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P Greaves

Publications and source records attributed to P Greaves.

At least 19 recordsLinked to original sources
PubMed2000

Patterns of cardiovascular pathology induced by diverse cardioactive drugs.

In the beagle dog, exaggerated hypotension and tachycardia following administration of high doses of vasodilating antihypertensive drugs are associated with vascular injury and characteristic patterns of myocardial necrosis and haemorrhage. Cardiac and vascular inflammation and necrosis also occur in dogs in association with different functional changes including severe hypertension and the effects that follow treatment with high doses of vasoconstrictor and pressor drugs. More recently, cardioactive drugs of novel classes such as the endothelin antagonists have also been shown to produce vascular damage in the beagle dog but in the absence of ischaemic myocardial damage or significant haemodynamic alterations that typically follow administration of high doses of vasodilating antihypertensive or pressor drugs. This underlines the importance of a careful analysis of the patterns of cardiovascular pathology, their dose, temporal and spatial relationships in the context of functional changes.

Animals↗
PubMed1999

First-postgraduate-year resident clinical time use on three specialty rotations.

OBJECTIVE: To compare in-hospital time uses by first-postgraduate-year (PGY1) residents during rotations in emergency medicine (EM), internal medicine (IM), and surgery (S). This article reports the clinical components of residency time use. METHODS: A cross-sectional, observational study of the clinical activities of EM PGY1 residents was performed while the residents were on duty during the three specialty rotations. The activities were recorded by an observer using a log with predetermined categories for clinical activities. A time-blocked, convenience sample of resident shifts was observed for each service rotation. The sample was proportional to the total number of hours for which a PGY1 resident was expected to be in the hospital during a rotation on that service. No attempt was made to sample the same resident at all time periods or on all rotations. Proportions were compared by chi2; alpha = 0.0001. RESULTS: Twelve PGY1 residents were observed for a total of 166 hours on S, 156 hours on IM, and 120 hours on EM. These hourly amounts were representative of a typical two-week span of service on each rotation for the residents. On average, the residents spent 57% of their time on clinical or service-oriented activities. During EM and IM rotations, the residents spent most of their time performing clinical information gathering and engaging in case management and data synthesis (52% of total clinical effort). Within this category, residents on EM were more involved with case discussion and review of ancillary test results than on IM (34% vs 20% of time in this category). Conversely, proportionately less time in this category was devoted to documentation on the EM vs IM rotation (56% vs 80%; p < 0.0001). The greatest opportunity to perform procedures was on the S rotation (31% of total clinical time vs 6% for other specialties; p < 0.0001). CONCLUSION: Awareness of the clinical activities performed on PGY1 rotations can help residency directors anticipate educational needs to balance their residents' experience. Since 29% and 42% of total clinical time on PGY1 EM and IM rotations, respectively, is focused on documentation, efforts to enhance charting skills and efficiency are warranted. Also, efforts to enhance PGY1 procedural experience outside of the S rotation appear warranted.

Adult↗
PubMed1998

Patterns of drug-induced cardiovascular pathology in the beagle dog: relevance for humans.

In toxicity studies, the examination of tissue sections for pathological changes is the principle method for the identification of organ toxicity and characterisation of the hazard of novel drugs for humans. Study of the patterns of pathological alterations also represents an important means of developing an understanding of the mechanism of toxicity. However as pathological change frequently represents a final common expression of diverse processes, additional functional information is often required for a clear understanding of the mechanisms of toxicity. This is exemplified in the evaluation of the effects of drugs on the beagle dog cardiovascular system where an understanding of mechanisms is crucial in the assessment of human risk. Particular patterns of drug-induced structural change in the myocardium or blood vessels are frequently linked to specific mechanisms of toxicity. However, assessment based on the interpretation of patterns of cardiovascular pathology alone may be misleading. Quite different changes in cardiac and vascular function or direct cellular toxicity may also be manifest by pathological features in common. Therefore, a clear understanding of mechanism frequently requires additional in vivo or in vitro physiological, pharmacological, biochemical or other mechanistic information. The beagle dog remains an important model for the study of cardiovascular toxicity because in this species, haemodynamic changes and pathological alterations can be related in a way that provides the basis for the safe study in humans of novel drugs with cardiovascular activity.

Animals↗
PubMed1997

Analysis of a commercially improved Penicillium chrysogenum strain series: involvement of recombinogenic regions in amplification and deletion of the penicillin biosynthesis gene cluster.

