TU-572, a potent and selective CD45 inhibitor, suppresses IgE-mediated anaphylaxis and murine contact hypersensitivity reactions

BACKGROUND: CD45, receptor-type protein tyrosine phosphatases (PTPases) are essential components of signaling through both the T cell receptor and the B cell antigen receptor. However, the functional significance of CD45 in the signaling pathway through the high-affinity immunoglobulin (Ig) E receptor has not yet been established. In this study, we demonstrate that the potent CD45 inhibitor negatively regulates IgE-dependent anaphylaxis and contact hypersensitivity reactions. METHOD: We have previously found that TU-572, 2-[(4-methylthiopyridin-2-yl)methylsulfinyl]-5-isopropoxybenzimidazole, had a potent and selective inhibitory effect against PTPase activity of CD45. Using a CD45 inhibitor, we examined in vitro and in vivo IgE-mediated responses. RESULTS: TU-572 potently inhibited histamine release from rat peritoneal mast cells and mouse systemic anaphylaxis reaction using monoclonal anti-dinitrophenyl (DNP) IgE and DNP-BSA. TU-572 also suppressed the immediate-type hypersensitivity response induced by repeated epicutaneous application of trinitrochlorobenzene in BALB/c mice. CONCLUSION: These findings revealed that the PTPase activity of CD45 played a critical role in signal transduction of IgE-mediated anaphylaxis in vitro and in vivo. PTPase inhibitors such as TU-572 are useful in the treatment of allergic diseases.     

Parvalbumin in rat cerebrum, cerebellum and retina during postnatal development

Radioimmunoassay and immunohistochemical studies were performed on the occurrence and distribution of parvalbumin-like immunoreactivity (PA-LI) in developing rat cerebrum, cerebellum and retina. No PA-LI was detected in the nervous tissues of the newborn animals. In the cerebrum, the PA-LI appeared in non-pyramidal neurons at the 2nd postnatal week and increased linearly until the 8th week. In the cerebellum, a rapid increase in the PA-LI took place at the 2nd week, with an enrichment of the antigen to Purkinje neurons. In the retina, amacrine cells contained PA-LI, the levels of which increased from the 2nd to 4th week. Regulation of intracellular Ca²⁺ concentration may be one of the important factors for the maturation of the central nervous system.     

Fibrinogen osaka IV: A congenital dysfibrinogenemia found in a patient originally reported in relation to surgery,now defined to have an Aα arginine-16 to histidine substitution

We discovered a congenital heterozygous dysfibrinogen in a patient and reported this case in relation to surgery some time ago (Jpn J Surg (1988) 18:43–46).³ Further studies on the isolated abnormal population of fibrinogen derived from this patient have revealed that fibrinopeptide A was not cleaved by ancrod, a snake venom-derived thrombin-like enzyme, but by thrombin, slowly but completely. The released fibrinopeptide A components, being the A, AY, and AP peptides, were all found to be abnormal, as evidenced by slightly earlier elution positions on high-performance liquid chromatography, compared with the normal counterparts. By analyzing their amino acid sequence, we have identified an arginine to histidine substitution at position 16 of the A chain, the thrombin cleavage site. Utilizing insolubilized abnormal fibrinogen, we confirmed that the polymerization site assigned to the central E domain, the A site, was exposed by thrombin, but not by ancrod. This dysfibrinogen, designated as fibrinogen Osaka IV, is the second abnormal molecule with an A arginine-16 to histidine substitution identified among Japanese families.     

