Biomedical subjects

F Kimura

Publications and source records attributed to F Kimura.

At least 19 recordsLinked to original sources

PubMed2003

Vigorous intake of oil emulsion caused by chronic food deprivation remains after recovery in rats.

Oil emulsion intake over a 30-min period was compared under different dietary conditions (ad libitum feeding and chronic food deprivation) and at various concentrations of oil in rats. The pattern of intake for each dietary condition was extremely different. Food-deprived rats ingested more emulsion when the solution was thicker but intake amount became less at too high a concentration. Ad libitum feeding rats ingested less emulsion than deprived rats with no difference among the concentrations. Rats on a restricted diet clearly differentiated between concentrations, selecting the thicker emulsion when provided two-bottle selection between 10% oil and some other concentration. On the other hand, rats fed ad libitum differentiated between only extremely weak solutions. The vigorous intake of oil emulsion induced by chronic food deprivation was maintained after 2 weeks of normal feeding. Significant difference between prior dietary conditions was maintained at lower concentrations. Dietary timing for food-deprived rats affected little on emulsion intake. These results indicate that response to oil emulsion intake differs by concentration in rats.

Animals↗

PubMed2003

Bisphenol A increases progesterone receptor immunoreactivity in the hypothalamus in a dose-dependent manner and affects sexual behaviour in adult ovariectomized rats.

Recently, we reported that bisphenol A (BPA), an endocrine disrupter, increased progesterone receptor (PR) mRNA in the preoptic area (POA) in adult ovariectomized rats. In the present study, we examined whether BPA also induced expression of PR proteins in both the POA and the ventromedial hypothalamic nucleus (VMH), and whether those proteins were involved in the induction of sexual behaviour. Two weeks after ovariectomy, rats received a subcutaneous (s.c.) injection of BPA, 17 beta-oestradiol or vehicle. Twenty-four hours after the injection, the rats were killed and their tissues were examined by immunocytochemistry. Some rats that received a s.c. injection of BPA, E2 or vehicle alone on the day before were injected with progesterone at 15.00 h and examined for sexual behaviour 5-7 h later. As expected, injection of 10 microg E2 significantly increased the number of PR immunoreactive cells in both the POA and the VMH compared to the number after injection of vehicle alone. In both the POA and the VMH, injection of BPA at a dose of 10 mg also significantly increased the number of PR immunoreactive cells compared to the number after injection of sesame oil alone. Furthermore, BPA induced a dose-dependent increase in the number of PR immunoreactive cells in both the POA and the VMH, demonstrating that the number of PR cells was significantly increased by as little as 100 microg of BPA. Ovariectomized (OVX) rats that were primed with 10 mg of BPA, followed by 1 mg of progesterone, displayed mainly rejection behaviour, but not lordosis as typically observed in OVX rats primed with E2 followed by progesterone. The present study suggests that BPA influences reproductive functions, including sexual behaviour even in adulthood, by altering the PR system in the hypothalamus.

Animals↗

PubMed2003

Lipopolysaccharide inhibits luteinizing hormone release through interaction with opioid and excitatory amino acid inputs to gonadotropin-releasing hormone neurones in female rats: possible evidence for a common mechanism involved in infection and immobilization stress.

