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Biomedical subjects

R F Brown

Publications and source records attributed to R F Brown.

At least 37 records · Page 2Linked to original sources
PubMed1997

Histopathological changes in Yucatan minipig skin following challenge with sulphur mustard. A sequential study of the first 24 hours following challenge.

Sulphur mustard (HD) or "mustard gas' is a potent vesicant chemical warfare agent whose biological effects in man have been well documented. The histopathological features of the developing cutaneous HD lesion in female Yucatan minipigs up to 24 hours post exposure are reported. Following challenge with HD vapour at a concentration of 12.0 mumol/cm2 a sequence of ultrastructural changes to keratinocytes occurred which were initially seen in the stratum basale. Condensation of nuclear heterochromatin and loss of euchromatin was accompanied by cytoplasmic swelling and culminated in focal epidermal necrosis which was evident at 24 h after the challenge. The melanocyte appeared to be the cell type most sensitive to HD challenge with a loss of cytoplasmic electron density in areas of the cytoplasm immediately surrounding the melanosomes, chromatin condensation, nuclear membrane blebbing with mitochondrial and generalized cytoplasmic swelling. Isolated complete cell necrosis and disruption were noted as early as 2 h following the challenge with generalized necrosis being seen from 12 h onwards. From 12 h onwards, areas of basement membrane degeneration were also observed. These appeared similar in ultrastructure to that observed in other animal model systems but did not progress to the large blisters so typical of the human lesion. Damage to the upper dermis took the form of an inflammatory response typified by vascular endothelial swelling and vacuolation, dermal oedema and inflammatory cell (mainly neutrophil) infiltration. There was some evidence of transitory epidermal damage outside the prescribed wound area. This finding may be of clinical importance when surgical treatments are being considered.

Animals↗
PubMed1997

Bacterial lipopolysaccharides induce peripheral nerve disturbances in rats that mimic human immune-mediated polyneuropathies.

A single injection of Escherichia coli lipopolysaccharide (LPS; i.v. and i.p.) reliably induced peripheral nerve disturbances in male Australian albino Wistar (AaW) rats. Signs developed 6 to 24 h after LPS inoculation and persisted only transiently. Most AaW rats had variable degrees of bilateral hind limb impairment, and rarely had forelimb, tail, or central impairment. Signs included gait abnormalities, proprioceptive loss, and to a lesser extent hind limb weakness and sensory deficits. Signs were more severe in male than female AaW rats and were induced in a number of genetically related rat strains (e.g., AaW and outbred Wistar and inbred Lewis rats, but not Sprague Dawley or inbred Fischer 344 rats). Development and severity of these signs were found not be related to animal body weight, but were dependent on LPS dose. Signs were not associated with LPS-induced alterations in pain perception, or occurrence of spontaneous pain, as indexed by tail-flick and hot-plate tests. Taken together, these data indicate that LPS induced transient peripheral nerve disturbances in rats, the severity of which was influenced by genetic, sex-related, and dose-related factors.

Animals↗
PubMed1996

Protein losing enteropathy as the initial manifestation of childhood systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multisystem organ disease, and involvement of the gastrointestinal system is relatively rare. We describe a 13-year-old girl who presented initially with abdominal pain, diarrhea, edema, and hypoalbuminemia. She was diagnosed with protein losing enteropathy (PLE) based on the significant increase of alpha 1-antitrypsin clearance in the stool. Two weeks after admission she developed clinical and serological findings that fulfilled the ACR criteria for SLE. Over 22 cases of lupus associated PLE have now been reported, but only 3 in children. Children with PLE should be evaluated for SLE. In addition, PLE should be suspected as a possible cause of unexplained edema and/or hypoalbuminemia in SLE.

Adolescent↗
PubMed1995

Antagonists of phosphatidylinositol 3-kinase block activation of several novel protein kinases in neutrophils.

