PubMed Health⌕ Search

Biomedical subjects

W H Butler

Publications and source records attributed to W H Butler.

At least 19 recordsLinked to original sources
PubMed1992

The histology and development of hepatic nodules and carcinoma in C3H/He and C57BL/6 mice following chronic phenobarbitone administration.

Male C3H/He and C57BL/6 mice were given diets containing sodium phenobarbitone (PB) to allow a daily intake of 85 mg/kg. Control and treated animals were killed at 5, 30, 40, 60, and 80 wk. Other mice were killed in extremis or at the end of the respective experiments: 91 wk for C3H/He and 100 wk for the C57BL/6 animals. A basophilic nodule was found in 1/5 control C3H/He mice at 30 wk; these nodules increased in number with time so that nodules of this type were found in approximately 70% of animals by 91 wk. Nodules were not found in control C57BL/6 mice until 80 wk, when they were found in 4% of mice. PB treatment markedly increased the number of hepatic nodules in both strains of mice. The additional nodule burden was due to the development of a second nodule type formed of large cells with a predominantly eosinophilic cytoplasm. C3H/He animals given PB for 60 wk and then returned to a control diet bore fewer nodules at 91 wk than treated mice killed at 60 or 91 wk. The cumulative incidence of carcinoma in control C3H/He and C57BL/6 mice was 28 and 4%, respectively. The incidence of carcinoma was not increased by PB treatment in either strain. It is concluded that both strains of mice behave in a qualitively similar way to PB administration, although they show considerable quantitative differences in terms of the time and number of nodules that develop. Furthermore, the increased nodule numbers associated with PB treatment were not accompanied by an increase in the number of carcinomas.

Animals↗
PubMed1991

An ultrastructural study of spontaneous and phenobarbitone-induced nodules in the mouse liver.

Male C3H/He mice were given 0 (control) or 85 mg/kg/day phenobarbitone (PB) in the diet. At 40, 60 and 93 weeks, groups of mice were killed and the ultrastructure of spontaneous and PB-induced liver nodules was examined. Treated mice showed typical centrilobular hypertrophy and eosinophilic nodules which may be considered as an end stage lesion. The nodule cells were similar in appearance to those in areas of centrilobular hypertrophy except for the presence of convoluted membranes which are considered to be indicative of proliferation. The incidence of carcinoma was not increased by PB treatment. The carcinomas from control and treated animals differed in their ultrastructure in that increased levels of smooth endoplasmic reticulum (SER) were seen in the carcinomas of the PB animals. The presence of SER proliferation in the carcinomas of PB animals suggests that carcinoma may respond to the enzyme-inducing effects of PB.

Animals↗
PubMed1991

Promutagenic lesions persist in the DNA of target cells for nitrosamine-induced carcinogenesis.

Immunohistochemical procedures for the location of O6-methylguanine (O6-meGua) permit detection of cells proficient for the metabolism of N-nitrosodimethylamine (NDMA) and deficient for the repair of this DNA lesion. Such cells are potentially at high risk for cancer induction and are present in various tissues. In animals maintained on a protein-deficient diet, the distribution and intensity of alkylation of individual cells is altered, particularly in liver where fewer cells apparently retain the capacity to metabolize the nitrosamine, thereby permitting increased levels of alkylation in other tissues. In the renal cortex, specific, O6-meGua-positive target cells for renal cancer induced by a single dose of NDMA in weanling rats persist at least up to the appearance of early lesions. Persistence of alkylated cells in several tissues indicates prospects for the detection of environmental exposure.

Alkylation↗
PubMed1991

Neuropathologic findings in patients receiving long-term vigabatrin therapy for chronic intractable epilepsy.

Vigabatrin is a new antiepileptic drug that acts by the irreversible inhibition of gamma-aminobutyric acid (GABA) aminotransferase. During animal safety testing, vigabatrin was found to cause reversible intramyelinic edema in the brains of rodents and dogs but not in primates. In humans, the drug is well tolerated, and extensive clinical, neurophysiologic, neurochemical, and psychometric testing has failed to demonstrate any evidence of neurotoxicity. Neuropathologic examination has now been carried out on 62 patients with refractory epilepsy, who were on vigabatrin therapy either prior to undergoing neurosurgery for their epilepsy or before death. A further ten similar cases have been included in the study from age-matched patients with refractory epilepsy who had not been treated with vigabatrin prior to surgery or death. None of the neuropathologic changes seen in the preclinical animals studies have been observed in the human cases. In no case was there considered to be any evidence of myelin microvacuolation or myelin sheath splitting that could be attributed to vigabatrin treatment. Demyelination has never been observed in either the animal or human material. These findings support the clinical tolerability seen in long-term treatment.

