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Biomedical subjects

R Nakagawa

Publications and source records attributed to R Nakagawa.

At least 37 records · Page 2Linked to original sources
PubMed2000

HLA-mismatched CD34-selected stem cell transplant complicated by HHV-6 reactivation in the central nervous system.

We report here a patient who suffered from PCR- confirmed human herpesvirus type 6 (HHV-6) meningoencephalitis after allogeneic purified CD34+ cell transplantation from his HLA-mismatched sibling donor, even though he had been on intense prophylaxis with i.v. ganciclovir (GCV), acyclovir (ACV) and gamma-globulin containing a specific antibody against HHV-6. Serological evaluation disclosed that both the donor and recipient had IgG antibody against HHV-6 before transplantation. His blood WBC count started to transiently increase on day 10, and all blood components had decreased by day 20. He then developed a severe headache and high blood pressure, and sporadic abnormal neurological findings including nystagmus and delirium. An analysis of cerebrospinal fluid (CSF) revealed 8 cells/microl, a glucose level of 130 mg/dl and a protein level of 201 mg/dl (normal, 50 mg/dl) on day 26. At the time, HHV-6 was detected only in CSF by a PCR-based method and he was diagnosed as having meningoencephalitis due to the local reactivation of HHV-6. Although he failed to respond to high-dose therapy with ACV (60 mg/kg/day) and gamma-globulin, the DNA of this virus disappeared from the CNS upon treatment with GCV (30 mg/kg/day) combined with the intraventricular infusion of alpha-interferon. His clinical course was further complicated with meningoencephalitis due to staphylococcus epidermidis, and he died of tentorial herniation on day 79 without the recovery of blood components. This experience may indicate that intense prophylaxis to prevent reactivation of HHV-6 in the CNS is essential for the management of such profoundly immunosuppressed patients.

Acyclovir↗
PubMed2000

Decrease of CD56(+)T cells and natural killer cells in cirrhotic livers with hepatitis C may be involved in their susceptibility to hepatocellular carcinoma.

CD56(+)T cells and CD56(+)natural killer (NK) cells are abundant in the human liver. The aim of this study was the further characterization of these cells in the liver with or without hepatitis C virus (HCV) infection. Liver mononuclear cells (MNC) were isolated from liver specimens obtained from the patients during abdominal surgery. In addition to a flow cytometric analysis, liver MNC and PBMC were cultured with the immobilized anti-CD3 Ab, IL-2, or a combination of IL-2 and IL-12 and their IFN-gamma production and the antitumor cytotoxicity were assessed. The liver MNC of HCV (-) patients contained 20% CD56(+)T cells whereas the same proportions decreased to 11% in chronic hepatitis livers and to 5% in cirrhotic livers. The proportion of NK cells also decreased in the cirrhotic livers. On the other hand, the populations of these cells in PBMC did not significantly differ among patient groups. The IFN-gamma production and the cytotoxicity against K562 cells, Raji cells, and a hepatocellular carcinoma, HuH-7 cells, greatly decreased in the cirrhotic liver MNC. In contrast, the cytotoxicity in PBMC did not significantly differ among the patient groups and was lower than that in the liver MNC of HCV (-) patients. CD56(+)T cells and NK cells but not regular T cells purified from liver MNC cultured with cytokines showed potent cytotoxicities against HuH-7 cells. These results suggest that a decreased number of CD56(+)T cells and NK cells in cirrhotic livers may be related to their susceptibility to hepatocellular carcinoma.

Aged↗
PubMed2000

Inhibition of DNA topoisomerases by nidulalin A derivatives.

Three cytotoxic dihydroxanthone derivatives, nidulalin A(1), F390B(2), and F390C(3) were evaluated for inhibitory activity against DNA topoisomerases. Compounds 1 and 2 inhibited DNA topoisomerase II with IC50 values of 2.2 microM and 16 microM, and 3 inhibited DNA topoisomerase I with an IC50 value of 5.9 microM.

Enzyme Inhibitors↗
PubMed2000

Cloning and sequence analysis of cDNA coding for a lectin from Helianthus tuberosus callus and its jasmonate-induced expression.

