Search PubMed⌕ Search

Biomedical subjects

R D Brown

Publications and source records attributed to R D Brown.

At least 199 records · Page 11Linked to original sources
PubMed1991

Antler cycle and endocrine parameters in male axis deer (Axis axis): seasonal levels of LH, FSH, testosterone, and prolactin and results of GnRH and ACTH challenge tests.

1. Antler cycles of six adult male axis deer of southern Texas were relatively well synchronized within the herd. The old antlers were cast from December to March and regenerated antlers polished between March and June. The rutting season occurred in June and July. 2. LH and FSH exhibited little seasonal variation (LH 0.7-1.3 ng/ml; FSH 32-65 ng/ml). Prolactin levels were lowest in December (20 ng/ml) and highest in June (115 ng/ml). Testosterone concentrations exhibited a distinct seasonal pattern: minimum in December (0.1 ng/ml) and maximum in May (1.75 ng/ml). 3. After GnRH challenge (100 micrograms given i.m. in November), maximal LH levels (reached 40-60 min after injection), varied from 7.7 to 11.2 ng/ml, and T levels varied from 1.3 to 1.6 ng/ml. 4. Twenty I.U. of ACTH (given in March), elevated cortisol levels from 4-8 micrograms/dl (pretreatment) to 16-21 micrograms/dl (140 min post-administration).

Adrenocorticotropic Hormone↗
PubMed1991

Single-dose, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children.

Ibuprofen was evaluated as an antipyretic agent in 178 children (aged 3 months to 12 years) to compare dosage (5 vs 10 mg/kg), establish absolute efficacy (with a placebo control group), determine relative efficacy (ibuprofen vs acetaminophen), evaluate maximum efficacy, and identify potential confounding variables. Ibuprofen 5 mg/kg was minimally effective in children less than 6 years of age who had an initial temperature of at least 38.8 degrees C (101.9 degrees F). Ibuprofen 10 mg/kg was more effective for febrile children. The area under the curve for temperature (or change in temperature) captured the net effect of each drug and provided the best estimate for efficacy comparison during a defined period. A linear correlation between initial temperature and measures of efficacy was observed. A twofold increase in efficacy was observed for children with an initial temperature less than 38.8 degrees C. A similar effect was noted for each treatment group. Age was also found to have confounding effects on antipyretic response. A complex interaction between antipyretic response, initial temperature, and age raises questions about the pharmacodynamics of the antipyretic response. We conclude that the most important variable in antipyretic study design is initial temperature. The influence of initial temperature on the magnitude of the response to an antipyretic drug is a previously unappreciated finding with potential impact on pharmacodynamic investigations of antipyretic medications. We describe this finding as nonlinear pharmacodynamics.

Acetaminophen↗
PubMed1991

Contact hypersensitivity response to o-benzyl-p-chlorophenol in mice.

o-Benzyl-p-chlorophenol was evaluated for its potential as a sensitizing agent for allergic contact hypersensitivity in mice. Female B6C3F1 mice were sensitized with 1.0, 3.0, and 10.0% o-benzyl-p-chlorophenol and challenged with 20.0% o-benzyl-p-chlorophenol. Doses of o-benzyl-p-chlorophenol were selected from assays for primary irritancy. Mice received 20 microliters by direct dermal application, for 5 days, to sites prepared by shaving, dermabrading and, in some mice, with intra dermal injection of Freund's complete adjuvant. The rest period was 7 days. Measurement of the contact hypersensitivity response in mice was by radioisotopic assay two days after challenge and mouse ear swelling test one and two days after challenge. Mice demonstrated statistically significant dose-dependent contact hypersensitivity response to o-benzyl-p-chlorophenol with or without adjuvant pretreatment.

Animals↗
PubMed1990

Interactions of nitroxides with plasma and blood: effect on 1/T1 of water protons.

