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BACKGROUND With the increase in endoscopic procedures, endoscopists are spending more time creating reports. Although medical reports have largely become electronic, most of the current reporting systems require manual operation. This study aimed to evaluate the efficacy of a novel endoscopic reporting system that uses voice recognition (VR) technology. METHODS We retrospectively reviewed consecutive patients who underwent esophagogastroduodenoscopy between September 2019 and March 2020 at a general hospital in Japan. The novel reporting system, used during endoscopic procedures, is equipped with VR and provides automatic responses by playing back recognized words. Differences in total time spent on the endoscopic procedure and report preparation between the manual entry (ME) and VR groups were evaluated using a propensity score matching method. RESULTS We enrolled 356 patients: 226 and 130 patients in the ME and VR groups, respectively. Propensity score matching created 101 matched pairs. After matching, the median report preparation time (311 vs. 383 s, P = 0.009) and median total time (765 vs. 842 s, P = 0.053) in the VR group were shorter than those in the ME group. The VR system independently shortened the total and report preparation times by 156 s (95% confidence interval, - 274 to - 37 s; P = 0.009) and 118 s (95% confidence interval, - 220 to - 15 s; P = 0.023), respectively, on multiple linear regression analysis. CONCLUSIONS The VR system could save the report preparation time and the total time. This novel system may improve the efficiency of endoscopy-related tasks.

Objective: This study evaluated the effects of ebastine on serum eosinophil cationic protein (ECP) levels in patients with bronchial asthma. Patients: Twenty patients with bronchial asthma (11 patients with atopic disease and nine with non-atopic disease) were enrolled in the study. Methods: In an open-label design, all patients received ebastine 10 mg/day for 4 weeks and serum ECP levels, peripheral blood eosinophil counts, morning peak expiratory flow rate (PEFR) and thresholds for airway hyper-responsiveness (Dmin in asthgraphy) were determined before and after treatment. Results: Serum ECP levels and peripheral blood eosinophil counts were significantly decreased. By disease type, no significant change was found in the non-atopic patients, while the serum ECP level was significantly (p < 0.001) decreased in the atopic patients. Furthermore, no significant change in Dmin was found, but PEFR was significantly (p < 0.019) increased in the atopic type. Conclusion: Ebastine not only inhibits type I allergic reactions, but may also inhibit airway inflammation by reducing serum ECP levels, particularly in patients with atopic bronchial asthma.

GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic β-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclization of the phenylpropanoic acid moiety of lead compound 1 produced fused phenylalkanoic acids with favorable in vitro agonist activities and pharmacokinetic profiles. Further optimization led to the discovery of dihydrobenzofuran derivative 9a ([(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate, TAK-875) as a potent, selective, and orally bioavailable GPR40 agonist, with a pharmacokinetic profile enabling long-acting drug efficacy. Compound 9a showed potent plasma glucose-lowering action and insulinotropic action during an oral glucose tolerance test in female Wistar fatty rats with impaired glucose tolerance. Compound 9a is currently in clinical trials for the treatment of type 2 diabetes mellitus.

Sclerosing lipogranuloma (SLG) is a rare disease that occurs in the male genital region. We report here three cases of SLG, including two of Y-shaped lesions in the penile base forming an intrascrotal mass, as well as a patient with a mass in the epidydimal region. All three lesions histologically exhibited formation of multiple granulomas consisting of multinucleated giant cells and epithelioid cells, in the fibroadipose tissue or around the epidydimis, in association with eosinophil infiltration. Membranocystic changes were found within the cytoplasm of multinucleated cells. In the two patients with scrotal lesions, membranocystic changes were positive for diastase-PAS reaction and on Sudan black B staining in dewaxed sections. CD68 staining was strongly positive in multinucleated giant cells and epithelioid cells. Most of the lymphocytes infiltrating the lesions were T cells associated with some S-100-positive dendritic cells. T-cell mediated immune reaction appears to be important in the histogenesis of SLG. The histogenesis is generally considered to be a foreign-body reaction to degenerated or damaged fatty tissue or lipids, but no apparent causative factors can be identified in some reported cases. All three patients in the present study had a good clinical course after biopsy or surgical excision. We thus report three cases of SLG including an unusual case in the epidydimal region, with some considerations regarding the histogenesis of SLG.

