Major basic protein binding to thrombomodulin potentially contributes to the thrombosis in patients with eosinophilia

Summary. The contribution of an eosinophil granule protein, major basic protein (MBP), to the pathogenesis of thrombosis seen in patients with eosinophilia was investigated. The sera from eosinophilic patients containing elevated levels of MBP inhibited thrombomodulin (TM) function as a cofactor for the thrombin-catalysed activation of protein C more significantly than those from normal individuals (means 48.5% v 17.4%, respectively). It was suggested that the binding of mature MBP in the sera to TM was electrostatic, because mature MBP (pi 10.9) bound to TM, whereas pro-MBP (pi 6.2) did not. The inhibition of TM cofactor activity by eosinophil granule proteins was mainly attributed to the mature MBP, because MBP-depleted eosinophil granule proteins did not inhibit TM cofactor activity significantly. This inhibition seemed to be due to the specific thrombin-binding to TM being blocked. We concluded that eosinophil granule proteins, particularly MBP, potentially contribute to the hypercoagulation seen in some conditions of eosinophilia, at least because of the inhibition of TM function as a cofactor of the anticoagulation system.     

A Metastatic Neuroblastoma with Long Survival in Adolescence

We report a 16-year 8-month-old girl with neuroblastoma (stageIII) who received surgery for abdominal masses four times duringa 52-month period. She is now treated with oral administrationof cyclophosphamide (2 mg/kg) and is in good condition eventhough she has several metastatic lesions. In this paper, we consider why a 16-year-old girl with a tumorof estimated stage III has had a long survival period of 52months. There seem to be three interesting points related toher long survival. The first is that the tumor response to thetreatments was good, particularly to a large dose of cyclophosphamide.The second is the histological observation of the tumor specimensobtained at four different occasions from the same or differentportions. The immature tumor cells of the primary tumor changedto ganglioneuroma during the first 30-month period, but thenewly appearing metastatic lymphnodes were histologically neuroblastoma.The third is her immunological condition during treatment. Thefact that her nonspecific humoral and cellular immune competenceremained in good condition seems to be a factor favorable forher good prognosis.     

IMAGING STUDY ON THE MODE OF DEVELOPMENT AND CHANGES IN AVASCULAR NECROSIS OF THE FEMORAL HEAD IN SYSTEMIC LUPUS ERYTHEMATOSUS: LONG-TERM OBSERVATIONS

To find out when and how avascular necrosis of the femoral head(ANFH) develops in patients with SLE who are receiving corticosteroids,we carried outa 3-yr prospective study using imaging methods.Twenty-three patients with SLE who were free of hip pain andradiographically negative were enrolled in the study. Initially,abnormal findings characteristic of ANFH were detected in eight(35%) and six (26%) patients on MRI and radionuclide uptakebone scanning, respectively. During a 3-yr observation periodabnormalities on MRI, bone scanning and radiography were foundin four, fiveand four patients, respectively and three patientsdeveloped hip pain. Analyses of imaging changes demonstratedthat only a small proportion of patients (2/8, 25%) who initiallyshowed abnormal MRI progressed to beradiographically positivefor ANFH over the 3 years. High doses of corticosteroids overthe 3-yr period were found to be responsible for the emergenceof change in MRI abnormalities. It is also suggested that abnormalMRI findings tend to develop either within a relatively shortinterval after the start of corticosteroid treatment or areassociated with the exacerbation of SLE. KEY WORDS: Magnetic resonance imaging, Radionuclide uptake scanning, Radiography, Prospective study, Corticosteroids, Exacerbation of systemic lupus erythematosus     

Evaluation of Dabigatran- and Warfarin-Associated Hemorrhagic Events Using the FDA-Adverse Event Reporting System Database Stratified by Age

Dabigatran and warfarin are oral anticoagulant drugs widely used for the prevention of stroke in patients with atrial fibrillation. The objective of this study was to evaluate the interaction between aging and dabigatran- and warfarin-induced gastrointestinal (GI) and nervous system hemorrhage using data available in the FDA Adverse Event Reporting System (FAERS) database.We analyzed reports of hemorrhagic events in the GI and nervous system recorded in the FAERS database between 2004 and 2014 using an adjusted reporting odds ratio (ROR).We demonstrated that dabigatran-associated GI hemorrhage was significantly increased in patients over the age of 80 years. The RORs of dabigatran increased with increasing age, although aging had little effect on warfarin-associated GI hemorrhage. The ROR for anticoagulant-associated nervous system hemorrhage was not significantly affected by aging, as compared to GI hemorrhage.Our results indicate that the excretion of dabigatran may be affected by aging, as compared to warfarin, likely due to renal function decline. Our results emphasize the need for physicians to closely monitor GI bleeding in aging patients, because it is closely related to renal function deterioration.     