Nitroxide stable free radicals (nitroxides) have potential utility as MRI contrast-enhancing agents with the additional capability of reflecting redox metabolism. In order to gain a better understanding of their potential interactions in vivo, we have studied the longitudinal NMRD profiles (1/T1 as a function of field strength) and ESR spectra for lipophilic and aqueous-soluble nitroxides in blood, plasma, and plasma components. Typical water-soluble nitroxides do not interact appreciably with blood, plasma, or plasma proteins. Fatty acid nitroxides do interact physically with blood, predominantly by intercalation within red blood cell membranes and binding to albumin. The latter interaction results in significantly enhanced relaxivity for the nitroxide/HSA complex. Relaxation of water protons in this case is dominated by inner sphere processes, ostensibly due to water molecules hydrogen bonded to nitroxide moieties. The rotational reorientation time for the complex, the electronic relaxation time, and the exchange time for the water molecule reversably bound to the nitroxide, all appear significantly to influence the correlation time (approximately 16 ns) for this inner sphere contribution.

Blood Proteins↗
PubMed1990

Relaxometry of brain: why white matter appears bright in MRI.

The remarkable success of magnetic resonance imaging of adult brain relates to the unusually large ratio of the longitudinal relaxation rates 1/T1 of white and gray matter, approximately 2:1 at physiological temperature and traditional imaging fields. Several investigators have conjectured that myelin is the source of the greater 1/T1 of white matter without, however, suggesting details of the molecular mechanisms responsible. From measurements of the magnetic field dependence of 1/T1 (NMRD profiles) of adult and neonatal gray and white matter at 5 and 35 degrees C, we find a thermally activated contribution to the NMRD profile of adult white matter that is not present in the profiles of either adult gray or neonatal gray and white matter. We attribute this contribution to myelin and develop a quantitative model that accounts for the unique relaxation behavior of myelinated white matter. We find that myelin water, 15% of the total, has a relatively short T1 that arises from an unexpectedly large interaction with myelin lipid; when cast in terms of an interaction over the entire myelin bilipid-water interface, it is sevenfold greater than the analogous protein-water interfacial interaction. Its magnitude remains to be accounted for, but cholesterol, known to alter the relaxation rates of lipid protons, may play an important role. The contribution of myelin to 1/T1 at physiological temperatures is attributed to thermally activated transmembrane diffusion of water and, hence, more rapid mixing of axonal and the rapidly relaxing myelin water molecules.

Adult↗
PubMed1990

Oligomerization and conformation change in solutions of calf lens gamma II-crystallin. Results from 1/T1 nuclear magnetic relaxation dispersion profiles.

From analyses of the magnetic field dependence of 1/T1 (nuclear magnetic relaxation dispersion [NMRD] profiles) of water protons in solutions of highly purified calf lens gamma II-crystallin, we find that monomers form oligomers at relatively low concentrations, which increase in size with increasing concentration and decreasing temperature. At approximately 16% by volume and -4 degrees C, the mean oligomeric molecular weight is approximately 120-fold greater than the monomeric value of 20 kD. Below this concentration, there is no indication of any substantive change in conformation of the monomeric subunits. At higher concentrations, the tertiary structure of the monomer appears to reconfigure rather abruptly, but reversibly, as evidenced by the appearance of spectra-like 14N peaks in the NMRD profiles. The magnitudes of these peaks, known to arise from cross-relaxation of water protons through access to amide (NH) moieties of the protein backbone, indicate that the high concentration conformation is not compact, but open and extended in a manner that allows enhanced interaction with solvent. The data are analogous to those found for homogenates of calf and chicken lens (Beaulieu, C. F., J. I. Clark, R. D. Brown III, M. Spiller, and S. H. Koenig. 1988. Magn. Reson. Med. 8:47-57; Beaulieu, C. F., R. D. Brown III, J. I. Clark, M. Spiller, and S. H. Koenig. 1989. Magn. Reson. Med. 10:62-72). This unusually large dependence of oligomeric size and conformation on concentration in the physiological range is suggested as the mechanism by which osmotic equilibrium is maintained, at minimal metabolic expense, in the presence of large gradients of protein concentration in the lens in vivo (cf Vérétout and Tardieu, 1989. Eur. Biophys. J. 17:61-68). Finally, the results of the NMRD data provide a ready explanation of the low temperature phase transition, and "cold-cataract" separation of phases, observed in gamma II-crystallin solutions; we suggest that the phases that separate are the two major conformers detected by NMRD.

