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Biomedical subjects

A Ichikawa

Publications and source records attributed to A Ichikawa.

At least 37 records · Page 2Linked to original sources
PubMed2001

Usefulness of dual-head coincidence gamma camera with thick NaI crystals for nuclear oncology: comparison with dedicated PET camera and conventional gamma camera with thin NaI crystals.

AIM: A comparative study of the images obtained with a dual-head coincidence gamma camera with thick NaI crystals (19 mm), a dedicated PET camera with BGO crystals and a conventional gamma camera with thin NaI crystals (9.5 mm) was conducted to clarify the clinical feasibility of a dual-head coincidence gamma camera with thick NaI crystals. METHODS: FDG images of 27 patients with malignant tumors were obtained by means of a dual-head coincidence gamma camera with thick NaI crystal and a dedicated PET camera with BGO crystals. The images of bone scintigraphy in 10 cancer patients obtained with the dual-head coincidence gamma camera were compared with those taken by a conventional dual-head gamma camera with thin NaI crystals. RESULTS: Patient-basis sensitivity in 27 patients with neoplasms and lesion-basis sensitivity of the dual-head coincidence gamma camera and the dedicated PET camera were 74.1% and 85.2% (n.s.), 66.7% and 72.2% (n.s.), respectively. The tumor to background FDG uptake ratio derived from the coincidence gamma camera was significantly lower than that derived from the dedicated PET camera (mean +/- s.d.; 3.48 +/- 3.77 vs. 8.12 +/- 8.92, p < 0.0001), but the tumor to background FDG uptake ratio obtained with both methods correlated well (r = 0.84, p < 0.001). Similar whole body bone scans were obtained with the dual-head coincidence gamma camera and the conventional dual-head gamma camera in all 10 patients. CONCLUSION: These results suggest that the dual-head coincidence gamma camera with thick NaI crystals has potentially high clinical applicability for community hospitals.

Adult↗
PubMed2001

Histamine deficiency suppresses murine haptoglobin production and modifies hepatic protein tyrosine phosphorylation.

Histidine decarboxylase (HDC) synthesizes endogenous histamine from histidine in mammals. HDC-deficient mice (HDC-/-), if kept on a histamine-free diet, have no histamine in their tissues. HDC-/- mice show multiple phenotypes. In this study we show that both the constitutively expressed and turpentine-induced level of an acute-phase protein, haptoglobin, is significantly lower in the serum of HDC-/- mice compared to that of wild-type animals. This effect was abolished if HDC gene-targeted mice received histamine-rich food. No differences were found when lipopolysaccharide (LPS) was used to induce the acute-phase reaction. Using specific antibodies to phosphorylated tyrosine, we showed that protein tyrosine phosphorylation (Y-P) of approximately 50- and 26- to 27-kDa liver proteins is significantly decreased in HDC-/- mice, but that the difference was largely diminished if the animals were kept on a histamine-rich diet, suggesting that the phenotype with lower haptoglobin production is diet inducible. Upon in vivo treatment with LPS, Y-P band intensity decreased, regardless of the presence or absence of histamine. Identification of elements of the signalling pathway with decreased phosphorylation may elucidate the molecular background of the effect of endogenous histamine in the hepatic acute-phase reaction.

Acute-Phase Reaction↗
PubMed2001

Upregulation of histidine decarboxylase mRNA expression in scleroderma skin.

The involvement of histamine in the pathogenesis of systemic sclerosis (SSc) has been suggested. Possible involvement of histamine and histidine decarboxylase (HDC), the synthesizing enzyme for histamine, in the formation of the skin abnormalities in SSc was studied. Skin histamine concentrations in SSc were significantly lower than in normal controls (P < 0.02). In situ hybridization with an HDC probe revealed that the expression of the HDC gene in SSc was greater than in normal controls. The number of cells and the mean grain number per cell expressing HDC mRNA were both significantly greater in SSc than in normal controls (both P < 0.01). These results show a reduction in histamine concentration and an elevated HDC gene expression in SSc skin, indicating an increase in both histamine release and HDC gene expression. The upregulation of histamine turnover appears to be involved in the formation of the skin abnormalities of SSc.

Adult↗
PubMed2001

Characterization of EP receptor subtypes responsible for prostaglandin E2-induced pain responses by use of EP1 and EP3 receptor knockout mice.