Several commercially improved strains of Penicillium chrysogenum have been shown to carry amplifications of the entire penicillin biosynthesis gene cluster. Analysis previously carried out using the strain BW 1890 has here been extended to the characterisation of other members of the SmithKline Beecham strain improvement series. We have determined the length of the amplicon to be 57.4 kb and shown a general increase in copy number and penicillin titre through the series. Sequence analyses of the promoter regions of the acvA, ipnA and aat genes in the high titre strain BW 1901, and comparisons with wild-type sequences have not identified any potentially titre-enhancing mutations. In addition, cDNA screening has failed to identify any further transcribed elements within the co-amplified region. The homogeneity of hybridisation patterns and the identification and analysis of a single copy revertant has shown that the amplification is of a direct tandem nature and we propose a model of chromatid misalignment and recombination as its mode of generation. Hybridisation analysis of penicillin non-producing mutants has indicated the loss, in all those investigated, of the entire penicillin biosynthesis gene cluster, similarities between the deletion junctions in these strains and comparison with previously published data indicating the presence of recombinogenic regions flanking the penicillin biosynthesis gene cluster.

Chromosome Mapping↗
PubMed1996

The evaluation of potential human carcinogens: a histopathologist's point of view.

Over 100 marketed drugs induce neoplasia when administered at high doses to rats and mice for periods of up to two years. Despite their diverse chemical structures and biological activities, these compounds produce a relatively limited range of tumour types in rodents, most commonly in the liver. Tumours usually develop only after long periods of time following high exposure to drug. The main exceptions are DNA-reactive anticancer drugs such as alkylating agents which produce tumours rapidly in rodents in several organs. In this laboratory, mouse carcinogenicity studies are performed using the C57BL/10J strain. This strain infrequently develops hepatic tumours spontaneously but it is sensitive to the effects of DNA-reactive carcinogens. Moreover, hepatic neoplasms regularly develop in male but not female C57BL/10J mice following long-term treatment with nongenotoxic drugs that produce hepatic enlargement associated with diverse hepatocellular effects. Studies in this strain with the tumorigenic liver enlarger, phenobarbitone, have shown that although such liver enlargement is characterised by a brief burst of hepatocyte replication, this is associated with persistent regional modulation of hepatic growth stimulatory and inhibitory factors and their associated receptors. These findings indicate that there is a sustained alteration to the internal hepatic environment characterised by regional alterations to the balance of hepatocyte mitogens and inhibitors of replication and their respective receptors. Thus, the development of hepatocellular tumours in C57BL/10J mice following two-year treatment with nongenotoxic drugs appears to be a regular response of an organ to an exaggerated and long-term disruption of its homeostasis. Agents that produce tumours in rodents in this way seem likely to pose little or no risk to humans if administered under appropriate clinical circumstances at doses which show no significant disruption of organ homeostasis. However, drugs that produce this type of response need to be distinguished from those that induce unusual and rapid patterns of tumour development because these agents may have high tumorigenic potency of potential hazard to humans.

Animals↗
PubMed1996

Home care accreditation with the community health accreditation program: part II: the process.

The CHAP accreditation process provides an external, objective marker for the clients served by an agency. This marker indicates that the agency has met national standards of organizational strength and quality. The process results in a detailed analysis of the organization's overall strengths and weaknesses and provides expert consultation regarding findings. This ongoing consultative relationship between CHAP staff members and/or site visitors and agency leadership provides a continued framework for organizational expansion and change to meet ever-changing health-care needs.

Accreditation↗
PubMed1993

Two-year carcinogenicity study of tamoxifen in Alderley Park Wistar-derived rats.

Tamoxifen, a nonsteroidal antiestrogen used widely in the treatment of breast cancer, was tested in a conventional 2-year carcinogenicity bioassay in rats, a species in which tamoxifen acts variably as a partial agonist and antagonist on different target tissues. Groups of 51 males and 52 females were given 5, 20, and 35 mg/kg of tamoxifen/day by gastric intubation in 0.5% hydroxypropyl methylcellulose at 5 ml/kg dose volume. There were 102 male and 104 female controls dosed with vehicle alone. Growth rate and food consumption were reduced in all treated groups. The major finding was a dose-related increase in the incidence of hepatocellular tumors which were first observed after 31 weeks of treatment in the top dose group. The majority of the neoplasms were hepatocellular carcinomas showing a well differentiated trabecular pattern. Some tumors were glandular in type. Mortality was increased in the 20 and 35 mg/kg dose groups compared with controls as a result of these tumors. By contrast, survival was greater than controls in rats given 5 mg/kg tamoxifen despite the presence of hepatocellular tumors due to a reduction in the number of pituitary tumors in females and less chronic renal disease in males. The mechanism of hepatic tumor induction by tamoxifen in rats is unclear. In view of the lack of genotoxic activity in conventional genotoxicity studies and lack of similar effect in mice or in humans, the findings may relate to a particular constellation of effects in rats. All other drug-induced changes in this study were nonneoplastic in nature and most appeared to be the result of hormonal perturbation since they were confined to endocrine organs or have been seen previously in rats treated for long periods with tamoxifen.

