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Biomedical subjects

B Toth

Publications and source records attributed to B Toth.

At least 37 records · Page 2Linked to original sources

Chemical oxidation and metabolism of N-methyl-N-formylhydrazine. Evidence for diazenium and radical intermediates.

N-Methyl N-formlhydrazine (1), a component of the mushroom Gyromitra esculenta, is a carcinogen. Its mode of action, however, is poorly understood. To determine the intermediates that may form during the metabolism of 1, we examined its oxidative chemistry, identified the products and inferred the intermediates on the basis of these products. The incubation of 1 with rat liver microsomes was also studied and the metabolites determined and quantified. Both the chemical and the microsome-mediated oxidation of 1 yielded formaldehyde and acetaldehyde. The formation of acetaldehyde requires (i) the oxidation of 1 to a diazenium ion (I) or diazene (II) and (ii) fragmentation of I/II to formyl and methyl radicals. It is suggested that these radical intermediates may be important in understanding and elucidating carcinogenesis by 1.

Acetaldehyde

Laryngeal lipoma.

We present a rare case of an intrinsic lipoma of the left false vocal cord in a 62-year-old man. The tumor was a manifestation of generalized lipomatosis. Successful endolaryngeal removal was accomplished.

Barium Sulfate

Oral administration of vanadate to streptozotocin-diabetic rats restores the glucose-induced activation of liver glycogen synthase.

Isolated hepatocytes from streptozotocin-diabetic rats failed to respond to a glucose load with an activation of glycogen synthase. This lesion was associated with severely decreased activities of glycogen-synthase phosphatase and of glucokinase. All these defects were abolished after consumption for 13-18 days of drinking water containing Na3VO4 (0.7 mg/ml), and they were partially restored after 3.5 days, when the blood glucose concentration was already normalized. In all conditions the maximal extent of activation of glycogen synthase in cells closely parallelled the activity of glycogen-synthase phosphatase.

Animals

Short-term hormonal control of protein phosphatases involved in hepatic glycogen metabolism.

The prominent protein phosphatases involved in liver glycogen metabolism are the AMD (ATP, Mg-dependent, type-1) and PCS (polycation-stimulated, type-2A) phosphatases. The glycogen synthase phosphatase activity, measured from the rate of activation of liver glycogen synthase, is virtually accounted for by AMD phosphatases; the bulk of the activity belongs to the glycogen-bound protein phosphatase G and a small part is present in the cytosol. The major part of the phosphorylase phosphatase activity present in the post-mitochondrial supernatant is shared by protein phosphatase G and cytosolic enzymes, and a minor part belongs to a microsomal AMD phosphatase. In the liver cytosol, the phosphorylase phosphatase activity is about equally distributed between AMD and PCS phosphatases. Studies in vivo as well as on isolated, perfused livers have shown that glucagon (which raises the level of cyclic AMP) as well as vasopressin (which increases the cytosolic Ca2+ concentration) decrease the phosphorylase phosphatase activity in liver extract or cytosol (filtered through Sephadex G-25) by about 25% within a few minutes. These effects were not additive, and the activity of glycogen synthase phosphatase was not affected. Conversely, insulin as well as glucose increased both phosphatase activities by about 25%, and these effects were additive. Vanadate mimicked the effect of insulin on the perfused liver. All the activity changes were only observed when the assays were performed at high tissue concentration. Upon subcellular fractionation all the effects were well expressed in the cytosol, but not in the particulate fraction (glycogen and microsomes). However, quantitatively the hormonal responses were largely lost during the fractionation procedure; they could be restored by recombination of the liver cytosol from a hormone-treated rat with the particulate fraction from either a treated or an untreated animal. It appears that the effects of glucagon, insulin and glucose are mediated by cytosolic, transferable effectors of the Vmax of protein phosphatases. These effectors are eluted in the void volume of a Sephadex G-25 column. Rats of the gsd/gsd strain, which have a genetic deficiency of hepatic phosphorylase kinase, responded to an injection of insulin plus glucose with a normal increase in the cytosolic phosphorylase phosphatase activity. In contrast, they failed to respond to glucagon as well as vasopressin. A transient 80% inhibition of the phosphorylase phosphatase activity could be induced in vitro in a concentrate liver cytosol from Wistar rats upon addition of MgATP.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals

Decreased activity and impaired hormonal control of protein phosphatases in rat livers with a deficiency of phosphorylase kinase.

