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ABSTRACT: Background and Objective. Cisplatin-based chemotherapy is widely recognized to cause severe gastrointestinal disorders like nausea, vomiting, and appetite loss. The aim of this study was to assess whether cisplatin-based transcatheter arterial infusion (TAI) chemotherapy reduces plasma ghrelin levels and food intake in hepatocellular carcinoma (HCC) patients. Methods. Seventeen patients with HCC who underwent cisplatin-based TAI chemotherapy (80-100 mg/body) were enrolled in this study. Changes in peptide hormones, including ghrelin and leptin, as well as cytokines, were measured before and after chemotherapy. Appetite was evaluated by visual analog scale (VAS) and food intake was scored by eleven stages (0-10). Results. Appetite and food intake were significantly decreased after chemotherapy (P < 0.05). Plasma acylated ghrelin levels before therapy and at day 1, day 7, and day 14 after chemotherapy were 10.4 ± 7.2, 4.7 ± 4.7, 11.7 ± 8.9, and 9.3 ± 6.6 fmol/mL, respectively. The level on day 1 was decreased significantly (P < 0.05). In contrast, the levels of leptin, granulocyte colony-stimulating factor (G-CSF), and monocyte chemotactic protein-1 (MCP-1) on day 1 were increased significantly (P < 0.05). Conclusions. TAI for HCC reduced plasma acylated ghrelin levels, appetite, and food intake significantly. In addition, it increased serum leptin levels.
ISRN gastroenterology. 01/2013; 2013:415450.
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Shoko Minemura,
Tomoaki Matsumura,
Makoto Arai,
Arata Oyamada,
Keiko Saito,
Sayuri Sazuka,
Masaru Tsuboi,
Daisuke Maruoka,
Takeshi Tanaka,
Tomoo Nakagawa, Tatsuro Katsuno,
Keiichi Ishida,
Goro Matsumiya,
Osamu Yokosuka
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ABSTRACT: Arterio enteric fistulas (AEFs) are rare. We herein report a case of a primary arterio enteric fistula of the rectum associated with Takayasu arteritis. A 77-year-old woman presented with acute massive hematochezia and was taken to our hospital. Colonoscopy revealed pulsatile extrinsic rectal wall compression with an exposed blood vessel. Transvaginal ultrasonography and Doppler ultrasound revealed a localized vascular growth laying on the dorsal surface of the uterus that showed an arterial blood-flow signal. We diagnosed the patient to have a pelvic aneurism that had formed a fistula within the rectal wall. We eliminated the aneurysm by ligating the drainage and feeder arteries. Following surgery, the patient did not experience any relapses of hematochezia.
Internal Medicine 01/2013; 52(3):359-362. · 0.94 Impact Factor
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Tomoaki Matsumura,
Makoto Arai,
Toru Sato,
Tomoo Nakagawa,
Daisuke Maruoka,
Masaru Tsuboi,
Sachio Hata,
Eiji Arai, Tatsuro Katsuno,
Fumio Imazeki,
Osamu Yokosuka
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ABSTRACT: To investigate whether flexible spectral color enhancement (FICE) improves diagnostic yields of capsule endoscopy (CE) for obscure gastro-intestinal bleeding (OGIB).
The study subjects consisted of 81 patients. Using FICE, there were three different sets with different wavelengths. Using randomly selected sets of FICE, images of CE were evaluated again by two individuals who were not shown the conventional CE reports and findings. The difference between FICE and conventional imaging was examined.
The overall diagnostic yields in FICE sets 1, 2, 3 and conventional imaging (48.1%) were 51.9%, 40.7%, 51.9% and 48.1%, respectively, which showed no statistical difference compared to conventional imaging. The total numbers of detected lesions per examination in FICE imaging and conventional imaging were 2.5 ± 2.1 and 1.8 ± 1.7, respectively, which showed a significant difference (P = 0.01).
The diagnostic yield for OGIB is not improved by FICE. However, FICE can detect significantly more small bowel lesions compared to conventional imaging.
