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Biomedical subjects

Hideo Yagi

Publications and source records attributed to Hideo Yagi.

At least 19 recordsLinked to original sources
PubMed2005

Adenovirus-mediated transfer of human placental ectonucleoside triphosphate diphosphohydrolase to vascular smooth muscle cells suppresses platelet aggregation in vitro and arterial thrombus formation in vivo.

BACKGROUND: Platelet-rich thrombus formation is a critical event in the onset of cardiovascular disease. Because ADP plays a significant role in platelet aggregation, its metabolism is important in the regulation of platelet activation and recruitment. Ectonucleoside triphosphate diphosphohydrolase (E-NTPDase) is a key enzyme involved in vascular ADP metabolism. We recently isolated 2 isoforms of E-NTPDase from the human placenta. The present study examined whether these isoforms suppress platelet aggregation and thrombus formation after adenovirus-mediated gene transfer to vascular smooth muscle cells (SMCs). METHODS AND RESULTS: We constructed adenovirus vectors expressing human placental E-NTPDase isoforms I (AdPlac I) and II (AdPlac II) or bacterial beta-galactosidase (AdLacZ). Vascular SMCs infected with AdPlac I expressed significant NTPDase activity and inhibited the platelet aggregation induced by ADP and collagen in vitro. In contrast, SMCs infected with AdPlac II and AdLacZ did not exert antiplatelet effects. To investigate the antithrombotic and antiproliferative effects of placental E-NTPDase isoform I in vivo, we generated thrombosis in rat carotid arteries by systemically administered rose Bengal and transluminal green light 5 days after gene transfer and examined neointimal growth 3 weeks after thrombus formation. Blood flow in AdLacZ-infected arteries rapidly deteriorated and vanished within 96+/-18 seconds of occlusive thrombus formation. In contrast, blood flow in AdPlac I-infected arteries was preserved for at least 10 minutes during irradiation. In addition, thrombus formation and subsequent neointimal growth were obviously suppressed. CONCLUSIONS: The local expression of placental E-NTPDase in injured arteries might prevent arterial thrombosis and subsequent neointimal growth.

Adenosine Triphosphatases↗
PubMed2005

The peripheral blood Valpha24+ NKT cell numbers decrease in patients with haematopoietic malignancy.

Valpha24TCR+ CD161+ NKT (Valpha24+ NKT) cells are activated by alpha-galactosylceramide and can exert anti-tumor activity against a variety of tumor cells. In this study, we assessed the Valpha24+ NKT cell numbers in peripheral blood (PB) from 30 healthy donors and 70 patients with haematopoietic malignancy including chronic myelogenous leukemia (CML), malignant lymphoma (ML), acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS). Here, we demonstrated that PB Valpha24+ NKT cell numbers were significantly decreased in all the patients with haematopoietic malignancy in comparison with that in healthy donors (P < 0.005). In particular CD4- CD8- Valpha24+ NKT cell numbers were more significantly decreased in the patients with haematopoietic malignancy (P < 0.0001).

CD4 Antigens↗
PubMed2005

[Clinical features and laboratory findings of thrombotic thrombocytopenic purpura associated with ticlopidine].

Ticlopidine is an antiplatelet agent that interferes with platelet membrane function by inhibiting adenosine diphosphate-induced platelet activation. It is used in an increasing number of cases of cerebrovascular disease, unstable angina, coronary artery stenting, and peripheral vascular diseases. It has rare but serious adverse reactions, including thrombotic thrombocytopenic purpura (TTP). TTP is a life-threatening disease, characterized by Moschcowitz's pentad: thrombocytopenia, microangiopathic hemolytic anemia, fluctuating neurological signs, renal failure, and fever. Recent advances in elucidating the proteolytic processing of plasma von Willebrand factor (VWF) multimers have established assays for VWF-cleaving protease (VWF-CP) activity and its inhibitor(autoantibodies). These assays apparently demonstrated that TTP patients have defective enzymatic activity with or without presence of the inhibitor. VWF-CP is now identified as a metalloproteinase belonging to the ADAMTS (A Disintegrin And Metalloproteinase domain, with ThromboSpondin type 1 motif) family, termed ADAMTS13. Cases of ticlopidine-associated TTP were first reported in 1991. This complication occurs in 1 in 1600 to 1 in 5000 patients who receive ticlopidine. It is known that they develop TTP within 2 to 8 wk of starting ticlopidine treatment and show severely deficient of ADAMTS13 activity with the presence of the inhibitor. These results suggest that ticlopidine or its metabolites induce the production of autoantibodies against ADAMTS13. As treatment, discontinuation of ticlopidine therapy and rapid initiation of plasma exchange is effective: the majority of patients completely recover and relapse is uncommon. It is thus recommended that physicians should perform complete blood count every 2 weeks for 12 weeks for rapid diagnosis. Physicians and patients should be aware of this fatal but curable complication of ticlopidine therapy.

