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.     

Rapidly growing calcified cerebellar astrocytoma in infants

We report the case of an infant with a cerebellar astrocytoma that showed marked calcification within only 6 months. In general, only slow-growing tumors tend to calcify. To our knowledge, no other case of such rapid calcification in cerebellar astrocytoma has been reported.     

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.     

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.     

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.     

Pharmacologic preconditioning effects: Prostaglandin E1 induces heat-shock proteins immediately after ischemia/reperfusion of the mouse liver

Prostaglandin E1 (PGE1) has several potential therapeutic effects, including cytoprotection, vasodilation, and inhibition of platelet aggregation. This study investigates the protective action of PGE1 against hepatic ischemia/reperfusion injury in vivo using a complementary DNA microarray. PGE1 or saline was continuously administered intravenously to mice in which the left lobe of the liver was made ischemic for 30 minutes and then reperfused. Livers were harvested 0, 10, and 30 minutes postreperfusion. Messenger RNA was extracted, and the samples were labeled with two different fluorescent dyes and hybridized to the RIKEN set of 18,816 full-length enriched mouse complementary DNA microarrays. Serum alanine aminotransferase and aspartate aminotransferase levels at 180 minutes postreperfusion were significantly lower in the PGE1-treated group than in the saline-treated group. The cDNA microarray analysis revealed that the genes encoding heat-shock protein (HSP) 70, glucose-regulated protein 78, HSP86, and glutathione S-transferase were upregulated at the end of the ischemic period (0 minutes postreperfusion) in the PGE1 group. Our results suggested that PGE1 induces HSPs immediately after ischemia reperfusion. HSPs might therefore play an important role in the protective effects of PGE1 against ischemia/reperfusion injury of the liver.     

Simulation for population analysis of Michaelis-Menten elimination kinetics

A simulation study was conducted to compare the cost and performance of various models for population analysis of the steady state pharmacokinetic data arising from a one-compartment model with Michaelis-Menten elimination. The usual Michaelis-Menten model (MM) and its variants provide no estimate of the volume of distribution, and generally give poor estimates of the maximal elimination rate and the Michaelis-Menten constant. The exact solution to the Michaelis-Menten differential equation (TRUE) requires a precise analysis method designed for estimation of population pharmacokinetic parameters (the first-order conditional estimation method) and also considerable computational time to estimate population mean parameters accurately. The one-compartment model with dose-dependent clearance (DDCL), in conjunction with the first-order conditional estimation or Laplacian method, ran approximately 20-fold faster than TRUE and gave accurate population mean parameters for a drug having a long biological half-life relative to the dosing interval. These findings suggest that the well-known MM and its variants should be used carefully for the analysis of blood concentrations of a drug with Michaelis-Menten elimination kinetics, and that TRUE, in conjunction with a precise analysis method, should be considered for estimating population pharmacokinetic parameters. In addition, DDCL is a promising alternative to TRUE with respect to computation time, when the dosing interval is short relative to the biological half-life of a drug. This work was supported in part by the Epilepsy Research Foundation, the Nakatomi Foundation, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science, and Culture of Japan.     

The limitation of staged repair in the surgical management of congenital complex heart anomalies with aortic arch obstruction

OBJECTIVE: Severe aortic arch obstruction including an interrupted aortic arch in congenital complex heart anomalies remains a challenge in surgical management. METHODS: Treatment and outcomes in 75 consecutive patients who underwent an aortic arch repair as the first step of the staged repair protocol between 1975 and 2000 were reviewed. Their ages at repair ranged from 1 day to 8.5 months. RESULTS: Cross-sectional postoperative follow-up data were available in all the patients. The follow-up period ranged from 0 to 27.6 years (mean: 7.3 +/- 7.3 years). There were 20 postoperative hospital deaths (27%) and 7 late deaths. The Kaplan-Meier estimate of survival was 81.3% +/- 4.5% at 1 month, 68.0% +/- 5.4% at 1 year, 65.0% +/- 5.5% at 5 years, 63.1% +/- 5.7% at 10 years, 63.1% +/- 5.7% at 20 years. By Cox regression analysis, body weight of 2.5 kg or less is the only independent determinant of postoperative mortality (p = 0.04, multivariable odds ratio: 2.50, [95% confidence interval: 1.02-6.1]). The aortic arch morphology, the primary cardiac lesion, or date of operation did not reach a statistically significant level to show correlation with mortality. Reintervention to reconstruct the aortic arch was performed at 9 occasions in 8 of the 55 patients who survived the primary operation (14.5%). The Kaplan-Meier estimate of the reintervention-free rate was 91.3% +/- 4.2% at 5 years, 85.5% +/- 5.6% at 10 years, 75.6% +/- 8.2% at 20 years. Using multivariable Cox regression analysis, interrupted aortic arch (versus aortic coarctation) was the only independent predictor of a shorter time to reintervention (p = 0.001, multivariable odds ratio: 16.1, [95% confidence interval: 3.2-80.2]). CONCLUSIONS: The staged repair protocol was associated with significant limitations in patient survival and with the development of recurrent aortic arch obstruction. Thus, a primary repair protocol may serve as an alternate approach, especially in patients with low weight or with an interrupted aortic arch.     

Quantification of tissue plasma volume in the rat by contrast-enhanced magnetic resonance imaging

Magnetic resonance imaging enhanced with a macromolecular contrast medium (MMCM), albumin-Gd-DTPA, was used to estimate the plasma volume in vivo in the myocardium, lung, liver, and skeletal muscle of 10 normal rats. The plasma volumes of the same tissues in a parallel group of six rats were estimated in vitro by a conventional radioisotopic technique (¹¹¹In-transferrin). Plasma volumes of myocardium, lung, liver, and skeletal muscle estimated by the MR technique (μl plas. ia cc-¹ of tissue) were 101,109,163, and 11.0, respectively, while plasma volumes measured by the In-transferrin radioisotope technique (mg plasma g-¹ of tissue) were 78.6, 215,143, and 11-2, respectively. Assuming a ratio of densities of aerated lung to blood of 0.45 and of other tissues to blood of 1.0, correlation between the methods was excellent (R² = 0.99) indicating that MR imaging enhanced with MMCM permits reliable in vivo estimation of tissue plasma volume in the rat.