World journal of gastrointestinal endoscopy. 09/2012; 4(9):421-8.
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ABSTRACT: OBJECTIVE: Low-dose proton pump inhibitors (PPIs) are often administrated as maintenance therapy for gastroesophageal reflux disease (GERD) and on-demand PPI therapy is a viable option for long-term management of GERD. The aim of this study is to investigate intragastric acidity during the first day following the administration of low-dose PPIs. SUBJECTS AND METHODS: The study employed a crossover design. The subjects were 10 healthy volunteers who were administrated lansoprazole 15mg (orally disintegrating) or rabeprazole 10mg. All subjects underwent pH monitoring with a wireless system during the first day after PPI administration. RESULTS: There was no significant difference in the average intragastric pH during the first day of administration of lansoprazole and rabeprazole (3.3±1.1 vs. 3.2±0.7, paired t test), although the pH was significantly higher with both drugs as compared with the baseline (1.8±0.4, P<0.01). The pH 4 holding time ratio during the first day showed no significant difference between lansoprazole and rabeprazole (35.2±22.4% vs. 34.3±15.0%), and was also significantly higher than at baseline (0.35±1.73%, P<0.01). The two PPIs differed with respect to the peak of the pH 4 holding time ratio. CONCLUSIONS: Lansoprazole 15mg and rabeprazole 10mg showed sufficient inhibition of intragastric acidity during the first day after PPI administration and the effects did not differ between drugs, although there was a difference in their time at which the peak effects were reached.
Gastroentérologie Clinique et Biologique 09/2012; · 0.80 Impact Factor
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ABSTRACT: Periodic surveillance colonoscopy is required for patients with ulcerative colitis to detect colitis-associated dysplasia at an early stage. However, sometimes colonoscopy may damage the fragile mucosa of patients with ulcerative colitis. The aim of this study was to devise a new method of surveillance colonoscopy for patients with mild to moderate ulcerative colitis.
The 'flicking method' of colonoscope insertion was recently developed by our team. It is a completely novel method that involves using the elastic force of the colonoscope to introduce it into the deeper regions while using colon mucosa patterns as a guide. The subjects were 66 hospital outpatients with ulcerative colitis who underwent colonoscopies during a 2-year period, from April 2006 to March 2008, with both the conventional insertion method and the flicking method.
Cecal intubation rate, insertion time, patient pain level, change in number of defecations pre- and post-colonoscopy, and change in severity pre- and post-colonoscopy were compared between the conventional and flicking methods. The flicking method was superior in all respects.
The flicking method is a novel colonoscope insertion method that is regarded as particularly useful in cases when the intestinal mucosa is fragile, as is the case with ulcerative colitis patients.
Digestive Endoscopy 09/2012; 24(5):343-7. · 1.19 Impact Factor
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ABSTRACT: There is increased interest in the Bn-receptor family because they are frequently over/ectopically expressed by tumors and thus useful as targets for imaging or receptor-targeted-cytotoxicity. The synthetic Bn-analog, [D-Tyr(6), β-Ala(11), Phe(13), Nle(14)]Bn(6-14) [Univ.Lig] has the unique property of having high affinity for all three human BNRs (GRPR, NMBR, BRS-3), and thus could be especially useful for this approach. However, the molecular basis of this property is unclear and is the subject of this study. To accomplish this, site-directed mutagenesis was used after identifying potentially important amino acids using sequence homology analysis of all BnRs with high affinity for Univ.Lig compared to the Cholecystokinin-receptor (CCK(A)R), which has low affinity. Using various criteria 74 amino acids were identified and 101 mutations made in GRPR by changing each to those of CCK(A)R or to alanine. 22 GRPR mutations showed a significant decrease in affinity for Univ.Lig (>2-fold) with 2 in EC2[D97N, G112V], 1 in UTM6[Y284A], 2 in EC4[R287N, H300S] showing >10-fold decrease in Univ.Lig affinity. Additional mutations were made to explore the molecular basis for these changes. Our results show that high affinity for Univ.Lig by human Bn-receptors requires positively charged amino acids in extracellular (EC)-domain 4 and to a lesser extent EC2 and EC3 suggesting charge-charge interactions may be particularly important for determining the general high affinity of this ligand. Furthermore, transmembrane amino acids particularly in UTM6 are important contributing both charge-charge interactions as well as interaction with a tyrosine residue in close proximity suggesting possible receptor-peptide cation-π or H-bonding interactions are also important for determining its high affinity.