Although monocyte infiltration is an important aspect of the host response to tumor growth, the mechanisms of recruitment and their impact on tumor growth are still unknown. The authors studied monocyte-endothelial interaction and the effect of chemokine CCL2 in orthotopic mouse pancreatic cancer.The rolling and adhesion of labeled monocytes in peritumoral and intratumoral areas were assessed by using an intravital microscope. Further, the effects of intratumoral injection or superfusion of CCL2 on in situ recruitment of monocytes and other immune cells and adhesion molecules were investigated.More monocytes were recruited in the peritumoral area than in the intratumoral area with increased vascular interaction, and the effect was more apparent by intratumoral CCL2 injection than superfusion. In both CCL2-treated groups infiltration of CD11b(+), CD68(+), and CD4(+) cells were increased, but the magnitude of increase was larger in intratumoral injection. Quantitative RT-PCR for the tumor tissue revealed that ICAM-1 expression was increased by the injection of CCL2.These results show intratumoral injection of CCL2 induces effective interaction between monocytes and endothelial cells in the peritumoral area of pancreatic cancer accompanied by the upregulation of ICAM-1 and may possibly become a tool for immunotherapy by promoting the infiltration of immune cells in cancers.

To develop effective drugs for hypogonadism, sarcopenia, and cachexia, we designed, synthesized, and evaluated selective androgen receptor modulators (SARMs) that exhibit not only anabolic effects on organs such as muscles and the central nervous system (CNS) but also neutral or antagonistic effects on the prostate. Based on the information obtained from a docking model with androgen receptor (AR), we modified a hit compound A identified through high-throughput screening. Among the prepared compounds, 1-(4-cyano-1-naphthyl)-2,3-disubstituted pyrrolidine derivatives 17h, 17m, and 17j had highly potent AR agonistic activities in vitro and good tissue selectivity in vivo. These derivatives increased the weight of the levator ani muscle without influencing the prostate and seminal vesicle. In addition, these compounds induced sexual behavior in castrated rats, indicating that the compounds could also act as agonists on the CNS.

The efficacy of Sparfloxacin (SPFX) for the control of bronchial asthma was evaluated in 26 patients with suspected Chlamydia pneumoniae infection. Patients were randomly allocated to receive SPFX 200 mg/day (n = 14) or control treatment (n = 12) for 21 days. Significant improvements in serum C-reactive protein levels, and significant decreases in peripheral eosinophil counts, serum eosinophil cationic protein (ECP) and sputum ECP were observed in the SPFX-treated group at day 21. SPFX-treated patients also had a significantly reduced frequency of asthma symptoms, reduced inhalant β2-stimulant use, and significant increases in morning peak expiratory flow. At the end of the study, C. pneumoniae was undetectable in two SPFX-treated patients who underwent polymerase chain reaction testing, but one control patient who was tested still had detectable levels of C. pneumoniae. These results suggest that SPFX could be used to control bronchial asthma in patients with suspected persistent C. pneumoniae infection.

Most cases of pancreatic cancer are inoperable when diagnosed. Since immunotherapy and antiangiogenic therapy have been reported to be promising for pancreatic cancer, we examined whether the combination of immunotherapy with dendritic cells (DCs) and the antiangiogenic drug TNP-470 induces tumor regression. Syngeneic mouse pancreatic adenocarcinoma cells were orthotopically inoculated into C57/BL6 mice. DCs with or without tumor lysate (TL) were administered i.p. at 4 and 5 weeks. TNP-470 was injected s.c. into tumor-bearing mice every other day from 4 weeks to 6 weeks. We compared anticancer effects in 6 groups: NT (no treatment), DC/TL− (DCs without TL), DC/TL+ (DCs pulsed with TL), TNP (TNP-470 alone), DC/TL–TNP (DC/TL− plus TNP-470) and DC/TL+TNP (DC/TL+ plus TNP-470). We measured tumor volume, mean vascular density (MVD) and vessel diameter by FITC-dextran using an intravital microscope; degrees of proliferation and apoptosis of cancer cells by PCNA and TUNEL; infiltrating lymphocytes and expression levels of VEGF and MMP-9 by immunohistochemistry and immunoblotting. Tumor volume and MVD were significantly suppressed in the treatment groups with prolonged survival rate, especially in the DC/TL+TNP group. There were no significant differences in apoptosis among the 6 groups except DC/TL+. The number of infiltrating CD4+ cells in the DC/TL+ group was higher than that in the NT group. VEGF expression was significantly suppressed in the treatment groups containing TNP-470, and MMP-9 was also suppressed in the groups containing DC/TL+. Our data suggested that TL-pulsed DCs combined with TNP-470 induced regression of mouse pancreatic cancer, possibly through induction of immune responses and suppression of angiogenesis. © 2005 Wiley-Liss, Inc.

