Biomedical subjects
Publications and source records attributed to A Takagi.
A 58-year-old male patient who had a huge false aneurysm as a late sequela of division of patent ductus arteriosus was surgically managed with success. It is noteworthy that 24 years had elapsed from the initial operation until recognition of the aneurysm. The pathogenesis and method of the surgical treatment are discussed.
Using a single skinned muscle fiber, the function of the contractile system and the sarcoplasmic reticulum (SR) were analyzed in the skeletal muscle of the mdx mouse. Activation of the contractile system by calcium ion and the maximum force generation was normal. Ca2+ uptake of the SR was normal as well as regulation of the Ca-induced Ca release (CICR) by Ca2+. However, contracture by caffeine was more prominent in mdx than in control mice. Ca2+ leaked more from the SR of mdx in the presence of EGTA and ATP or its analogue. These abnormalities are probably interrelated; increased leakage of Ca2+ might cause the enhanced response to caffeine, since Ca2+ itself facilitates Ca release by caffeine. The abnormal leakage of Ca2+ might also activate the Ca pump of SR in the resting state, which consume extra ATP and disturb energy metabolism.
Micronucleus induction in male F344 rat peripheral blood by potassium bromate (KBrO3), a rat renal carcinogen, and its inhibition by several antioxidants were studied using the acridine orange supravital staining method. The frequency of micronucleated reticulocytes (MNRETs) peaked 32 h after a single i.p. treatment of rats with KBrO3 at a dose of 60 mg/kg. Co-treatment with glutathione (GSH) or cysteine (Cys) i.p. at doses of 800 mg/kg and 400 mg/kg, respectively, 30 min before and 30 min after the KBrO3 treatment significantly inhibited the micronucleus induction by KBrO3. Daily i.g. administration of vitamin C for 5 days at a dose of 200 mg/kg/day was also effective in protecting against micronucleus induction by KBrO3 given on the 4th day. However, co-treatment with superoxide dismutase in liposome-encapsulated form by i.p. injection at a dose of 18,000 U/kg 30 min before and 30 min after the KBrO3 application exerted no effect. The results indicate that antioxidants, especially sulfhydryl compounds, have protective potential against the clastogenicity of KBrO3, also suggesting that active oxygen species may play an important role in its clastogenicity.
The roles of glutathione (GSH), cysteine, vitamin C, liposome-encapsulated superoxide dismutase (L-SOD) and vitamin E in preventing oxidative DNA damage and cytotoxicity in the rat kidney after administration of potassium bromate (KBrO3) to male F344 rats were investigated by measuring 8-hydroxydeoxyguanosine (8-OH-dG), an oxidative DNA product, lipid peroxidation (LPO) levels and relative kidney weight (RKW). Combined pre- and posttreatment of animals with 2 x 800 mg/kg GSH i.p. inhibited the increase of 8-OH-dG, LPO levels and RKW caused by 80 mg/kg KBrO3 i.p. administration. In contrast, pretreatment with 0.3 ml/kg diethylmaleate (DEM) i.p., a depletor of tissue GSH, was associated with elevation of 8-OH-dG, LPO levels and RKW after a 20 mg/kg KBrO3 i.p. treatment, which itself caused no change. Administration of KBrO3 itself reduced renal non-protein thiol levels, but this was inhibited by the two doses of exogenous GSH. Combined treatment with DEM and KBrO3 lowered the non-protein thiol level in the kidney more than did DEM treatment alone. Protective effects against the oxidative damage caused by KBrO3 were also observed for pre- and posttreatment with 400 mg/kg cysteine i.p., another sulfhydryl compound, and daily i.g. application of 200 mg/kg vitamin C for 5 days. However, no influence was evident after pre- and posttreatment with 18,000 U/kg L-SOD i.p. or daily i.g. 100 mg/kg of vitamin E for 5 days. The results suggest that intracellular GSH plays an essential protective role against renal oxidative DNA damage and nephrotoxicity caused by KBrO3.
We have systematically investigated a genetic defect resulting in a primary lipoprotein lipase (LPL) deficiency in a proband TN and his affected brother SN, both manifesting familial hyperchylomicronemia. Neither LPL activity nor immunoreactive LPL mass was detected in postheparin plasma from the two patients. Immunocytochemical and biosynthetic studies on the proband's monocyte-derived macrophages with rabbit anti-human LPL antiserum revealed that no immunochemically detectable LPL protein was found in either the cells or culture medium, whereas LPL having a molecular mass of 61 kD was detected in normal cells. No detectable LPL mRNA was identified from poly(A)+RNA of the proband's macrophages by Northern blot analysis, and grossly visible LPL gene rearrangement was not observed by Southern blot analysis. Sequence analysis of polymerase chain reaction-amplified LPL gene exons detected one base deletion of G (first position of Ala221) at base 916 in exon 5 which leads to a premature termination by a frameshift. This mutation, designated as LPLArita and resulting in the loss of an AluI restriction enzyme site, was newly identified. We further analyzed the LPL gene from the two patients and their family members by digestion with AluI. Both patients were homozygous for LPLArita allele, while their spouses did not have this mutation. As genetically expected, their children were all heterozygous for LPLArita. We conclude that primary LPL deficiency in the proband was caused by a lack of enzyme synthesis due to the absence of LPL mRNA resulting from one base deletion of G in exon 5, and that heterozygous LPLArita deficient subjects show almost half value of control LPL mass.