ADAM Proteins↗
PubMed2004

The Japanese experience with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome.

A total of 290 Japanese patients with thrombotic thrombocytopenic purpura-hemolytic uremic syndrome (TTP-HUS) were analyzed with respect to ADAMTS-13 activity and its inhibitor. Twenty-one patients (17 families) had Upshaw-Schulman syndrome, and 12 patients (six families) had familial HUS of undetermined etiology. The number of patients with acquired HUS and TTP was 44 and 213, respectively. In acquired TTP, patients with severe deficiency of ADAMTS-13 activity secondary to the presence of an inhibitor were high responders to plasma exchange, but others were low responders to plasma exchange. The former patients were associated with "idiopathic" TTP, drugs, and pregnancy, and the latter patients with malignancy and stem cell transplantation. Patients with autoimmune disease-associated TTP fit into both groups.

ADAM Proteins↗
PubMed2004

[Changes of ADAMTS13 activity and endothelial cell markers in TMA cases].

Severe deficiency of ADAMTS13 activity was recently found in patients with thrombotic thrombocytopenic purpura (TTP). The great advance associated with these basic and clinical studies on ADAMTS13 is the possible elucidation of the pathogenesis of TMA (thrombotic microangiopathy). However, the exact pathogenetic mechanism in TMA without severe deficiency of ADAMTS13 activity remains unknown due to heterogeneity of the disease. In this study, there were 7 patients with TTP, 7 with HUS, 3 with drug-induced HUS, 1 with VOD, and 1 with IVL out of 19 TMA patients with a moderate deficiency (6-70%) of ADAMTS13 activity. Five of the 7 TTP patients had a poor outcome. Plasma thrombomodulin and t-PA-PAI-1 complex levels in TMA patients with a moderate deficiency of ADAMTS13 activity were significantly higher than those in patients with a severe deficiency of ADAMTS13 activity. These data suggest that the etiology in these patients may be systemic vascular endothelial cell damage.

ADAM Proteins↗
PubMed2003

Molecular characterization of ADAMTS13 gene mutations in Japanese patients with Upshaw-Schulman syndrome.

We report here 7 new mutations in the ADAMTS13 gene responsible for Upshaw-Schulman syndrome (USS), a catastrophic phenotype of congenital thrombotic thrombocytopenic purpura, by analyzing 5 Japanese families. There were 3 mutations that occurred at exon-intron boundaries: 414+1G>A at intron 4, 686+1G>A at intron 6, and 1244+2T>G at intron 10 (numbered from the A of the initiation Met codon), and we confirmed that 2 of these mutations produced aberrantly spliced messenger RNAs (mRNAs). The remaining 4 mutations were missense mutations: R193W, I673F, C908Y, and R1123C. In expression experiments using HeLa cells, all mutants showed no or a marginal secretion of ADAMTS13. Taken together with the findings in our recent report we determined the responsible mutations in a total of 7 Japanese patients with USS with a uniform clinical picture of severe neonatal hyperbilirubinemia, and in their family members, based on ADAMTS13 gene analysis. Of these patients, 2 were homozygotes and 5 were compound heterozygotes. The parents of one homozygote were related (cousins), while those of the other were not. Molecular models of the metalloprotease, fifth domain of thrombospondin 1 (Tsp1-5), and Tsp1-8 domains of ADAMTS13 suggest that the missense mutations could cause structural defects in the mutants.

ADAM Proteins↗
PubMed2003

The mechanisms of recovery from cerebellar infarction: an fMRI study.