Animals↗
PubMed1990

Magnetic field dependence of 1/T1 of human brain tumors. Correlations with histology.

The authors have measured the magnetic field dependence of 1/T1 (nuclear magnetic relaxation dispersion, or NMRD profiles) of water protons of histologically characterized samples of astrocytomas, meningiomas, and lymphomas. The goal was to elucidate the determinants of 1/T1 of brain tumors at the cellular level and, in particular, to search for a possible correlation of the profiles with neoplastic properties, including degree of malignancy. Because of the recently demonstrated contribution of myelin to 1/T1 of white matter, careful histologic analyses were performed to correct for its presence. The range of magnitude of the profiles of differing types and grades of tumors correlates with the range of water content of these tumors; the correlation of water content with cellularity (density of cell nuclei in a histologic preparation), in turn, produces correlations of 1/T1 with tumor type. For all the tumors studied, 1/T1 is proportional to solids content; the constant of proportionality is relatively insensitive to tumor type and, for astrocytomas, grade of malignancy; and is about the same as that of normal gray matter. For low- and intermediate-grade astrocytomas that contain myelin, the myelin-specific contribution to 1/T1 has to be considered to make manifest the underlying correlations, which are best demonstrated at low fields, where the background contribution of water and dissolved oxygen is minimal. At high fields, where most imaging is done, a change in oxygen partial pressure, as for example from ischemia in very malignant tumors, is sufficient to alter 1/T1 significantly, reducing the intrinsic correlation between histology and 1/T1.

Astrocytoma↗
PubMed1990

Red cell folate assays: some answers to current problems with radioassay variability.

Red cell folate specimens were added to the Quality Assurance Program (QAP) of the Royal College of Pathologists of Australasia in 1986. The interlaboratory variation in the results of these red cell folate surveys has been persistently unsatisfactory. This study reports an investigation into the factors contributing to the wide variation of results reported in QAP surveys. Survey results were studied, replies to a questionnaire regarding methods sent to all participants were assessed and some new experimental studies were performed. Factors contributing to the poor QAP results include variation in dilution and diluent, calculation errors, failure to freeze the hemolysate prior to assay and to follow the kit manufactorer's instructions, stability of dithiothreitol, and variations in kit methods, especially in the release of bound folate by "boil" and "no-boil" methods. Photodecomposition and the form and concentration of ascorbate may also be significant. Adequate preparation of the hemolysate sample should ensure release of all protein-bound red cell folate with the reduction of all folates to a single form. Kit manufactures, users and the QAP committee can all contribute in all attempt to rectify current sources of error.

Ascorbic Acid↗
PubMed1990

Unruptured intracranial aneurysms and arteriovenous malformations: frequency of intracranial hemorrhage and relationship of lesions.

Among 91 patients with unruptured intracranial arteriovenous malformations (AVM's), 16 patients had 26 unruptured intracranial saccular aneurysms. An actuarial analysis showed the risk of intracranial hemorrhage among patients with coexisting aneurysm and AVM to be 7% per year at 5 years following diagnosis compared to 1.7% for patients with AVM alone. The difference in length of survival free of hemorrhage was significant (log-rank, p less than 0.0007). Several angiographic and clinical parameters were investigated to better understand the relationship of these lesions. The aneurysms occurred in similar percentages in patients with small, medium, and large AVM's. Twenty-five aneurysms were on arteries feeding the malformation system, almost equally distributed proximally and distally. Eleven aneurysms were atypical in location, and all arose from primary or secondary branch feeders to the malformation; 24 were on enlarged feeding arteries. Eleven (16%) of the 67 patients with high-flow AVM's had associated aneurysms, compared with five (21%) of the 24 patients with low-flow AVM's. Four (16%) of 25 low-shunt malformations and 12 (18%) of 65 high-shunt malformations had associated aneurysms. All five aneurysms associated with low-shunt malformations were on a direct arterial feeder of the malformation. These data suggest that the intracranial AVM's predispose to aneurysm formation within AVM feeding systems and that the mechanism is not simply based upon the high blood flow or high arteriovenous shunt in these systems.