The acute and subchronic toxicity studies on 2,2'-methylenebis (4-ethyl-6-tert-butylphenol) (MBEBP) were conducted using male and female Wistar rats. In acute toxicity test, the LD50 values were estimated to be greater than 10 g/kg BW by oral and intraperitoneal administration in each sex. In subchronic toxicity test, groups of 10 rats of each sex were fed a diet containing 0.2, 1.0 or 5.0% of MBEBP and examined at 4 and 12 weeks. Body weight gain was significantly depressed at doses of 1.0 and 5.0% in both sexes, but the depression in the 1.0% group was severer than that in the 5.0% group in males. Hematological analysis showed slight but significant decrease of hemoglobin in the 1.0 and 5.0% groups of both sexes. Urine analysis showed no remarkable changes in all treated rats of both sexes. In biochemical analysis of serum, decrease of triglyceride level and cholinesterase activity, and increase of amylase activity were observed in treated rats. Histopathologically, testicular atrophy and decrease of spermatogenesis were observed in male rats fed 1.0 or 5.0% MBEBP for 4 and 12 weeks and vacuolization of parathyroid gland cells was observed in female rats fed 1.0 and 5.0% MBEBP for 12 weeks. In subchronic test, the lowest observable adverse effect levels for MBEBP toxicity were estimated to be 171 mg/kg BW/day in male rats and 180 mg/kg BW/day in female rats.
The discrepancy between the low accumulation area (LAA) seen on 123I-IMP SPECT and the low density area (LDA) on X-ray CT was evaluated in 76 cases with chronic cerebrovascular disease. In 19 patients, LAA was larger than LDA beyond the vascular territory. Brain angiogram showed either obstruction or stenosis of the major arteries in as many as 59 percentages of this discrepancy group. In many patients of this group, cortical neurological symptoms were observed. In 37 patients in which the size of LAA was equal to that of LDA, abnormality of the major arteries was observed in only 7 percentages. These results indicated that the discrepancy mainly reflected the infarction due to irreversible ischemic change of perforate artery with the cortical low perfusion caused by the major artery disease. In some patients, the discrepancy was believed to show the remote effect caused by neurological pathway disturbance.
The effects of the antioxidants, glutathione (GSH) and its precursor cysteine (Cys) on oxidative damage induced by ferric nitrilotriacetate (Fe-NTA) were examined. Fe-NTA-associated oxidative stress caused the depletion of renal cellular GSH content. Administration of exogenous GSH and Cys suppressed 8-hydroxydeoxyguanosine (8-OH-dG) formation, an indicator of oxidative DNA damage and nephrotoxicity following Fe-NTA treatment. This suggests that generation of free radicals may be causally involved in oxidative lesion generation. Since lipid peroxidation was found to be inhibited only by GSH and not Cys treatment, this suggests that this effect and the DNA damage might be mediated by different pathways. Fe-NTA-associated oxidative stress in renal tubular cells might thus operate via both intracellular and external space modes.
To elucidate the relationship between peroxisome proliferation by perfluorinated compounds and oxidative DNA damage, perfluorooctanoic acid (PFOA), perfluorodecanoic acid (PFDA), perfluorobutyric acid (PFBA) and perfluorooctane (PFO) were administered to 6-week-old F-344 male rats. After a single intraperitoneal (i.p.) injection of PFOA, PFBA or PFO in corn oil at a dose of 100 mg/kg, significant increases of liver weight and 8-hydroxydeoxyguanosine (8-OH-dG) levels in liver DNA were observed in PFOA-treated rats. Oral administration of powdered diet containing 0.02% PFOA or 0.01% PFDA for 2 weeks resulted in significant increases of liver weight and 8-OH-dG levels in liver DNA in rats given both chemicals. On the other hand, no increase in 8-OH-dG levels in kidney DNA was found in either of the studies. Our results demonstrate that, as with other peroxisome proliferators (phthalic ester plasticizers and hypolipidemic drugs), PFOA and PFDA induced peroxisome proliferation also leads to organ specific oxidative DNA damage.
Changes in kidney levels of 8-hydroxydeoxyguanosine (8-OH-dG), lipid peroxidation (LPO), glutathione (GSH) and relative organ weight were examined 6, 24, 48, 72 and 96 h after a single i.p. administration of potassium bromate (KBrO3) at a dose of 70 mg/kg to male F344 rats. The 8-OH-dG level was significantly increased 24 h after the treatment at this dose and thereafter gradually decreased. On the other hand, significant elevation in LPO level was observed from 6 h after the treatment with a continuous increase up to a plateau at 48 h and no subsequent drop. GSH level was significantly raised from 6 to 72 h, and relative kidney weight varied in almost the same manner as the 8-OH-dG level. Investigation of the dose-response relation revealed the 8-OH-dG and LPO levels to be significantly increased from a dose of 40 mg/kg KBrO3 in a dose-dependent manner. The results suggest that enhanced formation of 8-OH-dG in kidney DNA due to KBrO3 is closely related to the increase in LPO levels.
