS binding and cAMP assays, respectively.

Animals↗
PubMed1998

The major trauma management study: an analysis of the efficacy of current trauma care.

BACKGROUND: An audit of the management and outcome of major trauma patients was carried out to determine ways in which the system of care may be improved. METHODS: The Major Trauma Management Study (MTMS) collected data prospectively on all consecutively admitted major trauma patients at eight major hospitals during a 12-month period. Outcome was studied using trauma and injury severity score (TRISS) and a severity characterization of trauma (ASCOT) analyses, as well as a preventable outcome analysis, which looked at survivors with complications or with a Glasgow Coma Score < 15 on discharge from hospital, as well as studying deaths. RESULTS: The group of 859 patients was more severely injured than most described previously, with a mortality of 14.8% and a mean injury severity score of 19.8. Formal ASCOT analysis indicated 2.25% fewer survivors than would be predicted by Major Trauma Outcome Study norms. Extrapolating the TRISS and ASCOT process to include those patients with missing data, and then comparing groups of matched severity with the norms, gave no statistically different outcome in the MTMS group of patients. Preventable outcome analysis revealed rates of preventable and potentially preventable (P/PP) outcomes of 32% among deaths and 8% among survivors. The types of management deficiencies responsible for P/PP outcomes are identified. CONCLUSIONS: The points of deficiency in a system of care have been identified, and the development of an integrated trauma system in Victoria, based upon these facts, is recommended. Children, the elderly, patients with head injuries and patients being transferred between hospitals would benefit from improvements to the system of care. The calculation of efficacy rate (0.95 for the MTMS patients) is recommended to accurately assess the system of care. Preventable Outcome Analysis is more relevant to auditing a system of trauma care in detail, than is ASCOT or TRISS. The MTMS has refined and defined the process so that it is reproducible in further comparative studies.

Critical Pathways↗
PubMed1991

Acute glaucomas: diagnosis and treatment.

Acute angle-closure glaucoma is an uncommon disorder that must be diagnosed and managed quickly and effectively to prevent visual loss. Several conditions may appear as an acute angle-closure glaucoma and must be recognized since, in certain cases, treatment may be different from that required for an acute angle-closure attack. Once an acute angle-closure attack has been successfully managed through medical treatment, a laser iridotomy is indicated to prevent an attack from recurring.

Acute Disease↗
PubMed1990

The effect of conjugated equine estrogens on ovariectomy-induced osteopenia in the rat.

The effect of estrogen replacement on ovariectomy-induced bone loss was evaluated in mature Sprague-Dawley rats. Undecalcified tibia of ovariectomized rats were processed for quantitative histologic assessment of cancellous bone in longitudinal sections from the primary and secondary spongiosa of the proximal metaphysis. Bone content in tissue specimens was quantified as the parameter B. Ar, two-dimensional bone mineral area. Estrogen, supplied as orally administered conjugated equine estrogens, prevented bone loss through 6 weeks of treatment. The effect of conjugated equine estrogens was dose-dependent, with significant protection against bone loss observed at doses of 10 micrograms/kg/day and higher.

Animals↗