Two lectins (designated as HTA I and HTA II) that seemed to be isolectins were found in Helianthus tuberosus callus. cDNA encoding HTA I was isolated from a ZAP Express expression library by immunoselection by using the anti-HTA antiserum. The sequence of this cDNA consisted of 432 bp nucleotides coding for a polypeptide of 143 amino acid residues (Mr, 15,314). When introduced into E. coli, the cDNA directed the synthesis of active HTA I as indicated by the hemagglutination activity. The deduced amino acid sequence showed homology with some lectins and jasmonate-induced proteins. When callus was cultured in the presence of methyl jasmonate (MeJA), the hemagglutination activity increased in a dose-dependent manner. The levels of expression of the HTA protein and of the corresponding mRNA also increased in the treated callus. In view of these results, HTA I is considered to be a jasmonate-induced protein.

Acetates↗
PubMed2000

Low numbers of megakaryocyte progenitors in grafts of cord blood cells may result in delayed platelet recovery after cord blood cell transplant.

Delayed platelet recovery is an inherent problem with cord blood cell transplantation (CBCT). To investigate this problem, the number of human megakaryocyte (MK) progenitor cells in cord blood (CB; n = 24) was measured and compared with that in G-CSF-mobilized peripheral blood stem cells (PBSC; n = 25). The median numbers of colony-forming units for MK (CFU-MK) that were detected by a serum-free assay system in CB and peripheral blood (PB) were 26 (range, 6-102)/10(5) nucleated cells (NC) and 37 (2-540)/10(5) mononuclear cells (MNC), respectively. The numbers of colony-forming units for granulocyte/macrophage (CFU-GM) were 88 (33-241)/10(5) NC in CB and 138 (6.3-1,250)/10(5) MNC in PB. The frequencies of CD34(+) cells in CB and PB were, respectively, 0.44% (0.10-1.07) and 0.98% (0.05-20.8). The numbers of CFU-MK in CB and PBSC were correlated with those of CD34(+) cells. The estimated number of infused CFU-MK in CBCT was 1/15 that of PBSC transplantation (PBSCT), based upon the above data and the widely used standard doses for both types of transplants. Further, the numbers of infused CFU-MK in patients who received allogeneic PBSCT at our institute were inversely correlated with the speed of platelet recovery. These data indicate that delayed platelet recovery after CBCT is simply due to the low number of CFU-MK contained in grafts.

Adolescent↗
PubMed2000

Antitumor activity of alpha-galactosylceramide, KRN7000, in mice with the melanoma B16 hepatic metastasis and immunohistological study of tumor infiltrating cells.

Liver metastasis of primary tumors is clinically a major problem. We examined the antitumor activity of KRN7000, an alpha-galactosylceramide, in mice with liver metastasis of the B16 melanoma. KRN7000 significantly inhibited tumor growth in the liver, and its potency was similar to that of interleukin-12. The KRN7000 administration resulted in a high percentage of cured mice, which acquired tumor-specific immunity. To study what kinds of antitumor effector cells participated in killing tumor cells, we then performed immunohistological analysis of tumor-infiltrating cells, and found that KRN7000 induced marked invasion of NK1.1+ cells, CD8+ cells, and F4/80+ cells (macrophages) into B16 tumor nodules. In addition, it appeared that KRN7000-treated, liver-associated macrophages possessed strong lytic activity against tumor cells. These results suggest that NK cells, NK1.1+ T (NKT) cells, cytotoxic T lymphocytes, and macrophages play an important role in killing tumor cells in the liver, and that KRN7000 may be useful for the treatment of cancer liver metastasis.

Animals↗
PubMed1999

Efficacy of the mobilization of peripheral blood stem cells by granulocyte colony-stimulating factor in pediatric donors.

The advantages/disadvantages of the use of peripheral blood stem cells (PBSCs) for allogeneic transplantation still need to be clarified, particularly in children. We compared the kinetics, efficacy, and safety of PBSC mobilization by granulocyte colony-stimulating factor (G-CSF) and collection by apheresis between healthy pediatric and adult donors. A total of 19 pediatric (median age, 6 years) and 25 adult healthy donors (median age, 37 years) were given 10 micro/kg/day of G-CSF for 5 consecutive days for PBSC mobilization, which were harvested by apheresis on days 5 and/or 6. All of the donors tolerated the whole procedures. Serum trough levels of G-CSF determined by ELISA were significantly lower in the 16 pediatric donors evaluated than in adults (n = 16) on days 3 and 4 (P < 0.05). Although the WBC counts on days 4 and 5 were significantly higher in adults than in children (P = 0.006 and 0.004, respectively), the numbers of circulating CD34+ cells/unit of blood were identical. The number of blood CD34+ cells collected per unit of blood processed was identical in both donor populations. We propose that PBSCs could be effectively mobilized and collected in small children so that they could be donors for adult patients.

