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M Sako

Publications and source records attributed to M Sako.

At least 55 records · Page 3Linked to original sources
PubMed1999

Clonal dissemination of T-lymphocytes in scid mice from familial hemophagocytic lymphohistiocytosis.

BACKGROUND: Although familial hemophagocytic lymphohistiocytosis (FHL) has been considered a disorder of T-cell dysfunction, there is no evidence of the clonal origin of T-cells in this disease. PROCEDURE: We engrafted mononuclear cells (MNCs) from five FHL patients into scid mice and examined the infiltration of human cells in mouse organs. The characterization of human cells that infiltrated in the mouse organs was then performed. RESULTS: A diffuse infiltration of human lymphoid cells was detected in scid mice treated with 1 x 10(6) MNCs from one of the five patients. These cells were positive for HLA-DR and CD3, but negative for CD4, CD8, CD20, and CD68, suggesting the infiltration of double negative (DN) T-cells. The MNCs from the other four patients induced murine lymphoma-like disease; T-cell lymphoma in one and lymphoma of unknown origin in three. The characterization of these human DN T-cells was performed. The analysis of the Vbeta repertoire showed no preferential usage of the Vbeta family in MNCs, while the dominant expression of Vbeta13 was detected in T-cells infiltrating in the spleen and lung. A Jbeta analysis showed the restricted usage of Jbeta1.2 for Vbeta13 in these cells, and the clonality of Vbeta13-Jbeta1.2 fragment was confirmed by a single-strand confirmation polymorphism analysis. The analysis of the Valpha repertoire showed that Valpha24 was exclusively used in these DN T-cells, but no usage of JalphaQ for Valpha24 was observed. CONCLUSIONS: A clonal expansion of T-cells was induced in scid mice by the engraftment of MNCs from an FHL patient. The infiltration of DN alphabeta T-cells bearing invariant Valpha24 T-cell receptor in mouse organs may provide a useful clue to the pathogenesis of FHL. In the patients whose MNCs induced murine lymphoma-like disease, some cytokines or unknown factors that stimulate the growth and the tumorigenicity of murine lymphocytes might be produced by the MNCs engrafted in scid mice. Further study is needed to confirm the validity of our experimental approach and the findings observed in scid mice by using more FHL samples.

Animals↗
PubMed1999

Lineage switch in childhood leukemia with monosomy 7 and reverse of lineage switch in severe combined immunodeficient mice.

Morphophenotypic lineage switches occur in a small percentage of those with acute leukemia, and the underlying mechanisms are not clear. In this study, we attempted to induce a lineage switch in acute myelocytic leukemia (AML) with monosomy 7, whose lineage had switched from acute T-lymphocytic leukemia (T-ALL) during chemotherapy, in severe combined immunodeficient (SCID) mice. Although the transplanted myeloid cells were engrafted in SCID mice without cytokine administration, T-ALL developed in SCID mice treated with recombinant human granulocyte-macrophage colony-stimulating factor or recombinant human interleukin 3. Analysis of the nucleotide sequences of the rearranged T-cell receptor gamma-chain (TCR-gamma) gene revealed that this lineage switch resulted from the selection of the T-lineage subclone in SCID mice, which had expanded at onset. In addition, we found that the T-lineage and myeloid cells belonged to the distinct subclones, which were different in TCR-gamma gene rearrangements, but were derived from a common clone with an identical N-ras gene mutation for both subclones. In in vitro cultures, only the myeloid subclone grew; the T-lineage subclone failed to grow even in the presence of recombinant human granulocyte-macrophage colony-stimulating factor or recombinant human interleukin 3. These results suggested that the initial diagnostic T-lymphoid subclone, whose growth was dependent on these cytokines and the hematopoietic microenvironment, emerged from a bipotential T-lymphoid/myeloid leukemic stem cell, and further genetic event(s) induced the myeloid subclone, which grew independently of these cytokines and the microenvironment.

Acute Disease↗
PubMed1999

Allogeneic hematopoietic stem cell transplantation for patients with hemophagocytic syndrome (HPS) in Japan.