Treatment of deoxyguanosine with H2O2 (56 mM) at 37 degrees C for 2 hrs resulted in the formation of 8-hydroxydeoxyguanosine (8-OH-dG). The formation of 8-OH-dG by H2O2 was increased about 3-folds in the presence of 78 microM L-histidine (L-His). The result suggests that oxidative DNA damage induced by H2O2 in vitro might be enhanced by L-His.
A 54-year-old male patient with heterozygous Protein C deficiency associated with the nephrotic syndrome and deep femoral artery thrombosis is described. He was admitted to the hospital because of nephrotic syndrome. A few days later, severe pain appeared in his left leg and a diagnosis of deep femoral artery thrombosis was made. Thrombectomy was performed immediately. His proteinuria disappeared in response to corticosteroid. He was found to have Protein C deficiency, antigen: 44%, activity 31%, which was also present in his father and son. Digital subtraction angiography (DSA) revealed the obstruction of left internal iliac and deep femoral arteries at their origins. Renal and hepatic biopsy revealed minor glomerular abnormalities, and chronic active hepatitis. The presence of heterozygous Protein C deficiency, nephrotic syndrome and chronic active hepatitis seem to cause marked decrease in serum Protein C level and deep femoral artery thrombosis. He is now under successful control with warfarin (1.7 mg/day) and bucolome (300 mg/day). It was reported that Protein C might have a suppressive effect on hypercoagulability in nephrotic syndrome. Therefore, Protein C deficiency may not counteract the hypercoagulable state and promote thrombus formation in the case. The present report is the first of a case of Protein C deficiency associated with nephrotic syndrome and arterial thrombosis.
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8-Hydroxydeoxyguanosine (8-OH-dG) was examined in the kidneys of rats after single i.p. administration of ferric nitrilotriacetate (Fe-NTA) for variable periods of time at various doses along with the measurement of lipid peroxidation and serum biochemical parameters and histopathological examination. Though lipid peroxide level increased rapidly and decreased sharply after reaching a much higher peak 1 h after treatment, significant higher levels of 8-OH-dG were observed at 1, 6 and 24 h after injection. On the other hand, the increase of 8-OH-dG formation was observed in a similar dose-dependent manner to the appearance of nephrotoxic responses in terms of serum biochemical and histopathological changes.
Five cases of congenital arteriovenous fistula in the gluteal region have been encountered in our department in the past 20 years. In all cases, the fistulous masses were in the connective tissue between the gluteal muscles and well-localized. Preoperative angiography showed the feeding arteries to be the superior gluteal, the inferior gluteal, and/or the lateral femoral circumflex arteries, and all the arteriovenous fistulae were excised almost completely with success. In this report, we emphasize the importance of precise estimation of the feeding arteries on preoperative angiography and ligating them before excising the fistulous masses, to ensure safe surgical treatment.
A 71-year-old man with a postoperative aortobronchial fistula was successfully treated. The fistula occurred between the left lower lobe and the descending thoracic aorta, to which a distal anastomosis of a temporary bypass graft had been placed during thoracic aortic aneurysmectomy 3 years before. For saving patients with this complication, early surgical treatment during episodes of intermittent hemoptysis is important. The use of an omentum pedicle flap for the isolation of the suture line is a important adjunct.
To elucidate the relationship between hepatic peroxisome proliferation and oxidative DNA damage induced by hepatocarcinogenic peroxisome proliferators, 3 agents, namely, di(2-ethylhexyl) phthalate (DEHP, aluminium clofibrate and simfibrate were fed at doses of 1.2%, aluminium clofibrate 0.5% and 0.5% in the diet, respectively, to male F-344 rats for up to 1 year. Evidence of hepatic peroxisome proliferation and 8-hydroxydeoxyguanosine (8-OH-dG) formation in liver and kidney DNA were assessed at 1, 2, 3, 6, 9 and 12 months. Peroxisomal beta-oxidation enzyme activities were increased 3- to 8-fold and catalase was elevated to 1.4- to 2.2-fold the control level by DEHP, aluminium clofibrate and simfibrate from months 1 to 12 of the treatment. 8-OH-dG levels in liver DNA of DEHP-, aluminium clofibrate- and simfibrate-fed rats were increased approximately 2-fold after 1 month, the tendency for elevation also being observed in the liver DNA at 2, 3, 9 and 12 months. The results thus clearly demonstrate that persistent peroxisome proliferation in the liver leads to continued specific oxidative DNA damage.
A significant increase of 8-hydroxydeoxyguanosine (8-OH-dG) was observed in the kidney DNA of rats given a renal carcinogen, the ferric complex of nitrilotriacetate (Fe-NTA) by single i.p. injection. By contrast, non- or weakly carcinogenic compounds, aluminum-nitrilotriacetate complex (Al-NTA), non-complexed NTA (Na2NTA) and ferric chloride had no effect on 8-OH-dG production in the kidney DNA. These results suggest the involvement of active oxygen radicals in Fe-NTA carcinogenesis.