Biochemical pharmacology 07/2012; 84(7):936-48. · 4.25 Impact Factor
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Takashi Kanaya,
Koji Hase,
Daisuke Takahashi,
Shinji Fukuda,
Katsuaki Hoshino,
Izumi Sasaki,
Hiroaki Hemmi,
Kathryn A Knoop,
Nachiket Kumar,
Mayuko Sato, [......],
Osamu Yokosuka,
Kiminori Toyooka,
Kumiko Nakai,
Ayako Sakamoto,
Yuuki Kitahara,
Toshi Jinnohara,
Stephen J McSorley,
Tsuneyasu Kaisho,
Ifor R Williams,
Hiroshi Ohno
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ABSTRACT: Intestinal microfold cells (M cells) are an enigmatic lineage of intestinal epithelial cells that initiate mucosal immune responses through the uptake and transcytosis of luminal antigens. The mechanisms of M-cell differentiation are poorly understood, as the rarity of these cells has hampered analysis. Exogenous administration of the cytokine RANKL can synchronously activate M-cell differentiation in mice. Here we show the Ets transcription factor Spi-B was induced early during M-cell differentiation. Absence of Spi-B silenced the expression of various M-cell markers and prevented the differentiation of M cells in mice. The activation of T cells via an oral route was substantially impaired in the intestine of Spi-B-deficient (Spib(-/-)) mice. Our study demonstrates that commitment to the intestinal M-cell lineage requires Spi-B as a candidate master regulator.
Nature Immunology 06/2012; 13(8):729-36. · 26.01 Impact Factor
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ABSTRACT: BACKGROUNDS AND AIMS: Gastric submucosal tumors (SMTs) are often detected during routine gastroendoscopy but little is known about their natural history. The aim of this study was to evaluate the natural course of gastrointestinal mesenchymal tumors (GIMTs) in the stomach. PATIENTS AND METHODS: From October 2001 to November 2011, a total of 228 gastric SMTs were evaluated by endoscopic ultrasonography (EUS). Based on the findings of EUS and enhanced CT, we diagnosed these tumors as lipomas, cysts, aberrant pancreases, extramural compressions, and GIMTs. The gastric GIMTs which were examined by EUS twice or more were included in this study and the factors associated with an increase in the size of gastric GIMTs were analyzed. RESULTS: Fifty GIMTs were followed by EUS twice or more. The mean age was 66.4±8.3 years old and the mean period of follow-up was 23.8±21.7 months. Fourteen (28%) of 50 GIMTs increased in size and the time taken for gastric GIMTs to double in size was 19.1±18.2 months. In multivariate logistic regression analysis, age (odds ratio [OR]=1.12, 95% confidence interval [CI]=1.03-1.21), non-upper area of the stomach (OR=5.08, 95%; CI=1.37-18.8) and the detection of an anechoic lesion on EUS (OR=5.90, 95%; CI=1.10-31.8) were the factors predicting an increase in size of gastric GIMTs. CONCLUSIONS: We evaluated gastric SMTs by EUS and clarified the factors predicting the growth of gastric GIMT. EUS is indispensable for the diagnosis and management of gastric SMTs.
Gastroentérologie Clinique et Biologique 05/2012; · 0.80 Impact Factor
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ABSTRACT: BackgroundTwo main functionally distinct monocytes phenotypes are known: the CD14hiCD16− “classical” and the CD14+CD16+ “proinflammatory” phenotypes. The latter phenotype is elevated in patients with ulcerative colitis (UC) and is suspected
to have a major role in the immunopathogenesis of UC.