Seventeen cases (age at onset, 1 month to 18 years; M/F, 9/8) of hemophagocytic syndrome which received allogeneic hematopoietic stem cell transplantation (SCT) in Japan during the period 1988-1998 are reported. The patients consisted of six familial inheritance-proven erythrophagocytic lymphohistiocytosis (FEL), five familial inheritance-unknown and infective agents-unknown HLH (of which two were highly likely to have been FEL with characteristic CNS signs), and six aggressive Epstein-Barr virus (EBV)-related HLH (of which two were natural killer cell-type large granular leukemia/lymphoma-associated hemophagocytic syndrome, EBV-NK-LGLL-HPS). All cases were treated intensively with immuno-chemotherapy, or with chemotherapy before SCT. As sources of SCT, 12 cases received bone marrow cells (sibling six, father one, URD five), two cord blood, two purified CD34-positive cells, and one PBSC. SCTs were successful in all 17 cases, apart from one receiving CD34-positive SCT. Following SCT, four patients relapsed and five died with a median follow-up of 23 months. Among the relapsed cases, the two EBV-NK-LGLL-HPS previously published as successfully transplanted were included. Among the fatal cases, three patients died from relapsed active disease and the remaining two from fatal post-SCT EBV-positive T cell lymphoma and extensive chronic GVHD, respectively. As of the end of September 1998, 10 patients are alive without disease for 3.5 months to 147 months, while two post-SCT patients are still having therapy for residual/recurrent disease. The Kaplan-Meier analysis showed a 2-year event-free survival after SCT as 54.0+/-13.0%.

Adolescent↗
PubMed1999

WASP is involved in proliferation and differentiation of human haemopoietic progenitors in vitro.

The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, immunodeficiency and eczema. X-linked thrombocytopenia (XLT) is a mild form of WAS with isolated thrombocytopenia. Both phenotypes are caused by mutation of the Wiskott-Aldrich syndrome protein (WASP) gene. In this study we investigated the role of WASP in the differentiation of CD34-positive (CD34+) cells isolated from the bone marrow of patients with WAS (n = 5) or with XLT (n = 4). Megakaryocyte colony formation was significantly decreased in patients with WAS when compared with normal controls. The formation of granulocyte-macrophage colonies and erythroid bursts were also decreased in WAS patinets. In contrast, in XLT patients, formation of all these colonies was normal. However, in vitro proplatelet formation of megakaryocytes induced by thrombopoietin was markedly decreased in both XLT and WAS. Electron microscopic examination revealed that megakaryocytes obtained from WAS or XLT patients grown in vitro had abnormal morphologic features, which seemed to be caused by defective actin cytoskeletal organization, including labyrinth-like structures of the demarcation membrane system and deviated distribution of the alpha-granules and demarcation membrane system. These observations indicate that WASP is involved in the proliferation and differentiation of CD34+ haemopoietic progenitor cells probably by its participation in signal transduction and in the regulation of the cytoskeleton.

Blood Platelets↗
PubMed1999

Retrograde transvenous obliteration of gastric varices.

PURPOSE: To evaluate the clinical efficacy, techniques, and complications associated with balloon-occluded retrograde transvenous obliteration of gastric varices. MATERIALS AND METHODS: Between December 1994 and November 1997, balloon-occluded retrograde transvenous obliteration was performed on 20 patients with gastric varices in danger of rupture and with gastrorenal shunts; three patients also had hepatic encephalopathy. The sclerosant was injected into the gastric varices during balloon occlusion. The degree of progression of the gastric varices and of collateral veins was classified into five grades, with grade 1 being least progression and grade 5 most progression; collateral veins that had developed were treated with embolization. Follow-up consisted of fiberoptic endoscopy and computed tomography. RESULTS: Technical success was achieved in all patients. Occlusion of collateral veins was essential for the occlusion of gastric varices with a grade greater than grade 2. The clinical symptoms of hepatic encephalopathy in the three patients improved remarkably. Follow-up endoscopy 3 months after the procedure revealed the disappearance of gastric varices in 15 patients and reduced variceal size in five. During the follow-up period, 19 patients had no recurrence of gastric varices; three patients had aggravation of the esophageal varices. CONCLUSION: Balloon-occluded retrograde transvenous obliteration is a feasible alternative to a transjugular intrahepatic portosystemic shunt for patients with large gastrorenal shunts or hepatic encephalopathy (or both).

Aged↗
PubMed1998

Elevation of the serum Fas ligand in patients with hemophagocytic syndrome and Diamond-Blackfan anemia.