An autopsy case of adenosquamous pancreatic cancer in a 61-year-old male patient with an elevated serum level of parathyroid hormone-related protein (PTH-rP) is reported. He was admitted to our hospital with a 1-month-long history of abdominal discomfort and progressive abdominal fullness. A computed tomography (CT) scan of the abdomen showed a retroperitoneal mass, approximately 10 cm in diameter, involving the pancreas, with round enhancement on contrast examination. Histological examination of a specimen taken by CT-guided needle biopsy suggested squamous cell carcinoma or transitional cell carcinoma. Laboratory data on admission revealed a high serum calcium level and high PTH-rP level. The calcium level initially responded to intravenous hydration, furosemide, calcitonin, and bisphosphonates, decreasing from 15.0 to 9.0 mg/dl. However, the hypercalcemia recurred after 10 days. The patient developed carcinomatous peritonitis and acute renal failure, and died on the 25th hospital day. Autopsy revealed a mass in the pancreatic body to tail, invading the retroperitoneum, with progressive carcinomatous peritonitis. Histological examination of the mass revealed infiltrating carcinoma, showing squamous differentiation with focal intracytoplasmic lumina formation, consistent with pancreatic adenosquamous carcinoma. Immunohistological examination showed positive staining for PTH-rP. Adenosquamous carcinoma of the pancreas is relatively rare; only a few cases associated with hypercalcemia and for which PTH-rP has been identified as a causative factor have been reported. This is the first case in which immunohistochemistry proved localized PTH-rP in adenosquamous pancreatic cancer cells, associated with persistent hypercalcemia.

Although the appendix is recognized as an inductive site of intestinal inflammation, lymphocyte migration to lymphoid tissues of the appendix has not been characterized. The authors investigated if there are specific features in T-lymphocyte adhesion to microvessels of the appendix compared to mouse Peyer's patches (PPs).T-lymphocyte interaction with postcapillary venules (PCVs) of lymph follicles of the appendix and PPs was observed using an intravital microscope. Antibodies against ICAM-1, MAdCAM-1, or anti-L-selectin were administered prior to lymphocyte administration, and in some experiments CCR7 on T-lymphocytes was desensitized by excess CCL21.The number of adhered T-lymphocytes reached the maximum value earlier in PCVs of PPs than in those of the appendix. T-lymphocyte adherence was significantly inhibited by anti-MAdCAM-1 at either the appendix or PPs, but adherence in the appendix was also significantly inhibited by anti-ICAM-1, suggesting a dependency on ICAM-1 in the appendix. Histologically, there was a significant ICAM-1 expression in the appendix. Desensitization of CCR7 suppressed T-cell adhesion in PCVs of the appendix and PPs to the same extent.ICAM-1 appeared to be more important in T-lymphocyte sticking in PCVs of the appendix compared with intestinal PPs, while MAdCAM-1 and CCR7 were shown to play important roles in T-lymphocyte adherence in all sites.

Background: Infrared light can penetrate tissue more deeply than visible light. Therefore, an infrared video endoscope may be useful for assessment of gastric submucosal vessels. However, the resolution of currently available infrared video endoscope systems has been unsatisfactory. A new infrared video endoscope system was developed and its clinical utility assessed for diagnosis of early stage gastric cancer. Methods: Twenty-five patients with early stage gastric cancer and 8 with gastric adenoma underwent endoscopy with the infrared video endoscope system after intravenous injection of indocyanine green. Result: Indocyanine green pooling did not appear in adenomas and some intramucosal gastric cancers, whereas it was noted in all submucosally invasive gastric cancers. Tumors not exhibiting indocyanine green pooling were intramucosal, well-differentiated adenocarcinomas of low height (flat-type cancers). Conclusion: These results suggest that our new infrared video endoscope provides valuable information about the submucosal aspect of early stage gastric cancer. Infrared video endoscopy may become a powerful technique for determining whether to perform endoscopic mucosal resection. (Gastrointest Endosc 2003;57:336-42.)

