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Biomedical subjects

T Green

Publications and source records attributed to T Green.

At least 19 recordsLinked to original sources
PubMed1992

Residential care for the long term mentally ill in Canterbury: options, costs and funding sources.

AIMS: To obtain estimates of the costs of the main options of care for the long term mentally ill and to compare different approaches to costing. METHOD: Resources used by samples of residents in extended hospital care (EC, n = 43), community staffed houses (SH, n = 30), boarding houses (BH, n = 43) and group homes (GH, n = 100) were identified and costed using both the expenditure and total resource concepts of cost estimation. RESULTS: Using the expenditure concept of cost SH was the most expensive at $773 per person per week, compared to $700 for EC, $189 for BH and $155 for GH. Using the resource cost approach, valuing all resources used, SH and EC were similar at $790, compared to $184 and $169 for BH and GH care. Nursing was the most costly input with striking differences between nursing costs in the four modes of care. CONCLUSIONS: The results indicate a gap in the spectrum of residential care options, between high and low cost care. Future funding arrangements will require improved linkage between needs assessment and resource provision.

Capital Financing↗
PubMed1992

A mechanism for the development of Clara cell lesions in the mouse lung after exposure to trichloroethylene.

Female CD-1 mice exposed to trichloroethylene (6 h/day) at concentrations from 20-2000 ppm developed a highly specific lung lesion after a single exposure, characterised by vacuolation of the Clara cells, the number of cells affected increasing with increasing dose level. At the highest dose levels pyknosis of the Clara cells was apparent. After 5 days of repeated exposures the lesion had resolved but exposure of mice following a 2-day break resulted in recurrence of the lesion. The changes in mouse lung Clara cells were accompanied by a marked loss of cytochrome P-450 activities. No morphological changes were seen in the lungs of rats exposed to either 500 or 1000 ppm trichloroethylene. Isolated mouse lung Clara cells were shown to metabolize trichloroethylene to chloral, trichloroethanol and trichloroacetic acid. Chloral was the major metabolite. Trichloroethanol glucuronide was not detected. In comparative experiments using mouse hepatocytes the major metabolites were trichloroethanol and its glucuronide conjugate. The activity of UDP-glucuronosyltransferase was compared in mouse lung Clara cells and hepatocytes using two phenolic substrates and trichloroethanol. Hepatocytes readily formed glucuronides from all three substrates whereas Clara cells were only active with the two phenolic substrates. The three major metabolites of trichloroethylene, chloral, trichloroethanol and trichloroacetic acid were each dosed to mice and of these metabolites, only chloral had an effect on mouse lung causing a lesion (Clara cell) identical to that seen with trichloroethylene. It is proposed that the failure of Clara cells to conjugate trichloroethanol leads to an accumulation of chloral which results in cytotoxicity. The known genotoxicity of chloral suggests that this lesion may be related to the development of lung tumours in mice exposed to trichloroethylene by inhalation.

Animals↗
PubMed1992

Methylene chloride--an inhalation study to investigate pathological and biochemical events occurring in the lungs of mice over an exposure period of 90 days.

Male B6C3F1 mice were exposed to 4000 ppm methylene chloride (MC) for 6 hr/day, 5 days/week for up to 13 weeks. Groups of mice were killed at intervals from Day 2 to Week 13. Whole lungs were examined morphologically, immunocytochemically, and biochemically. Biochemical and morphological examination was also performed on isolated Clara cells. The major initial morphological effect seen in lungs was acute Clara cell damage after one exposure to MC. However, this damage appeared to resolve after five consecutive daily exposures to MC. After a 2-day interval the Clara cell lesion reappeared on subsequent reexposure to MC. However, the severity of the lesion decreased over the duration of the study. The appearance and disappearance of the lesion in the Clara cell correlated well with the activity of cytochrome P450 monooxygenase in the Clara cell as assessed immunocytochemically (cytochromes P450IIB 1 and 2) in the whole lung and biochemically in the freshly isolated Clara cell (determined by ethoxycoumarin O-dealkylation and aldrin epoxidation). When there was a marked decrease in cytochrome P450 monooxygenase activity the lesion was not present. This suggested that with time the lung (Clara cell) has developed tolerance to MC possibly due to the inactivation of a cytochrome P450 isozyme. The glutathione S-transferase metabolism of MC by the lung cytosol remained virtually unaltered throughout the study. Events accompanying the discussed changes include (1) a significant increase in nonprotein sulfhydryl in the lungs of all exposed animals, (2) altered plating characteristics of the isolated Clara cells from exposed lungs after 24 hr in culture, and (3) an increase in the number of bronchiolar cells in the S-phase after the first exposure to MC. The study also demonstrates the advantages of target cell isolation and study over whole lung biochemical investigation alone.