Fas ligand (FasL) is a membrane protein that is expressed in activated T cells and natural killer cells. FasL binds to Fas on target cells and induces apoptosis. There exists a soluble form of FasL (sFasL), and sFasL also induces apoptosis of Fas-bearing cells. The serum sFasL concentrations were reported to be elevated in patients with large granular lymphocytic leukemia and natural killer cell lymphoma. In this study, we have measured serum sFasL concentrations in other hematological disorders, including severe aplastic anemia (SAA), hemophagocytic lymphohistiocytosis (HLH), and Diamond-Blackfan anemia (DBA). The serum sFasL concentration of age-matched healthy controls was 0.16 +/- 0.11 ng/mL (mean +/- SD, n = 22). The serum sFasL levels in the patients with HLH and DBA were 3.75 +/- 3.82 (n = 19; P < .0001, HLH v control) and 2.76 +/- 2.43 ng/mL (n = 6; P = .012, DBA v control), respectively. Serum interferon-gamma concentration was elevated in the patients with HLH (1.61 +/- 2.62 ng/mL) but not in those with DBA (below the detectable level). These results suggest that the Fas-FasL system plays a role, at least in part, in the pathophysiology of HLH and DBA.

Adolescent↗
PubMed1998

Clinical and epidemiologic studies of familial hemophagocytic lymphohistiocytosis in Japan. Japan LCH Study Group.

BACKGROUND AND PROCEDURE: The etiology of familial hemophagocytic lymphohistiocytosis (FHL), which is characterized by fever, hepatosplenomegaly, pancytopenia, and coagulopathy, remains unknown. We analyzed 43 FHL patients, all with affected siblings, in 18 families who were identified during the period 1986-1995 in Japan. RESULTS: The presence of consanguinity was evident in two families (11%). The majority of families lived in western Japan, where the frequency of consanguineous marriage is high. The incidence of FHL was significantly higher in the western island, Kyushu, than in other areas. The segregation ratio calculated for these families was 0.35 by the Weinberg proband method, showing the autosomal-recessive inheritance of the disease. Since the diagnosis of an FHL patient without affected siblings (sporadic case) is quite difficult, we calculated the possible number of sporadic cases; approximately 122 patients could be identified as sporadic FHL cases during the same period in Japan. Most of the clinical and laboratory findings were not distinguishable from those of other types of lymphohistiocytosis. However, atypical lymphoid cells with azurophilic granules in peripheral blood were observed in half of the patients at diagnosis, suggesting the clinical importance of this parameter for early diagnosis. Despite intensive therapy, the prognosis of FHL was extremely poor; but 4 of the 8 patients who have survived had received bone marrow transplantation (BMT), indicating the effectiveness of BMT for this disorder. CONCLUSIONS: The distribution of FHL in areas of highly frequent consanguineous marriage and the segregation analysis indicated a genetic factor in FHL. The identification of the genes for FHL is expected to contribute to a cure for this disorder, and might also enable FHL carrier detection and donor selection for BMT.

Adolescent↗
PubMed1998

Biomarker and morphological characteristics of Epstein-Barr virus-related hemophagocytic lymphohistiocytosis.

BACKGROUND: Viruses may induce primary as well as secondary hemophagocytic lymphohistiocytosis (HLH), but it may not be possible to discriminate between these two in patients with a negative family history. Among these HLH cases, fulminant and fatal virus-associated hemophagocytic syndrome (VAHS) occurs mostly in relation to Epstein-Barr virus (EBV) infection. Although the immunological characteristics of EB-VAHS were previously reported, data on non-EB-VAHS were sporadic and fragmentary. This study has compared the clearly distinguishable groups of EBV-positive vs. EBV-negative HLH cases. PROCEDURE: Among 26 patients with EBV-related HLH and 12 patients with non-EBV HLH, peripheral blood mononuclear cell (PBMC) subsets and serum concentrations of cytokines at the active phase of the disease were compared. Blood and bone marrow smears were also compared. RESULTS AND CONCLUSIONS: The frequency of the CD3+HLADR+ subset in PBMC (median 34.3% vs. 4.8%), of serum concentrations of interferon (IFN)-gamma (median 105 U/ml vs. 2.4 U/ml), and of soluble interleukin-2-receptor (sIL-2R) (median 14,700 U/ml vs. 3,412 U/ml) were significantly different between these two groups. Morphological characteristics were noted for EBV-related HLH cases. Mortality also differed between these two groups, 9/26 vs. 0/12 (P = 0.05). Data indicate pronounced immunological imbalance and poor prognosis in EBV-related HLH cases. These parameters could be useful for determining an EBV involvement as well as risk factors in the early care and treatment of HLH patients.