Several novel protein kinases are known to be rapidly activated in neutrophils stimulated with the chemoattractant fMet-Leu-Phe (fMLP). These kinases include a histone H4 protein kinase and several renaturable kinases with molecular masses of about 69, 63, 49, and 40 kDa. The renaturable kinases can catalyze the phosphorylation of a peptide that corresponds to residues 297-331 of the 47-kDa subunit of the NADPH-oxidase system (p47-phox). Previous studies have indicated that the activation of all of these protein kinases involves an uncharacterized stimulatory pathway and/or novel second messenger. The studies reported herein were undertaken to determine if phosphatidylinositol 3-kinase (PI3-K) is a component of this pathway. We report that certain chromosome derivatives (e.g. 2-(4-morpholinyl)-8-phenylchromone (LY294002)) and wortmannin, which inhibit PI3-K by distinct mechanisms, blocked activation of all of these novel kinases. These antagonists also inhibited the phosphorylation of p47-phox (about 50%) and O2.- release (about 80%) in cells stimulated with fMLP, but not with 4 beta-phorbol 12-myristate 13-acetate. A strong correlation exists between the amounts of these antagonists required to produce 50% inhibition of PI3-K in vitro and O2.- release in vivo. In contrast, a single atom substitution of LY294002 produced a compound (LY303511) that did not inhibit PI3-K. Compound LY303511 did not appreciably inhibit the activation of the novel protein kinases or O2.- generation. These data strongly suggest that PI3-K is involved in the activation of several novel protein kinases in neutrophils, one or more of which may be involved in O2.- release.

Androstadienes↗
PubMed1995

Investigation of neutrophil signal transduction using a specific inhibitor of phosphatidylinositol 3-kinase.

Neutrophils contain a multicomponent NADPH oxidase system that is involved in the production of microbicidal oxidants. Stimulation of human neutrophils with the peptide FMLP activates this respiratory burst enzyme to produce superoxide and also has been shown to result in activation of phosphatidylinositol (Ptdlns) 3-kinase. Treatment of human neutrophils with 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), a potent and specific inhibitor of Ptdlns 3-kinase, resulted in complete inhibition of Ptdlns 3-kinase activity as well as in inhibition of superoxide production in FMLP-treated neutrophils in suspension; FMLP-stimulated oxidant production in adherent cells was also abolished. Treatment of human neutrophils with PMA resulted in production of superoxide without activation of Ptdlns 3-kinase; LY294002 did not block superoxide production in neutrophils exposed to PMA. In addition, LY294002 did not inhibit cellfree NADPH oxidase activation, CD11b-dependent adhesion, actin polymerization in response to FMLP, or FMLP-induced calcium flux. These results suggest that the signal transduction pathway of the FMLP-receptor involves activation of Ptdlns 3-kinase, which is required for subsequent superoxide production induced by the chemotactic peptide. Furthermore, Ptdlns 3-kinase may be located directly upstream of protein kinase C or other protein kinases, which in turn activate the NADPH oxidase system.

Actins↗
PubMed1994

Dipyridamole directly inhibits vascular smooth muscle cell proliferation in vitro and in vivo: implications in the treatment of restenosis after angioplasty.

OBJECTIVES: The effect of dipyridamole on smooth muscle cell proliferation and prevention of intimal thickening after arterial injury was investigated. BACKGROUND: In addition to antiplatelet activity, dipyridamole also inhibits cell proliferation. We examined whether the antiproliferative action of dipyridamole on smooth muscle cells, as demonstrated here, has a direct effect on intimal thickening after vascular injury. METHODS: Cell proliferation was determined by measuring deoxyribonucleic acid (DNA) synthesis and by cell counting. The in vivo effect of locally delivered dipyridamole was determined in a rabbit model with carotid or femoral artery injury. RESULTS: Dipyridamole produced a dose-dependent inhibition of smooth muscle cell proliferation, producing 50% inhibition at 7 micrograms/ml. Structural analogues SH-869 and mopamidol were 10 to 100 times less effective than dipyridamole, suggesting that cell growth inhibition may be unrelated to the antiplatelet activity of dipyridamole. Inhibition of cell proliferation by dipyridamole was attenuated by increasing the serum concentration in the culture medium. Bypassing serum by local delivery of dipyridamole at the periadventitial site produced 63% inhibition (p < 0.05) of cell replication in balloon-injured arteries. Locally delivered dipyridamole also inhibited intimal thickening (20%, p < 0.05) after balloon injury. CONCLUSIONS: Dipyridamole inhibited smooth muscle cell proliferation in vitro. This activity was attenuated by serum proteins. Locally delivered dipyridamole inhibited cell replication in arteries and intimal thickening after balloon injury. These results suggest that although systemic treatment with dipyridamole may not be efficacious because of inadequate serum levels, its antiproliferative action on smooth muscle cells may reduce restenosis when the drug is delivered locally after coronary angioplasty.