A double bifurcated graft for abdominal aorta and bilateral iliac artery reconstruction

Revascularization of the hypogastric artery often tends to be neglected in aortoiliac reconstructive surgery; however, its incomplete revascularization can result in unfavorable complications such as buttock claudication or necrosis, vascular impotence, and colonic ischemia. Multiple vascular lesions in the abdominal aorta and bilateral iliac arteries were reconstructed using a newly designed double bifurcated graft in five male patients. All five patients demonstrated excellent graft limb patency and postoperative improvement of the ankle-brachial pressure index without any clinical signs of ischemia in regions of the hypogastric artery. Thus, we conclude that an aggressive approach toward hypogastric circulation maintenance is essential in aortoiliac reconstructive surgery. By using this double bifurcated graft, rapid and safe revascularization of the bilateral hypogastric arteries concomitant with the external iliac or femoral arteries can be performed.     

Gene therapy for renal anemia in mice with polycystic kidney using an adenovirus vector encoding the human erythropoietin gene

BACKGROUND: Recombinant human erythropoietin (rHuEPO) is primarily used for patients with anemia associated with end-stage renal disease. We evaluated the efficacy of EPO gene therapy using adenovirus vector for chronic renal failure mice expressing severe renal anemia. METHODS: Recombinant HuEPO gene transfer to mesothelial cells was performed in vitro and in vivo. Recombinant replication-deficient adenoviruses containing rHuEPO cDNA (AdCMVEPO), E. coli lacZ gene (AdCMVlacZ), or an nonexogenous gene (AdNull as control vector) driven by the cytomegalovirus promotor/enhancer were constructed. The oligosaccharides associated with the rHuEPO from AdCMVEPO-treated mesothelial cells were analyzed. For in vivo study, the DBA/2FG-pcy mouse, a model for human autosomal recessive polycystic kidney disease resulting in chronic renal failure with progressive anemia, was used. RESULTS: The sialylated oligosaccharides associated with the rHuEPO produced in AdCMVEPO-treated mesothelial cells occupied 78 +/- 0.7% of the total oligosaccharide pool. A single intraperitoneal administration of AdCMVEPO induced rHuEPO synthesis in the peritoneal cells and a marked increase in erythrocyte production. The maximal increase in hematocrit (43 +/- 4%) was observed on day 28, and it remained elevated for 40 days. CONCLUSION: These results indicate that intraperitoneal administration of AdCMVEPO improves renal anemia in mice with chronic renal failure and that the mesothelial cell is an appropriate target cell for gene transfer.     

Use of nicardipine during pheochromocytoma removal

Key words  nicardipine - pheochromocytoma - hemodynamic and hormonal change     

Glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) polymorphisms and urothelial cancer risk with tobacco smoking.

The objective of this study was to examine the association between the genetic polymorphism of glutathione S-transferase (GST) M1, T1 and N-acetyltransferase 2 (NAT2) genes and urothelial cancer risk in relation to smoking status. In this study, 325 Japanese patients with urothelial transitional cell carcinoma and 325 healthy controls were compared for frequencies of GSTM1, T1 and NAT2 genotypes. The frequencies of GSTM1 null genotype and NAT2 slow genotype were significantly higher in the cases than in the controls (adjusted odds ratio (OR) 1.37, 95% confidence interval (CI) 1.01-1.87, adjusted OR 3.09, 95% CI 1.69-5.63, individually). Furthermore, the risk of GSTM1 null genotype and NAT2 slow genotype was higher among smokers (adjusted OR 1.48, 95% CI 1.01-2.15, adjusted OR 4.28, 95% CI 1.96-9.36, individually). The regression analysis of cancer risk as a function of the amount of smoking showed that the susceptibility of people who had GSTM1 null genotype increased from 45 pack-years, while the susceptibility of people with NAT2 intermediate or slow genotype increased rapidly from 25 pack-years, compared with non-smokers. A multiplicative interaction between NAT2 intermediate or slow genotype and pack-years of smoking was found (P<0.001), but GSTM1 null genotype was not (P=0.06). Our results indicate that the GSTM1 null genotype and NAT2 intermediate or slow genotype are associated with an increased risk of urothelial cancer in relation to smoking amounts. Furthermore, the interaction between NAT2 intermediate or slow genotype and pack-years of smoking has a strong impact on urothelial cancer.