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Biomedical subjects

K Furusho

Publications and source records attributed to K Furusho.

At least 55 records · Page 3Linked to original sources
PubMed1997

A case of Robinow syndrome accompanied by partial growth hormone insufficiency treated with growth hormone.

We report on a 10-year-old Japanese girl with Robinow syndrome accompanied by partial growth hormone (GH) insufficiency. We started GH replacement therapy at the chronological age of 6.5 years. In this case, improvement in the growth velocity was remarkable, but bone maturation accelerated even more. In order to avoid further acceleration of bone maturation, we started to treat our patient at the chronological age of 9.8 years with GH combined with gonadal suppression therapy using a luteinizing hormone releasing hormone analogue. However, no improvement in height SDS for bone age was attained. Our observations suggest that the indication of GH therapy for patients with Robinow syndrome needs careful consideration.

Body Height↗
PubMed1996

RANTES and macrophage inflammatory protein 1 alpha selectively enhance immunoglobulin (IgE) and IgG4 production by human B cells.

We studied the effects of various chemokines including neutrophil-activating peptide 2 (NAP-2), beta-thromboglobulin (beta-TG), platelet factor 4 (PF-4), melanoma growth stimulating activity (GRO), gamma interferon-induced protein (IP-10), regulated on activation, normal T expressed and secreted (RANTES), macrophage inflammatory protein 1 alpha (MIP-1 alpha), MIP-1 beta, and monocyte chemotactic protein 1 (MCP-1) on Immunoglobulin (IgE) and IgG4 production by human B cells. None of these chemokines with or without interleukin (IL-4), anti-CD40 or -CD58 monoclonal antibody (mAb), induced IgE and IgG4 production by B cells from nonatopic donors. However, RANTES and MIP-1 alpha selectively enhanced IgE and IgG4 production induced by IL-4 plus anti-CD40 or -CD58 mAb without affecting production of IgM, IgG1, IgG2, IgG3, IgA1, or IgA2, whereas other chemokines failed to do so. Enhancement of IgE and IgG4 production by RANTES and MIP-1 alpha was specifically blocked by anti-RANTES mAb and anti-MIP-1 alpha antibody (Ab), respectively, whereas anti-IL-5 mAb, anti-IL-6 mAb, anti-IL-10 Ab, anti-IL-13 Ab, and anti-tumor necrosis factor-alpha mAb failed to do so. Purified surface IgE positive (slgE4) and slgG4+ B cells generated either in vitro or in vivo spontaneously produced IgE and IgG4, respectively, whereas sIgE- and sIgG4- B cells failed to do so. RANTES and MIP-1 alpha enhanced spontaneous IgE and IgG4 production in slgE+ and slgG4- B cells, respectively, whereas neither RANTES nor MIP-1 alpha did so in sIgE- or sIgG4- B cells. Purified sIgE4+ and sIgG4+, but not sIgE- or sIgG4- B cells, generated in vitro and in vivo expressed receptors for RANTES and MIP-1 alpha, whereas they failed to express receptors for other chemokines. These findings indicate that RANTES and MIP-1 alpha enhance IgE and IgG4 production by directly stimulating sIgE+ and sIgG4+ B cells.

Antibody Formation↗
PubMed1996

Normal mutation frequencies of somatic cells in patients receiving growth hormone therapy.

The number of reported cases of malignancy developing in growth hormone (GH) users worldwide has increased to more than 40. However, the causal relationship between GH administration and the occurrence of malignancies is still uncertain. We investigated somatic cell mutation frequencies (Mfs) or variant frequency (Vf) at three gene loci in patients with pituitary dwarfism receiving GH therapy to clarify the genetic effect of GH. Eighty-eight patients receiving GH therapy for at least 3 months and 42 age-matched healthy controls were studied. Mfs at hypoxanthineguanine phosphoribosyltransferase (HPRT) and T-cell receptor (TCR) loci in GH users were not significantly higher than in the controls. Although a few patients seemed to have a slightly increased Vf at the glycophorin A (GPA) locus, the difference was not statistically significant. In addition, there was no tendency for the Mfs (Vf) at these loci to increase with the duration of the GH therapy. These data seem to exclude the possibility that GH induces genetic instability in patients with pituitary dwarfism who are receiving GH therapy.

