Keiji Sano

Ebselen in Acute Ischemic Stroke A Placebo-Controlled, Double-blind Clinical Trial

BACKGROUND AND PURPOSE The effect of ebselen, a seleno-organic compound with antioxidant activity through a glutathione peroxidase-like action, on the outcome of acute ischemic stroke was evaluated in a multicenter, placebo-controlled, double-blind clinical trial. METHODS Patients diagnosed as having acute ischemic stroke who could receive drug treatment within 48 hours of stroke onset were enrolled. Oral administration of ebselen granules suspended in water (150 mg BID) or placebo was started immediately after admission and was continued for 2 weeks. The major end points were the Glasgow Outcome Scale scores at 1 month and 3 months after the start of treatment. The modified Mathew Scale and modified Barthel Index scores at 1 month and 3 months were also studied as secondary outcome measures. RESULTS Three hundred two patients were enrolled in the trial. Intent-to-treat analysis of 300 patients (151 given ebselen and 149 given placebo) revealed that ebselen treatment achieved a significantly better outcome than placebo at 1 month (P = .023, Wilcoxon rank sum test) but not at 3 months (P = .056, Wilcoxon rank sum test). The improvement was significant in patients who started ebselen within 24 hours of stroke onset but not in those who started treatment after 24 hours. There was a corresponding improvement in the modified Mathew Scale and modified Barthel Index scores. CONCLUSIONS Early treatment with ebselen improved the outcome of acute ischemic stroke. Ebselen may be a promising neuroprotective agent.

Prognostic impact of anatomic resection for hepatocellular carcinoma

Objectives:To evaluate the prognostic impact of anatomic versus nonanatomic resection on the patients’ survival after resection of a single hepatocellular carcinoma (HCC). Summary of Background Data:Anatomic resection is a reasonable treatment option for HCC; however, its clinical significance remains to be confirmed. Methods:Curative hepatic resection was performed for a single HCC in 210 patients; the patients were classified into the anatomic resection (n = 156) and nonanatomic resection (n = 54) groups. In 84 patients assigned to the anatomic resection group, segmentectomy or subsegmentectomy was performed. We evaluated the outcome of anatomic resection, including segmentectomy and subsegmentectomy, in comparison with that of nonanatomic resection, by the multivariate analysis taking into consideration 14 other clinical factors. Results:Both the 5-year overall survival and disease-free survival rates in the anatomic resection group were significantly better than those in the nonanatomic resection group (66% versus 35%, P = 0.01, and 34% versus 16%, P = 0.006, respectively). In the segmentectomy and subsegmentectomy group, the 5-year overall and disease-free survival rates were 67% and 28%, respectively, both of which were also higher than the corresponding rates in the nonanatomic resection group (P = 0.007 and P = 0.001, respectively). The results of multivariate analysis revealed that anatomic resection was a significantly favorable factor for overall and disease-free survivals: the hazard ratios were 0.57 (95% confidence interval, 0.32–0.99, P= 0.04), and 0.65 (0.43–0.96, P = 0.03). Conclusion:Anatomic resection for a single HCC yields more favorable results rather than nonanatomic resection.

Delayed neuronal death in the rat hippocampus following transient forebrain ischemia

SummaryAn unusual, slowly progressing neuronal damage has been reported to occur in the gerbil hippocampus following ischemia (Kirino 1982). Delayed neuronal death following ischemia has also been noticed in the rat four-vessel occlusion model (Pulsinelli et al. 1982). By light microscopy this slow neuronal injury in the rat was not different from the previously known neuronal ischemic cell change. This report lead us to the question as to whether neurons in the rat hippocampus are damaged rapidly following an initial latent period or deteriorate slowly and progressively until they display overt changes. To clarify this point, observation was done on the hippocampal CA1 sector of the rat following ischemia. Rats were subjected to four-vessel occlusion, and those which developed ischemic symptoms were perfusion-fixed. Although the change appeared very slowly and lacked microvacuolation of the cytoplasm, neuronal alteration was practically not different from classical ischemic cell change. By electron microscopy, however, the change was detectable when the neurons still appeared intact by light microscopy. An increase in the membranous organelles and deposition of dark substances were the initial manifestations. It seemed that the CA1 neurons deteriorated very slowly and progressively, and that they retained partial viability in the initial phase of the change. In spite of the difference in light-microscopic findings, the mechanisms underlying delayed neuronal death in the rat and gerbil hippocampus seemed to be identical.

