Inhibitory effects of prior low-dose X-irradiation on cold-induced brain injury in mouse.

We examined the inhibitory effects of low-dose X-irradiation on mouse brain tissue with cold-induced injury by comparing tissue samples from three groups of mice: control, sham-irradiated cold-exposed, and X-ray-irradiated (0.5 Gy) cold-exposed mice. The water content in brain increased significantly in the sham-irradiated group following the cold-induced injury relative to the control group. However, water content in brain tissue from the X-ray-irradiated group was significantly lower than that from the sham-irradiated group. Levels of antioxidants, such as superoxide dismutase and glutathione, in brain tissue from the X-ray-irradiated group were higher than those from the sham-irradiated group. Moreover, the cold injury-induced cell death, particularly apoptosis, while low-dose irradiation inhibited cell death, especially among glial cells, but not numeral cells. These findings suggest that prior low-dose X-irradiation activated antioxidant function and inhibited cold-induced brain injury.

Studies on possibility for alleviation of lifestyle diseases by low-dose irradiation or radon inhalation.

Our previous studies showed the possibility that activation of the antioxidative function alleviates various oxidative damages, which are related to lifestyle diseases. Results showed that, low-dose X-ray irradiation activated superoxide dismutase and inhibits oedema following ischaemia-reperfusion. To alleviate ischaemia-reperfusion injury with transplantation, the changes of the antioxidative function in liver graft using low-dose X-ray irradiation immediately after exenteration were examined. Results showed that liver grafts activate the antioxidative function as a result of irradiation. In addition, radon inhalation enhances the antioxidative function in some organs, and alleviates alcohol-induced oxidative damage of mouse liver. Moreover, in order to determine the most effective condition of radon inhalation, mice inhaled radon before or after carbon tetrachloride (CCl(4)) administration. Results showed that radon inhalation alleviates CCl(4)-induced hepatopathy, especially prior inhalation. It is highly possible that adequate activation of antioxidative functions induced by low-dose irradiation can contribute to preventing or reducing oxidative damages, which are related to lifestyle diseases.

Radon inhalation protects mice from carbon-tetrachloride-induced hepatic and renal damage.

We assessed whether radon inhalation provided protection from carbon tetrachloride (CCl4)-induced hepatic and renal damage in mice. Mice were subjected to intraperitoneal injection of CCl4 after inhaling approximately 18 kBq/m3 radon for 6 h. Radon inhalation significantly increased total glutathione (t-GSH) content and glutathione peroxidase (GPx) activity in the liver and kidney. Injection of CCl4 was associated with significantly higher levels of glutamic oxaloacetic transaminase (GOT) and alkaline phosphatase (ALP) activity and creatinine level in serum, and pretreatment with radon significantly decreased the GOT and ALP activity and creatinine level associated with CCl4 injection, suggesting that radon inhalation alleviates CCl4-induced hepatic and renal damage. The t-GSH contents and GPx activity in the liver and kidney of animals pretreated with radon were significantly higher than those of the CCl(4)-only group. These findings suggested that radon inhalation activated antioxidative functions and inhibited CCl4-induced hepatic and renal damage in mice.

Basic study on active changes in biological function of mouse liver graft in cold storage after low-dose x-irradiation.

We previously reported that low-dose X-irradiation alleviates ischemia-reperfusion injury such as mouse paw edema. In this study, we examined active changes in the biological function of mouse liver grafts in cold storage after low-dose X-irradiation. Mouse livers were sham-irradiated or were irradiated with 0.25, 0.5, 1.0, or 5.0 Gy of X-ray and stored for 4, 8, 24, or 48 h in preservation or saline solution. The results show that storage for 24 h in saline solution after 0.5 Gy irradiation significantly increased the activity of superoxide dismutase (SOD) and catalase. Following storage for 4, 8, or 48 h in preservation solution, lipid peroxide levels of the 0.5 Gy irradiated group were significantly lower than those of the sham irradiated group. Following storage for 24 h in preservation solution, the activity of SOD and catalase of the 1.0 Gy irradiated group were significantly higher than those of the sham irradiated group. Hepatocytes stored in saline solution were vacuolated. However, no vacuole formation was observed in hepatocytes stored in preservation solution. These findings suggest that low-dose irradiation significantly activates antioxidative functions of liver grafts. Moreover, the dose at which enhancement of antioxidative function occurs in livers stored in preservation solution, which contains glutathione, is significantly higher than that in saline solution.

No Different Sensitivity in Terms of Whole-Body Irradiation between Normal and Acatalasemic Mice.

To elucidate the radiosensitivity of an acatalasemic mouse, we examined the time and dose-dependency in the survival rates, the lymphocytes and the intestinal epithelial cells, and the antioxidant function after 3.0 to 12.0 Gy whole body irradiation. Results showed that no significant differences between acatalasemic mice and normal mice were observed in the survival rates and the histological changes in spleens and small intestine after each irradiation. The catalase activities in livers and spleens of acatalasemic mice were significantly lower than those of normal mice and the glutathione peroxidase activity in livers of acatalasemic mice was significantly higher than that of normal mice. At 10 days after 6.0 Gy irradiation, the catalase activities in livers of acatalasemic and normal mice and that in spleens of normal mice significantly decreased compared with no-irradiation control, and there were no differences between those catalase activities. The total glutathione content in acatalasemic mice was significantly higher than that in normal mice at 10 days after 6.0 Gy irradiation. These findings suggested that the radiosensitivity of acatalasemic mice in terms of whole body irradiation doesn't significantly differ from that of normal mice, probably due to compensated sufficient contents of glutathione peroxidase and total glutathione in acatalasemic mice.

