Effect of the free radical scavenger MCI-186 on spinal cord reperfusion after transient ischemia in the rabbit

Objective: Paraplegia remains a serious complication of aortic operations. The production of free radicals during reperfusion after transient ischemia is believed to induce secondary spinal neuronal injury, resulting in paraplegia. The aim of the present study was to clarify the protective effect and method of administration of antioxidants on the neurological and histological outcome in the animal model for reperfusion injury after transient spinal cord ischemia. Methods: New Zealand white rabbits underwent surgical exposure of the abdominal aorta that was clamped for 15 minutes to achieve spinal cord ischemia. Group A animals received two 10 mg/kg doses of 3-methyl-l-phenyl-2-pyrazolin-5-one (MCI-186) at the time of release of the aortic clamp and 30 minutes later. In group B, MCI-186, 5 mg/kg, was given three times, at the time of aorta clamp release, 30 minutes and 12 hours later. In group C (control group), one dose of vehicle was administered. Neurological status was assessed using modified Tarlov’s score until 168 hours after operation. Spinal cord sections were examined microscopically to determine the extent of ischemic neuronal damage. Results: Groups A and B animals had better neurological function than group C (p(0.001). In contrast, group C animals exhibited paraplegia or paraparesis with marked neuronal necrosis. The number of surviving neurons within examined sections of the spinal cord was significantly greater in group B than in group C (p(0.001). Conclusion: In a 15-minute ischemia-reperfusion model using rabbits, systemic repetitious administration of MCI-186, a free radical scavenger, was found to have a protective effect on the spinal cord neurons both neurologically and histologically. We postulate that the drug minimizes the delayed neuronal cell death for reperfusion injury after transient ischemia by reducing the free radical molecules. Moreover, it was thought that we could protect delayed neuronal cell death more effectively by administering MCI-18612 hours later.     

A case of chest wall rhabdomyosarcoma]

A 56-year-old man was admitted to our hospital with right chest pain. Chest X-ray, CT scan and MRI revealed a chest wall tumor and enlarged mediastinal lymph nodes. Percutaneous lung biopsy was performed, and the pathological diagnosis of pleomorphic rhabdomyosarcoma was obtained. The only significant abnormal laboratory finding was elevation of serum NSE (24.5 ng/ml). Although chemotherapy (VAC-ADM) and radiation therapy were performed, the patient died about 7 months after admission. To our knowledge, only 17 cases of chest wall rhabdomyosarcoma have been reported in Japan.     

In vivo evaluation of expressed protein function by PET]

Positron Emission Tomography (PET) allows in vivo visualization of the expression and function of protein using a radioligand. Quantitative analysis of serotonin transporter, receptors, and the function of P-Glycoprotein has been performed in living human brains. Furthermore, the relationship between the phenotype of those proteins and their genetic polymorphism has also been investigated. Regarding the effect of antipsychotics on dopamine D2 receptor, occupancy and its time-course have been measured in a living body using PET. This approach can provide in vivo pharmacological evidences of antipsychotics and establish a rational therapeutic strategy. PET is a powerful tool not only in the field of brain research but also drug discovery and individual medicine.     

Prenatal diagnosis of harlequin ichthyosis by fetal skin biopsy; report of two cases.

Two cases of harlequin ichthyosis were successfully diagnosed prenatally by fetal skin biopsy. The aborted fetuses were later confirmed to be afflicted with this very unusual skin disease. Both families had a previous history of harlequin ichthyosis. In performing the biopsy, it was found that amniotic fluid cytology can also be very helpful in the diagnosis of this kind of severe ichthyosis. With regard to these families, the disease may have been transmitted in an autosomal dominant fashion, and not in a recessive manner as is commonly believed.     

Enhancing Effects of Harman and Norharman on Induction of Preneoplastic and Neoplastic Kidney Lesions in Rats Initiated with N-Ethyl-N-hydroxyethylnitrosamine

The modifying potential of two nephrotoxic agents, harman and norharman, on N-ethyl-N-hydroxyethylnitrosamine (EHEN)-induced renal and hepatic carcinogenesis was investigated in male F344/DuCrj rats. Animals were given 0.1% EHEN in their drinking water for the first 2 weeks as an initiator. Subsequently, starting 3 weeks from the commencement, they were fed diet containing these compounds at concentrations of 1000, S00 or 0 ppm until week 26, and then killed for light microscopic examination. The mean numbers of renal tubular cell hyperplasias/cm² and those of tumors/cm² in rats given harman and norharman at 1000 ppm after initiation, but not at 500 ppm, were significantly increased as compared to the control values. However, neither compound modified liver carcinogenesis. It is concluded that harman and norharman show enhancing effects on rat kidney carcinogenesis, when ingested at dose levels which cause renal tubular damage.     

