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Biomedical subjects

J L Larson

Publications and source records attributed to J L Larson.

At least 37 records · Page 2Linked to original sources
PubMed1996

A non-bile duct origin for intestinal crypt-like ducts with periductular fibrosis induced in livers of F344 rats by chloroform inhalation.

To evaluate the toxic effects of prolonged exposure to chloroform vapors, female and male F344 rats were exposed to 0, 2, 10, 30, 90 and 300 p.p.m. chloroform by inhalation for 7 or 5 days/week for up to 13 weeks. The purpose of this study was to characterize a lesion that occurred in the livers of rats in the 300 p.p.m. exposure groups. Atypical glandular structures lined by intestinal-like epithelium and surrounded by dense connective tissue occurred in the livers of rats exposed to strongly hepatotoxic atmospheric concentrations of chloroform. Bile duct bromodeoxyuridine labeling indices as well as observations of the locations of the early lesions at the 3 and 6 week time points indicate that these lesions arose from a population of cells remote from the bile ducts. We refer to these lesions as intestinal crypt-like ducts with periductular fibrosis to distinguish them from true cholangiofibrosis. Here, intestinal crypt-like ducts with periductular fibrosis were seen only in rats exposed to 300 p.p.m. chloroform, and the multiplicity and severity of the lesions were greater in the right liver lobe. The lesion only occurred in association with liver necrosis and dramatic increases in hepatocyte labeling indices, while labeling indices in bile ducts in the same animals were not significantly different from controls. There was a treatment-related increase of transforming growth factor-alpha immunoreactivity in hepatocytes, bile duct epithelium, bile canaliculi and oval cells, and an increase in transforming growth factor-beta immunoreactivity in hepatocytes, bile duct epithelium and intestinal crypt-like ducts. Thus, intestinal crypt-like ducts with periductular fibrosis appeared to develop from a population of cells unrelated to bile ducts. Also, they occurred only in animals exposed to chloroform concentrations that induced significant hepatocyte necrosis and regenerative cell proliferation and were associated with increased growth factor expression or uptake.

Administration, Inhalation↗
PubMed1996

The toxicity of repeated exposures to rolipram, a type IV phosphodiesterase inhibitor, in rats.

Rolipram is a selective inhibitor of Type IV phosphodiesterase isozymes (PDE IV) which is often used as a baseline comparator for compounds in this class. To document the toxicological effects of rolipram, it was administered to female rats at 0, 10, 30 or 100 mg/kg/day orally for up to 2 weeks. One treatment-related death in the 100 mg/kg/day dose group was observed on day 3, and all rats at this dose level were considered moribund and euthanatized on day 5. Several clinical signs were observed in treated rats, including increased salivation, slight distention of the abdomen, emaciated appearance, and ataxia. After 14 days of treatment, the rats were necropsied and tissues examined microscopically. A number of compound-related histopathological changes were observed in rats receiving 30 or 100 mg/kg/day. Myocardial degeneration and necrosis, endocardial fibrosis, epicarditis, and arteritis/periarteritis of intramural and extramural coronary arteries were observed in the heart. A necrotizing vasculitis and inflammation were observed in the mesentery and interstitial areas of the liver, affecting medium-sized portal arteries and veins. Focal necrosis was also observed in the glandular mucosa of the stomach at these 2 dose levels. Other treatment-related effects included squamous hyperplasia and hyperkeratosis with or without ulceration in the nonglandular stomach of at least one animal from all treatment groups. Enlarged salivary glands were noted at necropsy in animals treated with 100 mg/kg/day, and this finding correlated microscopically with dilatation and degeneration of ducts and acini in the sublingual gland with secondary inflammation and edema. The results of this study demonstrate that rolipram, a selective inhibitor of the type IV class of PDE, can cause effects on the heart and vasculature of rats which heretofore have been ascribed only to selective inhibitors of the PDE III class of isozymes. Therefore, these organs should be closely examined in studies with other PDE IV inhibitors. In addition, the gastrointestinal tract and salivary glands were sites for rolipram-induced toxicity and may be targets of other PDE IV inhibitors.

Animals↗
PubMed1995

Modification of lipoperoxidative effects of dichloroacetate and trichloroacetate is associated with peroxisome proliferation.