Adolescent↗
PubMed1990

Immunophenotypic analyses of cultured hemopoietic mast cells.

Immunophenotypic analyses of immature stage (day 19-23), intermediate stage (day 28-32), mature stage (day 34-37), and older stage (day 42-44) human hemopoietic mast cells from colonies grown in semi-solid agar cultures were performed to study the ontogeny and identity of this cell type and its relationship to other leukocytes. Intermediate to mature stage mast cells were positive with the YB5.B8 mouse monoclonal antibody, (McAb) specific for human mast cells, whereas the reactivity of immature mast cells with this McAb was inconsistent and older cells were generally negative. Mast cells at all stages of maturation were strongly positive for IgE receptor sites and negative with the Bsp-1 McAb, specific for human basophils. Mast cells at all stages of maturation were also strongly positive with the monocyte McAbs RPA-M1 (CD11), positive with the monocyte McAb OKM5 and the monocyte/granulocyte McAbs BMA-210 and MY7 (CD13), strongly positive with the B-cell markers J5 (CD10) and anti-IgM, and positive with the plasma cell marker PCA-1 and to a lesser extent with the activated B-cell marker CD23. The mast cells were also strongly positive with anti-CD45 to the common leukocyte antigen and positive with an antibody to HLA-DR and an antibody to FVIIIC. They were negative for specific T-cell markers. The diversity of this phenotype supports the current concept that mast cells originate from the pluripotential progenitor cells in the bone marrow.

Antibodies, Monoclonal↗
PubMed1989

Temporal integration of alpha 1-adrenergic responses in BC3H-1 muscle cells. Regulation of glycogen phosphorylase activity.

Regulation of Ca2+-dependent glycogen phosphorylase activity by alpha 1-adrenergic and H1-histamine receptors has been examined in BC3H-1 muscle cells. Stimulation by either norepinephrine or histamine elevates the phosphorylase activity ratio within 5 s from a resting value of 0.37 +/- 0.03 to maximal values of 0.8-0.9. Phosphorylase activation by alpha-adrenergic agonists is sustained over 20-30 min of agonist exposure, whereas histamine exposure only transiently activates phosphorylase during the initial 5 min of stimulation. The initial activation of phosphorylase by either receptor is not attenuated by treated cells with Ca2+-deficient and [ethylenebis(oxyethylenenitrilo)]tetraacetic acid-supplemented buffer, whereas the response to sustained adrenergic stimulation depends largely, but not totally, upon extracellular Ca2+. The involvement of protein kinase C in agonist responses was tested by treating cells with phorbol 12-myristate 13-acetate. Phorbol 12-myristate 13-acetate inhibits receptor-mediated mobilization of intracellular Ca2+ (IC50 = 3.6 nM) yet activates phosphorylase independently of agonist. Phorbol 12-myristate 13-acetate has no effect on cellular 45Ca2+ fluxes in the absence of agonist. Thus, the two receptors coordinately regulate intracellular signaling through Ca2+- and protein kinase C-mediated pathways. alpha 1-Adrenergic receptors elicit sustained phosphorylase activation whereas H1-histaminergic receptors desensitize.

Calcimycin↗
PubMed1989

Flurbiprofen in post-partum women: plasma and breast milk disposition.

