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Biomedical subjects

C Robinson

Publications and source records attributed to C Robinson.

At least 361 records · Page 20Linked to original sources
PubMed1988

Dose-related antagonism of leukotriene D4-induced bronchoconstriction by p.o. administration of LY-171883 in nonasthmatic subjects.

Leukotriene D4 (LTD4) has been suggested as a proinflammatory mediator in asthma. We have investigated the inhibitory activity of the p.o. LTD4 antagonist LY-171883 (1-[2-hydroxy-3-propyl]-4-[4-(1H-tetrazol-5-yl)butoxy]phenyl]et hanone) on LTD4-induced bronchoconstriction in nonasthmatic subjects, in a double-blind, placebo controlled, randomized, cross-over study. Twelve subjects, mean age 26.3 +/- 1.7 years, participated. On 4 separate days, base-line measurements of forced expiratory volume in 1 second (FEV1) and maximum flow at 70% of vital capacity below total lung capacity (Vp30) were performed, after which subjects ingested either 50 or 200 or 400 mg of LY-171883, and then undertook a dose-response study with inhaled LTD4. Measurements of FEV1 and Vp30 were made at intervals for 8 min after inhalation of each dose of LTD4, and increasing doses administered until FEV1 had fallen by greater than 20% or the maximum cumulative dose of LTD4 (88.2 nmol) had been given. Cumulative dose-response curves were constructed on a logarithmic scale, and the provocation doses of LTD4 producing a 12% fall in FEV1 (PD12 FEV1) and a 30% fall in Vp30 (PD30Vp30) after placebo determined by linear interpolation to be 5.5 (0.9-176.4) and 1.2 (0.1-6.2) nmol, respectively. Following the 50-, 200- and 400-mg doses of LY-171883, the geometric mean PD12 FEV1 values were 7.0 (NS), 10.5 (NS) and 25.3 (P less than .01) nmol, respectively, whereas corresponding values for PD30Vp30 were 1.7 (NS), 2.6 (NS) and 6.1 (P less than .01) nmol.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetophenones↗
PubMed1987

Transport of proteins into chloroplasts. Partial purification of a thylakoidal processing peptidase involved in plastocyanin biogenesis.

Plastocyanin is synthesized in the cytoplasm as a larger precursor and transported across three membranes into the chloroplast thylakoid lumen. Processing to the mature size involves successive cleavages by a stromal and a thylakoidal peptidase. In this report we describe the partial purification and characterization of the thylakoidal peptidase involved. The enzyme has been purified 36-fold from Pisum sativum thylakoids after solubilization using Triton X-100. The peptidase processes the plastocyanin import intermediate to the mature size, but no further, and is capable of processing pre-plastocyanin to the mature size but at a lower rate. No detectable activity is displayed against non-chloroplast proteins or precursors of stromal proteins. The enzyme has a pH optimum of 6.5-7 and is activated by chelating agents such as EDTA and EGTA. No inhibitors of the peptidase have been found to date.

Biological Transport, Active↗
PubMed1987

Allelic forms of the alpha- and beta-chain genes encoding DQw1-positive heterodimers.

On chromosome 6, in the HLA region, the DQ subregion is located immediately centromeric to the DR subregion. Even though only three serological specificities to date have been officially recognized (DQw1, DQw2, and DQw3), it seems likely that the phenotypical polymorphism expressed by DQ molecules is much more complex. There are reasons to believe that fixed alpha-beta combinations exist, each of them associated with a different DR allele. DQw1 is a determinant present on DQ molecules that are found associated with DR1-, DR2-, and DRw6-positive haplotypes. By restriction fragment length polymorphism analysis, we recognized three allelic DQ-alpha and three allelic DQ-beta patterns associated with DQw1. In addition, one of these alpha/beta pairs associated with DR1, two with DR2, and a fourth with DRw6. We have obtained evidence using nucleotide sequencing that there are as many allelic forms of DQ-alpha and DQ-beta genes as there are different molecular DQ-alpha and DQ-beta patterns. The DQ-alpha and DQ-beta chains of DQw1-positive molecules each are encoded by at least three distinctly different allelic genes, and particular alpha/beta gene combinations are associated with the same DR alleles as their corresponding molecular alpha/beta pairs.