Pretreatment of male B6C3F1 mice with clofibric acid (CFA) or trichloroacetic acid (TCA) in the drinking water results in a marked decrease in the lipoperoxidative response as measured by the production of thiobarbituric acid reactive substances (TBARS) in mouse liver homogenates following acute dosing with TCA or dichloroacetic acid (DCA). Pretreatment with TCA or CFA also increased palmitoyl-CoA oxidase activity, microsomal 12-(omega) hydroxylation of lauric acid and expression of P450 4A isoforms. At the doses utilized, DCA-pretreatment did not increase the level of P450 4A protein, or markers of peroxisome proliferation. However, DCA-pretreatment did result in enhanced levels of TBARS, following acute dosing with DCA, compared to controls. Pretreatment with DCA, TCA, or CFA did not alter p-nitrophenol hydroxylation (an assay specific for P450 2E1), and no increases in immunodetectable P450 2E1, 4A, 1A1/2, 2B1/2 or 3A1 protein were observed. Assays from CFA- and TCA-pretreated mice suggest that the reduction in the TBARS response seen in TCA-pretreated animals results from activities associated with peroxisome proliferation. This might result from the induction of systems efficient in scavenging of peroxide intermediates or detoxification of aldehyde by-products of lipid peroxidation.

Animals↗
PubMed1995

Induced regenerative cell proliferation in livers and kidneys of male F-344 rats given chloroform in corn oil by gavage or ad libitum in drinking water.

These studies were designed to establish the dose response relationships for the induction of cytolethality and regenerative cell proliferation in the liver and kidneys of male F-344 rats given chloroform by gavage or in drinking water. Rats were administered oral doses of 0, 10, 34, 90 or 180 mg/kg/day chloroform dissolved in corn oil by gavage for 4 days or for 5 days/week for 3 weeks. A second group of rats was given chloroform ad libitum in the drinking water at concentrations of 0, 60, 200, 400, 900 or 1800 ppm for 4 days or 3 weeks. Bromodeoxyuridine (BrdU) was administered via an implanted osmotic pump 3.5 days prior to necropsy to label cells in S-phase. Cells having incorporated BrdU were visualized in tissue sections immunohistochemically and the labelling index (LI) evaluated as the percentage of S-phase cells. Rats treated with 90 or 180 mg/kg/day by gavage for 4 days had mild to moderate degeneration of renal proximal tubules and centrilobular hepatocytes. These alterations were absent or slight after 3 weeks of treatment. LI were increased in the kidney cortex only in the rats treated with 180 mg/kg/day for 4 days. A dose-dependent increase in LI was seen in rat liver after 4 days of treatment with 90 and 180 mg/kg/day by gavage, but the LI remained elevated after 3 weeks of treatment only at the 180 mg/kg/day dose. When chloroform was administered in the drinking water, no microscopic alterations were seen in the kidneys after 4 days of treatment. As a general observation, rats treated for 3 weeks with 200 ppm chloroform and greater had slightly increased numbers of focal areas of regenerating renal proximal tubular epithelium and cell proliferation than were noted in the controls, but no clear dose response relationship was evident. However, the overall renal LI was not increased at any dose or time point. Similarly, only mild hepatocyte vacuolation was observed in rats given 1800 ppm chloroform in the water for 3 weeks with no increase in the hepatic LI at any time point, even though the rats were consuming chloroform at a rate of 106 mg/kg/day at the 1800 ppm drinking water concentration. These data indicate more severe hepatic and renal toxicity when chloroform is administered by gavage than in the drinking water and a different pattern of regenerative proliferation in the kidney.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1995

Advanced cardiac life support: update on recent guidelines and a look at the future.

The objectives of this article are to provide an update of the American Heart Association (AHA) 1992 National Conference guidelines for cardiopulmonary resuscitation (CPR) and emergency cardiac care and to review the investigation and development of new methods of CPR which may be considered in future recommendations. Despite an organized approach to sudden cardiac arrest, survival in patients receiving CPR is in the range of 5-15%. The new AHA guidelines recommend standard manual CPR performed at a rate of 80-100 compressions/min and organized algorithms of advanced cardiac life support. These guidelines stress widespread community training and rapid response in the following sequence: (1) recognition of early warning signs, (2) activation of the emergency medical system (EMS), (3) basic CPR, (4) early defibrillation, (5) intubation, and (6) intravenous medication. Several new recommendations pertain specifically to in-hospital care and are, therefore, particularly relevant to physician management of cardiac arrest. The best predictor of survival in patients requiring circulatory support after cardiac arrest is attainable coronary and cerebral perfusion. Unfortunately, the minimal levels of end-organ perfusion required to sustain life are often difficult or impossible to achieve with standard manual cardiopulmonary resuscitation and several new techniques have therefore been introduced. The most promising of these techniques are (1) interposed abdominal compression, (2) pneumatic vest, and (3) active compression-decompression resuscitation. Each of these techniques offers unique advantages when compared with standard manual cardiopulmonary resuscitation. The 1992 National Conference recommendations provide a rational framework for the resuscitation of cardiac arrest victims. New methods of cardiopulmonary resuscitation are now available and investigation into these methods continues.(ABSTRACT TRUNCATED AT 250 WORDS)