Adolescent↗
PubMed1996

Thymidine kinase deficient cells with decreased TTP pools are hypersensitive to DNA alkylating agents.

The effect of mutational loss of thymidine kinase (TK) on the sensitivity to alkylating agents was investigated in promyelocytic, HL-60, and T-lymphoblastoid, Molt-3, human leukemia cell lines. Although both cell lines exhibited approx. 1% residual TK activity, only HL-60 TK deficient cells had a decreased intracellular TTP pool, i.e., 20% of that of the wild-type. When treated with N-methyl-N'-nitronitrosoguanidine or ethyl methanesulfonate, HL-60 TK deficient cells showed significantly increased killing and mutation frequencies at the hypoxanthine-guanine phosphoribosyl transferase (HGPRT) locus relative than did wild-type. Pretreatment of cells with O6-benzylguanine, an inhibitor of O6-alkylguanine-DNA alkyltransferase, partially abolished those differences. Molt-3 wild-type and TK deficient cells had similar cell survivals and HGPRT mutation frequencies following treatment with alkylating agents. These results indicate that TK deficiency, only when a concomitant decrease of TTP pool is detected, plays a pivotal role in the sensitivity to the cytotoxic and mutagenic effects of alkylating agents.

Antineoplastic Agents↗
PubMed1996

Methotrexate inhibits superoxide production and chemotaxis in neutrophils activated by granulocyte colony-stimulating factor.

Treatment of circulating human neutrophils with recombinant human granulocyte colony-stimulating factor (rhG-CSF) for 30 min augmented superoxide generation and chemotaxis induced by N-formylmethionyl-leucyl-phenylalanine (fMLP) in a dose dependent manner. When neutrophils were treated with 1 microM of methotrexate (MTX) for 60 min after incubation with rhG-CSF (10 ng/ml), the effects of rhG-CSF on superoxide generation and chemotaxis were inhibited by approximately 49 and 29%, respectively. Although inhibitory effects of MTX were also seen in neutrophils not pretreated with rhG-CSF, the degree of inhibition was much less. The addition of either hypoxanthine or guanosine at a concentration of 100 microM to the culture medium significantly attenuated the effects of MTX. However, in neutrophils obtained from a patient with Lesch-Nyhan syndrome, which lacked hypoxanthine-guanine phosphoribosyl transferase activity neither hypoxanthine nor guanosine had any rescue effect. These results suggest that MTX inhibits superoxide generation and chemotaxis in rhG-CSF-activated neutrophils, at least in part, by disturbing purine nucleotide biosynthesis.

Cells, Cultured↗
PubMed1996

Congenital bilateral perisylvian syndrome: first report in a Japanese patient.

A Japanese boy with congenital bilateral perisylvian syndrome is described. He had oropharyngoglossal dysfunction and severe dysarthria. Magnetic resonance imaging of the brain disclosed bilateral perisylvian malformations suggesting polymicrogyria. The patient also showed mental retardation, epilepsy, and poor motor skills.

Adult↗
PubMed1996

Elevated serum interferon gamma and interleukin-6 in patients with necrotizing lymphadenitis (Kikuchi's disease).

We investigated serum levels of interferon alpha, interferon gamma, tumour necrosis factor alpha, interleukin-2 (IL-2) and interleukin-6 (IL-6) in patients with necrotizing lymphadenitis (Kikuchi's disease) (NL). Four male patients, diagnosed as having NL following biopsy of the affected lymph nodes and by the clinical course, were included in this study. All four patients had higher than normal serum interferon gamma and IL-6 levels during the acute phase, which returned to normal levels during the convalescent phase. Interferon alpha, tumour necrosis factor alpha and IL-2 were, however, within the normal ranges. Our findings indicate the possibility that interferon gamma and IL-6 may play an important role in the pathogenesis of NL.

