Search PubMed⌕ Search

Biomedical subjects

A Poole

Publications and source records attributed to A Poole.

At least 19 recordsLinked to original sources
PubMed1995

Syk interacts with tyrosine-phosphorylated proteins in human platelets activated by collagen and cross-linking of the Fc gamma-IIA receptor.

Activation of human platelets by cross-linking of the platelet low-affinity IgG receptor, the Fc gamma receptor IIA (Fc gamma-RIIA), or by collagen is associated with rapid phosphorylation on tyrosine of the non-receptor tyrosine kinase syk. Phosphorylation is still observed, albeit sometimes reduced, in the presence of a combination of a protein kinase C inhibitor, Ro 31-8220, and the intracellular calcium chelator, BAPTA-AM, demonstrating independence from phosphoinositide-specific phospholipase C (PLC) activity. In contrast, the combination of Ro 31-8220 and BAPTA-AM completely inhibits phosphorylation of syk in thrombin-stimulated platelets. Phosphorylation of syk increases its autophosphorylation activity measured in a kinase assay performed on syk immunoprecipitates. Fc gamma-RIIA also undergoes phosphorylation in syk immunoprecipitates from platelets activated by cross-linking of Fc gamma-RIIA but not by collagen, suggesting that it associates with the kinase. Consistent with this, tyrosine-phosphorylated Fc gamma-RIIA is precipitated by a glutathione S-transferase (GST) fusion protein containing the tandem src homology (SH2) domains of syk from Fc gamma-RIIA- but not collagen-activated cells. Two uncharacterized tyrosine-phosphorylated proteins of 40 and 65 kDa are uniquely precipitated by a GST fusion protein containing the tandem syk-SH2 domains in collagen-stimulated platelets. A peptide based on the antigen recognition activation motif (ARAM) of Fc gamma-RIIA, and phosphorylated on the two tyrosine residues found within this region, selectively binds syk from lysates of resting platelets; this interaction is not seen with a non-phosphorylated peptide. Kinase assays on Fc gamma-RIIA immunoprecipitates reveal the constitutive association of an unidentified kinase activity in resting cells which phosphorylates a 67 kDa protein. Syk is not detected in Fc gamma-RIIA immunoprecipitates from resting cells but associates with the receptor following activation and, together with Fc gamma-RIIA, is phosphorylated in the kinase assay in vitro. These results demonstrate that syk is activated by Fc gamma-RIIA cross-linking and collagen, independent of PLC, suggesting that it may have an important role in the early events associated with platelet activation. The association of syk with Fc gamma-RIIA appears to be mediated through the tandem SH2 domains in syk and the ARAM motif of Fc gamma-RIIA. A similar interaction may underlie the response to collagen, suggesting that its signalling receptor contains an ARAM motif.

Amino Acid Sequence↗
PubMed1995

Preliminary findings of ophthalmological abnormalities in farmed halibut.

Ocular abnormalities occurring in farmed halibut at the Sea Fish Industry Authority Marine Farming Unit, Ardtoe, Argyll were investigated clinically and post mortem. A significant number of fish were found to have posterior polar cystic changes either causing scleral ectasia or gross degenerative posterior segment abnormalities with chorioretinal atrophy. Other ocular abnormalities included cataract formation and intraocular inflammation. In a small number of fish gas bubble formation in the anterior chamber was observed during capture and examination. It is possible that the lesions seen in these fish are a form of gas bubble disease although super-saturation, the cause of gas bubble disease previously reported in farmed fish, does not occur in the tanks in which these fish are housed. While this paper provides no answers with regard to the aetiopathogenesis of the lesions, it is hoped that it will stimulate discussion, leading to resolution of these questions through a multidisciplinary approach to the problem.

Animals↗
PubMed1995

Ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) and the tyrphostin ST271 inhibit phospholipase C in human platelets by preventing Ca2+ entry.