Adolescent↗
PubMed1999

Endogenous interleukin-8 (IL-8) surge in granulocyte colony-stimulating factor-induced peripheral blood stem cell mobilization.

The relationship between stem cell mobilization with granulocyte colony-stimulating factor (G-CSF) and the endogenous production of interleukin-8 (IL-8), macrophage inflammatory protein-1alpha (MIP-1alpha), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) was studied in normal donors for allogeneic peripheral blood stem cell (PBSC) transplantation. G-CSF was administered to 20 normal donors at a dose of 10 microg/kg/d for 5 days with aphereses on days 5 and 6 of G-CSF treatment. Cytokine serum levels were measured using an enzyme-linked immunosorbent assay (ELISA) before and during G-CSF treatment. Before treatment, the average level of IL-8 was 7.1 pg/mL, increasing to 207.0 pg/mL on day 5 and 189.1 pg/mL on day 6. Serum IL-8 levels correlated CD34(+) cell numbers (P =.0151 and P =.0005 on days 5 and 6, respectively) and colony-forming unit-granulocyte-macrophage (CFU-GM) numbers (P =.0019 and P =.0010 on days 5 and 6, respectively). Furthermore, preapheresis serum IL-8 levels correlated with the yield of CD34(+) cells (P =.0027). In contrast, before treatment, the average levels of MIP-1alpha, TNF-alpha, and IFN-gamma were 70.1, 4.03, and 3.84 pg/mL, respectively, and no significant changes in the levels of these cytokines were observed during G-CSF treatment. These studies suggest that IL-8 production may be critical to G-CSF-induced stem cell mobilization, although the underlying mechanism could not be clarified.

Adolescent↗
PubMed1999

Prevalence of specific allergic diseases in school children as related to parental atopy.

BACKGROUND: Our objective was to investigate the influence of parental allergy on the manifestations and course of allergic disease in children. METHODS AND RESULTS: A total of 15,234 school children aged 6 and 9 years were evaluated by means of questionnaires completed by their parents in a cross-sectional survey conducted in Tokushima, Japan. The prevalence and relative risk ratio (RRR) for parental allergy in children with atopic dermatitis, asthma and allergic rhinitis were 6.4% (RRR 2.5), 3.2% (RRR 2.4) and 15% (RRR 2.4), respectively. The risk of atopic dermatitis was particularly high in children whose parent had atopic dermatitis, with an RRR of 2.8 (father) and 3.7 (mother). Children with a parental history of asthma also had a high risk of that disorder (RRR of father 5.3, mother 6.2). However, the risk of allergic rhinitis was no different in children with a parental history of allergic rhinitis or from children with a parental history of asthma and atopic dermatitis. A history of allergic disease in both parents, especially of asthma and atopic dermatitis, increased the risk of allergic disease in the child. Milder symptoms, such as wheezy bronchitis, in schoolchildren were similarly related with the same hereditary tendency as the identical allergic disease. The disappearance of allergic symptoms with age also related to a hereditary component, being less likely in children with a history of parental allergy than in those without such an atopic history. CONCLUSIONS: The manifestations and course of allergic disease in school children relate to parental allergic disease.

Asthma↗
PubMed1999

Comparative evaluation of procedures with a Baxter CS-3000 cell separator for collecting peripheral blood cells from children.