Algorithms↗
PubMed1995

Toxicity and cell proliferation in the liver, kidneys and nasal passages of female F-344 rats, induced by chloroform administered by gavage.

Dose-response relationships were determined for the induction of cytolethality and regenerative cell proliferation in the established target organs (liver, kidneys, and nasal passages) of female F-344 rats given chloroform daily by gavage. Rats were administered chloroform dissolved in corn oil at doses of 0, 34, 100, 200 or 400 mg/kg/day for 4 consecutive days or for 5 days/wk for 3 wk. Bromodeoxyuridine (BrdU) was administered through an implanted osmotic pump 3.5 days prior to autopsy to label cells in S-phase. Cells in S-phase were visualized immunohistochemically in tissue sections and the labelling index (LI) calculated as the percentage of cells in S-phase. Mild degenerative centrilobular changes and dose-dependent increases in the hepatocyte LI were observed after administration of 100 mg or more chloroform/kg/day. Rats given 200 or 400 mg/kg/day for 4 days or 3 wk had degeneration and necrosis of the proximal tubules of the renal cortex. Regenerating epithelium lining proximal tubules was seen histologically and as an increase in LI. Dose-dependent increases in LI were observed in the kidneys at doses of 100 mg or more chloroform/kg/day at both 4 days and 3 wk. Two distinct treatment-induced responses were observed in specific regions of the olfactory mucosa lining the ethmoid region of the nose. A peripheral lesion was seen at all doses used and included new bone formation, periosteal hypercellularity and increased cell replication. A central lesion was seen at doses of 100 mg or more chloroform/kg/day and was characterized by degeneration of the olfactory epithelium and superficial Bowman's glands. These observations define the dose-response relationships for the liver, kidneys and nasal passages as target organs for chloroform administered by gavage in the female F-344 rat.

Animals↗
PubMed1994

Lack of chloroform-induced DNA repair in vitro and in vivo in hepatocytes of female B6C3F1 mice.

Chloroform has been shown to induce hepatocellular carcinomas in female B6C3F1 mice when administered by gavage, but not when given in drinking water. When administered in corn oil at the carcinogenic doses of 238 and 477 mg/kg, chloroform induced necrosis and sustained regenerative cell proliferation in the liver. To investigate the mode of action of tumor induction in the target cells, the ability of chloroform to induce unscheduled DNA synthesis (UDS) was examined in the in vitro and in vivo hepatocyte DNA repair assays. In the in vitro assay, primary hepatocyte cultures from female B6C3F1 mice were incubated with concentrations from 0.01 to 10 mM chloroform in the presence of 3H-thymidine. UDS was assessed by quantitative autoradiography. No induction of DNA repair was observed at any concentration. In the in vivo assay, animals were treated by gavage with 238 and 477 mg/kg chloroform in corn oil. Primary hepatocyte cultures were prepared 2 and 12 hr later, incubated with 3H-thymidine, and assessed for induction of UDS as above. No DNA repair activity was seen at either dose or at either timepoint. These negative results in the target organ are consistent with the concept that neither chloroform nor its metabolites are directly DNA reactive and that the carcinogenicity of chloroform is secondary to induced cytolethality and regenerative cell proliferation.

Administration, Oral↗
PubMed1994

Induced cytotoxicity and cell proliferation in the hepatocarcinogenicity of chloroform in female B6C3F1 mice: comparison of administration by gavage in corn oil vs ad libitum in drinking water.