Long-term outcome of extended hemihepatectomy for hilar bile duct cancer with no mortality and high survival rate.

Objective To demonstrate our strategy for hilar bile duct cancer and to elucidate prognostic factors and the surgeons role in long-term survival. Summary Background Data Extended hemihepatectomy is recognized as a curative treatment of hilar bile duct cancer but is not always safe because of the risk of postoperative liver failure. A safe and beneficial strategy is required. Methods Fifty-eight consecutive major hepatectomies for hilar bile duct cancer were reviewed retrospectively. Appropriate preoperative treatments, biliary drainage, and portal embolization were performed before major hepatectomies. The short- and long-term results of our strategy are presented and analyzed. Results Biliary drainage and portal embolization were performed in 39 patients (67.2%) and 31 patients (53.4%), respectively. Major hepatectomies comprised 27 extended right and 22 extended left hemihepatectomies and 9 hepatoduodenopancreatectomies. Operative morbidity and mortality rates were 43% and 0%, respectively. There was no postoperative liver failure. The overall 5-year survival rate was 40%. Univariate analysis showed that residual tumor status, lymph node involvement, and perineural invasion were associated with patients’ long-term survival. A surgical margin over 5 mm resulted in better long-term survival. The delay resulting from preoperative treatment was not detrimental to long-term survival. Multivariate analysis showed that lymph node involvement was the only prognostic factor. Conclusions Our strategy, which includes preoperative biliary drainage and portal embolization, led to a reduction in the risks associated with major hepatectomy for hilar bile duct cancer, and resulted in zero mortality. Surgeons should aim at complete clearance of the tumor with an adequate surgical margin to ensure optimal long-term survival.

Fine structural nature of delayed neuronal death following ischemia in the gerbil hippocampus.

SummaryAn unusual, delayed neuronal death (DND) has been noticed in the hippocampus of the Mongolian gerbil following brief ischemia (Kirino 1982). On day 1 following 5–10min of ischemia, light microscopy showed the CA1 pyramidal cells unchanged. On day 2, the cells showed massive growth of membranous cytoplasmic organelles instead of overt cellular disintegration. These neurons were destroyed extensively by day 4 after ischemic insult. Following longer ischemia (20–30min), however, the changes in the CA1 pyramidal cells appeared faster and resembled the wellcharacterized ischemic cell change (ICC). To further clarify the differences between ICC and DND, gerbils were submitted to transient 5–30min ischemia. They were perfusion-fixed following a given survival period and then processed for electron microscopy. Following transient ischemia, specimens showed slow cell changes with growth of cisterns of the endoplasmic reticulum (ER). In some CA1 neurons, the cytoplasm was shrunken and darkly stained, but they also displayed accumulation of ER cisterns. Occasionally, the CA1 cells demonstrated highly shrunken dark perikarya, no different than in ICC. These results indicate that DND seems to be the typical disease process of the CA1 sector and that a severer insult makes the change faster and more similar to ICC. ICC seems to occur when the CA1 pyramidal cells are damaged so severely that they cannot react with proliferous activity.

