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Biomedical subjects

R F Brown

Publications and source records attributed to R F Brown.

At least 19 recordsLinked to original sources
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↗
PubMed1990

Synthesis and biological evaluation of a series of parenteral 3'-quaternary ammonium cephalosporins.

The preparation and biological evaluation of a series of 7 beta-[2-(2-aminothiazol-4-yl)-2(Z)-methoximinoacetamido]cep halosporins, substituted at the 3'-position with monocyclic or bicyclic nitrogen-containing heterocycles are described. The resulting family of parenteral compounds displays a broad spectrum of antibacterial activity. Some compounds exhibit a similar level of Gram-negative activity to that of the "third-generation" cephalosporins with increased staphylococcal activity. The in vitro and in vivo antimicrobial activity, structure-activity relationships, beta-lactamase stability, and in vitro and in vivo pharmacological evaluations are presented.

Animals↗
PubMed1990

The histopathology of rat lung following exposure to zinc oxide/hexachloroethane smoke or installation with zinc chloride followed by treatment with 70% oxygen.

The effects of inhaled zinc oxide/hexachloroethane smoke (11,580 mg x min/m3) and intratracheally instilled zinc chloride (2.5 mg/kg body weight) have been studied in rat lung. The effects of subsequent treatment with 70% oxygen have been studied after both procedures. Both the inhalation of the smoke and instillation of zinc chloride produced similar effects that included pulmonary edema, alveolitis and, at a later stage, some fibrosis. After zinc chloride instillation, the pathological changes largely spared the periphery of the lung, while following smoke inhalation they were more diffuse. Subsequent oxygen administration had little effect on the development or progression of the pathological changes.

Administration, Inhalation↗
PubMed1990

Screening, diagnosis, and management of dyslipoproteinemia in children.

The authors provide an extensive and comprehensive review of dyslipoproteinemia in children. An effective program for CVD reduction in this population will include an accessible screening program to identify high-risk children, high-quality measurements of TC and LP-C, careful follow-up of screening results with multiple measurement to classify risk status and diagnose primary dyslipidemia, a key role for family and education, and consistent and long-term follow-up for diet and drug adherence, efficacy, and safety.

Adolescent↗
PubMed1989

The biochemical and pathological changes produced by the intratracheal instillation of certain components of zinc-hexachloroethane smoke.

Zinc chloride which is formed by igniting a mixture of zinc oxide and hexachloroethane in the production of white smokes has been shown to produce oedema when given to rats as a single instillation. The oedematous reaction, as assessed by histopathology and measurements of alveolar surface protein in lavage fluid, is variable, dose-dependent, and maximal at 3 days but at sub-lethal doses it regresses after 7 days. The parent compound, zinc oxide, does not produce these effects. In some animals there is evidence of a fibrogenic response at 7 days post-exposure although it is currently unknown whether or not this effect is progressive.

Animals↗
PubMed1988

The repeated dose toxicity of a zinc oxide/hexachloroethane smoke.

Mice, rats and guinea pigs were exposed to the smoke produced by ignition of a zinc oxide/hexachloroethane pyrotechnic composition, 1 h/day, 5 days/week, at three different dose levels, together with controls. The animals received 100 exposures except for the high dose guinea pigs, which underwent 15 exposures, because of high death rate during the first few days of exposure. The test material had very little effect on weight gain, but there was a high rate of early deaths in the top dose of mice. A variety of incidental findings was seen in both decedents and survivors, but organ specific toxicity was, with one exception, confined to the respiratory tract. The most important of these findings was a statistically significant increase in the frequency of alveologenic carcinoma in the high dose group mice (p less than 0.01) and a statistically significant trend in the prevalence of the same tumour over all dose groups and the controls. A variety of inflammatory changes was seen in the lungs of all species and some appeared to be treatment-related. Fatty change in the mouse liver was more common in the middle and high dose groups than the controls. The aetiology of the tumour incidence is discussed and it is pointed out that hexachloroethane and zinc, as well as carbon tetrachloride, which may be present in the smoke, may be animal carcinogens in appropriate circumstances. Carbon tetrachloride is a known human carcinogen.

Animals↗
PubMed1988

Use of enzyme immunoassay for the rapid diagnosis of Chlamydia trachomatis endocervical infection in female adolescents.