In the present study, the roles of Ca2+ and fibrinogen receptor occupancy in the regulation of phospholipase C by G protein-coupled and tyrosine kinase-linked receptor pathways in human platelets have been investigated. Agonist stimulation of phospholipase C was not altered significantly in the absence of stirring or in the presence of the fibrinogen receptor antagonist arginine-glycine-aspartate-serine, conditions that prevent platelet aggregation. Similarly, elevation of intracellular Ca2+ levels by the ionophores A23187 or ionomycin did not induce formation of inositol phosphates. In contrast, chelation of extracellular Ca2+ by ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) reduced formation of inositol phosphates by G protein receptor (thrombin)- and tyrosine kinase (Fc receptor and peroxovanadate)-regulated pathways. Similarly, short term exposure to Ni2+ ions, which also prevent Ca2+ entry, inhibited thrombin-stimulated formation of inositol phosphates. Loading of platelets with the intracellular Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid (BAPTA) markedly suppressed elevation of intracellular Ca2+ and formation of inositol phosphates in platelets stimulated by G protein receptor- and tyrosine kinase-regulated pathways. The greater inhibition of phospholipase C by BAPTA, relative to that induced by EGTA, is consistent with the more pronounced inhibition of intracellular Ca2+ elevation. The tyrphostin tyrosine kinase inhibitor ST271 also reduced intracellular Ca2+ levels and inhibited activation of phospholipase C. The degree of inhibition of phospholipase C by ST271 was slightly greater than that induced by EGTA but was not additive with the effect of EGTA, suggesting a common mode of action. It is concluded that elevation of intracellular Ca2+ regulates agonist-induced activation of phospholipase C and that this contributes to the inhibition of thrombin-induced formation of inositol phosphates by the tyrphostin ST271.

Blood Platelets↗
PubMed1994

Styrene production, use, and human exposure.

Styrene is an extremely important commodity chemical used extensively in the manufacture of numerous polymers and copolymers, including polystyrene, acrylonitrile-butadiene-styrene (ABS), styrene-acrylonitrile (SAN), styrene-butadiene latex, and styrene-butadiene rubber. Styrene is a component of cigarette smoke and automobile exhaust, and it may occur naturally at low levels in various types of foods. The highest potential human exposures to styrene occur in occupational settings, particularly those involving the production of large glass-reinforced polyester products such as boats, which require manual lay-up and spray-up operations. Substantially lower occupational exposures occur in styrene monomer and polymer production facilities. The general public is exposed to very low concentrations of styrene in ambient air, indoor air, food, and drinking water.

Environmental Pollution↗
PubMed1992

Does Graves' disease or thyrotoxicosis affect the prognosis of thyroid cancer.

Twenty-one patients who underwent surgical treatment for thyrotoxicosis and who were found at operation to have thyroid cancer are presented. Sixteen had Graves' disease and 5 had toxic nodular goiter. The group with Graves' is compared with 110 euthyroid patients with thyroid cancer who underwent their initial surgery in the same time period and who were of the same age (+/- 1 yr) and sex as the patients with Graves' disease. None of the thyrotoxic patients died during follow-up of 2-24 yr or developed subsequent metastases. The 1 patient with a local lymph node metastasis has not shown evidence of recurrence. Hypoparathyroidism appeared as a complication in only 1 patient. The size of tumors in the patients with Graves' disease was significantly smaller than in the euthyroid group. The course of the disease in both the patients with Graves' disease and the thyrotoxic group as a whole was relatively benign. This series does not support the recent suggestions that thyroid cancer in patients with Graves' disease is more aggressive than in either patients with toxic nodular goiter or euthyroid subjects. Patients with Graves' disease and thyroid cancer should be treated identically to other patients with thyroid cancer. Therapy should consist of total thyroidectomy followed by a postoperative 131I scan. Residual tissue or metastases found on the scan should be ablated with 6 GBq 131I. The patient should receive a suppressive dose of T4.

Adult↗
PubMed1990

In vivo biliary excretion and in vitro cellular accumulation of thyroxine by rats or cultured rat hepatocytes treated with a novel histamine H1-receptor antagonist.

