Acute hepatic failure in IFN-gamma-deficient BALB/c mice after murine coronavirus infection

We previously showed that an intraperitoneal infection with mouse hepatitis virus (MHV) persists in interferon-gamma (IFN-gamma)-deficient C57BL/6 (B6-GKO) mice and results in subacute fatal peritonitis, which bears a resemblance to feline infectious peritonitis. To examine the role of other host factors in MHV infection in mice, IFN-gamma-deficient mice with a BALB/c background (BALB-GKO) were infected intraperitoneally with MHV and compared with B6-GKO mice. In contrast to B6-GKO mice, BALB-GKO mice died within 1 week due to acute hepatic failure. The viral titer of the liver in BALB-GKO mice was significantly higher than that in B6-GKO mice. All hepatocytes in BALB-GKO mice were necrotic at 5 days post-infection, which was clearly distinct from large but limited lesion in the liver from infected B6-GKO mice. The serum alanine aminotransferase activity of infected BALB-GKO mice were higher than that of B6-GKO mice and was paralleled with the severity of the pathological changes and viral titers in infected mice. Administration of exogenous IFN-gamma to BALB-GKO partially inhibited the acute death. These results indicate that BALB-GKO and B6-GKO mice clearly show different diseases following MHV infection, although wild type counterparts of both mice apparently showed the same clinical course after MHV infection.     

Immunoreactivity of neoplastic and non-neoplastic monocytoid B lymphocytes for DBA.44 and other antibodies.

AIMS--To evaluate the immunoreactivities of neoplastic and non-neoplastic monocytoid B cells (MBC) and compare them with hairy cell leukemia (HCL) and mantle cell lymphoma (MCL). METHODS--An immunohistochemical study of paraffin wax embedded sections was done on surgically resected specimens of spleens with MBC clusters from patients with gastric cancer (14 cases), tonsils (five cases), and lymph node (two cases) showing lymphoid follicular hyperplasia (LFH), submandibular lymph nodes containing MBC in Sjögren's syndrome (one case). Extranodal organs affected by MCL (three cases) and monocytoid B cell lymphoma (MBCL) (seven cases), and spleens from HCL (four cases) were also studied. These specimens were fixed in 10% formalin and routinely processed for paraffin wax embedding. Fresh spleen specimens from patients with liver cirrhosis (one case) and gastric cancer (seven cases) were snap frozen. RESULTS--Mantle zone lymphocytes were DBA.44, CD74 positive and showed a weaker reaction for CDw75 than marginal zone lymphocytes and MBC, which were almost DBA negative. In neoplastic diseases tumour cells in MCL were DBA.44, CD74, and CDw75 positive. MBCL showed a positive reaction for CD74 and CDw75, but positivity for DBA.44 was observed in only one of seven cases. The HCL specimens, all positive for DBA.44, showed a weaker reaction for CD74 and a stronger reaction for CDw75 than either MCL and MBCL specimens. CONCLUSION--These results show that mantle zone lymphocytes and MCL more closely matched HCL for reactivity to DBA.44 than MBC and MBCL. Reactivities for DBA.44 and CDw75 were greater in MBCL compared with its non-neoplastic counterpart, MBC.     

Vascular relaxing mechanism of denopamine in isolated canine coronary,femoral, mesenteric,and renal arteries

Summary We investigated the mechanism of vascular relaxation produced by denopamine (deno), an oral positive inotropic agent that has selective ₁-adrenergic action. Deno concentration-dependently (0.1 µM–30 µM) relaxed ring segments of canine femoral, mesenteric, and renal arteries which were partially precontracted with 1 µm phenylephrine or norepinephrine, but did not relax those precontracted with 5 µM prostaglandin F₂ or 40 mM K⁺. The relaxation was not significantly inhibited by pretreatment with 10 µM propranolol or metoprolol. Deno produced a parallel rightward shift in concentration-response curves to phenylephrine in femoral and renal arteries. The Schild plot yielded linear regressions of slopes of 1.301 ± 0.106 and 0.823 ± 0.122, respectively, which were not significantly different from unity. The pA₂ values of Deno against phenylephrine in femoral and renal arteries were 5.41 ± 0.03 and 5.76 ± 0.06, respectively.On the other hand, Deno concentration-dependently (10 nM–10 µM) relaxed ring segments of canine coronary arteries which were partially precontracted with 5 µM prostaglandin F₂. The relaxation was significantly inhibited by pretreatment with 10 µM metoprolol.In conclusion, vascular smooth muscle relaxation by Deno was mediated through ₁-adrenergic action in canine coronary arteries and through the blocking effect of -adrenoceptors in canine femoral, mesenteric, and renal arteries.     

Anti-prothrombin antibodies combined with lupus anti-coagulant activity is an essential risk factor for venous thromboembolism in patients with systemic lupus erythematosus