Animals↗
PubMed1993

Crescentic cataracts in Alderley Park rats.

The ophthalmoscopic appearances and the clinical evolution of a previously poorly documented form of crescentic cataract was studied in over 2,000 untreated Alderley Park rats between 4 and 110 weeks of age. In addition, 401 ex-breeder females, 54 gonadectomized males, and 56 gonadectomized females of the same strain were studied. The light microscopic features of the lenticular changes were also examined in detail. The cataracts, crescentic in shape and originating dorsally at the lens equator, were mostly unilateral. They appeared from about 30 weeks of age and affected 4% of intact males and 14% of intact females by about 2 years of age. Fewer cataracts were found in ex-breeder females, and none were found in male or female gonadectomized rats up to 2 years of age. The cataracts developed rapidly and became fully formed in 3 months. Subsequently, most cataracts scarcely progressed. Only a few extended to involve the entire lens. Some appeared to regress completely. Histologically, affected lens fibers showed swelling, globular disintegration, and liquefaction, most marked in the cortex medial to the lens bow area and extending along the direction of the lens fibers in an anterior and posterior direction but only occasionally reaching the lens capsule. The cause of these age-related lenticular changes in the Alderley Park rat is uncertain, but these changes are important during the conduct of long-term studies with this strain because their incidence can be modulated by agents that alter sex hormone status.

Aging↗
PubMed1991

Long-term effects of an inotropic phosphodiesterase inhibitor (ICI 153,110) on the rat salivary gland, harderian gland, and intestinal mucosa.

The inotropic vasodilator, ICI 153,110, a phosphodiesterase inhibitor intended for the treatment of congestive heart failure, was administered to Alderley Park Wistar-derived rats for periods of up to 182 days. Treatment produced hypertrophy of salivary glands, hyperplasia of intestinal mucosa, and dacryoadenitis of the harderian gland. As the functions of these glandular tissues can be modified by factors which alter cyclic nucleotide metabolism, it is postulated that the glandular alterations produced by ICI 153,110 occurred as a result of phosphodiesterase inhibition.

Animals↗
PubMed1990

Isolation and characterisation of the crnA-niiA-niaD gene cluster for nitrate assimilation in Aspergillus nidulans.

Genomic clones containing the entire crnA-niiA-niaD gene cluster of Aspergillus nidulans have been isolated, and the structures of the niiA and niaD genes have been determined by nucleotide sequence analysis. This gene cluster is required for the assimilation of nitrate in A. nidulans, and the three genes encode a product required for nitrate uptake and the enzymes, nitrite reductase and nitrate reductase, respectively. The putative coding sequences, as deduced by comparison to cDNA clones of both niiA and niaD, are interrupted by multiple small introns, and the two genes are divergently transcribed. Identification and characterization of specific mRNAs involved in nitrate assimilation indicates that only monocistronic transcripts are involved, and that the approximate sizes of these transcripts are 1.6 kb, 3.4 kb and 2.8 kb for crnA, niiA and niaD, respectively. The results also indicate that control of niiA and niaD gene expression is mediated by the levels of mRNA accumulation, in response to the source of nitrogen in the growth medium. Two types of transcripts for niiA were observed.

Amino Acid Sequence↗
PubMed1990

Pathologic changes in blood vessels following administration of an inotropic vasodilator (ICI 153,110) to the rat.

ICI 153,110 is an inotropic vasodilator compound intended for the treatment of congestive heart failure. It was administered to rats at dose levels of 5, 10, and 250 mg/kg/day for up to 6 months as part of its preclinical development program. Detailed clinical investigations were conducted during the course of the study and histopathological examination took place after 28 days and 182 days of treatment as well as 42 days following cessation of dosing. Changes were identified in blood vessels in the greater proportion of animals from the high dose group, although some of the changes were also observed at lower dose levels. Vascular tissues from a variety of sites were affected, particularly those of the mesentery, splanchnum, heart, testis, and the pampiniform plexus. Early changes characteristic of acute injury such as arterial medial necrosis and inflammation occurred, which were distinguishable from those following chronic administration of the compound where there was a pronounced arterial and venous wall thickening and accompanying plexiform vasculopathy. The essential components contributing to the thickening were a smooth muscle hypertrophy and hyperplasia of the media. At the end of the period following withdrawal of dosing, vascular thickening was still present and arteritis showed an increased incidence relative to that seen at termination of the main test. Systemic hypertension was not detected during these studies. Vasodilation occurring at or near normal blood pressure, resulting in breakdown of vascular autoregulation and excessive critical wall tension, may have been the cause of the pathological changes. Our findings indicate that medial necrosis is an early component in a sequence of adaptive, destructive, and reparative changes not only following a chemically induced perturbation of the hemodynamic status in arteries and veins but also following a shift back to the "normal state" on withdrawal of compound.