Hereditary stomatocytosis: phenotypical expression of sodium transport and band 7 peptides in 44 cases

The clinical heterogeneity and the role of red cell membrane protein band 7 in membrane transport were studied in 44 patients with hereditary stomatocytosis with normal red cell membrane lipids. These patients were arbitrarily categorized into three phenotypes, based on the extent of sodium influx: hereditary stomatocytosis Type I: with markedly increased Na influx (8.90 +/- 3.39 mmol/lRBC/h); Type II: with moderately increased Na influx (2.10 +/- 0.79) and Type III with normal Na influx (1.31 +/- 0.13). The three groups of patients were compared with normal controls (1.29 +/- 0.14). The extent of anaemia and jaundice was almost identical in the three groups in the presence of nearly the same degree of stomatocytosis (I: 54.8 +/- 10.7%, II: 38.8 +/- 12.8, and III: 40.2 +/- 10.8). Approximately one third of the cases (14/44) with hereditary stomatocytosis showed no overt haemolysis even with marked stomatocytosis. Cell hydration was abnormal in Type I (MCV 119.6 +/- 8.5 fl, MCHC 29.3 +/- 1.8%) but normal in Types II and III (MCV 98.2 +/- 11.7, 94.1 +/- 8.5; MCHC 34.4 +/- 2.1, 34.5 +/- 2.2). These results indicate that there was no correlation between the extent of Na influx and either the degree of stomatocytosis or the extent of overt haemolysis. The role of band 7 in membrane transport was also studied. Three components (30 kD, 28 kD and 26 kD polypeptides) of band 7 were analysed by SDS-PAGE and NEPHGE/SDS-PAGE, and the content of these polypeptides were expressed as the ratio to band 5. The 30 kDa polypeptide in the three groups was nearly identical to that in normal controls (12.3 +/- 4.0), except for non-haemolysing patients in Type II. The 28 kD peptide was also decreased in five out of nine cases of Type II (25.7 +/- 5.6) as compared with normal controls (32.9 +/- 3.6) and cases of Type I (35.8 +/- 2.8) and Type III (32.7 +/- 2.9). No deficiency of this peptide was noted in Type I patients. No correlation was observed between the content of the 28 kD polypeptide and Na influx (r = 0.416), but the 26 kD polypeptide tended to be elevated in cases with overt haemolysis. These results suggest that band 7 may not be essentially involved in the formation of stomatocytic changes, although the presence of subtle defects in band 7 structure and function may not be ruled out. The present findings provide an important starting point to initiate further extensive investigations.     

Clinical characteristics of thrombotic microangiopathy following ABO incompatible living donor liver transplantation.

Thrombotic microangiopathy (TMA) may develop after living donor liver transplantation (LDLT), but the mechanism is not fully understood. We retrospectively analyzed all patients undergoing LDLT at our center, including TMA patients, to elucidate the clinical characteristics and presentation and to determine which patients have a higher risk of occurrence of TMA. In all, 57 adult patients were reviewed after LDLT at our institution. TMA was diagnosed by sudden and severe thrombocytopenia, followed by hemolytic anemia with fractionated erythrocytes in the blood smear. Clinical features were compared between the TMA group and the non-TMA group. Of the 57 patients, 4 were diagnosed with posttransplantation TMA. ABO blood group (ABO)-incompatibility, cyclophosphamide (CPA), and recipient blood group (type O) were closely correlated with the occurrence of TMA. Thrombocytopenia appeared 1 to 5 days before hemolytic anemia. Coagulative function markers stayed at the same level after TMA, while marked elevation was shown in fibrinolytic function markers such as plasminogen activator inhibitor type 1 (PAI-1). TMA occurred at a higher prevalence in ABO-incompatible graft recipients. Additional factors associated with ABO-incompatible transplantation, such as an overdose of immunosuppressants, may affect the likelihood of TMA. Sudden and severe thrombocytopenia presented before hemolytic anemia and the serum levels of PAI-1 correlated well with the clinical course of TMA. In conclusion, early recognition of thrombocytopenia and elevation of PAI-1 is crucial to diagnose TMA especially in ABO-incompatible LDLT.