Adolescent↗
PubMed1990

Chronic toxicity and oncogenicity studies of Macrodantin in Sprague-Dawley rats.

Chronic toxicity and oncogenicity studies of nitrofurantoin formulated as Macrodantin have been undertaken. The doses ranged from 12 to 116 mg/kg body weight/day. At 116 mg/kg/day, female rats showed a decreased weight gain. In the high-dose groups in the chronic toxicity study (males, 81 mg/kg/day; females, 116 mg/kg/day) there was an increase in testicular degeneration, sciatic nerve degeneration and fibrosis in both males and females, and an increase in focal biliary proliferation in females. There was no evidence of renal toxicity. There was no compound-related effect upon neoplasms at any site. In the oncogenicity study, an increase in focal biliary proliferation was observed in females given 31 or 56 mg/kg/day. There was no treatment-related increase in the incidence of neoplasms at any site. In particular there was no increase in the incidence of mammary or renal tumours. The observations in these studies indicate that therapeutic uses of Macrodantin would not present a carcinogenic hazard to man.

Animals↗
PubMed1990

Oncogenicity study of macrodantin in Swiss mice.

A carcinogenicity study of nitrofurantoin formulated as Macrodantin was undertaken. The doses used were 0.0, 50.0, 100.0 and 200.0 mg/kg/day. Increased mortality was observed in male mice given 200 mg/kg/day. Chronic toxicity was observed in the kidneys of male mice: the normally occurring chronic nephropathy was somewhat increased in severity. The gonads of both male and female mice showed evidence of atrophy and degeneration. The ovaries showed an increased incidence of multilobular cysts but no evidence of neoplasia. A significantly higher incidence of malignant lymphoma in the top-dose males was offset by a non-significant difference in the opposite direction in females. Reasons are given for regarding this as a chance finding. The observations in this study indicate that the therapeutic uses of nitrofurantoin would not present a carcinogenic hazard to man.

Animals↗
PubMed1990

Effects of methyl isocyanate on rat brain cells in culture.

Since the disaster in Bhopal, India, people exposed to methyl isocyanate (MIC) have complained of various disorders including neuromuscular dysfunction. In an attempt to get information about such dysfunction we have previously shown that MIC can affect muscle cells in culture. The present communication reports investigations into the effect of MIC on brain cells in culture. MIC was toxic to brain cells and the response was dose related. The observations were supported by light and electron microscopy.

Animals↗
PubMed1990

Ultrastructural features of diethylnitrosamine-induced lesions in the mouse liver.

Mice were given a single dose of diethylnitrosamine (DEN). After 12 and 15 months, the ultrastructural features of simple hepatic nodules and defined hepatocellular carcinomas were compared. The main difference between these two lesions is the presence of highly convoluted membranes in the hepatocytes of the carcinomas. A third population of nodules was also found which could not be easily classified at the light microscope level into either simple hepatic nodules or carcinomas. Ultrastructural examination of these lesions showed them to have areas resembling both simple hepatic nodules and carcinomas. Within both these areas hepatocytes with convoluted plasma membranes were observed. Changes in membrane pattern may be indicative of an altered cell growth pattern and the acquisition of invasive or metastatic properties. This provides further evidence suggesting that a sub-population of cells can be identified which has the potential to develop into overt carcinoma.

Animals↗
PubMed1979

Zonal changes in the rat liver after chronic administration of phenobarbitone in ultrastructural, morphometric and biochemical correlation.