Prostaglandin E2 (PGE2) is known to be the principal pro-inflammatory prostanoid and play an important role in nociception. To identify PGE receptor (EP) subtypes that mediate pain responses to noxious and innocuous stimuli, we studied them by use of EP1 and EP3 knockout (EP1(-/-) and EP3(-/-)) mice. PGE2 could induce mechanical allodynia in EP1(+/+), EP3(+/+) and EP3(-/-) mice, but not in EP1(-/-) mice. N-methyl-D-aspartate (NMDA), the substrate of nitric oxide (NO) synthase L-arginine, or the NO donor sodium nitroprusside administered intrathecal (i.t.) could induce allodynia in EP3(-/-) and EP1(-/-) mice. Activation of EP1 receptors appears to be upstream, rather than downstream, of NMDA receptor activation and NO production in the PGE2-induced allodynia. Although PGE2 produced thermal hyperalgesia over a wide range of dosages from 50 pg to 0.5 microg kg(-1) in EP3(+/+) mice, it showed a monophasic hyperalgesic action at 5 ng kg(-1) or higher doses in EP3(-/-) mice. The selective EP3 agonist, ONO-AE-248, induced hyperalgesia at 500 pg kg(-1) in EP3(+/+) mice, but not in EP3(-/-) mice. Saline-injected EP1(-/-) mice showed hyperalgesia, which was reversed by i.t. PGE2 in a dose-dependent manner. There was no significant difference in the formalin-induced behaviours between EP1(-/-) or EP3(-/-) mice and the cognate wild-type mice. These results demonstrate that spinal EP1 receptors are involved in the PGE2-induced allodynia and that spinal EP3 receptors are involved in the hyperalgesia induced by low doses of PGE2. However, the formalin-induced pain cannot be ascribed to a single EP receptor subtype EP1 or EP3.

Animals↗
PubMed2001

Extensive methylation of hMLH1 promoter region predominates in proximal colon cancer with microsatellite instability.

BACKGROUND & AIMS: Methylation of the hMLH1 promoter region has been suggested to cause microsatellite instability (MSI) in sporadic colorectal carcinoma (CRC). We studied the methylation profile in a wide region of the hMLH1 promoter and compared with the hMLH1 protein expression and MSI status in 88 cases of sporadic CRC. METHODS: Na-bisulfite treatment and polymerase chain reaction single-strand conformation polymorphism analysis was performed using 5 sets of polymerase chain reaction primers spanning the promoter region of the hMLH1 to examine methylation status. Results were compared with immunostaining using anti-hMLH1 monoclonal antibody and MSI status of the tumor samples. RESULTS: Methylation status was classified as full or partial methylation. Full methylation indicates the methylation of all CpG sites in the examined regions. Methylation of the hMLH1 promoter was observed in 88.9% (16 of 18) of CRCs showing high frequency MSI (MSI-H), among which 89% (14 of 16) had full methylation with reduced hMLH1 protein expression. All cases showing full methylation were proximal colon tumors with MSI-H. In cases with partial methylation, only the upstream region of the hMLH1 promoter was methylated. Partial methylation was also shown in 33.3% (6 of 18) of the normal mucosa of MSI-H cases. Frequencies of methylation were significantly correlated with female gender (P = 0.0009) and aging (P = 0.007). CONCLUSIONS: Full methylation of the hMLH1 promoter region and subsequent gene inactivation may play a crucial role in the carcinogenesis of MSI-H CRCs in the proximal colon. Methylation upstream of the hMLH1 promoter appears to be an early event in the carcinogenesis of MSI-H tumors.

Adaptor Proteins, Signal Transducing↗
PubMed2001

DNA variants of BAT-25 in Japanese, a locus frequently used for analysis of microsatellite instability.

BAT-25 is a DNA marker, intragenic to the c-kit protooncogene, assigned to 4q12, containing a polythymine tract, mostly repeats of 25 poly(T) (T25). The BAT-25 locus is frequently used in the analysis of microsatellite instability (MSI) in cancer tissues. The number of poly(T) repeats at BAT-25 is reported to be quasi-monomorphic and this property permits the easy identification of the MSI status. We report DNA variants of BAT-25, in one patient with hereditary nonpolyposis colorectal cancer presenting T21 and T25 alleles and another carrying T18 and T25 alleles in the analysis of 100 normal Japanese donors. Observed allelic frequencies were 0.5% for both T21 and T18 alleles. So far, DNA variants of BAT-25 locus have been reported in African Americans with relatively high frequencies, but not in Japanese.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2001

[Reproduction physiology and prostanoids].