Angioplasty, Balloon↗
PubMed1994

A specific inhibitor of phosphatidylinositol 3-kinase, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002).

Phosphatidylinositol (PtdIns) 3-kinase is an enzyme implicated in growth factor signal transduction by associating with receptor and nonreceptor tyrosine kinases, including the platelet-derived growth factor receptor. Inhibitors of PtdIns 3-kinase could potentially give a better understanding of the function and regulatory mechanisms of the enzyme. Quercetin, a naturally occurring bioflavinoid, was previously shown to inhibit PtdIns 3-kinase with an IC50 of 1.3 microgram/ml (3.8 microM); inhibition appeared to be directed at the ATP-binding site of the kinase. Analogs of quercetin were investigated as PtdIns 3-kinase inhibitors, with the most potent ones exhibiting IC50 values in the range of 1.7-8.4 micrograms/ml. In contrast, genistein, a potent tyrosine kinase inhibitor of the isoflavone class, did not inhibit PtdIns 3-kinase significantly (IC50 > 30 micrograms/ml). Since quercetin has also been shown to inhibit other PtdIns and protein kinases, other chromones were evaluated as inhibitors of PtdIns 3-kinase without affecting PtdIns 4-kinase or selected protein kinases. One such compound, 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (also known as 2-(4-morpholinyl)-8-phenylchromone, LY294002), completely and specifically abolished PtdIns 3-kinase activity (IC50 = 0.43 microgram/ml; 1.40 microM) but did not inhibit PtdIns 4-kinase or tested protein and lipid kinases. Analogs of LY294002 demonstrated a very selective structure-activity relationship, with slight changes in structure causing marked decreases in inhibition. LY294002 was shown to completely abolish PtdIns 3-kinase activity in fMet-Leu-Phe-stimulated human neutrophils, as well as inhibit proliferation of smooth muscle cells in cultured rabbit aortic segments. Since PtdIns 3-kinase appears to be centrally involved with growth factor signal transduction, the development of specific inhibitors against the kinase may be beneficial in the treatment of proliferative diseases as well as in elucidating the biological role of the kinase in cellular proliferation and growth factor response.

Adenosine Triphosphate↗
PubMed1994

Median nerve compression within the humeral head of pronator teres.

We describe a case of the pronator syndrome caused by compression of the median nerve by a fibrous band as the nerve passed through the humeral head of origin of pronator teres. This rare anatomical arrangement resulted in displacement of the median nerve to the anterior aspect of the medial humeral epicondyle and, as far as we are aware, has not previously been described as a site of compression neuropathy.

Elbow Joint↗
PubMed1993

The ultrastructure of rat lung following acute primary blast injury.

While a number of workers have described the effects of blast waves upon the lung at both the macroscopic and light microscopic level, studies involving the use of the electron microscope have not been reported. In the experiments reported here the ultrastructural changes seen in lungs from rats exposed to a blast wave impacting on the right side of the chest are described. Considerable damage to the right lower lobe was observed which took the form of tearing of the inter-alveolar septa with capillary rupture and intra-alveolar haemorrhage. Changes to the alveolar epithelium and type II pneumocytes were also noted. Lesions were also identified in the left lung; these included intra-alveolar oedema with a minimal amount of interstitial oedema together with increased pinocytosis and isolated rupture of the alveolar epithelium. 'Ballooning' of the endothelium into the lumen of the capillary was also observed. There was an indication that lesions noted in the left lung at the electron microscopic level may be progressive in the first 24 hours following injury.

Animals↗
PubMed1992

The inhibition of phosphatidylinositol 3-kinase by quercetin and analogs.

