The Protective Role of Glutathione, Cysteine and Vitamin C against Oxidative DNA Damage Induced in Rat Kidney by Potassium Bromate

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 × 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.     

Pharmacokinetics of fluorinated 2-nitroimidazole hypoxic cell radiosensitizers in murine peripheral nervous tissue.

We have previously reported that KU-2285, a 2-nitroimidazole with a fluorinated N1-substituent (-CH2-CF2CONH(CH2)nOH, n = 2), was a promising hypoxic cell radiosensitizer. In this study the pharmacokinetics of KU-2285 and its related compounds (n = 3 and n = 4) were compared with those of etanidazole (a 2-nitroimidazole with an N1-substituent of -CH2CONH(CH2)nOH, n = 2) and its related compounds (n = 3 and n = 4) to assess the effects of incorporation of a CF2 group. The lipophilicity of the fluorinated compounds was higher than that of etanidazole, as measured by the octanol/water partition coefficient. As the number of CH2 groups increased, the lipophilicity of the compounds in both the KU-2285 and etanidazole series increased. The brain tissue levels of the fluorinated compounds were as low as those of the etanidazole derivatives, while the biological half-lives of the fluorinated compounds in peripheral nervous tissues were shorter than those of related non-fluorinated compounds.     

Refractory hemolytic uremic syndrome improved by plasmapheresis using cryosupernatant fraction as a replacement fluid: A case report

A 52-year-old woman who had had 6 months of chemotherapy using mitomycin C and cisplatin for cervical cancer presented with hemolytic uremic syndrome. Conventional plasmapheresis using whole-plasma fraction was ineffective. However, plasmapheresis using the cryosupernatant fraction dramatically improved symptoms of hemolytic anemia and thrombocytopenia in this case. The activity of factor VIII in the cryosupernatant fraction of plasma as a replacement fluid decreased after removal of cryoprecipitate, indicating effective removal of von Willebrand factor. The pathogenesis of her hemolytic uremic syndrome may have been associated with von Willebrand factor multimers contained in the cryoprecipitate of plasma. Similar use of the cryosupernatant fraction of plasma could not be found in other reports of cases of hemolytic uremic syndrome. Plasmapheresis using the cryosupernatant fraction of plasma may improve refractory hemolytic uremic syndrome.     

Long-term follow-up studies in 211 patients with tetralogy of Fallot after corrective surgery over 10 years

A total number of 427 patients with tetralogy of Fallot who underwent corrective surgery between 1960 and March 1990, in whom 211 patients who survived the surgery over 10 years were evaluated for the follow-up studies. Hemodynamic and cardiac function studies were carried out in 101 patients at the mean interval of 15.7 years (ranges 2 to 21 years). Three methods indicated that patients with muscle resection and pulmonary valvulotomy without patch enlargement (NP) had worse results than the groups with RV patch below valve (RP) and with transannular patch (TP). Also, Holter ECG revealed ventricular arrhythmias in patients with NP were more common than the groups with RP and TP. Sixteen patients (13 with NP, 2 with TP and one with RP) were required reoperation for residual ventricular shunt in 13, residual pulmonary stenosis in 11 and tricuspid regurgitation in 2. All of these 16 patients survived operation and obtained excellent clinical status. It is concluded that patients with TOF after corrective surgery should be carefully followed with short term interval to prevent sudden death and postoperative complications.     

Development of GFAP-positive cells and reactive changes associated with cystic lesions in HTX rat brain.

HTX rat, a congenital hydrocephalic strain, develops ventricular dilatation and cystic cavities in the cerebral white matter after birth. To investigate the reactive changes in glial cells around these cavities, immunohistochemical staining for glial fibrillary acidic protein (GFAP), a specific marker protein of astrocytes, and bromodeoxyuridine (BrdU), a thymidine analogue, was carried out on 107 Wistar and HTX rat brains from birth to postnatal day (P) 26. Animals were divided into three groups: Group A, Wistar rats as normal controls; Group B, HTX rats with a normal structure or only mild ventricular dilatation without any lesion in the white matter; and Group C, HTX rats with severe ventricular dilatation and cyst formation in the white matter. Group B rats showed similar development of GFAP-positive (GFAP+) cells to that in Group A rats, both morphologically and quantitatively. On the other hand, Group C rats showed definite structural changes in GFAP+ cells around the cystic cavities from P5. These included enriched cytoplasm and thickened cell processes with increased GFAP expression, and enveloped most cyst walls from P10. However, quantitative examination of the percentage of GFAP+ cells in Group C rats showed a similar developmental profile to those in Group A and B rats. Furthermore, the labeling index of BrdU-positive cells, indicating S-phase cells, in the white matter in Group C rats showed a similar decreasing pattern to that in Group A and B rats from P1 to P26.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anorexia nervosa with neutropenia--response of neutrophils to G-CSF]