The plasma and milk disposition of flurbiprofen (FB) was assessed in healthy women during the early post-partum period after multiple doses of FB. The results confirmed that a pragmatic study design is an attainable requirement for definitive statements about the excretion of FB in transitional milk. Nine doses of FB (50 mg per dose) were administered during three days. Paired milk and plasma samples were obtained during this period of dosing as well as after the last dose. The plasma data were used to derive an equation, which was then used to simulate cumulative plasma profiles for multiple doses given at unequal time intervals. The observed data corresponded to the simulated cumulative profiles of FB in plasma. The plasma elimination half-life of FB during early lactation was slightly prolonged (mean 4.8 hrs) as compared to reported values for normal adult men. The peak plasma concentrations of FB were comparable to those reported for healthy volunteers. In 10 of 12 women (3-5 days post-partum) the FB concentration in breast milk was less than 0.050 micrograms/ml. In two women the milk concentrations of FB were 0.06, 0.07 and 0.07 micrograms/ml as found in only three samples. We conclude that, on the basis of dose found in milk, FB is safe for women breast feeding their infants in the early post-partum period.

Adult↗
PubMed1989

Profile of clinical pharmacologists in the United States.

The need for clinical pharmacology in research and education, drug development, and health care delivery is well known. However, a current profile of those working in the field is not available. The ACCP authorized a survey of clinical pharmacologists to provide such a profile. Members of the ACCP or ASCPT were solicited by mail with a self-assessment questionnaire. A response rate of 37% was obtained. Demographic findings agree well with a previous study2 limited to those with the M.D. Our results reveal that most clinical pharmacologists are between 30-59 years of age, have an MD, PhD or PharmD degree; most of those with MDs list their primary specialty as internal medicine, pediatrics, psychiatry, or anesthesiology. They affiliate with the respective departments (including pharmacology) in academia or hold positions in industry or government, but few are in clinical therapeutics per se. About 20% of those with only a MD or PharmD degree cite employment in health care delivery. However, a higher percentage of these respondents work in research and education rather than in drug development or health care delivery. For those with only a PhD, more work in drug development and research and education than in health care delivery. The highest proportion of respondents with any doctoral degree work in the Northeast. The average income is a function of rank, doctoral degree, specialty, department appointment, and type and location of employer. The profile of a typical clinical pharmacologist is presented. An analysis of clinical pharmacology manpower from several perspectives reveals a marked deficit, but the field itself is professionally and economically attractive. Lack of a well defined career track in academia and a poorly defined clinical role for MD clinical pharmacologists are proposed as reasons limiting entry of trainees. These and other results of the survey support an increased emphasis on training programs. Clinical pharmacologist involvement in health care delivery and drug development must be increased if the safe and effective use of new drugs is to be realized. Nine assessments and initiatives are formulated to accomplish this goal within the next decade.

Adult↗
PubMed1989

Identification of components in iodinated glycerol.

Iodinated glycerol (CAS no. 5634-39-9), therapeutically used as an expectorant and source of organically bound iodine, was analyzed to determine the purity and composition of the chemical samples used in carcinogenicity and toxicity studies. The manufactured product is described by the patent and chemical literature as a mixture of two isomeric iodopropylideneglycerols (structures 1 and 2). The results of our studies, however, indicate that the two principal components of the product were 3-iodo-1,2-propanediol (IPD) and glycerol (GLY). Analyses from GC-MS (full scan electron impact) and carbon-13 nuclear magnetic resonance spectrometry provided conclusive identification of these components. The quantification of IPD and GLY in one of two samples of commercial product using GC-flame ionization detection indicated concentrations of 33 and 17%, respectively (Sample A). Similar concentrations were determined for a second sample from the same source (Sample B), which was a gratis sample procured approximately nine years after Sample A. Numerous minor components were also observed in these two samples. These components were tentatively identified as condensation products of glycerol and iodine-containing analogues. The iodopropylideneglycerol compounds, described in the patent, were not observed in either of the two samples.

Carbon Isotopes↗