1. Livers from gsd/gsd rats, which do not express phosphorylase kinase activity, also contain much less particulate type-1 protein phosphatases. In comparison with normal Wistar rats, the glycogen/microsomal fraction contained 75% less glycogen-synthase phosphatase and 60% less phosphorylase phosphatase activity. This was largely due to a lower amount of the type-1 catalytic subunit in the particulate fraction. In the cytosol, the synthase phosphatase activity was also 50% lower, but the phosphorylase phosphatase activity was equal. 2. Both Wistar rats and gsd/gsd rats responded to an intravenous injection of insulin plus glucose with an acute increase (by 30-40%) in the phosphorylase phosphatase activity in the liver cytosol. In contrast, administration of glucagon or vasopressin provoked a rapid fall (by about 25%) in the cytosolic phosphorylase phosphatase activity in Wistar rats, but no change occurred in gsd/gsd rats. 3. Phosphorylase kinase was partially purified from liver and subsequently activated. Addition of a physiological amount of the activated enzyme to a liver cytosol from Wistar rats decreased the V of the phosphorylase phosphatase reaction by half, whereas the non-activated kinase had no effect. The kinase preparations did not change the activity of glycogen-synthase phosphatase, which does not respond to glucagon or vasopressin. Furthermore, the phosphorylase phosphatase activity was not affected by addition of physiological concentrations of homogeneous phosphorylase kinase from skeletal muscle (activated or non-activated). 4. It appears therefore that phosphorylase kinase plays an essential role in the transduction of the effect of glucagon and vasopressin to phosphorylase phosphatase. However, this inhibitory effect either is specific for the hepatic phosphorylase kinase, or is mediated by an unidentified protein that is a specific substrate of phosphorylase kinase.

Animals

Carcinogenesis by pentanal methylformylhydrazone of Gyromitra esculenta in mice.

Pentanal methylformylhydrazone (PMFH) given in propylene glycol as 52 weekly intragastric instillations on a 50 micrograms/g body weight basis, induced tumors of the lungs, liver and preputial glands in Swiss mice. The tumor incidences in these tissues were 72, 16 and 0% in the treated females, while these tumor incidences in the males of this group were 60, 2 and 12%, respectively. The corresponding tumor incidences in the propylene glycol instilled solvent control females were 26, 0 and 0%, whereas in the males of this group they were 22, 0 and 0%, respectively. Histopathologically, the tumors were classified as adenomas and adenocarcinomas of the lungs, benign hepatomas and squamous cell papillomas and carcinomas of the preputial glands. Pentanal methylformylhydrazone is an ingredient of the edible wild mushroom Gyromitra esculenta which is consumed by a segment of the human population around the world.

Adenocarcinoma

Aortic rupture and aortic smooth muscle tumors in mice. Induction by p-hydrazinobenzoic acid hydrochloride of the cultivated mushroom Agaricus bisporus.

p-Hydrazinobenzoic acid (HBA), an ingredient of the cultivated mushroom Agaricus bisporus, was given in hydrochloride form at a dosage of 0.125% in drinking water for life to randomly bred Swiss mice. Previous studies had demonstrated that either synthetic or naturally occurring hydrazines are carcinogenic in mice with the main tumors so-induced being peripheral angiomas and angiosarcomas. As a result of HBA treatment in the present experiments, smooth muscle cell tumors of the aorta and large arteries were induced in 14% of females and 42% of males, whereas the corresponding frequency of tumors in untreated female and male controls was 0 and 4%, respectively. Tumors were observed as early as at 17 weeks of age. Numerous experimental animals (32% of females and 50% of males) died of aortic rupture. Histopathologically, two major changes were observed to explain both the ruptures and tumors. First, the intimal and inner medial aspect of the aortic walls had undergone effacement with widespread fibrinoid necrosis, accompanied by medial elastinolysis. Second, a proliferation of cells arising in the media, benign in some aortae and frankly malignant in others, was strikingly positive by immunohistochemistry for cytoplasmic actin and myosin, moderately positive for desmin, weakly positive for vimentin, and negative for factor VIII-related antigen. When malignant, the tumors extended into the periaortic adventitial connective tissue. The tumors were classifiable as leiomyomas and leiomyosarcomas. Thus, HBA is an additional carcinogenic ingredient of the widely consumed mushroom, A. bisporus. A continuum from toxic tissue injury to cellular hyperplasia, dysplasia, and ultimate neoplasia is well-illustrated by HBA.

Agaricus

[Effect of heart diseases on premature labor].

The connection between the different heart diseases and premature births was studied. The incidence of premature births was more frequently in heart cases, while fetal retardation was similar to that of the control with exception of the group of the patients with acquired and operated heart diseases. Perinatal fetal mortality during birth was similar to the normal cases but higher in fetal retardation as in the general population of the pregnant women. In a worse condition of heart function the rates of premature birth, perinatal mortality and fetal retardation are more frequent than in a better circulatory state.--The contradiction found in the literature on this theme may have its cause that the effect of heart diseases affecting premature birth were not considered in its functional severity.

Adolescent

Cancer induction in mice by feeding of the uncooked cultivated mushroom of commerce Agaricus bisporus.

The cultivated mushroom of commerce in the Western hemisphere, Agaricus bisporus, was given p.o. to randomly bred Swiss mice for 3 days and was followed by semisynthetic diet for 4 days each week for life. The mice were 6 weeks old at the beginning of the experiment. As a result of treatment, tumors were induced in the bone, forestomach, liver, and lungs in the following incidences: 16, 38, 8, and 40% in females and 16, 28, 12, and 62% in males, respectively. The corresponding tumor incidences in the untreated controls were 0, 0, 0, and 26% in females and 0, 4, 2, and 34% in males, respectively. Histopathologically, the tumors were classified as osteomas and osteosarcomas, squamous cell papillomas and carcinomas of forestomach, benign hepatomas, and adenomas and adenocarcinomas of lungs. The investigation thus proves the carcinogenicity of uncooked Agaricus bisporus.