The safety and efficacy of apheresis using a newly developed procedure with a small volume separation container holder (SVSCH, Baxter) for the collection of PBSC from children with cancer were retrospectively compared with our historical experience with other procedures using different equipment and the CS-3000 plus cell separator. The procedures tested included the application of (a) specialized collection protocol 4 using the combination of an SVSCH and a small volume collection chamber (SVCC) (group A: 6 collections in 4 patients), (b) standard lymphocyte collection protocol 3 with GRANULO separation (G) and A-35 collection chambers (group B: 9 collections in 5 patients), and (c) modified collection procedure 1-120 with G and SVCC (group C: 7 collections in 3 patients). Although the retrospective nature of this study and the differences in the cohorts tested prevent a reliable analysis, the percent decrease in the peripheral platelet count after collection tended to be minimum in group A (11% +/- 5% versus 23% +/- 4% [B] or 17% +/- 4% [C]). Moreover, the largest number of CD34+ cells was collected in group A (8.7 +/- 9.4 x 10(5)/100 ml processed blood) compared with groups B (5.5 +/- 7.5 x 10(5)/100 ml processed blood) and C (4.0 +/- 2.8 x 10(5)/100 ml processed blood). These data suggest that a procedure incorporating SVSCH can be safely and effectively applied to small children and enables the selective collection of PBSC with less contamination by platelets, which is useful for subsequent cell processing.

Adolescent↗
PubMed1999

A novel combretastatin A-4 derivative, AC-7700, shows marked antitumor activity against advanced solid tumors and orthotopically transplanted tumors.

AC-7700, a novel combretastatin A-4 derivative, suppresses the growth of solid tumors by inhibiting tumor perfusion. We evaluated the antitumor activity of AC-7700 on solid tumors in two experimental models, an advanced tumor model (murine colon 26 (c26) adenocarcinoma, colon 38 (c38) adenocarcinoma, MethA fibrosarcoma, Sarcoma 180 (S180), Lewis lung carcinoma (3LL), human LS180 adenocarcinoma) and an orthotopically transplanted tumor model (c26), compared with that of cisplatin (CDDP). The maximum tolerable dose (MTD) of CDDP suppressed early-stage c26 and c38 tumor growth when treatment was started after the tumor volume (TV) reached 0.2-0.5 cm3, but it showed reduced activity against the same tumors at an advanced growth stage when TV exceeded 2 cm3. At its MTD, AC-7700 was active against all tumors tested except 3LL in both early and advanced growth stages, reducing the tumor mass and having a curative effect in advanced c38 tumors. AC-7700 was also effective on orthotopically transplanted c26 tumors, showing a comparable activity to that on subcutaneous tumors. Unlike flavon acetic acid, which damages tumor vasculature by inducing endogenous tumor necrosis factor-alpha production, AC-7700 potently suppressed the growth of advanced c26 tumors in athymic as well as euthymic mice. These results suggest that AC-7700 is a novel antivascular agent that may have potent activity against advanced-stage cancer in the clinical setting.

Animals↗
PubMed1999

[Blood PCB analysis by capillary column-gas chromatograph/quadruple mass spectrometer--comparison with packed column-electron capture detector/gas chromatograph].

The contents of polychlorinated biphenyls (PCBs) in the blood of Yusho patients (Y) and normal subjects (N) were analyzed, using a gas-chromatograph equipped with a capillary column/quadruple mass spectrometer (capillary column GC/MS). While the average of the content of blood PCBs was 679 ppt in N, those were 2960, 1480 and 1090 ppt in Y diagnosed previously as A, B and C patterns, respectively. The contents of non-ortho coplanar PCBs (3,3',4,4' Tetra-, 3,3',4,4',5-Penta- plus 3,3',4,4',5,5'-Hexa-CB) were 0.9-2.1 ppt in Y, and 0.8 ppt in N. The contents of eight mono-ortho coplanar PCBs having the toxic equivalency factors (TEFs) were 118-424 (Y) and 78 ppt (N), respectively. The differences between Y and N in the species of mono-ortho coplanar PCBs contained were observed as follows: 2,3,3',4,4',5- and 2,3,3',4,4',5'-Hexa-CB were predominant in Y, whereas 2,3,4,4',5-Penta-CB was a major congener in N. The levels of di-ortho coplanar PCBs (2,2',3,4,4',5,5' plus 2,2',3,3',4,4'5-Hepta-CB) were determined to be 195-608 and 98 ppt in Y and N, respectively. In both groups, the content of the former isomer was greater than the latter. Total TEQ values were 0.214-1.226 ppt in Y, and 0.148 ppt in N. The analyses were also performed by a conventional method in which a GC equipped with a packed column/electron capture detector (packed column GC/ECD) was used, and the results obtained were compared with those by capillary column GC/MS method. The results showed that the total PCB levels obtained by capillary column GC/MS method were 56-61% in Y and 67% in N of those obtained by packed column GC/ECD method.