Rats treated with temelastine (SK&F 93,944), a novel histamine H1-receptor antagonist, develop thyroid lesions characterized by hypertrophy and colloid depletion. To investigate the mechanism underlying the lesion the biliary clearance and hepatocellular accumulation of radio-labelled iodothyronines was measured in rats or cultured rat hepatocytes. Treatment with temelastine increased both the biliary clearance (approximately 300% of control) and hepatocellular accumulation (approximately 200%) of thyroxine (T4) but had little or no effect on tri-iodothyronine (T3). Chromatographic analysis of bile samples from temelastine-treated rats showed that the majority (approximately 78%) of T4 was present in the unconjugated form. This contrasted with data from phenobarbitone-treated rats which showed that approximately 80% of T4 in the bile was present as the glucuronide conjugate. Studies with cultured hepatocytes showed that the hepatocellular accumulation of T4 was energy dependent. At 4 degrees C the treatment-related increases in accumulation of T4 were abolished, suggesting that temelastine is specifically affecting the high affinity, energy dependent system which preferentially transports thyroxine into hepatocytes. Because temelastine is metabolized extensively, investigations were undertaken to discover if the hepatic effects were caused by the parent compound or an oxidative metabolite. The results showed that the hepatocellular accumulation of T4 remained increased in hepatocytes co-incubated with temelastine and 1-aminobenzotriazole (a suicide inhibitor of cytochrome P450), even though no measurable P450 could be found in the cells. Also, in studies with two major "rat" metabolites of temelastine, i.e. 93,944-Met I or 93,944-Met VIII, treatments failed to reproduce the responses seen with the parent compound.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Comparative toxicology of temelastine. A novel H1 antagonist in dog, rat, and monkey.

The toxicity of temelastine 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[(6-methylpyrid+ ++-3-yl) methyl]-4-pyrimidone a potent, selective, competitive histamine H1-receptor antagonist was examined in dogs and rats. The major toxicological response seen in the dog was marked, but intermittent and reversible, increases in the plasma activity of a number of liver-associated enzymes, viz alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), and alkaline phosphatase (ALP). The increases first seen in two male dogs treated for 30 consecutive days at a dose of 300 mg/kg became apparent at lower doses, i.e., 100 and 33.3 mg/kg/day, in 6- and 12-month studies. Although the increases were suggestive of hepatotoxicity, the only histological changes were increases in hepatocellular lipofuscin pigment and foci of macrophages seen in dogs treated at 300 mg/kg for 12 months. Rats treated for up to 12 months at doses as high as 300 mg/kg/day showed no treatment-related increases in plasma enzymes although increases in liver weights and hepatocellular lipofuscin pigment together with centrilobular hypertrophy were seen in the 300 mg/kg/day treatment group. To investigate differences in hepatic responsiveness between species dogs, rats, and monkeys were exposed to high concentrations of temelastine by continuous 24-hr intravenous infusion. The results of the study showed the dog to be most sensitive to the hepatic effects of temelastine. The major toxicological effect of temelastine in the rat was a histopathological lesion of the thyroid gland characterized by agglomeration and depletion of colloid, follicular epithelial hypertrophy and reduced follicular size. The no-effect dose for this lesion was between 10 and 33.3 mg/kg/day. These histopathological changes, characteristic of a "TSH-driven" thyroid gland, were not seen in the thyroid glands of dogs.

Alanine Transaminase↗
PubMed1989

Activities of enzymes of collagen biosynthesis and levels of type III procollagen peptide in the serum of patients with sarcoidosis.

Serum immunoreactive prolylhydroxylase (IRPH), galactosylhydroxylsyl glucosyltransferase activity (GGT) and amino-terminal propeptides of type III procollagen (Pro(III) peptide) were measured in fifty three patients with sarcoidosis (all having some degrees of pulmonary fibrosis). The levels of IRPH and Pro(III) peptide showed no relationships to the clinical assessment of the disease and while GGT activity was raised in approximately 80% of the patients there was no correlation between the size of the increases and the clinical activity of the disease. The results of this study would suggest that measurement of the above parameters offer no specificity in either diagnosing or assessing the clinical activity of sarcoidosis. The observed increases in serum GGT activity in affected patients would however suggest that measurement of this enzyme may be useful perhaps in more severe pulmonary fibrotic reactions.

Biomarkers↗
PubMed1989

Mechanistic investigation of species-specific thyroid lesions induced by treatment with the histamine H1 antagonist temelastine (SK&F 93944) in rats.

