Biomedical subjects
Publications and source records attributed to Y Takamatsu.
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A single intraperitoneal administration of methamphetamine (MAP) reduces cholecystokininlike immunoreactivity (CCK-LI) in medial prefrontal cortex (mPFC) of the rat brain. This report examines the effects of various dopamine (DA) receptor antagonists [haloperidol (HAL), sulpiride (SUL), YM09151-2 (YM), and SCH23390 (SCH)] on MAP-induced abnormal behaviors and the changes of CCK-LI in the rat mPFC. A single subcutaneous administration of HAL (0.25 mg/kg), YM (0.1 mg/kg), or SUL (250 mg/kg) significantly reduced the basal CCK-LI in mPFC by 20-40%; a selective D1 antagonist, SCH (up to 1.0 mg/kg), had no effect on basal CCK-LI. However, the reduction of CCK-LI induced by MAP (20-40%) was abolished by the pretreatment with HAL (0.025 and 0.25 mg/kg), YM (0.01 and 0.1 mg/kg), or SCH (1.0 mg/kg), without being affected by SUL (up to 250 mg/kg). This effect of DA antagonists on MAP-induced change in CCK-LI was associated with an inhibition of MAP-induced stereotyped behaviors. These data suggest that the CCK-containing neurons in rat mPFC are functionally related to the mesocortical DA system and may participate in a development of abnormal behaviors induced by MAP.
We conducted a clinical trial to increase the chemosensitivity of residual leukemic cells by combining G-CSF to marrow-ablative chemotherapy, including cytosine arabinoside (Ara-C), and facilitated by autologous blood cell transplantation (ABCT) for treatment of acute myelogenous leukemia (AML) in first complete remission. A total of 16 patients were consecutively treated with granulocyte colony-stimulating factor (G-CSF)-combined high-dose chemotherapy (busulfan, etoposide and Ara-C) followed by autotransplantation of peripheral blood progenitor cells, which had been collected after the consolidation chemotherapy. At a median follow-up time of 44.5 months, the probability of 5-year event-free survival was 74.5% with only three leukemic relapses. This preliminary observation suggests the effectiveness of G-CSF-combined conditioning and ABCT as a post-remission therapy for AML.
The safety and efficacy of myeloablative therapy followed by autologous peripheral blood stem cell transplantation (ABSCT) for acute myelogenous leukemia (AML) were evaluated in 60 patients. Peripheral blood stem cells (PBSC) were collected during recovery after consolidation chemotherapy. High-dose chemotherapy consisting of busulfan (16 mg/kg), etoposide (40 mg/kg), and cytosine arabinoside (3 g/m2 x 4) (BEA regimen) was used for pretransplant conditioning in 13 patients. For the remaining 47 patients, granulocyte colony-stimulating factor (G-CSF) was administered concurrently with the BEA regimen during conditioning. Unpurged, cryopreserved PBSC containing a median number of 5.4 x 10(8) MNC/kg or 12 x 10(4) CFU-GM/kg were reinfused at transplantation. The median number of days to granulocytes exceeding 500/microl and last platelet transfusion were 15 (8-44) and 24 (0->180), respectively. The 3-year probabilities of disease-free survival (DFS) and relapse were 78.6 and 21.4% for patients transplanted in first remission, 29.6 and 64.4% for those in second or third remission, and 11.1 and 77.8% for those in relapse, respectively. There were no transplant-related deaths within 100 days of transplantation. Age, disease status at transplantation, and number of induction chemotherapies to first complete remission were risk factors affecting the outcome of ABSCT. These results of ABSCT for AML in first remission warrant a prospective study of ABSCT as post-remission therapy.
A 76-year-old woman presented with spiking fever and right back pain. Ultrasonography (US) revealed that her right kidney was enlarged. Computed tomography (CT) showed the parenchyma was replaced by non-enhancing masses but the overall kidney shape was maintained. These findings were compatible with those of xanthogranulomatous pyelonephritis (XP). The nonenhancing masses on CT coincided with the multiple butter yellow nodules of the resected kidney and microscopically these lesions were proved to be abscesses with xanthoma cells. In this case, the US and CT findings reflected the pathological feature of XP and thus these techniques are thought to be useful for the diagnosis of XP.