A 50-year-old woman with anorexia nervosa was admitted for evaluation of neutropenia (WBC 1,600/microliters). Her bone marrow was gelatinous, and myeloid cells had decreased. Homogeneous substance deposited in the marrow, stained by alcian blue (pH 2.5), indicative of acid mucopolysaccharides. CFU-G and CFU-GM were decreased in number and myeloid pool in the bone marrow also decreased. Anti-neutrophilic antibody was negative. Neutropenia may be related to myeloid hypoplasia, due to increase of acid mucopolysaccharides replacing adipose cells in the bone marrow under long-term mal-nutritional state. Neutrophils markedly increased by administration of rhG-CSF 5.0 micrograms/kg/day for 14 days without the first peak. Serum G-CSF level did not increase (less than 60 pg/ml). It is effective to administer G-CSF to anorexia nervosa with neutropenia.     

Surgical treatment of acquired tricuspid stenosis]

There is no definitive surgical procedure for acquired lesions of the tricuspid valve (TV). From Feb, 1978, through March, 1990, the surgical treatment for the organic lesions of TV was performed in 10 patients, repair in 6 and TV replacement in 4. TV was repaired by commissurotomy, annuloplasty or valvuloplasty, or combination of them. When residual significant tricuspid regurgitation (TR) and/or stenosis (TS) was detected by intraoperative pulsed Doppler echocardiography after reparative procedures, TV was replaced. Follow-up periods ranged from 1 to 12 years (mean, 45.3 months). There was no early death, and late death was noted in one patient 32 months after operation. Preoperatively, 7 patients were in NYHA class IV and 3 in class III. Out of survivors, 7 are in class I and 2 in class II because of progression of mitral stenosis or coronary artery disease. Following surgery, the patients exhibited significant decrease in the cardiothoracic ratio (69.3 +/- 7.2 to 56.9 +/- 6.4%; p less than 0.01) and in the mean right atrial pressure (11.4 +/- 3.6 to 8.6 +/- 3.1 mmHg; p less than 0.05). The postoperative right ventriculography showed mild to moderate TR in 3 of 6 patients who underwent TV repair. In conclusion, TV repair could be a reasonable procedure for the organic TV lesions, although careful follow-up is recommended for residual TR.     

Marked improvement of delayed methotrexate-induced leukoencephalopathy treated with high-dose folinic acid

We report the case of a patient with delayed methotrexate (MTX)-induced leukoencephalopathy who showed a marked improvement both in clinical and neuroimaging findings after a high-dose of the active form of folinic acid (leucovorin) treatment. The patient developed progressive affective impairment accompanied by headache, nausea and vomiting after treatment with MTX during the chemotherapy for acute lymphoblastic leukemia, and diagnosed as delayed type MTX-induced leukoencephalopathy. After an intravenous injection of high-dose folinic acid (total 1920 mg), neurological deficits and white matter changes dramatically improved in a few weeks. Although delayed MTX-induced leukoencephalopathy may cause irreversible brain damage, an early treatment with high dose leucovorin may thus facilitate the marked improvement of clinical findings and white matter abnormalities.     

Intracerebral penetration of carteolol hydrochloride in rats

To elucidate the penetrability of carteolol, a β-adrenoceptor antagonist (β-blocker) into the brain of rats, intracerebral and serum concentrations of the compound were determined in male rats receiving single or repetitive oral administration of carteolol hydrochloride at 30 mg/kg. The time-course of the intracerebral concentration of carteolol following single IV administration of the compound at 10 and 30 mg/kg was also studied in male rats. A high-performance liquid chromatography method was used to determine the intracerebral and serum concentrations. Following single oral dosing, the intracerebral concentration of carteolol reached a maximum of 0.074 μg/g at 2 h postdosing and declined with a half-life of 3.7 h, and the C_max and AUC of carteolol in the brain were 12.5% and 19.8% of those in serum. The intracerebral and serum concentrations of carteolol were determined in male rats receiving repetitive oral dosing of the compound once daily for 7 days. The concentration of carteolol in the brain and serum at 1 h postdosing varied within a range of 0.059–0.091 μg/g and 0.321–0.443 μg/ml, respectively, throughout the dosing period, showing no changes in the penetrability of the compound into the brain due to repeated dosing. The concentration of carteolol in the brain and serum increased in a dose-dependent manner in rats receiving a single IV administration of the compound. The elimination half-life of carteolol in the serum and brain was 0.6–0.8 h and 1.3–1.7 h, respectively, in rats following single IV dosing of the compound. The half-life in the brain was about twice as long as that in the serum. The brain to serum concentration ratio was 0.306:0.499. From the above results, it was concluded that carteolol is distributed from the circulation to the brain with low penetrability. Received: 30 October 1996/Final version: 16 December 1996