Acute immobilization stress suppresses naloxone- and N-methyl-d-aspartate (NMDA)-induced, but not gonadotropin-releasing hormone (GnRH)-induced, luteinizing hormone (LH) release in ovariectomized oestrogen-primed rats. To explore whether a common mechanism may underlie inhibition of gonadotropin secretion by various stressors, we examined in the present study the effect of lipopolysaccharide (LPS) on LH release induced by progesterone, GnRH, naloxone and NMDA. The effect of LPS on Fos expression in GnRH neurones was also examined in association with its effect on steroid-induced LH release. Injection of progesterone (1 mg/rat) at noon induced an LH surge in the afternoon in ovariectomized rats pretreated with oestradiol benzoate. In these rats, the majority of hypothalamic GnRH neurones expressed Fos in the evening. Intravenous (i.v.) administration of LPS (10 micro g/rat) inhibited steroid-induced LH release and also reduced the Fos expression in GnRH neurones. In separate experiments, an i.v. injection of GnRH (50 ng/kg), naloxone (10 mg/kg) or NMDA (20 mg/kg) significantly elevated serum LH concentrations within 10 min. Pretreatment with LPS, which did not affect basal LH release or GnRH-induced LH release, inhibited naloxone-induced and NMDA-induced LH release. These results show that LPS has a suprapituitary site(s) of action to suppress the activity of GnRH neurones in female rats, and suggest that LPS affects the opioid, as well as the excitatory amino acidergic regulation of GnRH neurones. The similarity of effects of LPS and immobilization stress further suggests that a common mechanism is involved in inhibition of GnRH neurones by different stressors.

Animals↗

PubMed2002

Locally expressed CTLA4-Ig in a pancreatic beta-cell line suppresses accelerated graft rejection response induced by donor-specific transfusion.

AIMS/HYPOTHESIS: This study examined whether locally expressed CTLA4-Ig can suppress the accelerated islet allograft rejection that is induced by donor-specific transfusion. METHODS: CTLA4-Ig-transfected or parental MIN6 cells were transplanted subcutaneously into the right flank of streptozotocin-induced diabetic C3H/Hej mice with or without donor-specific transfusion. For donor-specific transfusion, spleen cells from C57BL/6 mice were injected i.v. at the time of transplantation. In other experiments, CTLA4-Ig-transfected and parental MIN6 cells were transplanted separately into each flank, together with donor-specific transfusion. Rejection was defined as a blood glucose concentration of more than 300 mg/dl in two consecutive measurements, and graft survival was confirmed by hyperglycaemia after the grafts were removed. The effect of an anti-CTLA4 antibody on the survival of CTLA4-Ig-transfected MIN6 cells was also examined. RESULTS: In 7 of 12 donor-specific transfusion sensitised mice, CTLA4-Ig-transfected MIN6 cells remained viable 20 days after grafting, whereas all parental MIN6 cells ( n = 10) were rejected promptly, within 14 days. The prolonged allograft survival was observed even in the absence of detectable levels of serum CTLA4-Ig, while the surviving allografts continued to produce CTLA4-Ig in situ. This protection was abrogated by an anti-CTLA4 antibody, but not by a control antibody. Furthermore, six animals that maintained normoglycaemia after the separate transplantation of parental and CTLA4-Ig-transfected MIN6 cells into each flank all showed abrupt hyperglycaemia after the CTLA4-Ig/MIN6 graft was removed, suggesting that this protection operated locally. CONCLUSION/INTERPRETATION: A beta-cell line genetically engineered to secrete CTLA4-Ig can protect a graft locally from the alloimmune response induced by donor-specific transfusion.

Abatacept↗

PubMed2002

Differential regulation of pituitary adenylate cyclase-activating peptide receptor variants in the rat suprachiasmatic nucleus.

Pituitary adenylate cyclase-activating peptide is densely distributed in the suprachiasmatic nucleus, which functions as the circadian pacemaker. A receptor for pituitary adenylate cyclase-activating peptide, denoted as PAC(1), exists in six variant forms. We used reverse transcriptase-polymerase chain reaction to identify the PAC(1) variants that are expressed in the suprachiasmatic nucleus. Dominant variant forms of PAC(1) in the suprachiasmatic nucleus were PAC(1)short, PAC(1)hip, and PAC(1)hop1. By in situ hybridization, we examined 24-h profiles of mRNAs for the identified receptor variants in the suprachiasmatic nucleus in constant darkness and during the light-dark cycle. In constant darkness there were clear circadian rhythms in PAC(1)short mRNA with a peak at circadian time 4 but no rhythmicity was observed in PAC(1)hip mRNA or PAC(1)hop1 mRNA. In light-dark cycles, on the other hand, PAC(1)hip mRNA displayed a bimodal rhythm with troughs at zeitgeber time 4 and 16 but PAC(1)hop1 mRNA stayed constant during the day. These results suggest that PAC(1) splice variants are differentially regulated in the rat suprachiasmatic nucleus.