Chloroform increases the incidence of liver tumors in B6C3F1 mice when administered in by gavage in corn oil, but not when given in the drinking water at similar daily doses. Since cytotoxicity and regenerative cell proliferation have been implicated in the tumorigenic process for this nongenotoxic agent, these effects of chloroform in corn oil and drinking water were evaluated under conditions similar to the two bioassays. Female B6C3F1 mice were administered oral doses of 0, 3, 10, 34, 90, 238, or 477 mg/kg chloroform dissolved in corn oil 5 days/week for periods of 4 days or 3 weeks, or were continually exposed to chloroform in the drinking water at concentrations of 0, 60, 200, 400, 900, or 1800 ppm for 4 days or 3 weeks, at which time they were necropsied. 5-Bromo-2'-deoxyuridine (BrdU) was delivered via osmotic pumps implanted 3.5 days prior to necropsy. Cell proliferation was evaluated as the percentage of hepatocytes that entered S-phase over 3.5 days (labeling index, LI), measured by immunohistochemical detection of BrdU incorporated into the DNA. Dose-dependent changes included centrilobular necrosis and markedly elevated LI in mice given 238 or 477 mg/kg chloroform in corn oil (the average daily doses that produced tumors in the cancer bioassay). The no-observed-effect level for histopathological changes was 10 mg/kg/day and for induced cell proliferation was 34 mg/kg/day for chloroform given in corn oil. Chloroform given in the drinking water did not increase the hepatic LI after either 4 days or 3 weeks in any of the dose groups, nor were any microscopic alterations observed in the livers, even though the cumulative daily amount of chloroform ingested in the 1800-ppm exposure group was 329 mg/kg/day. The sustained increase in LI in the livers of mice administered hepatocarcinogenic doses of chloroform in corn oil, but not for chloroform in drinking water, is evidence that chloroform-induced mouse liver cancer is secondary to events associated with induced cytolethality and cell proliferation. The triggering of these effects appears to be dependent on both the rate and duration of chloroform delivery to the target tissues. Thus, the most straightforward risk assessment for chloroform for this tissue would assign no increased cancer risk for dosing regimens that do not induce cytolethality and cell proliferation.

Administration, Oral↗
PubMed1994

The toxicity of 1-week exposures to inhaled chloroform in female B6C3F1 mice and male F-344 rats.

Detailed quantitative descriptions of the toxicity of inhaled chloroform are lacking, despite the fact that the majority of environmental exposures occur by this route. We investigated the ability of chloroform vapors to produce toxicity and regenerative cell proliferation in the livers and kidneys, the principal target organs for carcinogenicity of female B6C3F1 mice and male F-344 rats, respectively. Nasal passages were also examined for toxic responses. Rodents were exposed to chloroform vapors at concentrations of 0, 1, 3, 10, 30, 100, or 300 ppm for 6 hr/day for 7 consecutive days and necropsied on Day 8. Animals were administered bromodeoxyuridine (BrdU) via implanted osmotic pump for the previous 3.5 days before necropsy. Cell proliferation was quantitated as the percentage of cells in S-phase (labeling index; LI) measured by immunohistochemical detection of BrdU-labeled nuclei. Mice exposed to 100 or 300 ppm exhibited centrilobular hepatocyte necrosis and severe vacuolar degeneration of midzonal and periportal hepatocytes, while exposure to 10 or 30 ppm resulted in mild to moderate vacuolar changes in centrilobular hepatocytes. Slight, dose-related increases in the hepatocyte LI were observed for exposure concentrations of 10 and 30 ppm, while the LI was increased more than 30-fold in the 100 and 300 ppm groups. The kidneys of mice were affected only at the 300 ppm exposure, with approximately half of the proximal tubules lined by regenerating epithelium and an increased LI of tubule cells of 8-fold over control. In rats, mild centrilobular vacuolation was observed only in the livers of rats exposed to 300 ppm. The hepatocyte LI in rats were increased only at 100 and 300 ppm, 3- and 7-fold over control, respectively. In the kidneys of the male rats exposed to 300 ppm, about 25 to 50% of the proximal tubules were lined by regenerating epithelium. The LI for tubule cells in the cortex was increased at 30 ppm and above. In the nasal passages of rats, chloroform concentrations of 10 ppm and above induced histopathological changes that exhibited clear concentration-related severity. These lesions consisted of respiratory epithelial goblet cell hyperplasia and degeneration of Bowman's glands in olfactory mucosa with an associated osseous hyperplasia of the endo- and ectoturbinates in the periphery of the ethmoid region. These nasal lesions were not observed in mice. Knowledge of the dose-dependent responses in rats and mice will be valuable in assessing the potential risks to humans posed by inhaled chloroform and in setting exposure concentrations for longer-term studies.