Adolescent↗
PubMed1998

Favorable response to lymphoblastoid interferon-alpha in children with chronic hepatitis C.

BACKGROUND/AIMS: We investigated the efficacy of interferon therapy for the treatment of children with chronic hepatitis C virus infection. METHODS: Twenty-four out of 26 children completed the 6-month treatment with lymphoblastoid interferon-alpha and were followed for 12 months or longer. Response to interferon therapy was defined by assaying for circulating HCV-RNA, using a nested PCR, at 6-month intervals after the end of the therapy. RESULTS: At the end of treatment circulating HCV-RNA was undetectable in 18/24 patients and at 6 months in 12/24. Ten of these 12 primary responders have remained virus free for more than 2 years. One patient remained negative at 12 months. The remaining patient relapsed at 12 months. At 24 months 10 of 18 patients tested negative for HCV-RNA. Serum alanine aminotransferase was normal in 11/24 patients at the end of treatment, at 6 months 12/24 were normal, and at 12 months 11/12 were normal. In eight children with sustained response, repeated liver biopsies revealed a reduction in Knodell's scores for inflammation in the hepatic lobules and in the portal areas. In three of them neither plus nor minus strand of HCV-RNA was detectable in the liver tissue. Responders had a significantly lower level of viremia than non-responders. Side effects of interferon including fever, hair loss, neutropenia, and thrombocytopenia were not serious enough to warrant cessation of interferon treatment. CONCLUSIONS: Interferon therapy in children with chronic hepatitis C may be beneficial as evaluated by sustained loss of viremia as well as by primary response.

Adolescent↗
PubMed1998

Cord blood transplantation from sibling donors in Japan. Report of the national survey.

A joint national survey on cord blood transplantation (CBT) was conducted in Japan and 18 sibling CBTs were reported. Diseases of the patients were leukemia (ten), neuroblastoma (one), bone marrow failure (four) and inborn errors of metabolism (three). A volume of 50-141 ml of cord blood containing 27-197 x 10(7) nucleated cells was collected from sibling infants soon after delivery. HLA antigens were identical in 14 and one to three antigens mismatched in four. Engraftment of donor cord blood was achieved in 17 cases. Autologous hematopoiesis was recovered in one case. Days of engraftment were 13-29 days (median 19 days) for neutrophils (500/microliter), 18-67 days (median 30 days) for reticulocytes (2%) and 21-96 days (median 46 days) for platelets (50 x 10(3)/microliter). Acute GVHD was grade 0 in seven cases, grade I in five cases and grade II in one case in HLA-identical pairs, but became grade II in two cases and grade III in two cases in HLA-mismatched pairs. Chronic GVHD of limited type developed in two out of 17 evaluable cases, however both responded to immunosuppressive therapy. Altogether, 14 out of 18 patients are currently surviving 4-27 months following transplantation. Probabilities of overall survival and disease free survival were estimated to be 77.0 and 71.8% using Kaplan-Meier tests. These findings suggest the feasibility of cord blood transplantation from sibling donors and the possibility of unrelated cord blood transplantation. A cord blood banking system is necessary for the universal use of cord blood stem cells from unrelated donors.

Anemia, Aplastic↗
PubMed1998

Successful engraftment of unrelated cord blood stem cells for familial erythrophagocytic lymphohistiocytosis. Kinki Cord Blood Bank.

Familial erythrophagocytic lymphohistiocytosis (FEL) is an autosomal recessive disorder that can only be corrected by stem cell transplantation. One of our patients with FEL in second complete remission underwent successful cord blood stem cell transplantation (CBSCT); the donor was an HLA one-locus mismatched and unrelated individual. The conditioning regimen consisted of BU/CY/VP-16. The transfused cell dose was 6.8 x 10(7)/kg, which contained 1.36 x 10(5)/kg of CD34 cells and 3.4 x 10(4)/kg of CFU-GM. After CBSCT, there were no major infectious complications. Acute grade I GVHD was well controlled. Neutrophil counts reached >0.5 x 10(9)/l by day 20 and platelet counts reached >50 x 10(9)/l by day 40. Deficient natural killer activity returned to normal after the transplant. The patient recovered well more than 7 months after receiving CBSCT, without showing evidence of chronic GVHD. We recommend CBSCT for FEL patients who have no HLA-matched siblings or unrelated donors.

Child, Preschool↗
PubMed1998

Induction of long-term remission in advanced hepatocellular carcinoma with percutaneous isolated liver chemoperfusion.