Phosphatidylinositol (PtdIns) 3-kinase is an enzyme involved in cellular responses to growth factors. Quercetin (2-(3,4-dihydroxyphenyl)-3,5,7-trihydroxy-4H-1-benzopyrano-4-one), a naturally occuring bioflavinoid, was found to inhibit PtdIns 3-kinase with an IC50 of 1.3 micrograms/ml (3.8 microM); inhibition appears to be directed towards the ATP binding site of the kinase. Analogs of quercetin were also investigated as PtdIns 3-kinase inhibitors, with the most potent compounds exhibiting IC50's in the range of 1.7-8.4 micrograms/ml (5-19 microM). In contrast, genistein, a potent tyrosine kinase inhibitor of the isoflavone class, did not inhibit PtdIns 3-kinase significantly (IC50 greater than 30 micrograms/ml). These findings suggest that flavinoids may serve as potent inhibitors of PtdIns 3-kinase. Furthermore, the enzyme is much more sensitive to substituents at the 3-position of the flavinoid ring than are other protein and PtdIns kinases, suggesting that specific inhibitors of PtdIns 3-kinase can be developed to explore the biological role of the enzyme in cellular proliferation and growth factor response.

Animals↗
PubMed1992

The effects of ileocystoplasty on the development of renal failure in a rat model 5/6 nephrectomy.

We examined the effects of ileocystoplasty on renal function and bone mineral content in 160 juvenile male Wistar-Furth rats with and without renal insufficiency induced by 5/6 nephrectomy. At intervals up to 20 weeks blood, bone and kidney samples were obtained with the animals under anesthesia and then they were sacrificed. Serum parameters of renal function and calcium metabolism were measured. Samples of bone were analyzed for calcium, magnesium and phosphorus content. At 20 weeks after 5/6 nephrectomy renal function was decreased by approximately half. The decrease in renal function and the changes in renal histology were identical in animals with and without ileocystoplasty. Bone mineral content in the animals with renal insufficiency with or without ileocystoplasty was not different from sham operated animals or from animals with an ileocystoplasty and normal renal function. These studies demonstrate that ileocystoplasty per se does not hasten the progression to renal failure or produce bone demineralization in rats having moderate renal insufficiency.

Animals↗
PubMed1991

Losartan, a nonpeptide angiotensin II (Ang II) receptor antagonist, inhibits neointima formation following balloon injury to rat carotid arteries.

Angiotensin-converting enzyme inhibitors have been shown to inhibit intimal thickening following balloon catheterization of rat carotid arteries. To assess the role of the renin-angiotensin pathway and the angiotensin type-I (AT1) receptor in this effect, the nonpeptide Ang II antagonist losartan (DuP 753) or vehicle was infused continuously i.v. in rats from two days before to two weeks after balloon injury to the left common carotid artery; drug effects upon intimal thickening were examined histologically. Losartan produced a dose-dependent reduction in cross-sectional area of intimal lesions determined two weeks post balloon injury. At 5 mg/kg/day a nonsignificant 23% reduction of intimal area was observed. At the higher dose of 15 mg/kg/day, losartan produced a 48% reduction in intimal area (P less than 0.05) compared to the vehicle-infused group. The cellular density of the neointima was not affected by losartan, indicating a probable effect of the drug upon migration and/or proliferation of smooth muscle cells. In separate groups of non-ballooned rats, losartan infusions of 5 and 15 mg/kg/day produced significant rightward shifts (averaging 6.4- and 55-fold, respectively) in curves relating increases in blood pressure to intravenous Ang II in pithed rats determined between 2 and 16 days following initiation of losartan infusion. Mean arterial blood pressure (determined under alpha-chloralose anesthesia) was reduced following continuous losartan infusion for 6 days from 128 +/- 8 mm Hg (vehicle) to 105 +/- 8 mm Hg at 5 mg/kg/day (P less than 0.05), and 106 +/- 4 mm Hg at 15 mg/kg/day (P less than 0.05). Thus, losartan attenuated the vascular response to balloon catheter injury, and this effect was associated with functional block of vascular AT1 receptors. The results support a role for Ang II, acting via AT1 receptors, in myointimal thickening subsequent to balloon injury of rat carotid arteries.

Analysis of Variance↗
PubMed1991

166Holmium-containing glass for internal radiotherapy of tumors.