Prostanoids, which consist of prostaglandins (PGs) and thromboxane, are produced from arachidonic acid by cyclooxygenases (COXs) as a rate-limiting step, and they exert various biological actions. Classically, prostanoids are suspected to be closely related to female reproductive processes such as ovulation, luteolysis and uterine contraction, as well as pathological processes such as fever generation and pain modulation. Recently the cDNA cloning of a series of prostaglandin-synthesizing enzymes and receptors enabled us to clarify which isoform or subtype is involved in each reproductive process by generating individual gene-deficient mice. In late pregnancy, PGF2 alpha synthesized by COX-1 is essential for induction of parturition via luteolysis. Furthermore, impaired induction of COX-2 in the myometrium of PGF2 alpha receptor-deficient mice is accompanied with loss of parturition, suggesting that COX-2 is presumably responsible for producing uterotonic PGs. In early pregnancy, PGE2 synthesized by COX-2 induces the expansion of cumulus cells through EP2 receptor and contributes to ovulation and fertilization. These results may be useful in not only developing novel drugs in the reproductive area but also understanding and overcoming harmful reproductive side effects of classical and novel drugs in non-reproductive areas.

Animals↗
PubMed2000

Prostaglandin F2alpha-induced expression of 20alpha-hydroxysteroid dehydrogenase involves the transcription factor NUR77.

Prostaglandin F(2)alpha (PGF(2)alpha) binding to its receptor on the rat corpus luteum triggers various signal transduction pathways that lead to the activation of a steroidogenic enzyme, 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD), which in turn catabolizes progesterone. The molecular mechanism underlying PGF(2)alpha-induced 20alpha-HSD enzyme activity has not yet been explored. In this report we show, using mice lacking PGF(2)alpha receptor and pregnant rats, that PGF(2)alpha is responsible for the rapid and massive expression of the 20alpha-HSD gene at the end of pregnancy leading to a decrease in progesterone secretion. We also present evidence that PGF(2)alpha enhances 20alpha-HSD promoter activity. We have determined a region upstream of the -1590 position in the 20alpha-HSD promoter that confers regulation by PGF(2)alpha in ovarian primary cells. This region encompasses a unique transcription factor-binding site with a sequence of a NUR77 response element. Deletion of this motif or overexpression of a NUR77 dominant negative protein caused a complete loss of 20alpha-HSD promoter activation by PGF(2)alpha. NUR77 also transactivated the 20alpha-HSD promoter in transient transfection experiments in corpus luteum-derived cells (GG-CL). This induction required the NUR77-transactivating domain. We also show that PGF(2)alpha induces a very rapid expression of NUR77 that binds to a distal response element located at -1599/-1606 but does not interact with another proximal putative NUR77 response element located downstream in the promoter. A rapid increase in NUR77 mRNA was observed in mice corpora lutea just before parturition at a time when 20alpha-HSD becomes expressed. This increase in the expression of both genes was not seen in PGF(2)alpha receptor knockout mice. By using cyclosporin A and PGF(2)alpha treatment, we established that inhibition of NUR77 DNA binding in vivo prevents PGF(2)alpha induction of the 20alpha-HSD gene in the corpus luteum. Taken together, our results demonstrate, for the first time, that PGF(2)alpha induces in the corpus luteum the expression of the nuclear orphan receptor and transcription factor, NUR77, which in turn leads to the transcriptional stimulation of 20alpha-HSD, triggering the decrease in serum progesterone essential for parturition.

20-Hydroxysteroid Dehydrogenases↗
PubMed2000

Prostaglandin E(2) receptors, EP2 and EP4, differentially modulate TNF-alpha and IL-6 production induced by lipopolysaccharide in mouse peritoneal neutrophils.