Peripheral blood stem and progenitor cells (PBSC and PBPC), which circulate at very low levels during steady-state hematopoiesis, show a transient but marked increase during hematologic recovery from marrow-suppressive chemotherapy. To ensure rapid and sustained hematologic engraftment after autologous PBSC transplantation, sufficient PBSC or PBPC must be infused. To confirm the utility of granulocyte colony-stimulating factor (G-CSF) in chemotherapy-induced PBSC mobilization, we investigated the effect of G-CSF on PBSC mobilization in leukemia and lymphoma patients. The study design was such that PBSC mobilization with and without G-CSF was assessed in the same patients. The results indicate that PBSC mobilization can be enhanced significantly when G-CSF is given during the recovery phase postchemotherapy. Interestingly, progenitor cells of different lineages could be mobilized by G-CSF. We subsequently investigated the effect of increasing G-CSF dose on PBSC mobilization during steady-state hematopoiesis in healthy adult donors. The results indicate that not only committed but also primitive progenitor cells are mobilized into the circulation in a dose-and time-dependent manner when G-CSF at 5, 10, or 15 micrograms/kg was given on each of 5 days and leukapheresis was performed on day 6. From our data we estimate that sufficient PBSC for engraftment after allogeneic PBSC transplantation can be collected on day 5 of administration of G-CSF at 10 micrograms/kg and by 10-1 leukapheresis on days 5 and 6. Furthermore, we found that some G-CSF-mobilized PBSC retained their self-renewal capability. These observations suggest that hematopoietic stem cells for allogeneic PBSC transplantation can be mobilized by short-term administration of relatively high-dose G-CSF.
A 52-year-old male patient with chronic neutrophilic leukemia (CNL) with dysplastic features is described. He had a 2-year history of anemia followed by marked leukocytosis up to 57.5 x 10(9)/l with 88% segmented neutrophils. Bone marrow aspiration and biopsy showed hypercellular marrow with myeloid hyperplasia and 16% myeloblasts. There were also significant morphological abnormalities which included neutrophils with few granules, hypersegmented nucleus or Pelger-Heut anomaly, and micromegakaryocytes. Cytogenetic analysis disclosed a deletion of the long arm of chromosome 7 (7q-). He was diagnosed as having CNL with dysplastic features and was treated conservatively. However, leukemic transformation to acute myelogenous leukemia occurred within a year and he died 16 months after diagnosis. Neutrophilia is a feature not of myelodysplastic syndromes (MDS) but rather of myeloproliferative disorders such as CNL. However, this patient was considered to have MDS with increased proliferation and differentiation of neutrophilic lineage, because of marked myelodysplasia and poor prognosis.
We investigated surface immunophenotypes of peripheral blood mononuclear cells (PBMC) collected by cytotoxic and cytotoxic/G-CSF mobilization of peripheral blood stem cells (PBSC) from 38 patients with haematological malignancies in complete remission who underwent consolidation chemotherapy. PBMC were collected by leucapheresis during the haematopoietic recovery phase after intensive chemotherapy. G-CSF was used for mobilization of PBSC in 19 cases. Surface immunophenotyping of frozen-thawed PBMC was performed by flow cytometry. Our findings showed that monocytes and T cells were the two major cell components of PBMC. There were very few B cells in PBMC. Expression of CD45RO and HLA-DR was elevated in lymphocytes, suggesting that T cells in PBMC were activated. The percentage of CD34 positive cells were significantly increased in PBMC collected by cytotoxic/G-CSF mobilization (group 1) compared with PBMC collected by cytotoxic mobilization (group 2). There were significantly higher percentages of CD14 and CD33 positive cells in group 1 than in group 2. The percentage of CD4 positive lymphocytes positive for HLA-DR was significantly higher in group 1 compared with group 2. These observations indicated that PBMC contained a large number of monocytes and activated T cells, especially in cytotoxic/G-CSF mobilization.
In the process of screening for squalene synthase inhibitors from microbial fermentation products we have isolated a novel compound, named schizostatin (Fig. 1), from the culture broth of the mushroom, Schizophyllum commune SANK 17785. Schizostatin inhibited rat liver microsomal squalene synthase dose dependently and the IC50 value was 0.84 microM. The inhibition was competitive with respect to farnesylpyrophosphate with a Ki value of 0.45 microM.