Alleles↗
PubMed1987

Distribution of fluoride across human dental enamel, dentine and cementum.

This was determined across the entire width of sections from 20 mandibular premolars, containing enamel, coronal dentine, root dentine and cementum. An abrasive technique was used to sample all three dental tissues in a single experiment. In the profiles of fluoride distribution, fluoride concentration was thus precisely related to the position of the tissue sample. There was a marked increase in the fluoride content of coronal and root dentine, at least until the age of about 50 years. There had been uptake of fluoride by the root dentine and cementum throughout the life of the tooth. There was no evidence of any change in the fluoride content of enamel with age.

Adult↗
PubMed1987

The distribution pattern of fluoride concentrations in human cementum.

The distribution of fluoride across human cementum has been determined on 59 individual teeth taken post mortem from five subjects aged 30, 43, 54, 66 and 70 years. Eight teeth of different types were examined from each of the five subjects together with a further 19 teeth from the 54-year-old, making a total of 27 teeth from this subject. As in a previous study, F concentrations were generally higher towards the surface of the cementum, but there were considerable variations between F gradients. The teeth from each subject seemed to comprise a family of profiles, characteristic of the individual.

Adult↗
PubMed1987

Effects of hypercholesterolemia on the microsomal membrane fluidity of intimal-medial versus medial layers of swine aorta: implications for the pathogenesis of vasospasm.

The hypothesis was examined that hypercholesterolemia induces a decrease in arterial microsomal membrane fluidity. To investigate this hypothesis, the fluorescence anisotropy (r) of 1,6-diphenylhexa-1,3,5-triene was measured in aortic microsomes isolated from the intimal-medial (IM) and medial (M) layers of swine thoracic aortas. After 10 weeks of feeding a high fat (10% lard) diet, serum cholesterol increased 2.3-fold compared to 3.6-fold in pigs fed a similar diet supplemented with 2% cholesterol. Based upon differences in r, the membrane fluidity of the IM layer was significantly less than the M layers. The membrane fluidity of the IM layer was inversely related to the severity of hypercholesterolemia regardless of dietary treatment. There were no differences in membrane fluidity among the three dissected M layers and the membrane fluidity of these layers was refractory to changes in serum cholesterol. A decrease in the membrane fluidity of the IM layer may contribute to the abnormal regulation of vascular tone which underlies the development of vasospasm in atherosclerotic arteries.

Animals↗
PubMed1987

Prostaglandin D2 release from human skin mast cells in response to ionophore A23187.

1. Cells were dispersed from human foreskin by proteolytic digestion and enriched or depleted in mast cell content by density gradient flotation on discontinuous gradients of Percoll. 2. Cells were harvested at six interfaces on the density gradient. Mast cell purity ranged from 0.6-85.0%, compared to 5.5% in the unfractionated cells. 3. Challenge of the cells with the calcium ionophore A23187 resulted in release of both histamine and prostaglandin D2 (PGD2). In fractions depleted of mast cells, histamine release and net PGD2 generation were low, but increasing amounts of these mediators were released as mast cell purity was increased up to 59%. 4. Overall, there was a significant correlation between the net generation of PGD2 and histamine (r = 0.9234, P less than 0.001) and also between PGD2 release and mast cell number (r = 0.7475, P less than 0.001). 5. These data provide the first direct evidence of the capacity of the human cutaneous mast cell to synthesize and release PGD2.

Calcimycin↗
PubMed1987

Developmental stages in permanent porcine enamel.