Alternative Splicing↗

PubMed2002

GABA release in the medial preoptic area of cyclic female rats.

GABA is a potent regulator of gonadotropin-releasing hormone neurons in the hypothalamus. To determine the profile of GABA release in the medial preoptic area where the gonadotropin surge generator resides, an in vivo microdialysis study was performed in cyclic female rats. The microdialysis samples were collected and sequential blood samples (150 microl each) were also obtained, at 1-h intervals. During estrus and diestrus 1, GABA release in the medial preoptic area was relatively low. A small increase in the GABA release began in the afternoon of diestrus 1 and attained its peak in the morning of diestrus 2, but declined in the afternoon of that day. The GABA release markedly increased from late in the night of diestrus 2 through the morning of proestrus, when it attained its peak, and thereafter it declined sharply until the critical period of proestrus. A distinct preovulatory luteinizing hormone surge was observed in the afternoon of proestrus in all proestrous rats. From these results we suggest that the preovulatory elevation of the GABA release from the night through to the morning of proestrus, followed by a sharp decline, is closely associated with the onset of the preovulatory luteinizing hormone surge in cyclic female rats. The present study is the first to report the 4-day profile of GABA release in the medial preoptic area during the estrous cycle.

Animals↗

PubMed2002

Results of surgical treatment for intrahepatic cholangiocarcinoma and clinicopathological factors influencing survival.

BACKGROUND: The results of surgical treatment for intrahepatic cholangiocarcinoma (ICC) and specific factors influencing survival are still unclear. METHODS: Between 1984 and 2001, 62 patients with ICC underwent laparotomy, with a 77 per cent (48 patients) resectability rate. The tumours in these 48 patients were reviewed retrospectively to examine the relationship between gross appearance (mass forming, periductal infiltrating, intraductal growth, and mass forming plus periductal infiltrating) and patient survival, as well as the manner of recurrence. In patients with mass-forming and mass-forming plus periductal infiltrating types, univariate and multivariate analyses of potential prognostic factors were performed. RESULTS: The 1-, 3- and 5-year survival rates were 62, 38 and 23 per cent respectively. All patients with the intraductal growth type remained alive after intervals ranging from 8 to 72 months. Univariate analysis showed multiple hepatic lesions, liver capsule invasion, presence of cancer cells in the resection margin, and high serum carbohydrate antigen (CA) 19-9 level to be significant negative prognostic factors. Lymph node involvement, however, was not identified as a significant prognostic factor. With multivariate analysis, multiple hepatic lesions and high serum CA19-9 concentration were found to be significantly related to prognosis. The most frequent recurrence site was the remnant liver. CONCLUSION: These results suggest that the intraductal growth type of tumour should be treated as a distinct entity compared with other types of ICC. Multiple tumours and high serum CA19-9 level were signs of dismal prognosis, whereas not all patients with lymph node involvement had a poor prognosis.

Adult↗

PubMed2002

Butyl benzyl phthalate, an endocrine disrupter, inhibits pulsatile luteinizing hormone secretion under an insulin-induced hypoglycaemic state in ovariectomized rats.