Characterization of a patient with glycoprotein (GP) VI deficiency possessing neither anti-GPVI autoantibody nor genetic aberration

BACKGROUND: There have been only seven reported cases of glycoprotein (GP) VI deficiency. However, the pathogenesis of this disorder has not been well-elucidated. OBJECTIVES: We characterized a novel patient with GPVI deficiency and used these platelets to investigate the role of GPVI in normal hemostasis. PATIENT: A 31-year-old female with immune thrombocytopenic purpura who had been suffering from mild bleeding diathesis even after recovery from thrombocytopenia. RESULTS AND CONCLUSION: The patient's platelets did not aggregate in response to either convulxin or collagen-related peptide. Immunoblotting revealed complete absence of the GPVI molecule, whereas a significantly reduced but substantial amount of Fc receptor (FcR) gamma-chain was expressed. Platelet stimulation with convulxin did not induce tyrosine-phosphorylation of FcR gamma-chain, indicating a defect in GPVI-mediated signaling. Concerning the underlying pathogenesis, we found normal level of GPVI-mRNA expression, no aberration of the sequence of the entire coding region of GPVI, and presence of degraded GPVI in her plasma. However, no anti-GPVI autoantibody was detected either by the binding assay to GPVI-Fc2 fusion protein or by immunoblotting/immunoprecipitation using the patient's immunoglobulin. We thus consider that either a short-time exposure to anti-GPVI autoantibody or a continuous exposure to low titers of the autoantibody has resulted in persistent GPVI deficiency. Under high shear flow, the patient's platelets could not form large aggregates, although initial platelet attachment was obviously observed. These results suggest that GPVI deficiency in this patient resulted in defective platelet thrombi development, manifesting as bleeding diathesis. Furthermore, our observations indicate that coordination of GPVI with integrin alpha2beta1 is essential for physiological platelet thrombus formation.     

Biliary Scintigraphy with a New Scanning Agent, 99mTc-(SN)-pyridoxylidene-isoleucine

99mTechnetium-pyridoxylidene-isoleucine (hereinafter referred to as 99mTc-PI) is a new biliary scintiscanning agent. It has been evaluated in both health volunteers and patients with known surgical biliary tract diseases. It results in imaging of the liver in three minutes and the common bile duct and duodenum in 10-20 minutes. Its advantages as a diagnostic tool in disease of the hepatobiliary systems are in reducing the amount of radiotracer required, in shortening examination time and in producing scintigrams of higher resolution.     

Continuous expression of Bcl-xL protein during megakaryopoiesis is post-translationally regulated by thrombopoietin-mediated Akt activation, which prevents the cleavage of Bcl-xL

BACKGROUND: One of the important biological activities of thrombopoietin (TPO) is to prevent the apoptosis of megakaryocytes. As the antiapoptotic protein Bcl-xL, which has been proven to be indispensable for erythroid differentiation, is also abundantly expressed in megakaryocytes, it is assumed that Bcl-xL plays an important role in megakaryopoiesis. OBJECTIVES: We investigated the expression of Bcl-xL during megakaryopoiesis and the underlying regulatory mechanism. METHODS AND RESULTS: In stem cell-derived megakaryocytes, expression of Bcl-xL increased in the early and mid-stages of the differentiation. Both in vitro in cell culture and in vivo in an animal model, expression of Bcl-xL protein was maintained until the platelet-producing stage. TPO depletion caused significant decrease in Bcl-xL protein level without affecting its mRNA in both megakaryocytes and TPO-dependent megakaryocytic UT-7/TPO cells, suggesting that Bcl-xL protein level in TPO-dependent cells is post-translationally regulated. In agreement with this finding, we recognized the appearance of a 12-kD fragment of Bcl-xL upon TPO depletion. This cleavage of Bcl-xL was inhibited by a caspase-3-specific inhibitor. Furthermore, pretreatment of UT-7/TPO with a phosphatidylinositol 3-kinase (PI3 K) inhibitor resulted in the cleavage of Bcl-xL even in the presence of TPO. We thus hypothesized that PI3 K inhibits the activation of caspase-3 and consequent cleavage of Bcl-xL. To prove this, we prepared UT-7/TPO cells transfected with constitutively active Akt-1. When TPO was depleted, the transfectant was significantly less liable to caspase-3 activation and Bcl-xL cleavage. CONCLUSIONS: Bcl-xL protein is expressed throughout megakaryopoiesis until platelets are produced, and its expression level is at least in part post-translationally regulated through TPO-mediated Akt activation.     

Mandibular reaction time to auditory and visual signals in young and elderly subjects

Mandibular reaction time was measured in young and elderly volunteers. Each subject was instructed to open the jaw from the closed position and to close the jaw from the open position as quickly as possible after perceiving an auditory or visual signal. The reaction time of the elderly subjects to both signals was significantly slower than that of the young subjects. This was due almost entirely to prolongation of the premotor time component. There was no difference in the maximum velocity of the jaw movement between the two groups of subjects.