OBJECTIVE: The aim of this study was to report the long-term results of percutaneous isolated liver chemoperfusion with hepatic venous isolation and charcoal hemoperfusion (HVI-CHP) in patients with multiple advanced hepatocellular carcinoma (HCC). SUMMARY BACKGROUND DATA: The results of conventional chemotherapy including regional and systemic chemotherapy in patients with HCC remain dismal, and long-term survivors after treatment are rare among patients with multiple advanced HCC. In an effort to improve this situation, we previously developed a novel system of percutaneous isolated liver chemoperfusion with HVI-CHP. METHODS: Doxorubicin (60 to 150 mg/m2) was administered via the hepatic artery, under conditions of extracorporeal drug elimination by HVI-CHP in 28 consecutive patients with advanced HCC (39 total treatments). Hepatic venous isolation and charcoal hemoperfusion was accomplished mainly by the single catheter technique using a newly developed 4-lumen-balloon catheter, which was used to isolate and capture total hepatic venous outflow and, at the same time, to direct the filtered blood to the right atrium. RESULTS: Complete remission was achieved in five patients, of which four received repeated treatments (two or three times). Although 1 of 5 patients with complete remission died of pulmonary metastases at 8 months, the other 4 remain healthy and free of disease at 20, 24, 27, and 42 months after the first treatment. Partial responses were observed in 12 patients. Duration of response in responders (complete and partial) with repeated treatments was significantly longer than that with a single treatment (p = 0.01). The overall survival rate by the Kaplan-Meier method was 39.7% at 5 years. The treatments were well-tolerated, and the primary side effects were mild to moderate chemical hepatitis and reversible myelosuppression. CONCLUSIONS: The results suggest that percutaneous isolated liver chemoperfusion with HVI-CHP is an effective palliative treatment in the majority of patients and yields long-term complete remission in some patients with multiple advanced HCC.

Adult↗
PubMed1998

Syntheses of taxuspine C derivatives as functional inhibitors of P-glycoprotein, an ATP-associated cell-membrane transporter.

UV-Irradiation of taxinine and related compounds in acetonitrile induced a smooth transannulation between the C-3 and C-11 positions without any influence from the C-2, C-9 and C-10 substituents to give tetracyclic taxuspine C derivatives in almost quantitative yields. Photochemical transannular reaction of taxoids possessing a cinnamoyl group in the side-chain was accompanied by an E,Z-isomerization of the cinnamoyl moiety. Cellular accumulation of vincristine, a useful drug for cancer chemotherapy, in multidrug-resistant ovarian cancer cells was found to increase most effectively in the case of 5-O-benzoylated 5-O-decinnamoyltaxuspine C. This indicates that the 5-O-benzoylated taxuspine C derivative may be a promising functional inhibitor of P-glycoprotein, which acts as an ATP-associated efflux pump for cancer chemotherapeutic agents.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1998

Carboxyflavins, novel inhibitors of Taq DNA polymerase.

Carboxyflavins were found to be potent selective inhibitors of Taq DNA polymerase in a polymerase chain reaction. The inhibitions were dose-dependent, and complete inhibitions were observed at the concentration of 3.0 microM. Carboxyflavins were much less, or not sensitive to the DNA polymerases tested such as calf thymus DNA polymerase alpha, rat DNA polymerase beta, human immunodeficiency virus type 1 reverse transcriptase, the Klenow Fragment of E. coli DNA polymerase I and T4 DNA polymerase. To our knowledge, there is no other report of an agent that selectively inhibits only a thermophilic polymerase. Interestingly, the carboxyflavins were able to prevent DNA synthesis in the murine lymphoid leukemia cell line L1210 in vitro; almost complete inhibitory levels were achieved in the range of less than 10 microM.

Animals↗
PubMed1998

[Basic study of MR-dacryocystography].

We developed MR-dacryocystography as a non-invasive, safer imaging technique for canaliculi, the nasolacrimal duct and lacrimal sac by dropping saline solution and diluted Gd-DTPA solution into the eye. The diluted Gd-DTPA solution was found to create no local irritation in the eyes of rabbits and normal volunteers. Lacrimal sacs and ducts were well visualized in all of 10 normal volunteers by using the saline solution or the diluted Gd-DTPA solution. Canaliculi were visualized in 4-7 cases on thin-slice axial images. MR-dacryocystography was suggested to be a useful screening examination for lacrimal outflow disorders.

Adult↗