Enzyme immunoassay (EIA) has been proposed as an alternative to tissue culture for the detection of Chlamydia trachomatis in cervical specimens. The diagnostic efficacy of EIA was compared to tissue culture in 113 teenaged females attending an adolescent reproductive health program. Infection was diagnosed by tissue culture in 16% of subjects. Compared with tissue culture, EIA demonstrated a sensitivity of 100%, specificity of 88%, positive predictive value of 62%, and a negative predictive value of 100%. These data indicate that EIA is an acceptable alternative to tissue culture when screening for C. trachomatis endocervical infection in adolescent females.

Adolescent↗
PubMed1988

An investigation of possible models for the production of progressive pulmonary fibrosis in the rat. The effects of repeated intratracheal instillation of bleomycin.

Pulmonary fibrosis is a common later sequel to damage to the lung caused by a wide variety of agents. Bleomycin is an antineoplastic drug used in the treatment of squamous cell carcinomas and lymphomas. It is known to cause pulmonary fibrosis is both man and experimental animals. Bleomycin, dissolved in saline, was given by intratracheal instillation (dose = 0.5 U/animal; dose vol. = 0.5 ml/animal) to groups of at least 5 rats. Groups received either a single dose or 2, 3 or 4 doses each given a week apart. They were then sacrificed at periods of up to 90 days after the last dose. Subsequent histology revealed varying degrees of alveolitis, type II pneumocyte hyperplasia, alterations to alveolar structure including obliteration, degeneration, collapse and enlargement with significant interstitial fibrosis. The lesion appeared to be diffusely distributed throughout the lung. After a single dose or 2 doses regression of the lesion was observed with time following dosing whereas with 3 or 4 doses of bleomycin the changes increased progressively in extent and severity. Three or more doses of intratracheal instilled bleomycin appear to be a good model of progressive pulmonary fibrosis in the rat.

Animals↗
PubMed1987

Skull x-ray examinations after head trauma. Recommendations by a multidisciplinary panel and validation study.

The value of skull radiography in identifying intracranial injury has not yet been satisfactorily defined. A multidisciplinary panel of medical experts was assembled to review the issue of skull radiography for head trauma. The panel identified two main groups of patients--those at high risk of intracranial injury and those at low risk of such injury--and developed a management strategy for imaging in the two groups. The high-risk group consists primarily of patients with severe open or closed-head injuries who have a constellation of findings that are usually clinically obvious. These patients are candidates for emergency CT scanning, neurosurgical consultation, or both. The low-risk group includes patients who are asymptomatic or who have one or more of the following: headache, dizziness, scalp hematoma, laceration, contusion, or abrasion. Radiographic imaging is not recommended for the low-risk group and should be omitted. An intermediate moderate-risk group is less well defined, and skull radiography in this group may sometimes be appropriate. A prospective study of 7035 patients with head trauma at 31 hospital emergency rooms was conducted to validate the management strategy. No intracranial injuries were discovered in any of the low-risk patients. Therefore, no intracranial injury would have been missed by excluding skull radiography for low-risk patients, according to the protocol. We conclude that use of the management strategy is safe and that it would result in a large decrease in the use of skull radiography, with concomitant reductions in unnecessary exposure to radiation and savings of millions of dollars annually.

Brain Injuries↗
PubMed1987

Salmonella typhi 205aTy, a strain with two attenuating auxotrophic characters, for use in laboratory teaching.

The need for p-aminobenzoic acid of a previously reported pab mutant in a Salmonella typhi strain causes loss of virulence (mouse median lethal dose by the intraperitoneal route with mucin, ca. 10(7) CFU, versus less than 200 CFU for related pab+ strains). This strain, however, gave p-aminobenzoic acid-independent revertants at a low frequency (ca. 4 X 10(-10) per bacterium per generation). It was therefore given, by transduction and mutation, a transposon-generated, nonreverting (rate, less than 3 X 10(-11) per bacterium per generation) mutation at purA, causing a requirement for adenine; such a mutation in a wild-type strain caused about the same loss of virulence as the pab mutation. The pab purA strain, 205aTy, has mouse median lethal dose of ca. 5 X 10(7) and is expected to be unable to cause typhoid fever. Since strain 205aTy behaves like a typical Vi-positive S. typhi strain in nearly all common tests, we propose that it is a safe strain for use in laboratory teaching, proficiency testing, and the like.

4-Aminobenzoic Acid↗