Butyl benzyl phthalate (BBP) and bisphenol A (BPA), termed endocrine disrupters, are known to mimic oestrogen in their actions, and therefore there is concern about their effect on reproductive functions. Since it is reported that the inhibitory action of oestrogen on the pulsatile secretion of luteinizing hormone (LH) is enhanced under insulin-induced hypoglycaemia, whether this also applies to BBP and BPA was examined in the present study. In adult ovariectomized (OVX) rats, the pulsatile LH secretion 24 h after subcutaneous injection of 10 mg BBP (BBP-treated), 10 mg BPA (BPA-treated) or 100 ng 17beta-oestradiol (E2-treated), all of which were dissolved in sesame oil, was not changed significantly compared to that after the injection of sesame oil only. Furthermore, in oil-treated OVX rats, the pulsatile LH secretion immediately after intravenous injection of insulin (1.0 U) was not changed compared to that after saline injection. In BBP-treated OVX rats, the injection of insulin (1.0 U) significantly decreased the number of LH pulses as in E2-treated OVX rats. The injection of insulin did not significantly affect the amplitude of LH pulses in BBP-, BPA- and E2-treated OVX rats. The results indicate that the oestrogenic action of BBP is significantly enhanced by insulin-induced hypoglycaemia and thus the pulsatile LH secretion is inhibited. We suggest that weak oestrogenic endocrine disrupters may become harmful to reproductive functions even in adult female rats, if acting under a low energy state.

Animals↗

PubMed2001

Destabilization of chromosome 9 in transitional cell carcinoma of the urinary bladder.

The most frequent genetic alteration in transitional cell carcinoma of the urinary bladder (TCC) is loss of chromosome 9 which targets CDKN2A on 9p. The targets on 9q are not confirmed. Here, 81 advanced TCC specimens were investigated for loss of heterozygosity (LOH) and homozygous deletions (HD) on chromosome 9q using multiplex analysis of microsatellite markers. 41/81 tumours (51%) showed LOH on 9q, with LOH at all markers in 33 cases. Eight partial losses involved three regions in 9q12, 9q22.3, and 9q33- 9q34. No mutations were identified in the candidate tumour suppressor gene DBCCR1 in three tumours showing restricted LOH at 9q32-33. 22% of the specimens had HD at CDKN2A, but no HD was found on 9q. Two tumours had lost 9p only and five 9q only. 9q LOH was not related to tumour grade or stage and present or absent with equal frequency in recurrent TCC. LOH on 9q correlated with the extent of genome-wide hypomethylation (P < 0.0001) which extended into satellite sequences located in 9q12 juxtacentromeric heterochromatin. While the high frequency of chromosome 9q loss in TCC may reflect destabilization of the chromosome related to hypomethylation of repetitive DNA, the data are compatible with the existence of tumour suppressor genes on this chromosome arm.

Adult↗

PubMed2001

Intracerebroventricular administration of ghrelin rapidly suppresses pulsatile luteinizing hormone secretion in ovariectomized rats.

Ghrelin, an endogenous growth hormone (GH) secretagogue, is shown to increase food intake, which action is similar to that of orexin, also a hypothalamic peptide. Since orexin suppresses pulsatile LH secretion in ovariectomized (OVX) rats, the present study was undertaken to investigate whether ghrelin also suppresses LH secretion. Effects of intracerebroventricularly injected ghrelin (0.1 nmol/0.3 microl) were examined in OVX rats treated with a small dose of 17beta-estradiol (E(2)). After ghrelin injection, pulsatile LH secretions which were ongoing in these E(2)-treated OVX rats were significantly suppressed for about 1 h, whereas GH secretion increased, peaking at 30 min. The main parameter suppressed by ghrelin was the pulse frequency, not the pulse amplitude, suggesting the hypothalamus as the site of ghrelin action. This study provides evidence that ghrelin acts not only in the control of food intake but also in the control of LH secretion.

Analysis of Variance↗

PubMed2001

Effects of estrogen and progesterone on the expression of connexin-36 mRNA in the suprachiasmatic nucleus of female rats.

To determine the effects of ovarian steroid hormones on gap junction communication in the suprachiasmatic nucleus (SCN), we examined the effects of estrogen and/or progesterone on the expression of connexin-36 mRNA in the SCN and cerebral cortex (CX) of female rats. Ovariectomized adult rats were injected with 20 microg 17beta-Estradiol or sesame oil 48 h before sacrifice and further injected with 1.5 mg progesterone or sesame oil 24 h before sacrifice. Northern blot revealed that estrogen significantly increased the expression of connexin-36 mRNA in the SCN and this increase was inhibited by progesterone. On the other hand, the connexin-36 mRNA level in the CX was not affected by estrogen or progesterone. These results suggest that the gap junction with connexin-36 in the SCN is specifically regulated by ovarian steroid hormones of female rats.