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Osseointegrated implant bridges (OIB) have shown excellent results in the majority of cases. Since 1983, 1,022 fixtures has been applied to 241 superstructures in Tokyo Dental College Hospital. The aim of present study was to examine their functioning survival rate during recent ten years. The functioning survival rate of the superstructure of OIB has been almost 100% in both maxilla and mandible. Although 13.0% of these fixtures had to be removed in maxillary complete cases, only 3.3% of fixtures were removed in other cases. In maxillary complete cases, the functioning survival rate of OIB fixtures gradually decreases from 91% to 74% (91%, less than 3 years; 84%, between 3 and 7 years; 74%, more than 7 years), but it remained at about 97% for all periods in other cases. Apparently, the functioning survival rate of OIB fixture is generally determined within the period of one year, so almost the same rate is maintained thereafter. It is suggested that if more fixture numbers in the superstructure were applied to maxillary complete cases, the functional survival rate might improve.
The effects of Bestatin (Ubenimex, UBX) on normal hematopoiesis were investigated using long-term bone marrow cultures (LTBMC) to determine whether it might enhance hematopoiesis over a long period, as well as induce the release of cytokines. LTBMC were inoculated with 0.1 or 1.0 microgram/ml of UBX at the onset of culture and was added at each weekly medium change. The cellularity and the content of the progenitors in nonadherent layer were examined each week for 5 weeks; those from the adherent layer were examined at week 5. The number of the nucleated mature cells and that of the myeloid progenitors from the nonadherent layer increased significantly (approximately two-fold) following treatment with UBX vs controls. The total number of colonies and the number of myeloid progenitors, but not that of erythroid progenitors, from the adherent layer increased significantly (about 1.5-fold) following treatment with 1.0 microgram/ml UBX. The level of interleukin-6 (IL-6) in the culture supernatants was significantly increased one day after the addition of 1.0 microgram/ml UBX. Findings indicate that UBX stimulated both the production of mature cells and myeloid progenitors on normal hematopoiesis in LTBMC. This was mediated by an indirect action via IL-6 production.
Although hematologic reconstitution is usually rapid after autologous blood stem cell transplantation (ABSCT), there is an occasional delay in platelet recovery. We studied the hematologic recovery of 27 adult patients with hematologic malignancies who received marrow-ablative chemotherapy and ABSCT to determine whether or not the numbers of infused mononuclear cells (MNC), colony-forming units granulocyte/macrophage (CFU-GM), and colony-forming units megakaryocyte (CFU-Mk) were related to the speed of platelet recovery after ABSCT. Peripheral blood stem cells were collected using chemotherapy-induced mobilization with or without cytokine therapy. While the number of MNC infused did not show a significant correlation with time to platelet recovery as well as granulocyte and reticulocyte recovery, the logarithmic number of CFU-GM-infused did (p < 0.01). We also found a significant correlation between the logarithmic number of CFU-Mk-infused and the time to platelet recovery (p < 0.01). These findings suggest that the number of CFU-GM-infused is a reliable indicator of hematopoietic recovery and that the number of CFU-Mk-infused is no more reliable than CFU-GM for predicting platelet recovery after ABSCT.
Glutathione S-transferases (GSTs) are important as drug metabolizing enzymes mainly in the detoxication process. To assess individual differences in susceptibility to different chemicals, it would be useful to know the activity of specific GST isozymes in individuals. In order to study individual variability, typical substrates specific for the three major classes of GSTs were used not only as substrates but also as inhibitors using 17 organ-donor livers. Out of 17, 4 livers were low in the mu-form isozyme, judging from the depressed GST activity for trans-4-phenyl-3-buten-2-one (tPBO), a mu-class substrate. The range of tPBO activity exhibited more than 20-fold variation, while less than 2-fold variation was observed in the activities for 1-chloro-2,4-dinitrobenzene (CDNB), a non-specific substrate for alpha-, mu-, and pi-class GSTs. In addition to the conventional approach to assessing individual variability, well known substrates for GSTs, cumene hydroperoxide (CHP, alpha-class), tPBO (mu) and ethacrynic acid (EA, pi) were used as inhibitors against CDNB-GSH conjugation. CHP inhibited the CDNB-GSH conjugation in mu-depressed livers more potently than in the non-depressed livers, probably because CHP is a specific inhibitor for alpha-class GST. Inhibition by CHP may therefore be used to detect livers which are low in mu-form. The inhibition by tPBO was found to be weak and the variability was small (CV of 9% in 17 livers). EA potently inhibited GST activity with its inhibition constant (Ki) 2,000-fold lower than that of CHP. The small individual variation in inhibition by EA (CV of 6%) supported that EA is a universal but potent inhibitor against major GSTs contained in human liver.