Administration, Inhalation↗
PubMed1994

Induced cytolethality and regenerative cell proliferation in the livers and kidneys of male B6C3F1 mice given chloroform by gavage.

It has been reported that chloroform administered to male B6C3F1 mice at doses of 138 and 277 mg/kg/day in corn oil by gavage 5 days/week for 2 years resulted in incidences of hepatocellular carcinomas of 36 and 98% relative to an incidence in controls of 6%. Cytotoxicity and regenerative cell proliferation have been implicated in the tumorigenic process for this non-genotoxic compound. Although chloroform is known to be nephrotoxic in the male mouse, no treatment-related increase was observed in the frequency of kidney tumors. To better understand the relationship of these endpoints, this study evaluated chloroform-induced cytotoxicity and cell proliferation in the liver and kidney under conditions of the cancer study. B6C3F1 mice were administered oral doses of 0, 34, 90, 138, or 277 mg/kg/day of chloroform dissolved in corn oil for 4 days or 5 days/week for 3 weeks. Bromo-2'-deoxyuridine (BrdU) was administered via osmotic pumps implanted 3.5 days prior to necropsy to label cells in S-phase. Cell proliferation was evaluated in tissue sections immunohistochemically as the percentage of cells in S-phase (nuclear labeling index; LI). Mice given 34 and 90 mg/kg/day by gavage had mild degenerative changes in centrilobular hepatocytes after 4 days of treatment, which was absent at 3 weeks. Centrilobular necrosis was observed in mice given 138 or 277 mg/kg chloroform for 4 days, with increased severity of necrosis at 3 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Nasal toxicity of chloroform in male F-344 rats and female B6C3F1 mice following a 1-week inhalation exposure.

Chloroform is an important environmental water and air pollutant. Inhalation exposure of female B6C3F1 mice and F-344 rats for 6 hr/day for 7 consecutive days to 0, 1, 3, 10, 30, 100, or 300 ppm of chloroform resulted in concentration-dependent lesions in the nasal passages. Chloroform-induced changes included increased epithelial mucosubstances in the respiratory epithelium of the nasopharyngeal meatus, primarily in the rats. A complex set of responses was seen in specific regions of the ethmoid turbinates, predominantly in the rats. These lesions in the ethmoid region, which involved all of the endo- and ectoturbinates, were most severe peripherally and generally spared the tissue adjacent to the medial airways. These changes were characterized by atrophy of Bowman's glands, increased numbers of vimentin-positive cells in the periosteum, new bone formation, and increased numbers of periosteal cells in S phase as determined by bromodeoxyuridine incorporation. Additional changes were site-specific loss of mucosubstances and loss of immunocytochemical staining of acini and ducts of Bowman's glands for P450-2E1 and pancytokeratin, and loss of P450-2E1 immunostaining of the olfactory epithelium. The only change noted in the mice was increased cell proliferation without the osseous hyperplasia. The no-observed-effect level for these responses ranged from 3 to 100 ppm, with histological changes and induced cell proliferation being the most sensitive parameters. It is proposed that the osseous changes induced by chloroform exposure may be secondary to primary degeneration of adjacent Bowman's glands. The relevance of these changes to human health risks include potential damage to the sense of smell, but such effects would not be expected at the low levels of chloroform commonly encountered in the environment.

Administration, Inhalation↗
PubMed1993

Acute hepatotoxic and nephrotoxic effects of chloroform in male F-344 rats and female B6C3F1 mice.