AimTo selectively deplete circulating proinflammatory CD14+CD16+ monocyte phenotype.
MethodsSeven corticosteroid-naïve patients with UC (clinical activity index=8.7±1.3) and seven healthy subjects were included.
In patients with UC, granulocyte/monocyte adsorption (GMA) was done with an Adacolumn that selectively adsorbs leucocytes
of the myeloid lineage. Blood from all subjects at baseline and from the patients immediately after the first GMA session
was processed. Isolated monocytes were subjected to fluorescence-activated cell sorter analyses.
ResultsThe seven UC patients achieved remission (CAI ≤4) after 5–10 GMA sessions. GMA induced a strong fall in the ratio (%) of CD14+CD16+ to CD14hiCD16− monocytes, from 10.0±1.4 to 3.0±0.9. Further, expressions of α4 integrin (374.8±26.1 mean fluorescence intensity, MFI)
and CX3CR1 (49.5±4.6 MFI) were significantly high on CD14+CD16+monocytes as compared with on CD14hiCD16− monocytes (169.2±17.2 and 33.2±3.6 MFI, respectively). Additionally, GMA significantly increased the ratio of the CD14hiCD16−CCR2low “immature” monocytes from 3.74±0.62 to 8.11±0.56 MFI.
ConclusionsWe found high expressions of α4 integrin and CX3CR1 on monocytes in patients with active UC, known to promote the extravasation of CD14+CD16+ monocytes into the mucosa. GMA effectively depletes CD14+CD16+ monocytes and concomitantly increases CD14hiCD16−CCR2low “immature” monocytes; thus GMA was associated with the emergence of less inflammatory monocyte phenotype in circulation.
KeywordsUlcerative colitis-CD14+CD16+ monocytes-CD14hiCD16−CCR2low monocytes-α4 Integrin-CX3CR1-Adsorptive depletion of myeloid leucocytes
Digestive Diseases and Sciences 04/2012; 55(7):1886-1895. · 2.12 Impact Factor
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Eiji Arai,
Makoto Arai,
Tomoyuki Uchiyama,
Yoshinori Higuchi,
Kyoko Aoyagi,
Yoshitaka Yamanaka,
Tatsuya Yamamoto,
Osamu Nagano,
Akihiro Shiina,
Daisuke Maruoka,
Tomoaki Matsumura,
Tomoo Nakagawa, Tatsuro Katsuno,
Fumio Imazeki,
Naokatsu Saeki,
Satoshi Kuwabara,
Osamu Yokosuka
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ABSTRACT: It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of (13)CO(2) excretion (T(max)) in the (13)C-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of (13)CO(2) excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of (13)CO(2) excretion (T(max)) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 ± 22.7 min and 42.5 ± 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of (13)CO(2) excretion (T(max)) values without and with subthalamic deep brain stimulation after surgery were 44.0 ± 17.5 min and 30.0 ± 12.5 min (P < 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the (13)CO(2) excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of (13)CO(2) excretion (T(max)) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (Δghrelin) and changes in T(max) values (ΔT(max)) in the subthalamic deep brain stimulation trial after surgery (r = -0.20), and no association between changes in other characteristics and ΔT(max) post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinson's disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson's disease.
Brain 04/2012; 135(Pt 5):1478-85. · 9.46 Impact Factor
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ABSTRACT: The present study was performed to examine whether probiotics affect Toll-like receptor 4 (TLR4) expression in human colonic
epithelial cells. Culture supernatants or heat-killed bacteria of Bacillus mesentericus TO-A, Clostridium butyricum TO-A, and Streptococcus faecalis T-110 were applied to human colonic epithelial cells. Treatment with C. butyricum TO-A culture supernatant significantly reduced TLR4 mRNA level (×0.16), even in the presence of interferon-γ (IFN-γ; ×0.21)
as compared with untreated controls. High-performance liquid chromatography analysis showed that C. butyricum TO-A supernatant contains formate, acetate, and butyrate. Interestingly, TLR4 mRNA was significantly suppressed (×0.15–×0.22)
only when cells were treated with solutions containing butyrate. Electrophoretic mobility shift assay suggested that the binding
affinity of PU.1 to the promoter region of the TLR4 gene was markedly inhibited when the cells were treated with butyrate.