Inhibitory effects of prior low-dose x-irradiation on ischemia-reperfusion injury in mouse paw.

We have reported that low-dose, unlike high-dose, irradiation enhanced antioxidation function and reduced oxidative damage. On the other hand, ischemia-reperfusion injury is induced by reactive oxygen species. In this study, we examined the inhibitory effects of prior low-dose X-irradiation on ischemia-reperfusion injury in mouse paw. BALB/c mice were irradiated by sham or 0.5 Gy of X-ray. At 4 hrs after irradiation, the left hind leg was bound 10 times with a rubber ring for 0.5, 1, or 2 hrs and the paw thickness was measured. Results show that the paw swelling thickness by ischemia for 0.5 hr was lower than that for 2 hrs. At 1 hr after reperfusion from ischemia for 1 hr, superoxide dismutase activity in serum was increased in those mice which received 0.5 Gy irradiation and in the case of the ischemia for 0.5 or 1 hr, the paw swelling thicknesses were inhibited by 0.5 Gy irradiation. In addition, interstitial edema in those mice which received 0.5 Gy irradiation was less than that in the mice which underwent by sham irradiation. These findings suggest that the ischemia-reperfusion injury is inhibited by the enhancement of antioxidation function by 0.5 Gy irradiation.

Molecular analysis of the CLCNKB gene in Japanese patients with classic Bartter syndrome.

Deletions or mutations in the gene encoding the basolateral chloride channel CLC-Kb (CLCNKB) cause classic Bartter syndrome (MIM 602023), which is characterized by hypokalemic metabolic alkalosis, hyperreninemic hyperaldosteronism and hypercalciura. These patients are usually diagnosed during infancy or childhood due to failure to thrive and growth retardation. The purpose of this study was to investigate the underlying mutations in Japanese patients with classic Bartter syndrome. Seven Japanese patients from seven different families diagnosed as having classic Bartter syndrome were studied. Analysis of CLCNKB demonstrated a large deletion in two patients, a partial deletion in one patient and two mutations (DeltaL130 in exon 4 and W610X in exon 16) in the remaining four patients. DeltaL130 is a novel mutation, but W610X was previously reported in three unrelated Japanese patients. Six out of the seven patients were diagnosed due to typical characteristics of classic Bartter syndrome such as failure to thrive and poor weight gain however, one patient was asymptomatic with mild hypokalemia. In conclusion, we identified a novel mutation of the CLCNKB gene, DeltaL130. We did not determine whether the W610X mutation in our patients was from a common ancestor or if this mutation is frequent in Japan.

Newly recognized syndrome of metaphyseal undermodeling, spondylar dysplasia, and overgrowth: report of two adolescents and a child.

We report on a previously undescribed syndrome characterized by generalized skeletal alterations and overgrowth in three unrelated individuals: a boy who died at age 16 years, a 16-year-old girl, and a 15-month-old boy. The skeletal changes included bony overgrowth of the skull base, spondylar dysplasia, and undermodeling of the tubular bones. Bone age was accelerated in early childhood. Overgrowth, which was independent of GH-IGF axis, was of prenatal onset in the two boys, but postnatal in the girl. In the two adolescents, growth rate did not decline with age, and high-dose estrogen therapy failed to induce physeal fusion. Their adolescent height reached +4 approximately +7 SD of the mean. Delayed puberty in the girl and cryptorchidism and hypospadias in the younger boy raised the possibility that hypogonadism is a syndromic constituent. Molecular analysis of IGF2, GPC3, and FGFR3 in the older boy yielded no abnormalities.

Clinical evaluation of recombinant human growth hormone in Noonan syndrome.

The objective of this study was to investigate the effect of administration of recombinant human growth hormone (hGH) in patients with Noonan syndrome. hGH was administered (0.5 IU/kg/week) to 15 patients with Noonan syndrome over a 2 year period. Average patient age prior to therapy was 7.5 +/- 2.5 (mean +/- SD) yr, the height SD score was -2.8 +/- 0.7, and the pretreatment height velocity and bone age were 4.8 +/- 1.0 cm/yr and 5.8 +/- 2.1 yr, respectively. The height velocity in the year prior to treatment, and 0-12 and 12-24 months after commencing treatment was 4.8 +/- 1.0 cm/yr, 7.0 +/- 1.2 cm/yr, and 5.5 +/- 0.6 cm/yr, respectively. The height velocity in the first year of treatment was significantly greater (P = 0.0001, n = 14) than the pretreatment value, but there was no significant difference in the second year. The height SD scores at the commencement of treatment, and after 12 and 24 months of treatment were -2.8 +/- 0.7, -2.4 +/- 0.7, and -2.2 +/- 0.5, respectively. Bone age advanced by 1.1 +/- 0.5 yr in the 12 months after commencing treatment. We conclude that the use of hGH may be beneficial in the treatment of Noonan syndrome, although further research is required.