Patients with cerebellar infarction frequently make an excellent functional recovery. However, the mechanisms of functional recovery from cerebellar infarction remain unclear. Thus, functional MRI was used to investigate these mechanisms in six right-handed patients with complete recovery after cerebellar infarction, and nine right-handed normal subjects. The non-infarcted side of the cerebellum and the sensorimotor cortex contralateral to the non-infarcted side of the cerebellum were significantly activated during the infarcted-side hand movement. In the infarcted side of the cerebellum, intact regions were activated. Our results indicate that recovery from cerebellar infarction depends on reorganization in the infarcted side of the cerebellum, and recruitment of the cerebellocortical loop involving the cerebrum ipsilateral to the movement and the cerebellum contralateral to the movement.

Adult↗
PubMed2003

ADAMTS-13 cysteine-rich/spacer domains are functionally essential for von Willebrand factor cleavage.

A severe lack of von Willebrand factor-cleaving protease (VWF-CP) activity can cause thrombotic thrombocytopenic purpura (TTP). This protease was recently identified as a member of the ADAMTS family, ADAMTS-13. It consists of a preproregion, a metalloprotease domain, a disintegrin-like domain, a thrombospondin type-1 motif (Tsp1), a cysteine-rich domain, a spacer domain, additional Tsp1 repeats, and CUB domains. To explore the structural and functional relationships of ADAMTS-13, we prepared here 13 sequential COOH-terminal truncated mutants and a single-point mutant (ArgGlyAsp [RGD] to ArgGlyGlu [RGE] in the cysteine-rich domain) and compared the activity of each mutant with that of the wild-type protein. The results revealed that the truncation of the cysteine-rich/spacer domains caused a remarkable reduction in VWF-CP activity. We also prepared immunoglobulin G (IgG) fractions containing inhibitory autoantibodies against ADAMTS-13 from plasma from 3 patients with acquired TTP, and we performed mapping of their epitopes using the aforementioned mutants. The major epitopes of these antibodies were found to reside within the cysteine-rich/spacer domains. These results suggest that the ADAMTS-13 cysteine-rich/spacer domains are essential for VWF-CP activity.

ADAM Proteins↗
PubMed2003

Cerebral vasomotor reactivity to postural change is impaired in patients with cerebrovascular white matter lesions.

Vasomotor reactivity is decreased in terms of cerebral blood flow (CBF) response to hypercapnia in patients with cerebrovascular white matter (WM) lesions. This study evaluated whether vasomotor reactivity is altered during postural change in these patients. We examined 28 consecutive patients with cerebrovascular WM lesions, subgrouped into 19 with Schmidt scale 2 and 9 with scale 3 WM lesions. These patients were compared with 15 age-matched patients with lacunar infarction but without significant WM lesions and 6 controls without cerebrovascular disease. With blood pressure monitoring, brain SPECT scans were done in the supine and upright position using HMPAO as a tracer. The ratio of radioisotope (RI) counts in the frontal and parieto-temporal lobes to those in the cerebellar hemispheres (CBF ratio) was evaluated. In the comparison among the three groups, there were no significant differences in the changes of systemic blood pressure after rising. The baseline CBF ratio in the supine position was also not different among the three groups. After rising, the CBF ratio in each region of interest (ROI) did not change significantly in either lacunar infarction or control groups. By contrast, in patients with WM lesions, the CBF ratio in the frontal lobe decreased after rising (p < 0.0001). In the subgroup analysis, there was a significant increase in blood pressure 1, 2 and 3 min after rising (p < 0.05), with a higher tendency in the scale 3 WM lesion group as compared to the scale 2 WM lesion group. The CBF ratio was decreased in both frontal and parieto-temporal areas in the scale 2 WM lesion group, whereas this was significant only in the frontal areas in the scale 3 WM lesion group. Vasomotor reactivity is impaired in cerebrovascular WM lesions, suggesting a susceptibility to postural changes in these patients.

Aged↗
PubMed2003

Von Willebrand factor--cleaving protease activity in thrombotic microangiopathy after living donor liver transplantation: a case report.