Agaricales

The axial frontonasal flap revisited.

After 15 years of experience and 50 cases, we think that the axial frontonasal flap is of great value for the repair of large skin defects of the nose. This flap mobilizes all the skin cover of the nose located above the defect and the adjacent frontal skin and rotates it on a vascular pedicle existing at the level of the inner canthi. The excess of skin of the glabella is then transferred to the nose, and this large flap allows coverage of the defect without tension or distortion. The long-term results are very good, with a hardly visible repair in 26 of 50 patients, the long scar being very well hidden at the periphery of the nose.

Adult

Lack of carcinogenicity of agaritine by subcutaneous administration in mice.

Agaritine (A), an ingredient of the cultivated mushroom of commerce Agaricus bisporus, was administered by subcutaneous injection to two groups of randomly bred Swiss mice. In the first group the animals of both sexes were treated at a 100 micrograms/g body weight basis five times at weekly intervals, while in the second group the mice received a single A treatment of 100 micrograms/g body weight for females and 50 micrograms/g body weight for males. The administration of the compound resulted in no detectable carcinogenic effect in the animals. Since some of the breakdown products of A were shown to be carcinogenic in mice and the mushroom itself was found to be mutagenic, the field is discussed in the light of the obtained results.

Animals

Lack of tumorigenicity of sodium benzoate in mice.

Sodium benzoate was administered as a 2% solution in drinking water for life to randomly bred Swiss mice. Consumption of the chemical caused no detectable tumorigenic effect under the current experimental conditions.

Animals

Effect of Metamucil on tumour formation by 1,2-dimethylhydrazine dihydrochloride in mice.

The effect of the plant cellulose metamucil on the tumorigenicity of 1,2-dimethylhydrazine dihydrochloride (1,2-DMH) was studied in random-bred Swiss mice. Three groups of mice, which were 5, 6 and 6 weeks old at the beginning of the experiment, were given the following treatments: (1) metamucil (20%, w/w) in powdered diet for their lifespan; (2) 1,2-DMH, ten weekly subcutaneous injections at 20 mg/kg body weight; (3) combination of treatments given to groups 1 and 2. The administration of metamucil enhanced the appearance of colon tumours induced by 1,2-DMH in males only. Metamucil had no statistically significant effect on the development of tumours elicited by 1,2-DMH at seven additional sites. It was expected that a high amount of dietary fibre would inhibit carcinogenesis in the large intestine. Instead, metamucil increased the incidence of colon tumours induced by 1,2-DMH, although only in males.

1,2-Dimethylhydrazine

Head and neck manifestations of the chronic graft vs. host disease.

Bone marrow transplantations are being used with increasing frequency in the treatment of patients with leukemia and aplastic anemia. The graft-vs.-host disease (GVHD) is a serious complication that affects long-term survivors following bone marrow transplantation. It is the result of an immunologic reaction mounted by the grafted reticuloendothelial cells against the tissues of the recipient, and it affects multiple organ systems. Involvement of the skin and mucosal surfaces of the head and neck region, in particular the oral cavity, occurs in a large number of patients with GVHD. In this report we present four patients with GVHD in whom mucosal lesions and infections of the head and neck region were prominent features. Our observations indicate that the clinical and histological characteristics of these lesions vary according to the time elapsed from the onset of the disease. Therefore, clinical examination of the head and neck region and biopsy of the oral mucosa are important not only in the diagnosis of the GVHD, but also in the evaluation of its progress and response to treatment.

Adult

Enhancing effect of vitamin E on murine intestinal tumorigenesis by 1,2-dimethylhydrazine dihydrochloride.

The effect of the antioxidant vitamin E on the tumor-inducing ability of 1,2-dimethylhydrazine dihydrochloride (1,2-DMH) was investigated in randomly bred Swiss mice. Three groups of mice that were 6 weeks of age at the beginning of the experiment received the following treatments: a) vitamin E acetate [DL-alpha-tocopheryl acetate (TA)] at a 4% dose level in a powdered diet for life; b) 1,2-DMH, 10 weekly sc injections at 20 micrograms/g body weight; c) combination of a and b treatments. The administration of TA enhanced the tumorigenicity of 1,2-DMH, as evidenced by statistically significant incidences of tumors in the duodenum, cecum, colon, rectum, and anus. The present finding apparently is in contrast with the reported inhibitory effect of TA on colon carcinogenesis by 1,2-DMH.

1,2-Dimethylhydrazine

Tumorigenic action of repeated subcutaneous administration of N-methyl-N-formylhydrazine in mice.

N-Methyl-N-formylhydrazine (MFH), an ingredient of the edible false morel mushroom, was administered to Swiss mice as 40 weekly subcutaneous injections at 20 micrograms/g body weight for females and 10 micrograms/g body weight for males. The treatments gave rise to statistically significant incidences of lung tumors: 56% in females and 40% in males. The administration of the chemical resulted in no detectable carcinogenic effect in other organs. The findings are discussed in light of the results from earlier studies with this compound.

Animals