Previous studies demonstrated that chloroform given by oral gavage in corn oil caused an increased incidence of liver tumors in male and female mice and kidney tumors in male rats, while administration in drinking water resulted in an increased tumor incidence only in the kidneys of the male rats. The tumorigenicity of this nongenotoxic agent has been postulated to be linked with cytolethality and cell proliferation. This study examined the organ-specific toxicity of acute doses of chloroform. Male F-344 rats were given chloroform by gavage in corn oil at the bioassay doses of chloroform of 0 and 180 mg/kg body wt as well as 34 and 477 mg/kg and necropsied 24 hr later. Additional rats were given a single dose of 180 mg chloroform/kg and administered bromodeoxyuridine (BRDU) 2 hr prior to necropsy at 0.5, 1, 2, 4, and 8 days after chloroform treatment. Female B6C3F1 mice were given chloroform by gavage at the bioassay doses of 0, 238, and 477 mg/kg as well as 34 mg/kg and necropsied at 24 hr after treatment. Additional mice were given a single dose of 350 mg chloroform/kg, labeled with BRDU, and necropsied at 0.5, 1, 2, 4, and 8 days after treatment. The kidneys of male rats administered 34, 180, and 477 mg chloroform/kg exhibited mild to severe proximal tubular necrosis in a dose-dependent manner. A 20-fold increase in the labeling index (LI, the percentage of nuclei in S-phase) in the proximal tubule cells was observed 2 days after treatment with the bioassay dose of 180 mg/kg. The livers of male rats exhibited only slight to moderate multifocal centrilobular necrosis at 180 and 477 mg/kg. A 10-fold increase in the LI was observed in the liver of male rats given 477 mg/kg, but no increase was observed at the bioassay dose of 180 mg/kg. In contrast to male rats, female mice developed a dose-dependent centrilobular hepatic necrosis at 238 and 477 mg/kg. No renal lesions were observed in female mice at any dose. A peak increase in LI of 38-fold was observed in hepatocytes in the livers of female mice 2 days after treatment with 350 mg chloroform/kg, with only a 2-fold increase in LI observed in the kidneys. These data indicate that acute chloroform-induced cytolethality leads to increased cell proliferation and that the organ-specific pattern of toxicity is the same as the organ-specific pattern of tumor formation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1993

The role of dichloroacetate in the hepatocarcinogenicity of trichloroethylene.

The induction of hepatic tumors in B6C3F1 mice treated with trichloroethylene (TRI) has been attributed to its metabolism to trichloroacetate (TCA). Trichloroacetate is an effective peroxisome proliferator in mice at blood concentrations that are readily achieved with carcinogenic doses of TRI. Recent data has demonstrated that both TCA and dichloroacetate (DCA) are capable of inducing liver tumors in B6C3F1 mice. Although long recognized as a metabolite of TRI, little attention has focussed on the role DCA might play in the hepatocarcinogenic effects of TRI. There are significant differences in the effects of DCA and TCA on the liver of B6C3F1 mice. Trichloroacetate treatment induces peroxisome proliferation, increases lipid deposition, and results in a marked accumulation of lipofuscin in the liver with long-term exposures. Dichloroacetate induces a markedly enlarged liver associated with a cytomegaly and large accumulations of glycogen. The cytomegaly is associated with the development of focal areas of recurrent liver necrosis which in turn lead to high levels of cell proliferation in the area surrounding these lesions. Induction of peroxisomes with DCA is transitory and the accumulation of lipofuscin is much less evident than with TCA treatment. Studies of TRI metabolism demonstrate that blood levels of DCA produced are sufficient to account for the hepatocarcinogenic effects of TRI. The rather low concentrations of DCA found in the urine of mice treated with TRI relative to TCA concentrations are due to the much more rapid and complete metabolism of DCA. These data do not support the conclusion that the hepatocarcinogenic effects of TRI are simply related to peroxisome proliferation.

Animals↗
PubMed1993

Maximal inspiratory pressure. Learning effect and test-retest reliability in patients with chronic obstructive pulmonary disease.

Reliability of the maximal inspiratory pressure (Pimax) was examined by measuring Pimax once a week for 4 weeks in 91 patients with chronic obstructive pulmonary disease using an aneroid pressure gauge. Five Pimax trials were conducted at each test. From the first to the fourth test, the Pimax increased by a mean of 9 cm H2O (SD = 10). From the third to the fourth test, Pimax increased by a mean of 2 cm H2O and performance appeared to be plateauing. The test-retest reliability coefficient was r = 0.97 for Pimax measured at the third and fourth test session. The 95 percent confidence interval for the absolute difference in Pimax at the third and fourth test was 3 to 5 cm H2O. We conclude that performance of Pimax improves with practice in naive COPD patients and Pimax is reliable when measured with an aneroid gauge by experienced data collectors if patients are given sufficient practice.

Aged↗
PubMed1992

Quality of life after liver transplant.

The purpose of this study was to compare the quality of life and health related variables in two groups of liver transplant patients, one at 2 years or less after transplant and the other at more than 2 years after transplant. Both groups reported a high overall quality of life and an above average health status. Long-term transplant patients reported significantly more health-related functional impairment and a tendency toward higher levels of depressed and anxious moods. The high quality of life suggested that patients were coping effectively with the realities of life, despite health-related functional impairment.