This study suggested that butyrate produced by C. butyricum TO-A downregulates TLR4 mRNA level in human colonic epithelial cells.
Digestive Diseases and Sciences 04/2012; 52(11):2963-2971. · 2.12 Impact Factor
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ABSTRACT: Genome-wide association studies have revealed a link between autophagy-related (ATG) genes and susceptibility to Crohn's disease. This suggests underlying involvement of autophagy impairment in the pathogenesis of Crohn's disease. This study was performed to investigate the pathophysiological importance of autophagy impairment in intestinal epithelial cells exposed to TNF-α.
Human colonic epithelial cells (HT-29) and rat small intestinal epithelial cells (IEC-18) were used. Formation of phosphatidylethanolamine-conjugated microtubule-associated protein light chain 3 (LC3-II) was monitored as a marker of autophagy. Autophagy was inhibited using 3-methyladenine or short interfering RNA targeting ATG5 and ATG16L1.
TNF-α treatment elicited a significant dose-dependent increase in LC3-II protein levels, thus autophagy is induced in the presence of TNF-α. Combined autophagy inhibition and TNF-α treatment induced a marked increase in the number of detached cells and a decrease in activated integrin β1 protein levels. Trypan blue staining indicated 70-80 % of the detached cells were alive, suggesting that these cells became detached not because they were killed but because of dysfunction of cellular adhesion.
This is the first study indicating that intestinal epithelial cells with impaired autophagy lose their adhesive capacity in the presence of TNF-α. These observations indicate that impairment of autophagy leads to disruption of the intestinal epithelial cell layers in TNF-α-rich environments.
Digestive Diseases and Sciences 03/2012; 57(8):2022-30. · 2.12 Impact Factor
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Daisuke Takahashi,
Koji Hase,
Shunsuke Kimura,
Fubito Nakatsu,
Masumi Ohmae,
Yasushi Mandai,
Toru Sato,
Yasuhiro Date,
Masashi Ebisawa,
Tamotsu Kato,
Yuuki Obata,
Shinji Fukuda,
Yuki I Kawamura,
Taeko Dohi, Tatsuro Katsuno,
Osamu Yokosuka,
Satoshi Waguri,
Hiroshi Ohno
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ABSTRACT: Epithelial cells that cover the intestinal mucosal surface maintain immune homeostasis and tolerance in the gastrointestinal tract. However, little is known about the molecular mechanisms that regulate epithelial immune functions. Epithelial cells are distinct in that they are highly polarized; this polarity is, at least in part, established by the epithelium-specific polarized sorting factor adaptor protein (AP)-1B. We investigated the role of AP-1B-mediated protein sorting in the maintenance of gastrointestinal immune homeostasis.
The role of AP-1B in intestinal immunity was examined in AP-1B-deficient mice (Ap1m2(-/-)) by monitoring their phenotypes, intestinal morphology, and epithelial barrier functions. AP-1B-mediated protein sorting was examined in polarized epithelial cells from AP-1B knockdown and Ap1m2(-/-) mice.
Ap1m2(-/-) mice developed spontaneous chronic colitis, characterized by accumulation of interleukin-17A-producing, T-helper 17 cells. Deficiency of AP-1B caused epithelial immune dysfunction, such as reduced expression of antimicrobial proteins and impaired secretion of immunoglobulin A. These defects promoted intestinal dysbiosis and increased bacterial translocation within the mucosa. Importantly, AP-1B deficiency led to mistargeting of a subset of basolateral cytokine receptors to the apical plasma membrane in a polarized epithelial cell line and in colonic epithelial cells from mice. AP1M2 expression was reduced significantly in colonic epithelium samples from patients with Crohn's disease.
