Biomedical subjects
Publications and source records attributed to K Furuya.
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The metabolism of two nasal carcinogens, N'-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), was investigated using cultured nasal septa of F344 rats. The explants were cultured with 14C-labeled N-nitrosamines, and unbound metabolites present in the medium were quantitated by high-performance liquid chromatography. The results indicated that the mucosa of the nasal septum had a marked capacity to metabolize NNN and NNK to hydroxylated products which were released into the culture media. Extensive activation by alpha-carbon hydroxylation of NNN (preferentially 2'-carbon hydroxylation) and NNK was observed, whereas no deactivation by pyridine N-oxidation could be detected. Microautoradiographic studies of explants showed that binding of radioactivity occurred preferentially in the respiratory and olfactory epithelia and in the subepithelial glands of the nasal mucosa. The results suggest that reactive metabolites of NNN and NNK are formed within the target tissue rather than being transported from the liver to the nasal mucosa. The results also show that the culture of nasal septa can be used to ascertain the role of the nasal mucosa in the activation of nasal-specific carcinogens.
An analysis of 105 autopsy cases (77 male, 28 female) of hepatocellular carcinoma (HCC) showed that 90 cases (85.7%) were associated with liver cirrhosis, of which 75 cases (83.3%) were of the macronodular type. Hepatitis B surface antigen (HBsAg) was detected with orcein stain in the hepatic tissue in 58 cases (55.2%). The incidence of HBsAg in cases of HCC patients with cirrhosis (58.9%) was higher, but not significantly, than that in those without cirrhosis (33.3%). The mean age of HBsAg-positive cases was five years less than that of HBsAg-negative cases, the age distributions therefore being significantly different.
Amputees wearing conventional prostheses have often found difficulty when conforming with the conventions of Japanese social life, since the prosthesis is not well adapted to walking in bare feet or sitting cross-legged. The authors described a modified prosthesis with a spring-loaded rotation mechanism that can be initiated unobtrusively and a modified foot piece in which the ankle motion is transmitted via a lever arm to a joint placed more anteriorly than usual. Nearly 250 patients have been fitted with the prosthesis and 40 have undergone laboratory gait analysis. The results indicate a walking cycle and foot pressure pattern more closely resembling the normal, than that obtained by other prosthetic systems.
The present study revealed that the IgG immunoglobulins of normal or non-immune rabbit IgG and anti-bovine serum albumin, anti-ovalbumin, anti-bovine IgG and anti-p-chlorobenzoic acid antibodies could non-specifically bind to bis-(p-chlorophenyl)-acetic acid (DDA) coupled to omega-amino-hexyl Sepharose (AHS) by the use of strengthened hydrophobic interactions dependent on the concentration of NaCl. The main binding site on the adsorbent of DDA-substituted AHS (DDA-AHS) was found to be the DDA ligand. The hydrophobic potency of the DDA ligand was thought to be more effective than that of p-chlorobenzoic acid coupled to AHS. Out study also demonstrated that two different binding sites capable of interacting the DDA ligand were contained in IgG molecules. One was located in the Fc region and the other in the Fab region. The former had an ability to adhere to the DDA-AHS adsorbent in the presence of NaCl of 3 M or over, while the latter showed heterogeneous binding behavior depending upon its antibody specificity. Differences in the chromatographic distribution among the whole IgG immunoglobulins including anti-DDA antibody were found by a hydrophobic salting-out chromatography (HSOC) method on a DDA-AHS column. It was therefore assumed that when whole IgG proteins were subjected to HSOC on a DDA-AHS column, the hydrophobic binding site in the Fc region played a decisive role at high salt concentrations of 3 M or over, while the hydrophobic binding site in the Fab region played a major role at intermediate and low salt concentrations of 2 M or below. Thus, by taking advantage of this HSOC method, whole IgG or its Fab molecules possessing very strongly hydrophobic binding sites to promote high quantum yields of 8-anilinonaphthalene-1-sulfonate (ANS) fluorescence can be easily separated. We concluded that the ligand of DDA is a probe for the hydrophobic regions in IgG immunoglobulins.
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Administration of butylated hydroxyanisole (BHA), a widely used food additive, has been found to inhibit the carcinogenic and toxic effects of various chemicals in animal models. To study the relationship of dietary BHA to the acute toxicity of methylazoxymethanol (MAM) acetate, a colon-specific carcinogenic compound, groups of female CF1 mice were fed NIN-07 diet containing 0, 300, 1000, 3000 or 6000 ppm BHA or a semipurified diet containing 0 or 6000 ppm BHA for 4 wk, and were injected ip with MAM acetate (20 mg/kg body weight) at the end of the first 2 wk and again 4 days later. At levels of 300-6000 ppm, BHA was found to protect against death caused by MAM acetate. The mortality rates in MAM-treated mice were 80 and 92% in those fed the diets with no BHA and 0 and 1% in those fed 6000 ppm BHA, and were inversely related to the amount of BHA in the diet. The protection was associated with increased levels of hepatic cytochrome P-450 and b5 and with a reduction in necrotic changes in the liver.