Behavioral changes after focal cerebral ischemia by left middle cerebral artery occlusion in rats

Behavioral changes after occlusion of the left middle cerebral artery (MCA) in rats were investigated for 16 weeks. Impairment of motor coordination and incidence of neurological deficits including hemiplegia and abnormal posture were present for the first 2 and 4 weeks after MCA occlusion, respectively. Learning behavior in one-trial passive avoidance task was disturbed for the entire 16-week period when rats were trained at days 3 after MCA occlusion. Reacquisition was also impaired when rats were retrained on 8 weeks after MCA occlusion. Except for synchronized EEG at days 2 after MCA occlusion, significant changes in spontaneous movement and EEG were not observed in the MCA-occluded group. These results suggest that this rat model of MCA-occlusion is useful for quantitatively measuring functional changes in chronic phase of focal cerebral ischemia.

Selective vulnerability of the hippocampus to ischemia--reversible and irreversible types of ischemic cell damage.

Publisher Summary The hippocampus, among those vulnerable regions, is the area where anatomic, physiologic, and behavioral can be studied. For understanding the basic mechanism of ischemic neuronal damage, the hippocampus has proven to be one of the most suitable systems for experimental study. There is ample time to examine the CAI neurons before these cells totally lose their viability. Most of the population of nerve cells in the particular location in the hippocampus behaves almost synchronously and therefore it is easier to focus the attention than in a system where the neuronal change is scattered more sparsely. The chapter discusses the “vascular theory” that seems to be unsatisfactory to explain the cell damage in a circumscribed region of the hippocampus. In contrast, there is increasing evidence that the ischemic damage to hippocampal neurons is related to the chemical characteristics and interconnection of individual neurons in the complex circuitry of the brain.

Atrophy of the ipsilateral substantia nigra following middle cerebral artery occlusion in the rat

Following occlusion of the left middle cerebral artery in the rat, marked atrophy was observed in the ipsilateral substantia nigra in and after the second week. The mechanism of this neuropathological change in the substantia nigra, which is remote from the site of infarction, may be explained by transsynaptic, neurotransmitter-mediated disinhibition as a result of infarction of the striatum.

Correlation between rCBF and histological changes following temporary middle cerebral artery occlusion.

Correlations between changes in regional, cortical, cerebral blood flow (rCBF) and histological changes in the corresponding brain regions were examined following middle cerebral arterial occlusion in 24 cats. In all animals, the duration of arterial occlusion was 2 hours followed by 2 hours of recirculation. The animals were divided into 2 groups according to the severity of the observed histological damage. Severe cortical damage was observed in 8 cats (Group A), and, in the remaining 16 cats, little or no cortical damage was seen (Group B). There was a statistically significant difference between these 2 groups in the average rCBF values during ischemia. During recirculation, there was a prompt and uniform recovery of rCBF in animals in group B but a marked diversity of rCBF ranging from hyperemia to oligemia in animals in group A. This diversity of rCBF reflects inhomogeneous blood flow. This study indicates potential hazards for surgical revascularization in the acute stage of stroke when brain damage has progressed beyond a certain level.

Vein reconstruction in modified right liver graft for living donor liver transplantation.

ObjectiveTo report the authors’ experience with hepatic vein reconstruction and plasty in living donor liver transplantation for adult patients. Summary Background DataA right liver graft without the middle hepatic vein (MHV) trunk (modified right liver graft) can cause severe congestion of the right paramedian sector. However, the need for MHV reconstruction has not been fully recognized. MethodsFrom June 2000 to December 2001, 30 adult patients received a modified right liver graft. Major MHV tributaries were preserved and reconstructed under the authors’ criteria. Plasty of recipient hepatic veins for a wide outflow orifice was performed when necessitated. The regeneration of paramedian and lateral sectors of the grafts was examined by computed tomography 1 and 3 months after the operation. ResultsMHV tributaries were reconstructed in 18 grafts. Plasty of recipient hepatic veins was performed in 15 patients. All patients survived the operation. The regeneration of paramedian and lateral sectors was equivalent. ConclusionsA modified right liver graft can provide satisfactory surgical results if hepatic vein reconstruction and plasty are performed using the present techniques.