Child↗
PubMed1996

Nephropathy and growth hormone deficiency in a patient with mitochondrial tRNA(Leu(UUR)) mutation.

A mitochondrial A 3243 G mutation in the tRNA(Leu(UUR)) gene was first described as a common cause of MELAS syndrome (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like syndrome). This same mutation is also the cause of a totally different disorder, a subtype of diabetes mellitus which is inherited maternally and often associated with sensorineural hearing loss. In this paper, we report on a Japanese boy with A 3243 G who developed a previously undescribed combination of symptoms, nephropathy and growth hormone deficiency. The patient first presented with short stature and moderate mental retardation. Growth hormone (GH) provocation tests showed deficient growth hormone secretion. During the course of follow up, he presented with progressive nephropathy followed by the development of diabetes mellitus. The results of laboratory tests and renal biopsy were against incidental association of known types of nephropathy. On PCR-RFLP analysis, the percentage of mutated mtDNA was higher in the renal biopsy specimen than 12 peripheral blood leucocytes. Our case suggests that mitochondrial diseases should be taken into account when there is nephropathy of unknown cause. In addition, the presence of growth hormone deficiency may account for part of the mechanism leading to short stature commonly seen in these patients.

Blotting, Southern↗
PubMed1996

Vasoactive intestinal peptide enhances immunoglobulin production and growth in human plasma cells via mechanisms that may involve protein kinase C.

The effects of various neuropeptides on human plasma cells were studied. Of the various neuropeptides tested, vasoactive intestinal peptide (VIP) enhanced Ig production and growth in human plasma cell lines, IM-9 and AF-10, and in plasma cells generated in vivo (four out of four patients with plasma cell leukemia) and in vitro. In contrast, other neuropeptides (neuropeptide Y, somatostatin, substance P, peptide YY, neurokinin A, calcitonin gene-related peptide, chole-cystokinin octapeptide, and beta-endorphin) were ineffective. Moreover, VIP-induced enhancement was specifically blocked by VIP receptor antagonist. Among the various cytokines, IL-6, GH, and insulin-like growth factor I (IGF-I) also enhanced Ig production and thymidine uptake in plasma cells. However, VIP-induced enhancement was not mediated by IL-6, GH, or IGF-I because antibodies to these cytokines failed to block VIP-induced enhancement. Phorbol 12,13 dibutyrate enhanced Ig production and thymidine uptake in plasma cells, and the Phorbol 12,13 dibutyrate-induced enhancement was blocked by H7 (a protein kinase C inhibitor) but not by H8 (a protein kinase A inhibitor). Similarly, VIP-induced enhancement was blocked by H7 but not by H8. Collectively, VIP enhances plasma cell responses via mechanisms that may involve protein kinase C.

Cell Division↗
PubMed1996

Effect of CYP2C polymorphisms on the pharmacokinetics of phenytoin in Japanese patients with epilepsy.

We examined the effect of CYP2C9/19 polymorphisms on the pharmacokinetics of phenytoin in 17 Japanese patients with epilepsy. The maximal elimination rate (Vmax) of phenytoin was slightly decreased (up to 14%) in patients with CYP2C19 mutations for the defective allele. The Vmax values in patients with a CYP2C9 mutation for the heterozygous Ile/Leu359 allele were 40% lower than those in patients with wild-type CYP2C9 for the homozygous Ile359 allele. These findings suggested that the genetic polymorphism of CYP2C isoenzymes plays an important role in the pharmacokinetic variability of phenytoin, and that the mutation in CYP2C9 proteins is a determinant of impaired metabolism of the drug.

Anticonvulsants↗
PubMed1996

Population pharmacokinetics of phenytoin in Japanese patients with epilepsy: analysis with a dose-dependent clearance model.