Administration, Inhalation↗
PubMed1992

Multiple primary cutaneous plasmacytomas.

BACKGROUND: Cutaneous plasmacytoma is an uncommon tumor and is mostly seen in the context of end-stage multiple myeloma. Only 20 cases of primary cutaneous plasmacytoma have been documented. A significant proportion of these patients went on to develop systemic disease with a poor prognosis. In a number of patients, however, the abnormal clone of plasma cells may arise in the skin and never progress to multiple myeloma involving the bone marrow. OBSERVATIONS: We describe a patient who developed multiple primary cutaneous plasmacytomas after a possible insect bite reaction. The monoclonality of the tumor cells is demonstrated using immunohistochemical techniques. He has been treated vigorously with chemotherapy and local radiotherapy and remains well 3 years after diagnosis. Bone marrow has been harvested for use as an autologous bone marrow transplant in the event of systemic relapse. CONCLUSIONS: Unlike previous reports of this rare entity, this case documents the monoclonality of tissue plasma cells with immunohistochemical techniques. As cutaneous plasmacytomas have been reported with an early significant mortality, unlike extramedullary plasmacytomas elsewhere, we have advocated combination chemotherapy and cryopreservation of uninvolved bone marrow for future autologous bone marrow transplantation should systemic myelomatosis develop in the patient.

Adult↗
PubMed1991

Efferent pathways in the reflex control of gastric emptying in rats.

Previous studies have established that acid, hypertonic, or protein-rich liquid test meals delay gastric emptying by reflex pathways involving the extrinsic innervation of the gut. To characterize the efferent pathways involved in these reflexes, we have studied the emptying of liquid test meals in control rats and in rats after celiac ganglionectomy, pyloroplasty, and treatment with guanethidine or 6-hydroxydopamine, and in rats with circulating vasoactive intestinal polypeptide (VIP) antibodies. The results suggest that the action of hypertonic solutions on gastric emptying requires an intact celiac ganglion, that acid requires an intact pylorus, and that the action of protein-rich meals is suppressed by VIP antibodies. Sympathetic adrenergic neurons do not apparently mediate the gastric emptying of any of these solutions. The results suggest that there are at least three different reflexes by which the different components of a mixed meal might control gastric emptying. The results are also consistent with the idea that vagovagal reflexes mediate the action of protein-rich solutions on gastric emptying in rats.

Animals↗
PubMed1991

Species differences in carcinogenicity: the role of metabolism and pharmacokinetics in risk assessment.

Attempts to improve quantitative risk assessments inevitably lead to the use of additional biological data in the risk calculation. The need for more data increases further when differences in response between laboratory animals result in uncertainty in the choice of either the species or the tumour incidence on which to base the risk assessment. Of the many stages of carcinogenesis, the first stage, which involves the uptake and activation of the chemical, is probably the most understood and is by far the easiest to measure experimentally. A review of the use of metabolism and pharmacokinetics in risk assessment reveals how this type of data can explain species differences, the shape of the dose-response curve and even determine the relevance of the animal carcinogenicity data to man. A number of chlorinated hydrocarbons are used to illustrate each of these points.

Biotransformation↗
PubMed1990

Perchloroethylene-induced rat kidney tumors: an investigation of the mechanisms involved and their relevance to humans.