Adult↗
PubMed1999

Surgical management of infants with mitral valve stenosis or atresia without diminutive ascending aorta.

The surgical strategy in infants with mitral valve stenosis or atresia without diminutive ascending aorta remains to be established, including the potential for biventricular repair as a definitive operation. Our surgical experience of six infants with mitral valve stenosis (4 patients) or atresia (2 patients) without diminutive ascending aorta was evaluated based on three important factors: left ventricular volume; the nature of the systemic outflow obstruction; and the type of mitral valve anomaly. Two patients with systemic outflow tract diameter less than 65% of normal underwent systemic outflow tract reconstruction, and the other patients with outflow tract diameter more than 68% of normal were able to maintain systemic circulation without repair. Only one patient with mitral valve stenosis without left ventricular outflow tract obstruction underwent a successful open mitral valvotomy as a biventricular repair after first-stage palliation. The left ventricle of the other patients did not grow after first-stage palliation. Due to progressive subaortic narrowing, pulmonary artery banding should be avoided in patients with mitral atresia due to absent atrioventricular connection who are future Fontan candidates. Most patients with this lesion can be expected to become candidates for safe Fontan-type repair.

Aorta↗
PubMed1999

Synthesis and antitumor activities of amino acid prodrugs of amino-combretastatins.

The synthesis and antitumor activity of water-soluble amino acid prodrugs of amino-combretastatins were reported. Among the synthesized compounds, 7e (CS-39-L-Ser HCI, AC-7700) showed enhanced antitumor activity and decreased toxicity in a Colon 26 murine adenocarcinoma model. Compound 7e showed improved solubility and was easily formulated for in vivo administration. Compound 7e was cleaved to generate the parent compound, CS-39, in the whole blood of mice as well as man, possibly by the action of amino peptidase on the erythrocyte membrane.

Animals↗
PubMed1998

Novel B-ring modified combretastatin analogues: syntheses and antineoplastic activity.

A series of B-ring modified combretastatin analogues were synthesized and their inhibitory activity against microtubule assembly, cytotoxic activity against Colon 26 adenocarcinoma cancer cell line were evaluated. Among these, pyridone derivative (19) showed strong antimitotic activity and cytotoxicity, along with excellent water-solubility.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Syntheses and antitumor activity of cis-restricted combretastatins: 5-membered heterocyclic analogues.

A series of cis-restricted combretastatin analogues with 5-membered heterocycles were synthesized and their inhibitory activity against microtubule assembly and cytotoxic activity against the colon 26 adenocarcinoma cancer cell line were evaluated. Some of the heterocyclic analogues showed potent antitubulin activity and cytotoxicity. Compounds 16 and 35 showed marked tumor growth suppression in the colon 26 murine tumor model.

Animals↗
PubMed1998

Selection of DNA binding sites for human transcriptional regulator GATA-6.

The DNA-binding sites for transcriptional regulator GATA-6 were selected and amplified by means of a PCR-mediated random-site selection method involving filter binding and gel-mobility shift analysis using the zinc finger region of human GATA-6 fused with GST. Sequencing and comparison of the selected clones suggested that (A/T/C)GAT(A/T)(A) is the consensus binding sequence, which is similar to the GATA motif (A/T)GATA(A/G) and the gastric motif (G/C)PuPu(G/C)NGAT(A/T)PuPy. GATA-6 also binds to a similar sequence containing the GATC but not the GATG sequence. These results indicated that GATA-6 shows broader sequence specificity as to DNA binding. However, adenine is favored on both sides of the core for strong binding [AGAT(A/T)A], and the order of binding is GATA > GATT > GATC. Full-length human GATA-6 expressed in COS-1 cells showed essentially the same binding specificity, suggesting that the zinc finger region of GATA-6 mainly contributes to the selection of the binding sequence. Furthermore, the non-RI method presented in this paper is convenient for determination of the binding sites of other DNA-binding proteins.

Binding Sites↗