The tumor initiating activities on mouse skin of benzo[b]fluoranthene, (B[b]F), benzo[j]fluoranthene (B[j]F), benzo[k]fluoranthene (B[k]F] and three of their dihydrodiols, 9,10-dihydro-9,10-dihydroxybenzo[b]fluoranthene (B[b]F-9,10-diol), 9,10-dihydro-9,10-dihydroxybenzo[j]fluoranthene (B[j]F-9,10-diol), and 8,9-dihydro-8,9-dihydroxybenzo[k]fluoranthene (B[k]F-8,9-diol) were evaluated. Among the parent hydrocarbons, B[b]F was the most potent tumor initiator, with activity greater than that of B[j]F but less than that of benzo[a]pyrene. B[k]F also showed tumor initiating activity, in contrast to its lack of complete carcinogenic activity on mouse skin. B[b]F-9,10-diol, which can form a bay region dihydrodiol epoxide, was as active as B[b]F. B[j]F-9,10-diol, which would form its dihydrodiol epoxide in a four sided pseudo-bay region, was less active than B[j]F. B[k]F-8,9-diol was inactive. These results, together with parallel metabolic studies, suggest that the formation of bay region dihydrodiol epoxides may not be the major activation mechanism in benzofluoranthene tumorigenesis.
Using dogs, we experimentally produced devascularized areas in the small intestine and colon and took quantitative measurements of the submucosal local blood flow using the hydrogen clearance method.. In the area slightly toward the ischemic side of the devascularized margin, local blood flow is less on the mesenteric side in both the ileum and the colon, and microcirculation is better maintained in the colon that in the ileum. When the anastomosis was performed in the area in which the local blood flow on the mesenteric side was 60 per cent of the control value in the ileum or 70 per cent in the colon, recovery of the control value was achieved by the seventh postoperative day. When anastomosis was performed in the area in which the local blood flow on the mesenteric side was 15 per cent of the control value in the ileum and 22 per cent of the control value in the colon, the flow on the mesenteric side did not recover to the level of the control value by the seventh postoperative day, and anastomotic leakage occurred in some dogs. All anastomotic leakage occurred on the mesenteric side. The local blood flow rate at the point at which the last signal was detected by Doppler ultrasound flowmeter after moving Doppler probe from the devascularized margin toward the ischemic side was 57 per cent of the control value in the ileum and 54 per cent of that in the colon. Such levels of blood flow are considered sufficient for successful healing of tissue after an anastomosis.
The histogenesis of perianal squamous cell carcinomas induced by subcutaneous and intraperitoneal injection of 1,2-dimethylhydrazine dihydrochloride (DMH) and painting of methylazoxymethanol (MAM)-acetate on the anal region was investigated in 212 female BALB/c mice. Painting of MAM-acetate and injection of DMH induced similar benign and malignant tumors and hyperplastic lesions in the anal region. In chronological studies on animals given DMH subcutaneously, cystic or solid squamous lesions, foci of immature sebocytes, sebaceous hyperplasias and sebaceous adenomas were identified. These lesions seemed to be precursors of carcinomas that developed in the same region, and originated from hair follicles or sebaceous glands of the pilosebaceous complexes, but not from the anal mucosa. In mice treated with DMH, the incidence of perianal carcinomas was high in groups with high incidences of colon carcinomas.
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Planned deliveries have been attempted with the administration of prostaglandins E2 and F2 alpha since 1978. Eight hundred and eighteen prostaglandins-induced and 729 uninduced deliveries from January, 1978 to July, 1980 were statistically analyzed. The uninduced deliveries included 465 spontaneous and 264 stimulated labors. The cervical ripening was considered the basic requirement stimulated labors. The cervical ripening was considered the basic requirement for labor induction for the first year of study. However, spontaneous labor onset or the membranes rupture occurred before the induction in 52.4% of cases, where babies were large enough (3,052.6 +/- 33.4g, mean +/- SE, n = 154). Therefore, the cervical factor was excluded from the essential requirement for induction. Since the beginning of 1979, labor induction has been performed based on gestational age (38 weeks or more) and uterine fundal length (32cm or more). Laminaria tents were inserted into the unfavorable cervix the night before induction. Delivery time in the day, duration of labor, and birth weight of babies in the induced group were 2.04 +/- 0.18 p.m., 8.0 +/- 0.3 hours and 3,138.8 +/- 12.3g, respectively. Apgar scores and the amount of postpartum hemorrhage were not significantly different from those in the uninduced group. Similar results were obtained between the laminaria subgroup with unfavorable cervix and the non-laminaria subgroup with ripe cervix in the induced primigravidas.