Animals↗
PubMed1989

Polyarteritis in a beagle.

A 13-month-old Beagle became anorectic and had fever, stiff gait, and tenderness in the inguinal region. Clinical signs of disease were associated with neutrophilia and a decrease in the albumin-to-globulin ratio. The dog became clinically normal for 5 days after 3 days of treatment with penicillin G and dihydrostreptomycin. Clinical signs of disease recurred, and the dog was euthanatized after failing to respond to administration of a trimethoprim-sulfamethoxazole combination for 9 days. Disseminated arteritis was seen in the testes, epididymides, mesentery, coronary arteries, aorta, and thyroid gland. Lesions were seen in large and medium-sized arteries and varied from acute necrotizing arteries to a chronic lesion with organization and recanalization of thrombi. The clinical signs of disease resembled those of Beagle pain syndrome, described in laboratory Beagles.

Animals↗
PubMed1989

Renal and hepatic toxicity of a benzopyran-4-one in the Cynomolgus monkey.

The administration of PD 119819, a novel benzopyran-4-one brain dopamine autoreceptor agonist, to Cynomolgus monkeys was followed by deposition of needle-like drug crystals in the bile canaliculi, hepatocytes, proximal renal tubules and renal parenchyma. The crystals were associated with a granulomatous inflammation, and histological and biochemical evidence of hepatic and renal cell damage. Although metabolism differences may be the reason why primates, but not rodents, developed these changes, this form of crystallization appeared to be primarily a result of the insolubility of PD 119189 at alkaline pH.

5'-Nucleotidase↗
PubMed1987

A cytochemical study of the livers of rats treated with diethylnitrosamine/phenobarbital, with benzidine/phenobarbital, with phenobarbital, or with clofibrate.

Male Sprague-Dawley rats were treated with clofibrate (CLOF) in the diet for 2 years or with 4 i.p. injections of either diethylnitrosamine (DEN) or benzidine (BZ) followed by phenobarbital (PB) in the diet for 67 weeks, or just with PB for 41 weeks. Animals were killed at frequent intervals, some while still on treatment and others after 3 or 6 months withdrawal of treatment. The livers were subjected to cytochemical measurements of the parenchyma, foci, nodules and carcinomas. The parenchyma of the CLOF groups showed, in general, increases in glucose-6-phosphate dehydrogenase (G-6PD), alpha-glycerophosphate dehydrogenase (alpha-GPD), 5'-nucleotidase (5'-Nu), acid phosphatase (AP) and catalase and decreases in uricase and glutathione (GSH). CLOF induced a low incidence of GSH positive foci; nodules showed universally lower levels of catalase and GSH. In the DEN/PB and BZ/PB groups the parenchyma showed increases (even before PB treatment started) in G-6PD and in gamma-glutamyl transpeptidase (gamma-GT) and decreases in GSH. DEN raised and BZ lowered 5'-Nu. Neither initiator affected alpha-GPD. Both initiators caused a high incidence of foci positive for G-6PD and for gamma-GT; nodules induced by DEN/PB were mainly positive for gamma-GT and showed an erratic response to the other parameters. Carcinomas, found only after DEN/PB, were all positive for G-6PD and, with one exception, all were negative for alpha-GPD, 5'-Nu, AP and GSH. All changes regressed within 3 months of withdrawal of CLOF but not after withdrawal of PB from DEN-initiated animals. In conclusion G-6PD, alpha-GPD and 5'-Nu may be useful histocytochemical parameters for studying the precarcinogenic hepatic changes and nodules induced by peroxisome proliferators and by genotoxic hepatocarcinogens.

Administration, Oral↗
PubMed1987

Periarteritis in a beagle colony.

Primary periarteritis, an uncommon necrotizing vasculitis in the dog, was found to affect, almost exclusively, the major branches of the coronary arteries in a number of young beagle dogs. The arteritis was mainly distributed in the proximal segment of the right coronary artery. Immunocytochemical studies failed to identify immunoglobulin deposits in the lesions and the cause of the arteritis remains unknown. It is important to be aware of this spontaneous condition and its regional distribution since certain cardiovascular drugs may also produce necrotizing arteritis at similar sites.

Animals↗