The expression and function of prostaglandin (PG) E(2) receptors were examined in mouse neutrophils exudated into the peritoneal cavity by casein treatment. Expressions of the EP2 and EP4 receptors were detected in neutrophils by Northern blot, but those of EP1 and EP3 receptors were not detected by RT-PCR. EP2-selective agonist, ONO-AE1-259, and EP4-selective agonist, ONO-AE1-329, stimulated cAMP formation in the cells. PGE(2) affected the TNF-alpha and IL-6 production in lipopolysaccharide (LPS)-treated neutrophils; it suppressed the TNF-alpha production and enhanced the IL-6 production. The PGE(2) effects were mimicked by dibutyryl cAMP. This is the first study of the enhancement of IL-6 production by cAMP-elevating reagents in neutrophils. Using neutrophils from EP2- and EP4-deficient mice in combination with EP2- and EP4-selective agonists, it was found that the augmentation of IL-6 was mediated mainly by the EP2 receptor and the suppression of TNF-alpha by the EP4 receptor and partially by the EP2 receptor. These findings indicate that casein-induced peritoneal neutrophils express Gs-coupled PGE(2) receptors, EP2 and EP4, which might differentially regulate the LPS-induced production of TNF-alpha and IL-6.

Animals↗
PubMed2000

Impaired bone resorption to prostaglandin E2 in prostaglandin E receptor EP4-knockout mice.

Prostaglandin E(2) (PGE(2)) acts as a potent stimulator of bone resorption. In this study, we first clarified in normal ddy mice the involvement of protein kinase A and induction of matrix metalloproteinases (MMPs) in PGE(2)-induced bone resorption, and then identified PGE receptor subtype(s) mediating this PGE(2) action using mice lacking each subtype (EP1, EP2, EP3, and EP4) of PGE receptor. In calvarial culture obtained from normal ddy mice, both PGE(2) and dibutyryl cyclic AMP (Bt(2)cAMP) stimulated bone resorption and induced MMPs including MMP-2 and MMP-13. Addition of an inhibitor of protein kinase A, H89, or an inhibitor of MMPs, BB94, significantly suppressed bone-resorbing activity induced by PGE(2.) In calvarial culture from EP1-, EP2-, and EP3-knockout mice, PGE(2) stimulated bone resorption to an extent similar to that found in calvaria from the wild-type mice. On the other hand, a marked reduction in bone resorption to PGE(2) was found in the calvarial culture from EP4-knockout mice. The impaired bone resorption to PGE(2) was also detected in long bone cultures from EP4-knockout mice. Bt(2)cAMP greatly stimulated bone resorption similarly in both wild-type and EP4-knockout mice. Induction of MMP-2 and MMP-13 by PGE(2) was greatly impaired in calvarial culture from EP4-knockout mice, but Bt(2)cAMP stimulated MMPs induction similarly in the wild-type and EP4-knockout mice. These findings suggest that PGE(2) stimulates bone resorption by a cAMP-dependent mechanism via the EP4 receptor.

Animals↗
PubMed2000

Inhibitory effects of PGD2, PGJ2 and 15-deoxy-delta12,14-PGJ2 on iNOS induction in rat mesenteric artery.

PGD2 and its metabolites PGJ2 and 15-deoxy-delta12,14-PGJ2 have been reported to inhibit iNOS induction in cultured vascular smooth muscle cells. The present study was undertaken to determine whether these prostanoids inhibit iNOS induction in the isolated rat mesenteric artery. The artery without endothelium was incubated with and without lipopolysaccharide (LPS) at 37 degrees C for 6 hrs, then washed and mounted in an organ bath to measure isometric changes in tension. L-arginine but not D-arginine (10(-6) - 10(-3) M) induced concentration-dependent relaxations only in the artery preincubated with LPS, the relaxations of which were attenuated by L-N(G)-nitroarginine methyl ester (LNAME, 10(-4) M), a non-selective iNOS inhibitor, and 1400W (10(-5) and 10(-4) M), a selective iNOS inhibitor. Co-treatment of cycloheximide (10(-5) M), a protein synthesis inhibitor, or actinomycin D (10(-7) M), an RNA synthesis inhibitor with LPS inhibited the development of relaxing ability in response to L-arginine, indicating iNOS induction by LPS. PGD2, PGJ2 and 15-deoxy-delta12,14-PGJ2 but not PGE2, PGI2 or PGF2alpha also inhibited the development of relaxing ability in response to L-arginine when added during incubation with LPS. Incubation of the artery with LPS at 37 degrees C for 6 hrs markedly increased production of nitric oxide (NO), which was abolished by 15-deoxy-delta12,14-PGJ2 (10(-5) M). An imunohistochemical study using antibody against murine iNOS showed that 15-deoxy-delta12,14-PGJ2 (10(-5) M) inhibited the expression of iNOS protein in isolated rat mesenteric arteries. These results demonstrated that PGD2 and its metabolites inhibit iNOS induction by LPS in isolated rat mesenteric arteries, resulting in reduced relaxing ability in response to L-arginine.