Lifetime exposure to perchloroethylene by inhalation has been shown to cause a low incidence of renal tumors in male rats. The mechanisms responsible for the induction of these tumors have been investigated following exposure of rats to perchloroethylene by oral gavage (1500 mg/kg for up to 42 days) or by inhalation (400 ppm for 28 days). Comparisons have been made between rats and mice in vivo and between rats, mice, and humans in vitro. High doses of perchloroethylene given by gavage have been shown to be toxic to the rat kidney, causing increases in urinary markers of kidney damage. A marked accumulation of protein droplets (alpha-2u-globulin) was seen in the P2 segment of the kidney proximal tubules. This response were not seen after inhalation exposure to 400 ppm perchloroethylene for 28 days and hence may not be associated with the tumors seen at this dose level. Protein droplet formation was seen after exposure to 1000 ppm perchloroethylene, suggesting that 400 ppm is below the threshold dose required to induce this response. Perchloroethylene has been shown to be metabolized by glutathione conjugation in the liver, resulting in the formation of a mutagenic cysteine conjugate which is activated by the kidney enzyme beta-lyase. Levels of the mercapturic acid of perchloroethylene have been compared in rat and mouse urine. The enzyme kinetics of hepatic glutathione conjugation and renal beta-lyase activation have been compared in rat, mouse, and human tissues in vitro. Results of these studies are consistent with the rat being the species susceptible to kidney tumors. Although human kidney was shown to contain beta-lyase, glutathione conjugation of perchloroethylene could not be detected in human liver. Perchloroethylene-induced male rat kidney tumors may be a result of chronic toxicity, protein droplet nephropathy, and genotoxicity from the beta-lyase pathway. These mechanisms appear to have little relevance to humans.

Administration, Inhalation↗
PubMed1990

Species differences in carcinogenicity: the role of metabolism in human risk evaluation.

The assessment of human risk from exposure to chemicals is frequently confounded by differences in response to those chemicals in laboratory animals. In many cases, the basis of the species differences is differences in metabolism and pharmacokinetics. Since metabolic and pharmacokinetic data are readily accessible in both laboratory animals and humans, risk assessments can be significantly improved if these data are incorporated into the process. Several chlorinated solvents, perchloroethylene, trichloroethylene, and methylene chloride, have been investigated, and the species differences in carcinogenicity have been shown to be the result of pharmacokinetic differences between the species. The rates of metabolism of these chemicals have been measured in rats and mice in vivo, and the species differences observed have been reproduced in vitro using tissue fractions and hepatocytes. Identical experiments have been carried out using human tissues. The results of these studies together with species-specific physiological parameters have been used in a mathematical model to predict human cancer risk over a wide range of exposures. This approach provides both an explanation for the species differences in response to these chemicals and also a more rational approach to human risk assessment.

Animals↗
PubMed1990

Gastric emptying in rats: role of afferent neurons and cholecystokinin.

Peptone, acid, and hyperosmolal saline delay gastric emptying in conscious gastric fistula rats. We have now studied the emptying of these solutions in animals pretreated with capsaicin to lesion small diameter primary afferents and in rats with both a gastric and duodenal cannula. In capsaicin-treated rats, hyperosmolal saline did not significantly inhibit gastric emptying, whereas the inhibitory action of acid and peptone was reversed but not abolished. In control rats, the action of peptone was inhibited by the selective cholecystokinin antagonist L364,718, but in capsaicin-treated rats, L364,718 enhanced the action of peptone in delaying gastric emptying. In rats with a duodenal cannula approximately 5 cm from the pylorus, intragastric peptone or hyperosmolal solutions only delayed emptying when the duodenal cannula was closed; in contrast, intragastric acid inhibited gastric emptying when the duodenal cannula was open or closed. The results suggest 1) that all three test meals delay emptying by mechanisms depending at least in part on afferent neurons; 2) peptone delays emptying by at least two mechanisms: one is mediated by cholecystokinin A-type receptors and afferent neurons, and the other requires neither these receptors nor small diameter afferents; and 3) acid, but not peptone or hyperosmolal saline, regulates emptying by an action localized to the stomach or proximal duodenum. The results suggest that there are several different reflex pathways by which liquid test meals act to delay gastric emptying.