Defective plasma activity of Von Willebrand factor (VWF)-cleaving protease (CP) and/or the inhibitors against this protease has been shown to have a pathological role in several forms of thrombotic microangiopathy (TMA). This report describes a patient for whom a diagnosis of TMA was made immediately after living donor liver transplantation. In this patient, activity of VWF-CP and its inhibitor were analyzed serially. At the onset of the disease, VWF-CP activity was quantified as 17%. Inhibitor against this protease was positive, with a titer of 0.6 Bethesda U/mL, and its inhibitory activity was quantified as 3.8 Bethesda U/mg immunoglobulin G. Laboratory parameters and clinical features were significantly improved after induction of plasma exchange (PE) with fresh frozen plasma and concurrent cessation of tacrolimus therapy. The inhibitors disappeared after one session of PE. However, VWF-CP activity after a transient increase and again decreased to subnormal levels after completion of PE. Nevertheless, this did not result in disease recurrence. In view of sustained VWF-CP activity at disease onset and the absence of definite correlations between levels of this protease and clinical features, abnormality of this enzyme system had no essential role in the pathogenesis of TMA in this case. Clinical findings suggest that TMA was tacrolimus-induced.

ADAM Proteins↗
PubMed2002

Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity.

von Willebrand factor (VWF) is synthesized primarily in vascular endothelial cells and secreted into the plasma as unusually large VWF multimers. Normally, these multimers are quickly degraded into smaller forms by a plasma metalloproteinase, VWF-cleaving protease (VWF-CP). Decreases in the activity of this enzyme result in congenital and acquired thrombotic thrombocytopenic purpura (TTP). The human VWF-CP has recently been purified. Cloning of the corresponding cDNA revealed that the 1,427-aa polypeptide is a member of the ADAMTS gene family, termed ADAMTS13. Twelve rare mutations in this gene have been identified in patients with congenital TTP. Here, we report missense and nonsense mutations in two Japanese families with Upshaw-Schulman syndrome, congenital TTP with neonatal onset and frequent relapses. The comparison of individual ADAMTS13 genotypes and plasma VWF-CP activities indicated that the R268P, Q449stop, and C508Y mutations abrogated activity of the enzyme, whereas the P475S mutant retained low but significant activity. The effects of these mutations were further confirmed by expression analysis in HeLa cells. Recombinant VWF-CP containing either the R268P or C508Y mutations was not secreted from cells. In contrast, Q449stop and P475S mutants were normally secreted but demonstrated minimal activity. Genotype analysis of 364 Japanese subjects revealed that P475S is heterozygous in 9.6% of individuals, suggesting that approximately 10% of the Japanese population possesses reduced VWF-CP activity. We report on a single-nucleotide polymorphism associated with alterations in VWF-CP activity; it will be important to assess this single-nucleotide polymorphism as a risk factor for thrombotic disorders.

ADAM Proteins↗
PubMed2002

Successful treatment of a young infant who developed high-titer inhibitors against VWF-cleaving protease (ADAMTS-13): important discrimination from Upshaw-Schulman syndrome.

We report herein the case of a 9-month-old female infant with acquired thrombotic thrombocytopenic purpura (TTP), which was initially suspected to be either Upshaw-Schulman syndrome (USS or a congenital TTP) or hemolytic uremic syndrome (HUS) because of onset of clinical signs in infancy and accompanying diarrhea. She received combination therapy of plasma exchange, steroid pulse, and high-dose intravenous immunoglobulin infusion that was initiated before the definitive diagnosis, which resulted in excellent clinical improvement. The retrograde analysis of plasma ADAMTS-13 activity and its inhibitor showed a lack of this enzyme activity and the presence of a high-titer IgG inhibitor (200-320 Bethesda units/mL) to this enzyme activity. From our experience, it was suggested that we should recognize the possibility of the patient with acquired TTP in infancy and the importance of plasma exchange therapy for management of its clinical symptoms.

ADAM Proteins↗
PubMed2002

Deterioration in learning and memory of inferential tasks for evaluation of transitivity and symmetry in aged SAMP8 mice.