AP-1B is required for proper localization of a subset of cytokine receptors in polarized epithelial cells, which allows them to respond to cytokine signals from underlying lamina propria cells. The AP-1B-mediated protein sorting machinery is required for maintenance of immune homeostasis and prevention of excessive inflammation.
Gastroenterology 05/2011; 141(2):621-32. · 11.68 Impact Factor
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ABSTRACT: Deficiency of Smad3, an intracellular mediator of TGF-β, was shown to significantly accelerate re-epithelialization of the colonic mucosa. This study was performed to investigate the molecular mechanisms by which Smad3 controls colonic epithelial cell proliferation and crypt formation. Smad3(ex8/ex8) C57BL/6 mice were used in this study and wild-type littermates served as controls. The number of proliferating cells in the isolated colonic epithelium of Smad3(-/-) mice was significantly increased compared to that in wild-type littermates. Protein levels of the cell cycle inhibitors p21 and p27 were significantly decreased, while that of c-Myc was increased in the isolated colonic epithelium from Smad3(-/-) mice. In the colonic tissue of wild-type mice, cell proliferation was restricted to the bottom of the crypts in accordance with nuclear β-catenin staining, whereas proliferating cells were located throughout the crypts in Smad3(-/-) mice in accordance with nuclear β-catenin staining, suggesting that Smad3 is essential for locating proliferating cells at the bottom of the colonic crypts. Notably, in Smad3(-/-) mice, there was loss of EphB2 and EphB3 receptor protein expression, critical regulators of proliferating cell positioning, while EphB receptor protein expression was confirmed at the bottom of the colonic crypts in wild-type mice. These observations indicated that disturbance of the EphB/ephrin B system brings about mispositioning of proliferating cells in the colonic crypts of Smad3(-/-) mice. In conclusion, Smad3 is essential for controlling number and positioning of proliferating cells in the colonic crypts and contributes to formation of a "proliferative zone" at the bottom of colonic crypts in the normal colon.
Biochemical and Biophysical Research Communications 01/2011; 405(4):521-6. · 2.48 Impact Factor
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Tomoaki Matsumura,
Makoto Arai,
Sayuri Sazuka,
Masaya Saito,
Yoshie Takahashi,
Daisuke Maruoka,
Takuto Suzuki,
Tomoo Nakagawa,
Toru Sato, Tatsuro Katsuno,
Fumio Imazeki,
Osamu Yokosuka
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ABSTRACT: Capsule endoscopy (CE) is used widely for determining the cause of obscure gastrointestinal bleeding (OGIB). However, negative findings still arise from CE examination. The aim of this study was to determine the factors associated with negative findings on CE in patients with OGIB.
A total of 134 patients who underwent CE for overt (n = 104) or occult (n = 30) OGIB between October 2007 and April 2010 were included. The clinical backgrounds of the patients (age; sex; the use of anti-coagulant, anti-platelet drugs or NSAIDs; comorbidity and the timing of CE examination after bleeding) were noted.
The overall diagnostic yield of CE in detecting the relevant findings was 50% (n = 67). Multivariate analysis revealed that the use of anti-platelet drug and the timing of CE (≥ 16 days) were predictive factors for negative findings on CE (odds ratio 2.69 [1.01-7.21], p = 0.048 and odds ratio 2.32 [1.01-5.33], p = 0.047, respectively). Among the patients with the use of low-dose aspirin (LDA, n = 28) as anti-platelet drug, cessation of it before CE was the only predictive factor for negative findings on CE (odds ratio 12.0 [1.72-83.5], p = 0.012).
In the patients with OGIB, the use of LDA and the cessation of it before CE made it difficult to detect the cause of bleeding by CE. This might indicate that the source of OGIB related to LDA heals immediately after cessation of the drugs or is a very small lesion that could not be detected by CE.