Afferent Pathways↗
PubMed1990

Changes in metabolism during toxicity tests.

1. During rodent chronic toxicity studies metabolism may vary according to the age of the animal, or as a result of the effect of the chemical on its own metabolism, or as a result of the toxic properties of the chemical. 2. Foetal and newborn animals are lacking in many, but not all, metabolic enzymes and during the first 30 days of life there is differential development of these enzymes to adult levels. Thereafter activity may remain relatively constant, continue to increase or alternatively decline, occasionally to negligible levels. Typically, metabolism studies used for registration of new pesticides or for evaluation of industrial chemicals are conducted in young adult animals where most enzyme systems are fully developed. 3. At present there are no regulatory requirements for monitoring metabolism during chronic toxicity studies of these two groups of chemicals. Nevertheless, in selected cases monitoring of changes during such studies can be of value in understanding the mechanism of toxicity and the effects observed. 4. Parameters to be studied are discussed, and specific examples are given of the consequences of metabolic changes on the subsequent development of tumours.

Age Factors↗
PubMed1989

A single dose of cilazapril improves diastolic function in hypertensive patients.

We studied the effect of a single dose of cilazapril, 5.0 mg orally, on systolic and diastolic cardiac function in eight hypertensive patients using a double-blind crossover placebo-controlled design. All patients had concentric left ventricular hypertrophy (measured by echocardiography), unimpaired systolic function (measured by radionuclide ventriculography), and long-standing hypertension treated by a combination of beta-blockers and diuretics. Radionuclide scintigraphy was performed with cilazapril and placebo, given one week apart. A two-week washout period of all cardioactive drugs preceded the study. Within three hours after oral administration of cilazapril, the time to peak filling rate of the left ventricle, expressed as a percentage of diastole, was reduced from 44.5 +/- 13.2 percent to 31.2 +/- 7.2 percent (p less than 0.05). Systolic blood pressure was also significantly reduced by cilazapril. Heart rate was slightly reduced. Left ventricular ejection fraction, peak filling rate, and the absolute time to peak filling rate were not significantly altered. Cilazapril improves a sensitive index of diastolic cardiac function in hypertensive patients.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Efficacy and safety of flosequinan, given over 3 days, evaluated by continuous hemodynamic monitoring.

The hemodynamic effects of flosequinan, a new balanced vasodilator, were evaluated in 12 patients with chronic congestive heart failure. The drug was added to diuretics and digitalis and given as an oral dose of 100 mg, once daily in the morning, over 3 days, and hemodynamic monitoring was performed before the first dose and for 72 h thereafter. Hemodynamic improvement, peaking between 1 and 2 h after oral administration, was observed on all 3 days. On day 1 pulmonary capillary wedge pressure (PCWP) was reduced from 27.8 +/- 8.6 to 13.0 +/- 3.1 mm Hg and cardiac output (CO) increased from 3.3 +/- 0.6 to 4.5 +/- 0.9 liters/min (p less than 0.05). After 12-16 h the effect was slightly attenuated but remained significant at 24 h. A similar response was observed after the doses given on days 2 and 3. At 72 h PCWP was 15.5 +/- 4.1 mm Hg and CO 3.8 +/- 1.1 liters/min (p less than 0.05 for the difference from baseline). Heart rate was slightly increased only at 2 h after the dose. Pulmonary arterial and right atrial pressure and systemic and pulmonary vascular resistances were significantly reduced (except for systemic resistance at 72 h). In conclusion, flosequinan produces hemodynamic improvement in patients with chronic congestive heart failure. The response to subsequent doses is similar to the response to the first dose.

Aged↗
PubMed1989

The effect of cilazapril on systolic and diastolic cardiac function in hypertensive patients.