The population pharmacokinetic parameters of phenytoin were estimated using routine therapeutic drug monitoring data from 116 epileptic patients. The 531 serum concentration values at steady-state after repetitive oral administration were analyzed using a nonlinear mixed effects model (NONMEM) program designed for estimation of population pharmacokinetic parameters. A one-compartment model with dose-dependent clearance was used for the pharmacokinetic analysis of phenytoin. The volume of distribution (V) was estimated to be 1.231/kg in a typical 42-kg patient, assuming that the bioavailability of orally administered phenytoin is 100%. The maximal elimination rate (V(max)) and the Michaelis-Menten constant (K(m)) were 9.80 mg/d/kg and 9.19 micrograms/ml, respectively. The parameter of power function of weight to adjust V and V(max) was estimated to be 0.463. In addition, K(m) for phenytoin appeared to be 16% increased in patients receiving zonisamide concurrently. The population pharmacokinetic parameters of phenytoin will be useful for designing dosage regimens in epileptic patients.

Adolescent↗
PubMed1995

Prostaglandin E2 at priming of naive CD4+ T cells inhibits acquisition of ability to produce IFN-gamma and IL-2, but not IL-4 and IL-5.

We investigated the effect of prostaglandin E2 on the acquisition of cytokine-producing ability by naive CD4+ T cells in human cord blood. Naive CD4+ T cells were stimulated for 3 days with mouse monoclonal anti-CD3 Ab, then washed and expanded in IL-2-containing medium for 3 more days. These activated T cells produced IL-2, IL-4, IL-5, and IFN-gamma upon stimulation with PMA and ionomycin. PGE2 added at priming of naive T cells inhibited the production of IL-2 and IFN-gamma, but not of IL-4 and IL-5, in a dose-dependent manner. This change in the cytokine production profile induced by PGE2 was maintained in T cells restimulated with anti-CD3 in the absence of PGE2, expanded by IL-2, and stimulated with PMA and ionomycin. The mRNA expression of IFN-gamma and IL-2, but not that of IL-4, was also decreased in these cells. Forskolin and dibutyryl cAMP had a similar effect. PGE2 must exist at an early stage of T cell activation to inhibit priming for IL-2 and IFN-gamma production. PGE2 also showed this effect, even in the presence of exogenous IFN-gamma, at the primary stimulation. These results indicate that PGE2 inhibits the acquisition of the ability to produce IL-2 and IFN-gamma by acting directly on naive T cells. Our results suggest that PGE2 plays a role in facilitating the development of the Th2-type cytokine production profile.

Animals↗
PubMed1995

Selection and partial characterization of calcium ionophore (A23187) resistant cells.

We have selected calcium ionophore (A23187)-resistant cells (AR-7) in a human promyelocytic leukemia cell line, HL-60. AR-7 showed approximately 8.5-fold resistance to A23187 compared with the wild type cells after continuous exposure for 3 days. AR-7 had cross resistance to ionomycin (4.6-fold) and thapsigargin (340-fold) which can also increase intracellular Ca++. Similar magnitude of resistance to apoptosis, as defined by characteristic morphology and internucleosomal DNA fragmentation, induced by these agents was observed after 4 hr of incubation. However, both the elevation of intracellular Ca++ following stimulation with various concentrations of A23187 and the sensitivity to anti-cancer agents including etoposide, 1-beta-D arabinofuranosylcytosine, and hydroxyurea were comparable between the two cell types. This cell line is considered to be useful for exploring the mechanism(s) of cell death, especially apoptosis, induced by calcium ionophore.

Antineoplastic Agents↗
PubMed1995

Selective inhibition of spontaneous IgE and IgG4 production by interleukin-8 in atopic patients.