Monitoring of the spinal cord function by evoked spinal cord potentials (ESP) has come to be used widely with the establishment of a safe technique using an epidural electrode and the great improvement in medical electronic devices. According to other investigations ESP has been recorded through an electrode placed in the posterior epidural space, it is well known that residual ESP can be actually recorded after transection of the posterior half of the spinal cord and that ESP shows no change after a small transection of the anterior column. If ESP originating from the anterior half of the spinal cord is recorded, it is very useful for monitoring during anterior decompression surgery for myelopathy such as ossification of the posterior longitudinal ligament and cervical spondylosis. The purpose of this report is to analyse ESP originating from the anterior half of the spinal cord experimentally and further investigate the ESP monitoring clinically. Sixty cats were used in this study. ESP recording principally consisted of stimulation to the spinal cord at the level of thoracic or lumbar region and recording of ESP with a monopolar electrode placed in the cervical epidural space. Changes in the ESP after transection and compression of the spinal cord were analysed. Anterior vertebrectomy and laminectomy at C2 and C6 were performed for the purpose of placing an electrode correctly and facilitating transection or compression of the spinal cord. Recording electrodes were placed on both the anterior and posterior surfaces of the dura mater at C2. As the result of this study, it is apparent that there exists the ESP originating from the anterior half of the spinal cord. Such ESPs are more accurately recorded through an anterior placed electrode rather than through that placed posteriorly.
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The tumor initiating activity on mouse skin of 5-hydroxymethylchrysene (5-HOMeC), a major metabolite of the carcinogen, 5-methylchrysene (5-MeC), was investigated. After an initiating dose of 30 microgram, with promotion by tetradecanoylphorbol acetate, 5-HOMeC induced skin tumors in 90% of the animals, with 9.5 tumors/mouse, 5-MeC gave a 75% incidence of skin tumors with 6.2 tumors/mouse. The tumorigenic activities after a 10 microgram initiating dose were; 5-HOMeC, 45% skin tumor-bearing animals and 2.6 tumors/-mouse; 5-MeC, 55% skin tumor-bearing animals and 5.6 tumors/mouse. In contrast, 6-hydroxy-methylchrysene was inactive. To investigate the mechanism of activation of 5-HOMeC, 3-fluoro-5-hydroxymethylchrysene (3-F-5-HOMeC) and 7-fluoro-5-hydroxymethylchrysene (7-F-5-HOMeC) were prepared and assayed for tumor initiating activity at a dose of 30 microgram. 7-F-5-HOMeC gave 95% tumor-bearing animals and 7.9 tumors/animal whereas 3-F-5-HOMeC gave only 5% tumor-bearing animals and 0.1 s/animal. The inhibition of tumorigenicity by substitution of fluorine at the 3-position, but not the 7-position of 5-HOMeC is strictly analogous to results obtained previously with 5-MeC and suggests a similar mechanism of activation for both compounds. The metabolites formed upon incubation of 5-HOMeC with cofactors and the 9000 x g supernatant from Aroclor pretreated rats were separated by h.p.l.c. The 1,2-dihydrodiol and 7,8-dihydrodiol of 5-HOMeC were identified. The major phenolic metabolite was identified as 1-hydroxy-5-hydroxymethylchrysene. In the in vitro metabolism of 7-F-5-HOMeC under the same conditions, we identified the 1,2-dihydrodiol but not the 7,8-dihydrodiol. In the metabolism of 3-F-5-HOMeC, oxidation in the 1-4 ring was inhibited relative to that observed in the metabolism of 5-HOMeC. These results suggest that 5-HOMeC is activated primarily through formation of its 1,2-dihydrodiol.
Two potent inhibitors of prostaglandin biosynthesis, thielavin A (C31H34O10) and B (C29H30O10), were isolated from cultures of Thielavia terricola. Both of these compounds were shown to be structurally related to depsides, thus consisting of three hydroxybenzoic acid groups. Concentrations required for 50% inhibition of the conversion of 14C-arachidonic acid into prostaglandins F2 alpha plus E2 by microsomes of ram seminal vesicles were 12 microM for thielavin A and 9 microM for thielavin B, respectively. Of the enzymatic steps involved in prostaglandin synthesis, thielavin A specifically inhibited the conversion of arachidonic acid into prostaglandin H2, while prostaglandin E2 synthesis from the endoperoxide was the most sensitive to thielavin B. Thromboxane A2 synthesis from prostaglandin H2 in bovine platelet microsomes were inhibited by 50% at concentrations of 150 and 350 microM of thielavin A and B, respectively. Thielavin B was significantly effective on carrageenan-induced oedema of rats when administered intravenously but on on oral administration. The anti-inflammatory activity was not detectable with thielavin A either on intravenous injection or on oral administration.