Scandinavian journal of gastroenterology 12/2010; 46(5):621-6. · 2.08 Impact Factor
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ABSTRACT: Two main functionally distinct monocytes phenotypes are known: the CD14(hi)CD16(-) "classical" and the CD14(+)CD16(+) "proinflammatory" phenotypes. The latter phenotype is elevated in patients with ulcerative colitis (UC) and is suspected to have a major role in the immunopathogenesis of UC.
To selectively deplete circulating proinflammatory CD14(+)CD16(+) monocyte phenotype.
Seven corticosteroid-naïve patients with UC (clinical activity index = 8.7 +/- 1.3) and seven healthy subjects were included. In patients with UC, granulocyte/monocyte adsorption (GMA) was done with an Adacolumn that selectively adsorbs leucocytes of the myeloid lineage. Blood from all subjects at baseline and from the patients immediately after the first GMA session was processed. Isolated monocytes were subjected to fluorescence-activated cell sorter analyses.
The seven UC patients achieved remission (CAI <or=4) after 5-10 GMA sessions. GMA induced a strong fall in the ratio (%) of CD14(+)CD16(+) to CD14(hi)CD16(-) monocytes, from 10.0 +/- 1.4 to 3.0 +/- 0.9. Further, expressions of alpha4 integrin (374.8 +/- 26.1 mean fluorescence intensity, MFI) and CX(3)CR1 (49.5 +/- 4.6 MFI) were significantly high on CD14(+)CD16(+)monocytes as compared with on CD14(hi)CD16(-) monocytes (169.2 +/- 17.2 and 33.2 +/- 3.6 MFI, respectively). Additionally, GMA significantly increased the ratio of the CD14(hi)CD16(-)CCR2(low) "immature" monocytes from 3.74 +/- 0.62 to 8.11 +/- 0.56 MFI.
We found high expressions of alpha4 integrin and CX(3)CR1 on monocytes in patients with active UC, known to promote the extravasation of CD14(+)CD16(+) monocytes into the mucosa. GMA effectively depletes CD14(+)CD16(+) monocytes and concomitantly increases CD14(hi)CD16(-)CCR2(low) "immature" monocytes; thus GMA was associated with the emergence of less inflammatory monocyte phenotype in circulation.
Digestive Diseases and Sciences 11/2009; 55(7):1886-95. · 2.12 Impact Factor
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ABSTRACT: The mammalian bombesin (Bn) peptides, neuromedin B (NMB) and gastrin-releasing peptide (GRP), have widespread actions in many tissues, and their effects are mediated by two closely related G-protein-coupled receptors, the NMBR and GRPR. Little is known about the structural determinants of NMBR selectivity for NMB, in contrast to GRP selectivity for the GRPR, which has been extensively studied. To provide insight, chimeric NMBR-GRPR loss-of-affinity and gain-of-affinity mutants were made, as well as NH(2)-terminally truncated NMBR and point mutants using site-directed mutagenesis. Receptors were expressed in Balb-3T3-cells or CHOP cells, and affinities were determined. NMB had 115-fold greater affinity for NMBR than GRPR. Receptor-chimeric studies showed that NMBR selectivity for NMB was primarily determined by differences in the third extracellular (EC3) regions of GRPR-NMBR and adjacent upper-transmembrane-5 (TM5) region. In this region, 24 NMB gain-of-affinity GRPR mutants or NMBR loss-of-affinity point/combination mutants were made. Three gain-of-affinity mutant GRPRs [[A198I] (EC3), [H202Q] (EC3), [S215I] (upper TM5)] had increased NMB affinity (2.4-21-fold), and these results were confirmed with NMBR loss-of-affinity mutants [I199A,Q203H,I215S-NMBR]. The combination mutant [A198I,S215]GRPR had the greatest effect causing a complete NMB gain-of-affinity. The importance of differences at position 199NMBR or 203NMBR was studied by substituting amino acids with various properties. Our results show that NMBR selectivity for NMB is due to differences in the EC3 of NMBR-GRPR and the adjacent upper-TM5 region. Within these regions, isoleucines in NMBR [position 199 (EC3)] (instead of A198GRPR) and in 215NMBR (TM5) (instead of S214GRPR), as well as Q203NMBR (instead of H202GRPR) are responsible for high NMB-affinity/selectivity of NMBR. The effect at position 199 is primarily due to differences in hydrophobicity of the substitution, whereas steric factors and charge of the substitution at position 203 were important determinants of NMB selectivity.