Animals↗

PubMed2001

Axillary pheromones modulate pulsatile LH secretion in humans.

We examined the effect of axillary compounds on pulsatile secretion of serum luteinizing hormone (LH). Axillary compounds were collected from donor women in the follicular phase (FP) and the ovulatory phase (OP) and were treated with isopropyl alcohol (IPA). The recipient was not exposed to either axillary compounds or IPA for the first 4 h and was exposed to FP or OP compounds, or to IPA, during the next 4 h. The frequency of the LH pulse was increased by FP compounds and was decreased by OP compounds, but the LH pulse frequency was not changed by IPA. Therefore, in humans, pheromones may play a role in the modulation of the timing of ovulation by changing the frequency of pulsatile LH secretion.

Adult↗

PubMed2001

t(11;14)(q23;q24) generates an MLL-human gephyrin fusion gene along with a de facto truncated MLL in acute monoblastic leukemia.

More than 20 different partner genes with MLL have been cloned from leukemia cells with translocations involving chromosome 11 band q23 (11q23). All reported partner genes fused in-frame to MLL and the fusion cDNA encode chimeric MLL proteins with a significant portion derived from the partner genes. We analyzed one patient with de novo acute monoblastic leukemia with t(11;14)(q23;q24) and identified that a human homologue of gephyrin (human gephyrin) fused with MLL. Gephyrin is a rat glycine receptor-associated protein, which forms submembranous complexes and anchor glycine or gamma-aminobutyric acidA receptors to microtubules. Alternative splicing of human gephyrin gene created two different forms of fusion cDNA. In one form, human gephyrin gene fused in-frame to MLL exon 9, and the chimeric product had COOH terminus of human gephyrin protein, including the tubulin binding site. In the other, the reading frame terminated shortly after the fusion point. As a result, only seven amino acids with no known function were attached to the NH2 terminus of MLL protein. The functional significance of this de facto truncated MLL gene product is not clear.

Aged↗

PubMed2001

Impairment of maze learning in rats by restricting environmental space.

We previously reported that the restriction of environmental space attenuates spontaneous locomotor activity and hippocampal acetylcholine release. To examine the effect of the restriction of environmental space on spatial learning function, male rats were individually housed in a cylindrical large cage (diameter=35 cm) or small cage (diameter=19 cm) for 5 days. Eight-arm radial maze performance was examined to evaluate spatial learning and memory functions. The task was performed once a day between 21:00 and 22:00 h in the dark phase. Although all rats learned and performed the task, those in the small cage had lower scores and took more trial time than those in the large cage. These results suggest that the restriction of environmental space impairs spatial learning in the dark phase in rats.

Acetylcholine↗

PubMed2001

Antitumor immunity induced by irradiated tumor cells producing macrophage colony-stimulating factor.

We previously reported that administration into mice of mouse lymphoid leukemia L1210 cells engineered to secrete macrophage colony-stimulating factor (M-CSF) could lead to tumor rejection. Here, we demonstrate that inoculation with irradiated M-CSF-producing cells protects mice against a subsequent challenge with unmodified parental tumor cells. We used 2 experimental protocols: the inoculation with irradiated M-CSF-producing L1210 cells (EM5) before the challenge with parental cells and after the challenge with parental cells. Both protocols effectively improved the survival rate of mice compared with protocols in which irradiated non-M-CSF-producing L1210 cells (EM-mock) were inoculated. Inoculation with 1 x 10(2) irradiated EM5 cells was sufficient to prolong the survival time of mice subsequently challenged with 1 x 10(4) parental cells. In vivo depletion experiments with administration of antibodies suggested the involvement of CD4+ T cells, CD8+ T cells, and natural killer (NK) cells in the antitumor effect. Consistent with these findings, the cytotoxic T lymphocyte activity of splenocytes from EM5-inoculated mice was higher than that from EM-mock-inoculated mice, and L1210 tumors were heavily infiltrated by CD4+ T cells and NK cells as well as macrophages in EM5-inoculated mice.