Anti-prothrombin antibodies (anti-prothrombin) and anti-beta2-glycoprotein I antibodies (anti-beta2-GP I) are the most common and characterized anti-phospholipid antibodies (aPL) detected using specific enzyme-linked immunosorbent assay (ELISA) systems. Recently, lupus anti-coagulant (LA) activity detected by a phospholipid-dependent coagulation assay was reported to be associated with anti-prothrombin and/or anti-beta2-GP I. Here we show that the co-existence of IgG anti-prothrombin and LA activity might be an essential risk factor for venous thromboembolism (VTE) in patients with systemic lupus erythematosus (SLE). We examined not only the levels of antibodies to prothrombin and anti-beta2-GP I (both IgG and IgM isotypes) using an ELISA system, but also LA activity detected using both diluted Russell's viper venom time (dRVVT) and STACLOT LA test in 124 patients with SLE. The SLE patients were divided into four groups according to the results of ELISA and LA assay results for each aPL: group A, ELISA+ and LA+ group B, ELISA+ and LA-; group C, ELISA- and LA+ group D, ELISA- and LA-. Regarding IgG anti-prothrombin, the prevalence of VTE was significantly higher in group A (16/35 cases, 45.7%, P < 0.001, Fisher's exact probability test) than in the other groups (B, 2/30, 6.7%; C, 1/22, 4.5%; D, 1/37, 2.7%). With respect to IgM anti-prothrombin and IgG or IgM anti-beta2-GP I, the prevalence of VTE was higher in both groups A and C than in group D, but no statistical difference in prevalence was found between groups A and C. Multivariate logistic regression analysis of risk factors for VTE confirmed that the co-existence of IgG anti-prothrombin and LA activity was the only significant risk factor for VTE (odds ratio, 19.13; 95% confidence intervals, 4.74-77.18).     

Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration

Stem cell factor (SCF) has crucial roles in proliferation, survival, and differentiation of hematopoietic stem cells and mast cells through binding to c-Kit receptor (KIT). Chemotaxis is another unique function of SCF. However, little is known about the intracellular signaling pathway of SCF/KIT-mediated cell migration. To investigate the signaling cascade, we made a series of 22 KIT mutants, in which tyrosine (Y) residue was substituted for phenylalanine (F) in the cytoplasmic domain, and introduced into BAF3 cells or 293T cells. On stimulation with SCF, BAF3 expressing KIT(WT)(WT) showed cell migration and Ca(2+) mobilization. Among 22 YF mutants, Y567F, Y569F, and Y719F showed significantly reduced cell migration and Ca(2+) mobilization compared to WT. In Y567F, Lyn activation on SCF stimulation decreased and C-terminal Src kinase (Csk) suppressed KIT-mediated Ca(2+) influx and cell migration, suggesting that Y567-mediated Src family kinase (SFK) activation leads to Ca(2+) influx and migration. Furthermore, we found that p38 mitogen-activated protein kinase (p38 MAPK) and Erk1/2 were also regulated by Y567/SFK and involved in cell migration, and that p38 MAPK induced Ca(2+) influx, thereby leading to Erk1/2 activation. In Y719F, the binding of phosphatidylinositol 3'-kinase (PI3K) to KIT was lost and KIT-mediated cell migration and Ca(2+) mobilization were suppressed by PI3K chemical inhibitors or dominant-negative PI3K, suggesting the involvement of Y719-mediated PI3K pathway in cell migration. Combination of Csk and the PI3K inhibitor synergistically reduced cell migration, suggesting the cooperation of SFK and PI3K. Taken together, these results indicate that 2 major KIT signaling pathways lead to cell migration, one is Y567-SFK-p38 MAPK-Ca(2+) influx-Erk and the other is Y719-PI3K-Ca(2+) influx.     

A hairy B cell lymphoproliferative disorder resembling hairy cell leukemia

This case report describes a hairy B cell lymphoproliferative disorder (HBLD) with clinical and hematological features resembling hairy cell leukemia. The patient was a 29-year-old female who demonstrated atypical lymphocytes in her peripheral blood. Physical examination demonstrated splenomegaly, but there were no palpable superficial lymph nodes. Hematological examination showed a leukocyte count of 10.6 x 10(3)/mm3 with 41% atypical lymphocytes. Bone marrow examination showed a normal cellular and an atypical lymphocyte count of 42%. The atypical lymphocytes had microvilli and prominent membranous ruffles on their surfaces. Atypical lymphocytes expressed CD5- CD10- CD11c+ CD19+ CD20+ CD23- CD25- on the surface of the cells on examination by with a fluorescence activated cell sorter. Although these findings were similar to hairy cell leukemia, Japanese variant, the surface marker of the kappa chain and lambda chain was unbiased and studies of immunoglobulin gene rearrangements and expression showed polyclonal proliferation of B cells. Therefore, we diagnosed this patient as having HBLD. Because she did not demonstrate anemia or thrombocytopenia, she is not currently receiving medication. To date, the atypical lymphocyte count has not changed.     

Coronary collateral vessels during the early period of acute myocardial infarction: their development]

The aim of this study was to investigate the incidence and development of coronary collateral circulations in patients with acute myocardial infarction (AMI). We categorized 165 patients with persistent 100% occlusion of the infarct-related artery into 6 groups according to the time from the onset of AMI to angiography. Group I consisted of 55 patients evaluated within 6 hours after the onset of AMI; Group II, 28 patients, between 6 and 12 hours after the onset; Group III, 12 patients, between 12 and 24 hours after the onset; Group IV, 11 patients, between 2 and 13 days after infarction; Group V, 46 patients, between 14 and 44 days after infarction; and Group VI, 13 patients, more than 45 days after infarction. Collateral vessels were applied a numerical score between 0 and 3 according to the degree of opacification of the native vessel distal to the occlusion. In 58%, 79%, 67%, 73%, 89%, and 92%, patients of Groups I to VI had evidence of collateral vessels, respectively. Well-developed collaterals were observed in 24% of Group I compared with 50%, 58%, 55%, 73% and 69% of patients in Groups II to VI, respectively. The mean coronary collateral scores were 0.9 +/- 0.1, 1.4 +/- 0.2, 1.4 +/- 0.3, 1.6 +/- 0.4, 2.0 +/- 0.2 and 2.2 +/- 0.3 for Groups I to VI, respectively. Patients with preinfarction angina had more well-developed collateral circulations than did patients without it, however, there was no significant correlation between the duration of previous angina and extent of coronary collaterals.