Journal of Pharmacology and Experimental Therapeutics 08/2009; 331(1):265-76. · 3.83 Impact Factor
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ABSTRACT: Fibrocytes contribute to wound healing and are uniquely defined by coexpression of hematopoietic and mesenchymal cell markers. In this study, trafficking of fibrocytes was determined in a murine model of colitis induced by administering 3% dextran sodium sulfate (DSS) for seven days. Colonic tissues were immunostained for CD45, collagen type I (Col I), and alpha-SMA. On day 0, there were no CD45(+)Col I(+) cells in colonic tissues. However, on day 7 when inflammatory cells showed remarkable accumulation, oval-shaped CD45(+)Col I(+) fibrocytes were obvious in the submucosal layer. On day 14 when colonic tissues were in the healing phase, numerous spindle-shaped CD45(+)Col I(+) fibrocytes were observed. Emergence of CD45(+)Col I(+) fibrocytes preceded the appearance of alpha-SMA(+) myofibroblasts. Oval-shaped fibrocytes recruited as early as the inflammatory phase of colitis are likely to differentiate into spindle-shaped fibrocytes in the healing phase, suggesting that fibrocytes may promote wound healing in inflamed colonic tissues.
Digestive Diseases and Sciences 03/2009; 55(2):253-60. · 2.12 Impact Factor
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ABSTRACT: After a 17-year-old woman with ulcerative colitis was treated with granulocyte apheresis, chest imaging showed multiple nodular infiltrates, including one which seemed to have a cavity. Wegener's granulomatosis was suspected because proteinase-3 anti-neutrophil cytoplasmic antibody levels were increased. Transbronchial lung biopsy specimen showed nonspecific findings. Chest imaging showed clearing of pulmonary infiltrates without any therapy or discontinuation of mesalazine, which is known to cause lung toxicity. To the best of our knowledge, this is the first report of extra-intestinal pulmonary complications of ulcerative colitis with elevated proteinase-3 anti-neutrophil cytoplasmic antibody resembling Wegener's granulomatosis and spontaneous improvement.
Internal Medicine 02/2008; 47(13):1211-4. · 0.94 Impact Factor
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ABSTRACT: The present study was performed to examine whether probiotics affect Toll-like receptor 4 (TLR4) expression in human colonic epithelial cells. Culture supernatants or heat-killed bacteria of Bacillus mesentericus TO-A, Clostridium butyricum TO-A, and Streptococcus faecalis T-110 were applied to human colonic epithelial cells. Treatment with C. butyricum TO-A culture supernatant significantly reduced TLR4 mRNA level (x0.16), even in the presence of interferon-gamma (IFN-gamma; x0.21) as compared with untreated controls. High-performance liquid chromatography analysis showed that C. butyricum TO-A supernatant contains formate, acetate, and butyrate. Interestingly, TLR4 mRNA was significantly suppressed (x0.15-x0.22) only when cells were treated with solutions containing butyrate. Electrophoretic mobility shift assay suggested that the binding affinity of PU.1 to the promoter region of the TLR4 gene was markedly inhibited when the cells were treated with butyrate. This study suggested that butyrate produced by C. butyricum TO-A downregulates TLR4 mRNA level in human colonic epithelial cells.
Digestive Diseases and Sciences 11/2007; 52(11):2963-71. · 2.12 Impact Factor