Animals↗

PubMed2001

Gastrointestinal stromal tumor of the lesser omentum: report of a case.

We describe herein an extremely unusual case of a gastrointestinal stromal tumor (GIST) of the lesser omentum. A 45-year-old man was admitted to our hospital with an intra-abdominal mass that was subsequently misdiagnosed as a submucosal tumor of the stomach. The tumor arose from the lesser omentum and was removed without difficulty. Histologically, the tumor was composed of spindle-shaped cells with an interlacing bundle pattern, and immunohistochemical examination showed that it was positive for myeloid stem cell antigen (CD34), but negative for HHF35 and S-100 protein. These findings were consistent with a GIST lacking myogenic features and neural attributes. The patient had an uneventful postoperative course, and was free of recurrence when last seen 11 months after his operation.

Gastrointestinal Neoplasms↗

PubMed2001

Follicle-stimulating hormone receptor gene mutations are rare in Japanese women with premature ovarian failure and polycystic ovary syndrome.

OBJECTIVE: To determine whether the known inactivating FSH receptor gene mutations are present in Japanese women with secondary amenorrhea because of premature ovarian failure (POF) and polycystic ovary syndrome (PCOS). DESIGN: Clinical and molecular studies. SETTING: An outpatient clinic in a university hospital. PATIENT(S): Fifteen women with idiopathic POF, 38 women with PCOS, and three normal controls. INTERVENTION(S): Extraction of DNA from blood samples for subsequent polymerase chain reaction (PCR). MAIN OUTCOME MEASURE(S): PCR fragments digested with MunI, BsmI, and HhaI were compared in patients and controls. PCR fragments were also analyzed by denaturing gradient gel electrophoresis (DGGE) and direct sequencing. RESULT(S): No inactivating mutations reported thus far in exons 6, 7, 9, and 10 of the FSH receptor gene were identified in Japanese women with POF and PCOS. DGGE analysis of PCR fragments of exon 10 also revealed no FSH receptor gene mutations in this region. CONCLUSION(S): Although we cannot exclude the presence of point mutations in other regions of the FSH receptor gene, the described FSH receptor mutations may be uncommon in Japanese patients with POF and PCOS.

Adult↗

PubMed2001

Defibrinogenating effect of batroxobin (Defibrase) in rats and inhibition of migration of human vascular smooth muscle cells by the plasma of batroxobin-treated rats in vitro.

The defibrinogenating effect of batroxobin (Defibrase) in male Wistar rats and the inhibitory effects of the plasma of batroxobin-treated rats on the migration of human vascular smooth muscle cells (SMCs) were investigated in vitro. At 1 h after a single intravenous injection of 3.0, 10.0 or 30.0 BU/kg batroxobin (ten rats in each group), the fibrinogen levels in the plasma of the rats decreased to 88.3, 66.2 and 16.5%, respectively, of that in the plasma of control saline-treated rats (261.0+/-26.7 mg/dl). When the plasma from the batroxobin-treated rats was added to Dulbecco's modified Eagle's medium at a concentration of 0.2% for a vascular SMC migration assay and incubated in a modified Boyden's chamber system at 37 degrees C for 24 h, significant inhibitory effects on vascular SMC migration were observed in the 10.0 (P<0.05) and 30.0 BU/kg (P<0.01) batroxobin-treated rats. The plasma of batroxobin-treated rats as well as standard rat fibrinogen induced vascular SMC migration in a fibrinogen content-dependent manner except the plasma of the 30.0 BU/kg batroxobin-treated rats. Moreover, the rat serum (0.1 approximately 5.0%) did not show any activity on vascular SMC migration in the present experimental system. These results indicate that the plasma fibrinogen significantly influences vascular SMC migration, and that the inhibitory effect of the plasma of batroxobin-treated rats on vascular SMC migration is related to the defibrinogenating action of batroxobin in vivo.

Animals↗