This study examined age-dependent deficits in the learning and memory of inferential tasks, using an established senescence-accelerated mouse model in age-related brain dysfunction (SAMP8) and its genetically related inbred strain (SAMR1). The mice learned two sets of nonspatial odor-odor pairs by association learning successively (i.e., A-->B, X-->Y, then B-->C, Y-->Z). They were tested in transitive inference (i.e., A-->C, X-->Z) and symmetrical inference (i.e., C-->B, Z-->Y). In the probe test of A-->C, X-->Z transitive inference, 1-month-old SAMP8 and control SAMR1 at the same age significantly chose the alternative based on transitive inference, but 4- and 7-month-old SAMP8 performed at a random chance level, in comparison with unambiguous inference by control SAMR1 at the same ages. During the test of C-->B, Z-->Y symmetrical inference, SAMP8 at 1 month of age made errors as frequently as control SAMR1 at the same age, but SAMP8 at 4 and 7 months of age made more errors than SAMR1 at the same ages. At 4 and 7 months of age, SAMP8 made more errors than 1-month-old SAMP8. Control SAMR1 did not show such an age-related deficient. These results indicate that SAMP8 mice have age-related learning and memory deficits in the ability to perform inferential tasks. Age-related hippocampal dysfunction is suggested to be the cause of these age-related deficits in old SAMP8 mice during the performance of inferential tasks mediated by declarative memory.

Aging↗
PubMed2002

Von Willebrand factor-cleaving protease and Upshaw-Schulman syndrome.

Vascular endothelial cell (EC)-produced plasma von Willebrand factor (vWF) plays a critical role in primary hemostasis through its action of anchoring platelets onto the injured denuded subendothelial matrices under high shear stress. Unusually large vWF multimers (UL-vWFMs), present in plasma immediately after release from ECs, are most biologically active, but they are soon cleaved and degraded into smaller vWFMs by a specific plasma protease, termed vWF-cleaving protease (vWF-CPase), in normal circulation. Recent studies on the relationship between UL-vWFMs and vWF-CPase, together with its autoantibody (inhibitor) have brought about a clear discrimination between thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Furthermore, a congenital deficiency of this enzyme activity has been shown to cause Upshaw-Schulman syndrome, a complex constitutional bleeding diathesis. Successful purification of vWF-CPase revealed that this enzyme is composed of a single polypeptide with a molecular mass of approximately 190 kd, and its complementary DNA cloning unambiguously indicated that it is uniquely produced in the liver and its gene is located on chromosome 9q34. The messenger RNA of vWF-CPase had a span of 4.6 kb, and its enzyme was designated ADAMTS 13. The predicted complete amino acid sequence of this enzyme consisted of 1427 residues, including a signal peptide, a short propeptide terminating in the sequence RQRR, a reprolysin-like metalloprotease domain, a disintegrin-like domain, a thrombospondin-1 repeat (TSP1), a cysteine-rich domain, an ADAMTS spacer, 7 additional TSP1 repeats, and 2 CUB domains.

ADAM Proteins↗
PubMed2002

Predicting response to plasma exchange in patients with thrombotic thrombocytopenic purpura with measurement of vWF-cleaving protease activity.

BACKGROUND: Severe deficiency of vWF-cleaving protease (vWF-CPase) activity was recently found in patients with thrombotic thrombocytopenic purpura (TTP). Although the survival of patients with TTP has been dramatically improved with plasma exchange (PE), there are still many patients who are refractory to PE and immunosuppressive therapy. STUDY DESIGN AND METHODS: The activities of vWF-CPase and its inhibitor were measured in 27 patients with nonfamilial TTP and hemolytic-uremic syndrome (HUS) to examine the relationship between the clinical variables and vWF-CPase activity. RESULTS: Eight of nine patients with HUS had more than 40 percent of vWF-CPase activity, whereas one had 28 percent of the normal level at the acute phase. Ten of 12 TTP patients with a good outcome had a severe deficiency of vWF-CPase activity and its inhibitor, whereas four of six patients with a poor outcome had a moderate deficiency of vWF-CPase activity along with a lack of the inhibitor. PE produced normalization of the vWF-CPase activity and neutralization of the inhibitor in TTP patients with a good outcome; however, some TTP patients with vWF-CPase inhibitor had relapsed and required an immunosuppressive therapy. The response to the combination therapy with PE and immunosuppressive treatment was poor in TTP patients without a severe deficiency of vWF-CPase activity. CONCLUSION: Assays of vWF-CPase activity and its inhibitor may be useful for predicting the response to therapy and the outcome of patients with TTP. In some patients, nonfamilial TTP with a poor prognosis may not be caused by a constitutional or acquired deficiency of vWF-CPase with its inhibitor. Although PE and immunosuppressive therapy are effective in patients with nonfamilial TTP and a vWF-CPase inhibitor, other therapeutic modalities may be needed for nonfamilial TTP with unknown etiology.

ADAM Proteins↗