Muscular amyloid angiopathy with amyloidgenic transthyretin Ser50Ile and Tyr114Cys

Among patients with familial amyloid polyneuropathy (FAP), those with transthyretin Val30Met mainly show distally predominant weakness and atrophy, whereas some FAP patients, including those with transthyretin Ser50Ile and Tyr114Cys, show muscle weakness and atrophy that is dominant proximally, simulating myopathy. To clarify the cause of proximally dominant muscular atrophy in patients with FAP transthyretin Ser50Ile and Tyr114Cys, we investigated the distinctive features of muscle specimens of patients with FAP, 3 of who had Val30Met, 2 Ser50Ile, and 2 Tyr114Cys transthyretin. All specimens showed transthyretin amyloid around blood vessels and perimysium, and neurogenic denervation patterns. The amount of amyloid around the vessels was much greater in patients with FAP Ser50Ile and Tyr114Cys than in Val30Met patients. Muscular amyloid angiopathy may contribute to motor nerve injury that, in turn, may lead to amyotropic changes in patients with FAP Ser50Ile and Tyr114Cys.     

Selective embolization of the splenic vein in patients with hepatic encephalopathy and splenorenal shunt

Obliteration of portal-systemic shunts is effective for portosystemic encephalopathy but is often associated with complications such as retention of ascites and worsening of esophageal varices. Selective embolization of the splenic vein was performed on six patients with hepatic encephalopathy and splenorenal shunts. Hepatic encephalopathy was not observed in four patients after the procedure. Neither retention of ascites nor rupture of esophageal varices was observed because postoperative elevation of portal venous pressure was not as great as that seen when shunt obliteration is performed. This procedure can be an effective and safe treatment option for hepatic encephalopathy with a splenorenal shunt.     

Glucose attenuating local anesthetic-induced hemolysis

BACKGROUND: The effect of glucose on local anesthetic-induced neural damage has not been fully studied. We examined the effect of glucose on hemolysis induced by local anesthetics. METHODS: The mean EC50 values (the local anesthetic level that causes destruction of half of the red blood cells in vitro) of lidocaine HCl, tetracaine HCl and dibucaine HCl were determined with 0% and 7.5% glucose contained in Krebs solution at pH 6.4. RESULTS: The mean EC50 values of lidocaine HCl, tetracaine HCl, and dibucaine HCl in 0%-glucose Krebs solution were 6.51%, 0.45%, 0.17%, respectively, which increased significantly to 7.05%, 0.64% and 0.23%, in 7.5% glucose Krebs solution at pH 6.4. CONCLUSIONS: Glucose may have a protective role in local anesthetic-induced neural damage.     

Plasminogen activator inhibitor-1 is a downstream mediator of the PGP9.5-related oncogenic pathway in esophageal squamous cell carcinoma

BACKGROUND & MATERIALS AND METHODS: Recently, it has been proved that PGP9.5 is an oncogene candidate for squamous cell carcinomas. To examine the PGP9.5-related oncogenic pathway, we tested for global patterns of gene expression in cancer cells following PGP9.5 gene introduction using an oligonucleotide microarray approach. RESULTS: Plasminogen activator inhibitor-1 (PAI-1) was identified as an overexpressed gene in a PGP9.5-expressed esophageal squamous cancer cell line. To confirm the data obtained, we performed Northern analysis using a PGP9.5 or a PAI-1 cDNA probe and found that PAI-1 mRNA was induced by PGP9.5 expression in NUEC1 cells. We further examined endogenous PGP9.5 and PAI-1 expression in 6 esophageal cancer cell lines. One cell line (NUEC2) with PGP9.5 expression exhibited PAI-1 expression, suggesting the possibility that PGP9.5 might induce PAI-1 directly or indirectly. CONCLUSION: These results suggested that PAI-1 might be a novel downstream mediator of PGP9.5 in esophageal squamous cell carcinomas.     

A devised method of hepatic and splenic arterial infusion chemotherapy after transcatheter peripancreatic arterial embolization for patients with advanced pancreatic cancer

We previously reported the clinical efficacy based on hepatic and splenic arterial infusion chemotherapy (HSAIC) for patients with advanced pancreatic cancer after transcatheter peripancreatic arterial embolization (TPPAE). However, this medical treatment pointed out a few problems in which the method had its complexity and a limited use of embolus micro-coil numbers. Then, we tried to improve the method in solving those problems. In order to reduce the embolus micro-coil numbers for TPPAE, we divided the micro-coil into several parts. We also devised the method of HSAIC. We used one catheter with a side hole, so that the catheter was able to supply a therapeutic drug for arterial infusion chemotherapy, both to the common hepatic artery and splenic artery. The effective rate for eleven cases was 72.7%, and there were no significant differences from the cases treated with the conventional method of TPPAE-HSAIC. Therefore, the devised treatment was considered to be an easy and useful method for TPPAE and HSAIC.     