Activities of Daily Living↗
PubMed1992

Metabolism and lipoperoxidative activity of trichloroacetate and dichloroacetate in rats and mice.

Trichloroacetate (TCA) and dichloroacetate (DCA) have been shown to be hepatocarcinogenic in mice when administered in drinking water. However, DCA produces pathological effects in the liver that are much more severe than those observed following TCA treatment in both rats and mice. To identify potential mechanisms involved in the liver pathology, the biotransformation of TCA and DCA was investigated in male Fischer 344 rats and B6C3F1 mice. Rodents were administered 5, 20, or 100 mg/kg [14C]TCA or [14C]DCA as a single oral dose in water. Elimination was examined by counting radioactivity in urine, feces, exhaled air, and carcass. Blood concentration over time curves were constructed for both TCA and DCA at the 20 and 100 mg/kg doses. Analysis of the data reveals two significant differences in the systemic clearance of TCA relative to DCA. First, DCA was much more extensively metabolized than TCA. More than 50% of any single dose of TCA was excreted unchanged in the urine of both rats and mice. In contrast, less than 2% of any dose of DCA was recovered in the urine as the parent compound. Second, while the blood concentration over time curves for TCA were similar in rats and mice, the blood concentrations of DCA were markedly greater in rats compared to those in mice, both when DCA was administered and when DCA resulted from metabolism of TCA. DCA was detected in the urine of TCA-treated animals and chloroacetate was found in the urine of DCA-treated animals. These metabolic products would be expected to arise from a free radical-generating, reductive dechlorination pathway. To evaluate the ability of acute doses of TCA and DCA to elicit a lipoperoxidative response, additional groups of mice were administered 0, 100, 300, 1000, and 2000 mg/kg TCA or DCA and thiobarbituric acid-reactive substances (TBARS) measured in liver homogenates. Both TCA and DCA enhanced the formation of TBARS in a dose-dependent manner, thereby providing further evidence of a reductive metabolic pathway. DCA was found to be the more potent of the chlorinated acetates in increasing TBARS formation in the livers of both rats and mice. In view of these data, it appears that the more extensive metabolism and rapid rate of elimination of DCA relative to TCA and the more potent lipoperoxidative activity of DCA may be important factors in the pathological effects associated with DCA treatment.

Administration, Oral↗
PubMed1992

Species differences in the metabolism of trichloroethylene to the carcinogenic metabolites trichloroacetate and dichloroacetate.

Differing rates and extent of trichloroethylene (TCE) metabolism have been implicated as being responsible for varying sensitivities of mice and rats to the hepatocarcinogenic effects of TCE. Recent data indicate that the induction of hepatic tumors in mice may be attributed to the metabolites trichloroacetate (TCA) and/or dichloroacetate (DCA). The present study was directed at determining whether mice and rats varied in (1) the peak blood concentrations, (2) the area under the blood concentration over time curves (AUC) for TCE and metabolites in blood, and (3) the net excretion of TCE to these metabolites in urine in the dose range used in the cancer bioassays of TCE, and to contrast the kinetic parameters observed for TCE-derived TCA and DCA with those obtained following direct administration of TCA and DCA. Blood and urine samples were collected over 72 hr from rats and mice after a single oral dose of TCE of 1.5 to 23 mmol/kg. The AUC values from the blood concentration with time profiles of TCE, TCA, and trichloroethanol (TCOH) were similar for Sprague-Dawley rats and B6C3F1 mice. Likewise, the percentages of initial TCE dose recovered as the urinary metabolites TCA and TCOH were comparable. Nevertheless, the peak blood concentrations of TCE, TCA, and TCOH observed in mice were much greater than those in rats, while the residence time of TCE and metabolites was prolonged in rats relative to that of mice. DCA was detected in the blood of mice but not in rats. The blood concentrations of DCA observed in mice given a carcinogenic dose of TCE (15 mmol/kg) were of the same magnitude as those observed with carcinogenic doses of DCA. In conclusion, the net metabolism of TCE to TCA and TCOH was similar in rats and mice. The initial rates of metabolism of TCE to TCA, however, were much higher in mice, especially as the TCE dose was increased, leading to greater concentrations of TCA and DCA in mice approximated those produced by carcinogenic doses of the chlorinated acetates makes it highly likely that both compounds play a role in the induction of hepatic tumors in mice by TCE.

Administration, Oral↗