Developing permanent teeth of different ages were obtained from Danish Landrace pigs. Visibly distinct zones on their enamel surfaces were shown to correspond to changes in chemical composition previously reported for other species. The time of appearance, rate of progress and duration of each stage was determined for each tooth type.

Animals↗
PubMed1987

Primary and secondary effector cells in the pathogenesis of bronchial asthma.

The immediate and late asthmatic reactions provoked by inhaled allergens have provided useful models enabling the dissection of individual inflammatory cells and their mediators that may contribute to the pathogenesis of asthma. The immediate reaction is considered to be mast cell-mediated on the basis that about 50% of the response is inhibitable by potent and selective H1-receptor antagonists such as terfenadine and astemizole. Additional inhibition (approximately 30%) by the potent cyclooxygenase inhibitor flurbiprofen implies an important role for prostanoids in the immediate response, the most likely mast cell-derived product being prostaglandin (PG) D2. In man, PGD2 is selectively metabolised to 9 alpha 11 beta-PGF2, a unique prostaglandin which shares with PGD2 contractile properties on guinea-pig and human airways smooth muscle. The inability of piriprost, a potent leukotriene synthesis inhibitor, to influence the allergen-provoked immediate reaction raises the possibility that sulphidopeptide leukotrienes play a minor role in this response. The late asthmatic reaction is considered to resemble clinical asthma since it is accompanied by increased responsiveness of the airways to a wide range of stimuli. The late reaction in man is inhibited by nedocromil sodium (4 mg) but only marginally attenuated by salbutamol (200 micrograms) if both drugs are administered prior to allergen challenge. Since salbutamol, in the dose administered, is a potent mast cell-stabilising agent, these findings must question the obligatory role of mast cell mediator release in the pathogenesis of the late response.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1987

Cholinergic-mediated bronchoconstriction induced by prostaglandin D2, its initial metabolite 9 alpha,11 beta-PGF2, and PGF2 alpha in asthma.

In this study, we have investigated the contribution of cholinergic-mediated bronchoconstriction in the airway response provoked by inhaled prostaglandin (PG)D2, its metabolite 9 alpha, 11 beta-PGF2, and PGF2 alpha, which are generated during mast cell activation in vivo and are potent bronchoconstrictor agonists in humans. The effect of prior inhalation of 1 mg ipratropium bromide (IB) on the bronchoconstrictor response to inhaled methacholine (MCh), PGD2, 9 alpha, 11 beta-PGF2, and PGF2 alpha was determined in 7 allergic asthmatic subjects by measuring changes in SGaw, FEV1, and Vmax30. Methacholine, PGD2, and 9 alpha, 11 beta-PGF2 caused concentration-related bronchoconstriction with PGD2 and 9 alpha, 11 beta-PGF2 being between 45 and 112 times more potent than MCh (p less than 0.05), depending on the method used to measure airway caliber. Preinhalation of IB displaced the concentration response curves to MCh between 69- and 196-fold to the right, and this was significantly greater than that observed with PGD2 (12- to 23-fold, p less than 0.02) and 9 alpha, 11 beta-PGF2 (12- to 22-fold, p less than 0.02). Ipratropium bromide inhibited the bronchoconstriction achieved with the highest concentration of agonist by 73 to 91% with MCh, 46 to 79% with PGD2, and 32 to 38% with 9 alpha, 11 beta-PGF2. Ipratropium bromide did not affect the bronchoconstriction pattern to inhaled PGF2 alpha, irrespective of the nature of the response. We conclude that although PGD2 and 9 alpha, 11 beta-PGF2 are potent contractile agonists of human smooth muscle in vitro, bronchoconstriction observed with these mediators in vivo results from a combination of both direct and cholinergic-mediated mechanisms.

Adult↗
PubMed1987

9 alpha,11 beta-prostaglandin F2, a novel metabolite of prostaglandin D2 is a potent contractile agonist of human and guinea pig airways.