Temelastine (SK&F 93944), an H1 histamine receptor antagonist, induces thyroid histopathological lesions in the rat, indicative of thyroid follicular cell stimulation, at oral doses of 10-33 mg/kg body weight/day. These changes do not occur in the dog or mouse. Endocrinological short-term studies support an increased thyroid follicular activity (increased radioiodide accumulation) with decreased circulating thyroxine (T4) at oral doses at or above 300 mg/kg body weight/day and increased circulating thyroid stimulating hormone (TSH). This is thought to be responsible for the thyroid follicular stimulation following Temelastine treatment. No direct inhibition of thyroid function occurs. Temelastine produces these species-specific changes by enhancing thyroxine clearance from the circulation in the rat, but not in the dog or mouse. In vitro studies with cultured rat hepatocytes suggest that the mechanism behind these changes is a drug-induced increase of hepatocellular T4 binding and uptake which leads to an enhanced metabolic clearance of the hormone.

Animals↗
PubMed1989

1-Naphthol--single and repeated dose (30-day) oral toxicity studies in the mouse.

The oral toxicity of 1-naphthol in Charles River CD1 mice was investigated in single (2, 1 and 0.5 g/kg body weight) and 30-day repeat dosing (200, 100 and 50 mg/kg body weight) studies. In the single-dose study, animals dosed by oral gavage at 2 g/kg body weight either died or were killed in extremis between 15 and 90 min after dosing, and although the animals treated at 1 g/kg body weight survived to the end of the study (14 days post-dosing), one male in the 0.5 g/kg body weight dose group was killed in extremis approximately 2 hr after treatment. Acute dosing was associated with histopathological lesions seen in the kidneys and stomachs of mice from all treatment groups. The kidney lesions consisted of degeneration of the distal tubule epithelium, papillary necrosis and tubular dilatation. Gastric changes characterized by splitting of the epithelium of the forestomach and sloughing of the superficial epithelium of the glandular mucosa were generally accompanied by vascular congestion and acute inflammatory cell infiltration. In the 30-day study, mice dosed by oral gavage at 50 and 100 mg/kg body weight tolerated the treatment well, as did the female mice treated at 200 mg/kg body weight. Three male mice in the 200 mg/kg body weight group did, however, show gastric histopathological effects. Two of the mice (one killed in extremis on the fourth day of the study with the other surviving treatment) showed focal mucosal erosion, and a third (killed in extremis on the twentieth day of the study) exhibited peeling of the mucosa of the forestomach. Both of these gastric lesions were considered to be related to treatment at 200 mg/kg body weight. None of the mice in the 30-day study showed any kidney lesions or changes in haematology or clinical chemistry parameters.

Administration, Oral↗
PubMed1989

In vitro accumulation of thyroid hormones by cultured rat hepatocytes and the biliary excretion of iodothyronines in rats treated with a novel histamine H2-receptor antagonist.

The administration of SK&F 93479, a novel histamine H2 antagonist, to Wistar rats has been shown to produce thyroid lesions associated with an increased clearance of plasma thyroxine (T4) and elevated plasma TSH concentrations. To determine if these changes were mediated via an increase in the hepatic clearance of thyroid hormones, the biliary clearance and hepatic accumulation of iodothyronines were measured in rats and cultured hepatocytes treated with SK&F 93479. Both the in vitro and in vivo results showed that treatment with SK&F 93479 caused an increased hepatic accumulation (approx. 200% of control) and biliary excretion (2-3-fold control values) of T4 but had little or no effect on T3 uptake. The in vitro studies showed that the treatment related increase in hepatic thyroxine accumulation was temperature and therefore probably energy dependent, while inhibition of cytochrome P-450 dependent enzyme activity did not alter the accumulation of T4 suggesting that the parent compound and not some oxidative metabolite was responsible for the hepatic effects. Chromatographic analysis of bile from SK&F 93479 and phenobarbitone-treated rats showed that in the latter animals 81% of the T4 was present as the glucuronide conjugate (consistent with enzyme induction) whereas in the SK&F 93479-treated rats only 25% was present as the conjugate with 75% being in the unconjugated form. These studies show that SK&F 93479 increases the hepatic accumulation and biliary clearance of T4 by a novel mechanism not associated with liver microsomal enzyme induction.

Animals↗
PubMed1989

Trainee surgery in teaching hospitals: is there a cost?