Alterations in the liver of rats subjected to 24 days of continuous administration of phenobarbitone have been supplied bu subcellular fractionation, conventional electron microscopy and morphometric analysis. The increase in wet weight of the liver was found to result from a combination of cellular hypertrophy, hyperplasia and an enlarged hepatic blood space. In the centrilobular zone all the hepatocytes underwent a substantial proliferation of total ER, became enlarged and had an increased blood supply. However, in the periportal zone phenobarbitone caused changes in only 45% of the hepatocytes, the remainder being apparently resistent or tardy. An overall dramatic increase in hepatic RER was both measured and observed but the response involved hepatocytes in which the RER had proliferated as well as those which were depleted of RER or had stacks and cisternae that were severely shortened and dispersed. These alterations are discussed in relation to changes in RER after administration of agents causing hepatonecrosis. Possible reasons for the inability of other workers to detect a phenobarbitone-induced increase in RER are also put forward. After subcellular fractionation and corection for centrifugation losses into the 9500 g pellet, using the microsomal marker cytochrome P-450, phenobarbitone-induced increase in total ER was substantially less than that found by morphometric analysis. This indicates that during the preparation of microsomes a substantial proportion of intracellular membranes, having different metabolic and synthetic properties to those finally isolated, are discarded and emphasizes the need to exercise care when using microsomal preparations.

Animals↗
PubMed1979

Cellular progression of neoplasia in the subcutis of mice after implantation of 3,4-benzpyrene.

An implantation model has been used to investigate the cellular progression of chemically induced subcutaneous neoplasia in the mouse. Implantation of 3,4-benzpyrene induced persistent changes in the normal process of connective tissue formation around the implant. Light-microscope and autoradiographic studies have shown a temporal progression from aberrant filter- or muscle-associated cells through proliferative foci to large invasive sarcoma. Electron microscopy revealed that presarcomatous cell foci consisted of one of two different cell types. These were either spindle cells with ultrastructural characteristics similar to foreign-body-induced sarcoma, or cells with the ultrastructural features of rhabdomyosarcoma. The subsequent appearance of two histological groups of sarcoma that were ultrastructurally similar to the cells of the early proliferative foci indicated that both elements may progress to form tumours. However, the constituent cells of both groups of tumours displayed a broad histological and ultrastructural spectrum and the marked similarity between the undifferentiated cells of each suggested that both may have arisen from diverse differentiation of a common pluripotential cell such as the pericyte.

Animals↗
PubMed1978

Histochemical observations on nodules induced in the mouse liver by phenobarbitone.

This study describes the histochemical reactions seen in nodules of the mouse liver. The nodules were obtained from 13 animals treated for over 80 weeks with phenobarbiotone and three untreated mice. The morphology of the lesion depends upon the preparative techniques and only two lesions with persistent abnormal trabecular pattern metastasised. A varying pattern of histochemical reaction was seen. The aniline hydroxylase reaction was dense in simple nodules and in centrilobular areas of phenobarbitone-treated mice but was weak in the abnormal trabecular lesions. These results suggest that it is possible to predict behavioural characteristics of mouse hepatic nodules on the basis of certain morphological characteristics.

Animals↗
PubMed1978

The hepatotoxicity of 3-amino-1,2,4-triazole and carbon disulphide in phenobarbitone-treated starved rats.

In phenobarbitone-treated starved male rats 1 g/kg 3-amino-1,2,4-triazole produced moderate liver necorsis and increased the serum glutamic-pyruvic transaminase activity. If half an hour after the administration of aminotriazole animals were exposed for 4 h to 2.0 mg/l CS2, the necrotic damage in the liver was larger and the serum glutamic-pyruvic transaminase activity higher than in rats not exposed to CS2. Carbon-disulphide in phenobarbitone-treated starved male rats caused only a very slight increase in the serum transminase activity in spite of the widespread hydropic degeneration in the liver. These experiments indicated that increase in serum transaminase activity is the consequence of necrosis and not hydropic degeneration; aminotriazole is hepatotoxic in rats when microsomal enzymes are induced and the hepatotoxicity of aminotriazole and carbon disulphide is potentiated by the administration of the other compound.

Alanine Transaminase↗
PubMed1978

Long-term effects of phenobarbitone-Na on male Fischer rats.