Animals↗
PubMed2000

Fundamental study of hot spot detectability in 3-dimensional positron emission tomography.

The purpose of this study was to investigate the detectability of small hot lesions with the 3-dimensional transmission/emission (3D T/E) acquisition mode in FDG-PET scan. The correlation of target detectability, target size, target to non-target uptake ratio (T/N ratio) and standardized uptake value (SUV) were studied. Small hot lesions ranged from 4.4 mm to 36.9 mm in diameter were located in cylindrical phantom. The images of phantoms with a T/N ratio of 2.0, 4.0, 6.0, 8.0, 9.6, 13.2, 17.5, 23.8 and 30.3 were obtained with 2-dimensional transmission/emission (2D T/E) scan and 3D T/E scans. Targets in diameter more than 10.6 mm in diameter with an actual T/N ratio ranged from 6.0 to 30.3 could be identified on the images obtained with all the 2D T/E and 3D T/E acquisition modes. The detectability efficiency of small hot target in 2D T/E and 3D T/E scans was as same (77.8%). The T/N ratio of targets from 2D T/E images was 30% to 48.4% different to that from 3D T/E image, and the SUV of the target from the 2D T/E images was almost the same as that from 3D T/E images. This study revealed that 3D T/E scanning had similar hot spot detectability to 2D T/E scanning; 3D T/E and 2D T/E scanning had the same faculty for semiquantitative analysis using SUV. These findings may be helpful for the diagnosis and understanding of 3D T/E FDG-PET in hot lesion detection.

Fluorine Radioisotopes↗
PubMed2000

Distribution and function of prostanoid receptors: studies from knockout mice.

Recent developments in the molecular biology of the prostanoid receptors has allowed the investigation of the physiological roles of each individual receptor type and subtype. The following article reports the prostanoid receptor distributions deduced from Northern blot and in situ hybridization analyses, summarizes the phenotypes of each receptor knockout mice, and discusses recent studies investigating the effects of each receptor deficiency on the inflammatory response and female reproductive processes. The combination of expression pattern and knockout analyses enabled us to determine which receptor expressed in a particular cell is important for the maintenance of normal and/or pathological physiology. The results from these analyses may be useful in the development of novel therapeutics that can selectively manipulate prostanoid-mediated actions.

Animals↗
PubMed2000

Prolonged gestation does not extend survival of uterine natural killer lymphocytes in mice deleted in the receptor for prostaglandin F2alpha.

During decidualization in mice and women, expansion of the Natural Killer (NK) cell lineage occurs within the uterus. In rodents, peak numbers of uterine (u)NK cells are reached at mid-gestation. The population then declines and residual cells are shed with the placenta. Decidualization, but not a fetus, is required to induce division and maturation of uNK cells. Mechanisms regulating the decline in uNK cells are unknown. To determine if the conceptus or its products have regulatory roles on uNK cell survival during normal gestation, a histological time course study was undertaken of implantation sites in mice ablated in the gene for the Prostaglandin F2alpha receptor (PGF2alphaR). These females experience normal gestation but fail to initiate labour and delivery. Their pregnancies extend a further 4-7 days before onset of maternal compromise. Large numbers of uNK cells were present in PGF2alphaR null mice by gestational day (gd) 10 and numbers had begun to decline at gd 14. By gd 18, very few uNK cells remained and no uNK cells were found at day 22 of extended gestation. Thus, the population history of uNK cells in PGF2alphaR null mice resembles that of uNK cells in normal mice, suggesting that the placenta, its products, the fetus and PGF2alpha are not factors that influence the rate of uNK cell decline in late gestation.

Animals↗
PubMed2000

Synthesis and structure-activity relationships of a new class of selective EP3 receptor agonist, 13,14-didehydro-16-phenoxy analogues of prostaglandin E1.

A series of 13,14-didehydro-16-phenoxy analogues of prostaglandin E1 was synthesized and their agonistic activity on EP receptor subtypes was evaluated. 13,14-Didehydro-16-phenoxy-1-decarboxy analogues, 7e and 7f, display highly selective activity on the EP3 receptor subtype, thus, their utility as a selective anti-ulcer agent can be expected.

Alprostadil↗