The morbidity rate for 2858 patients undergoing thyroidectomy over the 10 year period January 1977-December 1986 was examined and related to the involvement of a surgical trainee in the operative procedure. There was no overall difference in specific complication rates related to the surgical procedure, being 13.8% when the procedure was undertaken by a consultant, and 13.1% when a surgical trainee was involved in the procedure. There was a significant increase (P = 0.0025) in operative time increasing from 127 min for the consultant to 146 min when the trainee was involved (a 15% increase). There was no significant difference in bed stay for any of the groups. Surgical trainees can be safely taught operative skills under supervision without risk of increased complications. There is a cost, however, to the hospital system in terms of increased demands on time and operative facilities.

Costs and Cost Analysis↗
PubMed1989

Characterization of excessive collagen production during development of pulmonary fibrosis induced by chronic silica inhalation in rats.

The activation of collagen synthesis during development of silicotic fibrosis was studied in rats exposed, in dusting chambers, to respirable SiO2 for periods of 2, 4, 6 or 12 months. Control animals were exposed similarly to clean air or TiO2. Development of fibrosis was followed by histological examination, measurement of lung weight and determination of lung collagen content (as hydroxyproline). A steady increase in lung weight and collagen content together with changes in cellularity and metabolic activity of the lungs, as ascertained by chemical determination of DNA and RNA, were measured in the lungs of the SiO2-exposed animals. Hybridization of total lung RNA, extracted at each time point, with cDNA probes specific for type I and type III procollagen mRNA levels showed that the development of fibrosis was associated with increased levels, as compared to age matched controls, of pulmonary procollagen mRNAs. Interestingly, the highest levels of procollagen mRNAs were observed in young (pretreatment control) animals, suggesting that during pulmonary development collagen metabolism in lungs is even greater than during development of fibrosis. In rats exposed to SiO2 the increase in type III procollagen mRNA occurred earlier than the increase in type I procollagen mRNAs. These observations demonstrate both age-dependent and silicosis-related changes in pulmonary procollagen mRNA levels. The results suggest that development of silicosis is associated with an altered capacity of the lungs to regulate collagen accumulation.

Administration, Inhalation↗
PubMed1988

Comparison of the toxicity of orally administered L-triiodothyronine (T3) in rat and cynomolgus monkey.

Oral administration of L-triiodothyronine (L-T3) (0.015-1 mg/kg) for 30 days to mature rats or cynomolgus monkeys resulted in both species in a high mortality at 1 mg/kg (after 2 weeks of treatment) and a progressive loss in body weight. Dose-related elevations in plasma marker enzymes occurred, mainly after 1-2 weeks of treatment. The approximate no-effect dose for these changes was around 0.015-0.020 mg/kg for both rat and primate. The large elevations of leucine aminopeptidase (LAP) at 1 mg/kg L-T3 in monkey indicated hepatocellular toxicity although in the rat such large increases in alanine aminotransferase (ALT) and glutamate dehydrogenase (GLDH) were not seen. L-T3 also showed little toxicity to rat hepatocytes in vitro. High concentrations of L-T3 (7 x 10(-9) to 7 x 10(-7) M) had minimal effects on parameters of cell viability such as lactate dehydrogenase (LDH) leakage, chromium-51 release and [3H]leucine incorporation. Urinary enzymes in the rat showed a similar profile to those in plasma. Large rises in alkaline phosphatase (AKP) and N-acetyl glucosaminidase (NAG) at 1 mg/kg indicated possible proximal tubular damage although this was not supported histologically. Clinically, in both species L-T3 appeared more toxic to males than females but this was not supported histologically. The histological lesions observed were different in the 2 species. In the monkeys there was extensive lipid vacuolation of hepatocytes and changes in thyroid and adrenal cortex. In the rat there was fine, non-lipid vacuolation of hepatocytes and thyroid changes. In the rat, 2 previously unreported lesions were also noted. There were multinucleated cells in the renal distal tubular epithelium, and focal fibroplasia of serosal surfaces of abdominal viscera.

Acetylglucosaminidase↗
PubMed1988

Use of general anesthesia in dental care of the child with sickle cell anemia. A case report.

This article reviews the clinical manifestations of sickle cell anemia and describes the dental management, with the use of general anesthesia, of a child affected by the disease and exhibiting some of its complications. The discussion stresses the vital importance of awareness of the possible complications of sickle cell anemia and sickle cell trait in the safe and successful management of patients requiring dental care that includes the use of general anesthesia.

Anemia, Sickle Cell↗