The effects of interleukin (IL)-8 on spontaneous IgE and IgG4 production in atopic patients were studied. IL-8 inhibited IgE and IgG4 production by purified surface (s) IgE+ and sIgG4+ B cells, respectively, while it had no effect on IgG1, IgG2, IgG3, IgM, IgA1, and IgA2 production by corresponding sIg+ B cells. The IL-8-induced inhibition was counteracted by IL-6 and tumor necrosis factor-alpha (TNF-alpha) and was blocked by anti-IL-8 monoclonal antibody (MoAb). Conversely, the addition of anti-IL-6 MoAb and anti-TNF-alpha MoAb, in the absence of IL-8, inhibited IgE and IgG4 production by sIgE+ and sIgG4+ B cells, respectively. Purified sIgE+ and sIgG4+ B cells expressed IL-6 receptors (R), TNF-alpha R, and IL-8R, and they produced IL-6 and TNF-alpha, but not IL-8. IL-8 had no effect on IL-6R or TNF-alpha R, while it abrogated IL-6 and TNF-alpha production in these cells. In contrast, slgG1+, slgG2+, slgG2+, slgG3+, slgM+, slgA1+, and slgA2+ B cells expressed IL-6R and TNF-alpha R but not IL-8R, and they produced IL-6 and TNF-alpha. IL-8 had no effect on IL-6R and TNF-alpha R, or on TNF-alpha and IL-6 production in these cells. These results indicate that IL-8 inhibits spontaneous IgE and IgG4 production in slgE+ and slgG4+ B cells, respectively, by inhibiting the endogenous production of IL-6 and TNF-alpha.

Antibodies, Monoclonal↗
PubMed1995

Association of high molecular weight DNA fragmentation with apoptotic or non-apoptotic cell death induced by calcium ionophore.

Calcium ionophore (A23187)-induced high molecular weight (HMW) and internucleosomal DNA fragmentation were investigated in human leukemia cell lines. An apoptosis-sensitive cell line, HL-60, showed HMW, internucleosomal DNA fragmentation and morphological changes of apoptosis by A23187. MOLT-4, which is resistant to apoptosis, exhibited only HMW DNA fragmentation and died of necrosis under the same conditions. Autodigestion experiments suggested the endonucleolytic activity to cause HMW fragmentation in the cytoplasm of both cell lines. The activity was more dependent on Mg2+ than Ca2+ in HL-60, whereas it was Ca(2+)-dependent in MOLT-4. These results suggest that HMW DNA fragmentation is not specific to apoptosis.

Apoptosis↗
PubMed1995

Effect of hydrocortisone on spontaneous IgE and IgG4 production in atopic patients.

The effect of hydrocortisone on spontaneous human IgE and IgG4 production in atopic patients was studied. In cultures of mononuclear cells, hydrocortisone (HC) enhanced IgE and IgG4 production without affecting the production of IgM, IgA1, IgA2, IgG1, IgG2, or IgG3. In contrast, testosterone, beta-estradiol, progesterone, aldosterone, gonadotropin, and prolactin were without effect. HC had to be added at the initiation of culture to achieve this enhancing effect. IL-4 and IL-13 also enhanced spontaneous IgE and IgG4 production in mononuclear cells. However, the enhancement of IgE and IgG4 production by HC was not mediated by IL-4 or IL-13, as the addition of anti-IL-4 or anti-IL-13 Ab did not block the HC-induced enhancement. HC also enhanced IgE and IgG4 production in purified B cells, whereas neither IL-4 nor IL-13 did so. IL-5, IL-6, and TNF-alpha also enhanced IgE and IgG4 production in purified B cells; however, neither anti-IL-5, anti-IL-6, nor anti-TNF-alpha mAbs blocked the HC-induced enhancement. Purified surface (s)IgE+ and sIgG4+ B cells spontaneously produced IgE and IgG, respectively, whereas sIgE- and sIgG4- B cells failed to do so. HC enhanced IgE and IgG4 production in sIgE+ and sIgG4+ B cells, respectively, without affecting proliferation, whereas HC failed to induce IgE and IgG4 production in sIgE- and sIgG4- B cells, respectively. These results indicate that HC may selectively stimulate sIgE+ and sIgG4+ B cells.

B-Lymphocytes↗