Diastolic function may be impaired in hypertensives even before alterations occur in systolic function. We studied the effect of a single dose of cilazapril, 5 mg orally, on systolic and diastolic cardiac function in 20 hypertensive patients using a double-blind crossover placebo controlled design. All patients had mild to moderate concentric left ventricular hypertrophy, preserved systolic function and long standing hypertension (for a period of 11.9 +/- 9.0 years). Radionuclide scintigraphy was performed with cilazapril and placebo, given one week apart. A two-week washout period of all cardioactive drugs preceded the study. Within one hour of oral administration of cilazapril blood pressure was significantly lowered. The absolute time to peak filling rate of the left ventricle, as well as the time to peak filling rate expressed as a percentage of diastole, were reduced from 176 +/- 34 to 158 +/- 33 msec (P less than 0.01) and from 46 +/- 10% to 37 +/- 8% (P less than 0.02) (reduction by 9% and 18.4%, respectively). Heart rate, left and right ventricular ejection fraction and peak filling rate was not significantly altered. Placebo had no significant effect. The effect of cilazapril is most probably related to afterload reduction. In conclusion; cilazapril seems to improve diastolic cardiac function in hypertensive patients. Long-term therapy may result in improvement of other, less sensitive indices of diastolic dysfunction.

Administration, Oral↗
PubMed1988

Macromolecular interactions of inhaled methylene chloride in rats and mice.

The in vivo interaction of methylene chloride and its metabolites with F344 rat and B6C3F1 mouse lung and liver DNA was measured after inhalation exposure to 4000 ppm [14C]methylene chloride for 3 hr. DNA was isolated from the tissues 6, 12, and 24 hr after the start of exposure and analyzed for total radioactivity and the distribution of radioactivity within enzymatically hydrolyzed DNA samples. Covalent binding to hepatic protein was also measured. A further group of rats and mice were dosed intravenously with [14C]formate after exposure to nonradiolabeled methylene chloride for 3 hr to determine the pattern of labeling resulting from incorporation of formate into DNA via the C-1 pool. Low levels of radioactivity were found in DNA from lungs and livers of both rats and mice exposed to [14C]methylene chloride. Two- to fourfold higher levels were found in mouse DNA and protein than in rat. Chromatographic analysis of the DNA nucleosides showed the radioactivity to be associated with the normal constituents of DNA. No peaks of radioactivity were found that did not coincide with peaks of radioactivity present in hydrolyzed DNA from formate-treated rats and mice. Under the conditions of this study there was no evidence for alkylation of DNA by methylene chloride in either rats or mice.

Administration, Inhalation↗
PubMed1988

The role of trichloracetic acid and peroxisome proliferation in the differences in carcinogenicity of perchloroethylene in the mouse and rat.

Fischer 344 rats and B6C3F1 mice of both sexes were exposed to 400 ppm perchloroethylene (PER) by inhalation, 6 hr/day for 14, 21, or 28 days or to 200 ppm for 28 days. Increased numbers of peroxisomes were seen under the electron microscope and increased peroxisomal cyanide-insensitive palmitoyl CoA oxidation was measured (3.6-fold increase in males and 2.1-fold increase in females) in the livers of mice exposed to PER. Hepatic catalase was not increased. Peroxisome proliferation was not observed in rat liver or in the kidneys of either species. Trichloracetic acid (TCA), a known carcinogen and hepatic peroxisome proliferating agent, was found to be a major metabolite of PER. Blood levels of this metabolite measured in mice and rats during and for 48 hr after a single 6-hr exposure to 400 ppm PER showed that peak blood levels in mice were 13 times higher than those seen in rats. Comparison of areas under the curves over the time course of the experiment showed that mice were exposed to 6.7 times more TCA than rats. The difference in metabolism of PER to TCA in mice and rats leads to the species difference in hepatic peroxisome proliferation which is believed to be the basis of the species difference in hepatocarcinogenicity. Peroxisome proliferation does not appear to play a role in the apparent carcinogenicity of PER in the rat kidney.

Administration, Inhalation↗