Male inbred Fischer rats were fed phenobarbitone-Na at a level of 500 parts/10(6) in the diet for 1 week, followed by 1000 parts 10(6) for 103 weeks at which time the survivors were killed. Thirty-three treated rats survived to 80 weeks. Before 80 weeks, no animals showed hyperplastic lesions. Of the 33 rats surviving 80 weeks and more, 11 had foci of nodular hyperplasia. These foci were usually small, but one animal killed at 102 weeks had a lesion of 0.75 cm diameter, which compressed the surrounding liver. In one case was evidence of local invasion or metastasis found. All the livers had evidence of parenchymal cell damage. No evidence of nodular hyperplasia was found in the controls. It is concluded that there is no evidence to suggest that phenobarbitone-Na induced neoplasm in the liver of male Fischer rats.

Animals↗
PubMed1978

A comparison of the changes induced in rat liver by feeding low levels of aflatoxin B1 or an azo dye.

(1) Rats have been given 6 weeks' feeding with low levels of the hepatocarcinogens aflatoxin B1 and 2-methyl dimethyl aminoazobenzene (2-Me-DAB). (2) It has been confirmed that 3 weeks' feeding with either toxin is sub-carcinogenic, whereas 6 weeks' feeding results in a high incidence of hepatocarcinoma. (3) The changes occurring in the liver during this feeding have been monitored by histological examination and zonal rotor centrifugation. (4) Marked similarities have been observed between the time courses of development of changes induced in the liver by the two carcinogens. Little change is observed after 2 weeks' feeding with the toxins. The greatest change occurs after 3 weeks' feeding, which results in tissue necrosis and the loss of a large proportion of the tetraploid hepatocyte nuclei. (5) A compensatory proliferation of predominantly diploid hepatocytes takes place in the presence of a continuing supply of either of the carcinogens. This indicates that not only does feeding each carcinogen induce the production of a population of hepatocytes resistant to the cytotoxicity of the inducing agent, but that the population is also resistant to the cytotoxicity of the other carcinogen.

Aflatoxins↗
PubMed1977

Hepatic structure and function after modified jejunoileal bypass surgery for obesity.

The most serious adverse effect of standard intestinal bypass for obesity is the high incidence of hepatic dysfunction and death from hepatic failure. We therefore examined the long-term effects of a modified form of jejunoileal bypass (in which a greater continuous length of ileum is retained), on liver function in 120 patients. Substantial weight loss (119-0+/-SD 23-3 kg to 82-3+/-18-8 kg) occurred during the first nine months after surgery, accompanied by a significant rise in serum concentrations of bilirubin, alanine transferase, and alkaline phosphatase, and a significant reduction in albumin concentrations. Biochemical changes were unrelated to weight loss or halothane anaesthesia. After weight stabilisation liver function reverted to normal, and four years after bypass sulphobromophthalein retention and hepatic histology did not differ from those in obese controls. There were two postoperative deaths. Three other patients died during the period of rapid weight loss with severe hepatic steatosis. While transient mild impairment of liver function is common after modified jejunoileal bypass, clinically significant hepatic dysfunction is a rare and unexplained early complication.

Adult↗
PubMed1977

Vascular changes in the lungs of rats after the intravenous injection of pyrrole carbamates.

The effects on the lung of some synthetic compounds related to monocrotaline pyrrole have been studied and compared with those previously found with that compound. When injected into a systemic vein doses of pyrrole mono- and dicarbamate produced acute pulmonary oedema. Pyrrole alcohol and ethyl carbamate had no such effect and although furyl carbamate did not cause pleural effusion in rats it did so in mice. Like monocrotaline pyrrole, when injected into other vessels the pyrrole carbamates produced oedema in the region of the first capillary bed encountered. When colloidal carbon was injected intravenously after the pyrrole carbamates, carbon "labelling" was seen in both the post-capillary venules and the capillaries of the lungs. On the whole, venular "labelling" occurred before capillary "labelling" which was best seen when the carbon was injected more than 4 hr after the pyrrole. The distribution of the carbon as seen by electron microscopy is described. No "labelling" was seen after furyl carbamate. The effects of the synthetic pyrrole esters were similar to those of monocrotaline pyrrole. Although both the pyrrole carbamates were less active on a molecular basis they had a broader action on the pulmonary vasculature causing venular as well as capillary "labelling". To affect the lungs acutely the compound had to have the pyrrole ring structure and at least one ester side-chain.

Animals↗