Endogenous factors regulating neuronal death induced by radical stress

Neurons in the central nervous system (CNS) are vulnerable to radical stress caused by reactive oxygen species, including nitric oxide (NO). Those radicals play crucial roles in glutamate neurotoxicity associated with ischemic brain injury and a wide range of neurodegenerative disorders. In our previous studies, we have shown evidence suggesting that glutamate neurotoxicity is regulated by certain endogenous substances such as neurotrophins, nicotinic acetylcholine, prostanoids and vitamins. Based on those findings, we have used the term 'neuroprotective factor' for endogenous substances possessing protective activity against glutamate neurotoxicity, and have further searched for a candidate with unique structure. We isolated a novel neuroprotective substance named 'serofendic acid' derived from fetal calf serum. The compound exhibited potent protective action against neurotoxicity induced by glutamate and by an NO donor without inhibiting glutamate receptors. Electron spin resonance analysis demonstrated that serofendic acid had no direct scavenging activity on NO, but was capable of inhibiting the generation of a hydroxyl radical, a presumed 'executor' radical in the nitric oxide-mediated neurotoxic cascade. The chemical structure was determined by mass spectrometry and nuclear magnetic resonance spectroscopy, and was confirmed by synthesis. The structure was unique among known endogenous substances because the compound was a sulfur-containing atisane type diterpenoid. The discovery of serofendic acid may provide a new scope for the investigation of low-molecular weight bioactive factors promoting the survival of CNS neurons.     

Apoptosis-inducing effect of a new bisphosphonate,YM529, on various hematopoietic tumor cell lines

In recent years, it has been reported that bisphosphonates inhibited the cell cycle of myeloma cells to inhibit cell proliferation directly, and it was also reported that bisphosphonates induced apoptosis of myeloma cells in vitro. Recently, YM529 was developed as a new third-generation bisphosphonate. In our experiment, we investigated whether YM529 showed an antitumor effect on hematopoietic tumor cell lines other than myeloma, and we compared YM529 with YM175, which had a relatively more potent antitumor effect than that of existing bisphosphonates. We found that YM529 inhibited cell proliferation in various hematopoietic tumor cell lines (acute promyelocytic leukemia cell line HL-60, chronic myeloid leukemia cell line K562, histiocytic lymphoma cell line U937, lymphoblastic leukemia T cell line Jurkat, acute lymphoblastic leukemia T cell line MOLT-4, lymphoblastic leukemia B cell line CCRF-SB) including myeloma (myeloma cell line HS-Sultan) dose-dependently and time-dependently to a degree equivalent or superior to that in myeloma, and induced apoptosis at a lower concentration as compared with YM175. We confirmed many dead cells as well as apoptosis based on the detection of the nuclei with separate globular structure, the activation of caspase-3, and the decrease in mitochondrial transmembrane potential. Therefore, it is concluded that further utilization of YM529 can be expected against hematopoietic tumor cells in the future.     

Ionic strength influences hemolytic action of dibucaine hydrochloride

BACKGROUND: Little is known about effect of ionic strength on local anesthetic toxicity. Using human erythrocytes, hemolytic action of dibucaine in solutions of various ionic strength was investigated. METHODS: The critical micellar concentration (CMC) of dibucaine and the dibucaine level that causes destruction of half of the red blood cells in vitro (EC50 value) were determined in solutions of various ionic strength. RESULTS: The mean CMC values of the dibucaine solutions adjusted to ionic strength 0.15, 0.30, 0.45 and 0.90 with NaCl, were 35.3, 22.6, 15.9 and 9.6 mM, respectively. The mean EC50 values of these solutions measured at 5 sec were 22.5, 16.0, 12.6 and 8.2 mM, respectively, and those at 30 min were 4.9, 4.5, 4.5 and 2.6 mM, respectively. There was a significant correlation between mean CMC values and mean EC50 values at 5 sec but not at 30 min in the solution of the same ionic strength. CONCLUSIONS: These findings indicated that the mechanism of dibucaine-induced hemolysis within a few seconds is through membrane lysis, whereas dibucaine-induced hemolysis at 30 min is caused by another mechanism. Because each mechanism is enhanced by high ionic strength, dibucaine dissolved in salt solution should not be administered intrathecally.     

Evaluation of intraarterial infusion chemotherapy for liver metastasis from gastric cancer FEM: combination therapy of 5-FU, epirubicin and MMC

OBJECTIVE: We evaluated the effectiveness of FEM (5-FU, epirubicin, MMC) therapy. SUBJECTS: Data for 111 patients with liver metastasis from gastric cancer were collected from January 1977, until June 2003 (synchronous: 74 cases, asynchronous: 37 cases). Thirty patients were H1, 20 were H2 and 61 were classified as H3. METHODS: The patients were divided into the following groups: Group A: Resection of the primary lesion and hepatic resection (n = 10), Group A1: Hepatic resection only (5 cases), Group A2: Hepatic resection and intraarterial infusion (5 cases). Group B: Resection of the primary lesion (n = 67), Group B1: Resection of the primary lesion only (46 cases), Group B2: Intraarterial infusion (21 cases). In Groups A2 and B2, FEM therapy was applied to A2a (4 cases) and B2a (8 cases). Non-FEM therapy was applied to A2b (1 case) and B2b (13 cases). Group C consisted of 34 cases in which resection of the primary lesion was not undertaken. Survival rates were then compared. RESULTS: 1-year survival rates and 50% survival period for each group were as follows: Group A: 33%, 5.9 months; Group B: 22%. 4.8 months; and Group C: 6%, 3.9 months, respectively. One case from Group A2a and 2 cases from Group B2a have survived for 3 years or longer. CONCLUSION: 1) We treated 3 patients with liver metastasis from gastric cancer who survived for 3 years or longer. 2) Resection of the primary lesion along with hepatic intraarterial infusion therapy (in addition to hepatic resection), especially in combination with FEM therapy, provided an extended length of survival.