Aluminosilicate glass containing the beta-emitter 166Ho was tested for tumor cell killing effectiveness with the BT-20 human mammary carcinoma cell line as a model. Incubation of BT-20 cells with 166Ho glass partially inhibited DNA replication and completely blocked growth in cells located within 1.0 mm of the radioactive fiber. Growth of BT-20 tumor xenografts in nude mice was dramatically inhibited by injection of 2-5 microns fragments of 166Ho glass (200 microCi/tumor). The results suggest that 166Ho glass would be an effective modality for deposition of intense beta- radiation for localized internal radiotherapy of tumors.

Animals↗
PubMed1991

Biochemical and cellular mechanisms of pulmonary fibrosis.

This review summarizes the manner in which a variety of agents may induce fibrogenic reactions in the lung. The extent of reaction is dependent on dose, time scale of exposure, and chemical reactivity. The regime of multiple dosing with chemicals or gases with recovery periods is important in disease progression. The means by which biochemists and histopathologists assess fibrosis, the advantages and disadvantages of each of the methods as related to subjectivity, quantitation, and speed of analysis are compared. The mechanisms which control the step from fibrogenesis (a potentially reversible reaction) to fibrosis (irreversible) may be linked to the maturation of collagen, calcification, or the formation of cross-linked protein masses. Attention is given to hydroxylysine cross-links in newly formed "fibrotic" collagen but focusses on gamma-glutamyl-epsilon-lysyl cross-links formed by calcium-dependent transglutaminases. It is suggested that these enzymes, released by replacement epithelial cells, could be responsible for the formation of stabilized protein masses in the lung, thus contributing to a progressive fibrosis.

Animals↗
PubMed1991

Electron microscopy of rat lung following a single acute exposure to perfluoroisobutylene (PFIB). A sequential study of the first 24 hours following exposure.

The histopathology of rat lung has been studied after an acute exposure to perfluoroisobutylene (PFIB) at a concentration of 638 mg/m3 (78 p.p.m.) for 1.5 min giving a Ct = 957 mg min/m3 for the first 24 h following exposure. Within 5 min of exposure changes to the bronchioles and peribronchial alveoli were observed which took the form of alterations to cilial structure, increased pinocytosis and electron lucency, with occasional vesicle formation of type I alveolar epithelial cells. Intercellular leakage with minimal fluid accumulation in the alveolar spaces was also seen. The very rapid action of PFIB strongly suggests a direct action by the compound. There then followed the gradual development of pulmonary oedema which was visible histologically 2-3 h post exposure with deaths occurring from 7 h onwards. Animals sacrificed at 24 h post exposure showed evidence of widespread pulmonary oedema and alveolar interstitial infiltration by lympho-mononuclear cells and macrophages.

Animals↗
PubMed1991

Effects of experimental sarin intoxication on the morphology of the mouse diaphragm: a light and electron microscopical study.

A sublethal dose of sarin (GB, isopropyl methylphosphonofluoridate) was administered to mice. The animals were killed up to 28 days after dosing. Following excision, diaphragms were divided into two halves and used for ultrastructural examination and light microscopy. Planar sections of diaphragm showed muscle fibre degeneration and predominantly mononuclear infiltration, notably at 24 h. Semithin toluidine blue-stained sections and ultrastructural studies demonstrated hypercontraction with gross disruption of sarcomeres including loss of Z and A bands, which appeared to be associated with neuromuscular junctions. All changes were rapidly regressing by 7 days.

Animals↗
PubMed1990

Comparative reactivity of 1-carba-1-dethiacephalosporins with cephalosporins.

Nine matched pairs of cephalosporins and their 1-carba-1-dethiacephalosporin analogues have been compared with regard to microbiological activity, beta-lactam carbonyl infrared absorption, and aqueous stability. In general the microbiological activity of the pairs of compounds were very similar across a broad range of bacteria. The infrared absorption bands for the beta-lactam carbonyls of the pairs indicated a general trend for the 1-carba-1-dethiacephalosporins to absorb at lower frequencies than the corresponding cephalosporins. All of the 1-carba-1-dethiacephalosporins did however present a striking stability enhancement over their cephalosporin counterparts at pH = 10 or 11 in water. This marked contrast of MIC similarity with the observed differences in chemical reactivity clearly demonstrates hydroxide ion catalyzed hydrolysis is not a good model for transpeptidase activity unless the compounds comprise a limited domain of structural type.

Cephalosporins↗