Prostaglandin (PG) D2, the predominant prostanoid released from activated mast cells in humans is initially metabolized by reduction of the C-11 keto function to yield 9 alpha,11 beta-PGF2. In this study the airways effects of 9 alpha,11 beta-PGF2 were compared with those of its epimer 9 alpha,11 alpha-PGF2 (PGF2 alpha) and PGD2. 9 alpha,11 beta-PGF2 was a potent contractile agonist of isolated guinea pig trachea and 4-mm human airways in vitro; the potencies of the PGs relative to PGD2 (= 1.00) being 0.65 (NS) and 4.08 (P less than 0.001) for 9 alpha,11 beta-PGF2, and 0.52 (P less than 0.01) and 2.40 (P less than 0.001) for PGF2 alpha, respectively. When inhaled by asthmatic subjects, 9 alpha,11 beta-PGF2 was a potent bronchoconstrictor agent, being approximately equipotent with PGD2 and 28-32 times more potent than histamine (P less than 0.01). These studies suggest that 9 alpha,11 beta-PGF2 is at least equipotent with PGD2 as a bronchoconstrictor agonist, and in being a major metabolite of PGD2, could contribute to the bronchoconstrictor effect of this mast cell-derived mediator in asthma.

Adult↗
PubMed1987

Environmental and psychosocial determinants of sudden death.

The risk factors for sudden coronary heart disease (CHD) death have been well described. Sudden CHD deaths should be classified as those occurring in individuals with and those in individuals without a prior history of clinical heart disease. The extent of coronary artery disease, left ventricular dysfunction, and cardiac arrhythmias are the primary pathophysiologic determinants of ventricular fibrillation and sudden death. Psychosocial factors influence the threshold of response to the numerous physical and social environmental stimuli that can precipitate sudden death. The degree of pathology is probably inversely related to the intensity of the stimuli necessary to precipitate sudden CHD death. In the presence of extensive disease the precipitants of sudden deaths are probably ubiquitous in the environment and unlikely to be prevented. Thus, prevention of the basic cardiac disease is of higher priority.

Alcohol Drinking↗
PubMed1986

Ionophore-dependent generation of eicosanoids in human dispersed lung cells. Modulation by 6,9-deepoxy-6,9-(phenylimino)-delta 6,8-prostaglandin I1 (U-60,257).

6,9-Deepoxy-6-9-(phenylimino)-delta 6,8-prostaglandin I1, a prostacyclin analogue reported to inhibit sulphidopeptide leukotriene formation in animals, was evaluated for its pharmacological activity against eicosanoid and histamine release from human dispersed lung cells (HDLC). In the absence of drug, challenge of HDLC with A23187 (2.5 microM) increased immunoreactive eicosanoid generation by factors of 7.6 for prostaglandin (PG) D2, 9.1 for TXB2, 3.2 for PGF2 alpha, 2.0 for 5-HETE, 6.3 for LTC4, in association with a twofold increase in histamine release. When exogenous [14C]-arachidonic acid was added to HDLC simultaneously with A23187 challenge, radiolabelled eicosanoids were recovered in the supernatant, but on separating the products by radio-thin layer chromatography the proportions of individual eicosanoids were not significantly different from unchallenged cells. With endogenous arachidonate, U-60,257 was a potent inhibitor of i-LTC4 generation at 1 microM, but between 3 and 300 microM there was a concentration-related reversal of this inhibition. The effects of U-60,257 on the metabolism of exogenous [14C]-arachidonic acid were also studied. Under these circumstances the drug was a potent inhibitor of both 5-HETE and 5,12-diHETE formation, without significantly affecting the formation of other mono-HETES. In agreement with previous endogenous substrate experiments there was a concentration-dependent inhibition of TxB2 formation from exogenous arachidonic acid. These findings highlight the complex pharmacological actions of U-60,257 which appear dependent on the source of arachidonic acid substrate.

Arachidonic Acid↗