Four forms of the Drosophila Ca2+/calmodulin-dependent protein kinase II are generated from a single gene by alternative splicing (Ohsako et al. (1993) J. Biol. Chem. 268, 2052-2062). We identified a fifth form of the cDNA encoding the enzyme expressed in the ovary, unfertilized egg and early embryos by reverse transcription-polymerase chain reaction, which suggests that it is maternally derived. The fifth form was also generated from the gene by alternative splicing and was identical to the cDNA encoding the 530-amino-acid polypeptide, the longest of the four forms previously identified, except that it lacked exon 11. Three splicing derivatives which lost one amino acid from the 509- and 530-amino-acid polypeptides were also found in 4 to 10 h embryos.
A technique for the rapid detection of cytomegalovirus (CMV) antigen-positive blood leucocytes (CMV antigenaemia) was evaluated in 15 marrow transplant patients as a means of diagnosis and for monitoring CMV-associated disease. CMV antigenaemia was determined by direct immunoperoxidase staining of leucocytes with a peroxidase-labelled monoclonal antibody, HRP-C7, which binds an immediate-early antigen of human CMV. CMV antigenaemia occurred in 7/15 marrow transplant patients (47%) and was initially detected between 4 and 6 weeks after transplantation. CMV-associated diseases developed in 3/15 patients (20%). All patients with CMV-associated disease had a relatively large number of CMV antigen-positive leucocytes, exceeding 10 per 50,000 white blood cells (WBCs). In the remaining 12 patients, CMV antigen-positive leucocytes were less than 10 per 50,000 WBCs or were undetectable. CMV-associated disease did not develop in these patients during the period of monitoring. CMV antigen-positive leucocytes were detected more frequently in patients who developed acute graft-versus-host disease (GVHD) or haemorrhagic cystitis than in those without such complications. CMV antigens were detectable from 1 to 4 weeks before the onset of CMV-associated disease which allowed initiation of ganciclovir treatment at an early stage. The degree of CMV antigenaemia paralleled the clinical symptoms and signs, higher degrees of antigenaemia being associated with more significant disease. Thus, the detection of CMV antigen-positive blood leucocytes is useful for the diagnosis and monitoring of CMV-associated disease following bone marrow transplantation.
We analyzed the surface phenotype of CD34-positive (CD34+) cells in peripheral blood (PB) during the period of hematopoietic recovery following myelosuppressive chemotherapy. A significantly higher proportion of PB CD34+ cells coexpressed the CD13 and CD33 myeloid antigens (80.8%, 78.1%, respectively) than did BM CD34+ cells (45.8%, 37.8%, respectively) (both p < 0.01). In particular, the CD13 positivity of PB CD34+ cells harvested with granulocyte colony-stimulating factor (G-CSF) was significantly higher than that of those without G-CSF. Most of the PB CD34+ cells possessed the HLA-DR antigen, and less than 10% of the CD34+ cells coexpressed a mature cell antigen, such as CD14, GPA or Plt-1. The administration of G-CSF enhanced the appearance of significantly larger amounts of CD13+ 34+ and CD33+ 34+ cells (both p < 0.01). This G-CSF mobilization also resulted in an increased number of CD13- 34+ and CD33- 34+ cells and all types of colony-forming cells. On the other hand, macrophage colony-stimulating factor administration exerted little influence on the mobilization of PB CD34+ cells. Thus, G-CSF seemed to induce not only an expansion of circulating hematopoietic stem cells but also the myeloid differentiation of stem cells.
We describe a patient with acute myelogenous leukemia (AML) who received his second autologous blood stem cell transplantation (ABSCT) following a G-CSF-combined pre-transplant conditioning regimen. The patient underwent ABSCT during first remission but suffered a relapse 8 months later. After achieving second remission, he was prepared for his second ABSCT; recombinant human granulocyte colony-stimulating factor (rhG-CSF) was administered in combination with Ara C, in addition to the same conditioning regimen as that used before the first ABSCT. There was no increase in regimen-related toxicity after this second G-CSF-combined conditioning regimen when compared with that observed after the first ABSCT. To date, the patient's second remission following the second ABSCT has lasted 26 months, which has exceeded that following the first ABSCT. The G-CSF-combined pretransplant conditioning regimen for ABSCT may be effective in the treatment of high-risk AML by increasing the chemosensitivity of the residual leukemic cells.