Endoscopic mucosal resection with a cap-fitted panendoscope is a useful, effective, and safe technique. The effectiveness and safety of a newly designed larger but softer cap was compared in this study with the conventional hard cap. The soft cap has a significantly larger diameter (18 mm) compared with that of the hard cap (16.5 mm).Eighty-three patients who underwent mucosal resection of gastric lesions were included in analysis. The diameter, resection specimen depth, and the rate of en bloc resection were compared. The operability of the endoscope with the cap attached, patient tolerance, and safety of the procedure were analyzed.Mean diameter (+/- SEM) of specimens resected with the soft cap was larger: 22.1 (+/- 0.7) versus 15.8 (+/- 0.3) mm (p0.001). The specimen was also thicker: 1.54 (+/- 0.10) versus 1.08 (+/- 0.11) mm (p0.001). Use of the soft cap led to higher rate of en bloc resection: 66.7% versus 43.2% (p0.05). The operability of the endoscope with the larger, softer cap attached was similar to that when the hard cap was used. Both caps were equally safe.The soft cap is safe and useful for mucosal resection of larger gastric lesions. Its use increases the rate of en bloc resection.

症例は75歳の男性. 右側腹部の瘻孔からの腸液, 便汁の排泄を主訴に近医より当科紹介となった. 喀痰検査で結核菌が検出されGaffky3号で, 胸部単純X線写真では右上肺野に浸潤影を認めた. 大腸内視鏡検査では, 回盲弁直上に輪状狭窄を認め, これより口側には通過不能で, 瘻孔造影では, 腸管皮膚瘻から続く拡張した小腸が造影された. 腸結核の診断にて手術を施行した. 回盲部は炎症の波及により周囲と一塊となり, 回腸末端部は拡張, 肥厚しており, 瘻孔部を含めて右半結腸切除術を施行した. 切除標本では回腸末端部の多発した潰瘍の1つに瘻孔が連続しており, 病理組織学的には結核菌は証明されなかったが, Langhans型巨細胞を伴う類上皮性肉芽腫を認めた. 腸結核は一般に腸管壁の水平方向へ伸展し, 深部方向へは拡がりにくく瘻孔を形成することは極めてまれであり, 本症例は興味ある症例と考えられた.

Platelet-activating factor (PAF) is a potent phospholipid mediator with diverse biological activities in addition to its well-known ability to stimulate platelet aggregation. Pharmacologic studies had suggested a role for PAF in pregnancy, neuronal cell migration, anaphylaxis, and endotoxic shock. Here we show that disruption of the PAF receptor gene in mice caused a marked reduction in systemic anaphylactic symptoms. Unexpectedly, however, the PAF receptor–deficient mice developed normally, were fertile, and remained sensitive to bacterial endotoxin. These mutant mice clearly show that PAF plays a dominant role in eliciting anaphylaxis, but that it is not essential for reproduction, brain development, or endotoxic shock.

A 57-year-old woman complained of anal bleeding. She had undergone radical hysterectomy followed by radiation total 60 gray for the treatment of uterus cancer 8 years prior. Colonoscopic examination was performed, and laterally spreading tumors were detected in the transverse, descending, and sigmoid colon. Histopathological findings of operated specimen were compatible with radiation colitis, and mucinous adenocarcinoma existed in this region and invaded to the subserosa with lymphonodi metastasis. She died of peritonitis carcinomatosa 8 months later.

Autoantibodies against heat shock protein (hsp) 60 have been reported to be detected in sera of non-obese diabetic mice, in an experimental model of IDDM. However, there are only a few studies which have examined IDDM patients for antibodies against mammalian hsp60. We produced murine hsp60 derived from pancreatic beta cells which has high homology to human hsp60 and examined antibodies against the hsp60 in IDDM patients using an enzyme-linked immunosorbent assay. We extended the analysis to patients with other immune-mediated diseases and non-insulin-dependent diabetes mellitus (NIDDM). Positive sera for hsp60 antibody were more frequently detected in 13 out of 84 IDDM (15.5%) and 5 out of 25 rheumatoid arthritis patients (20%), when compared to healthy subjects (1/85; 1.2%, P0.001 and P0.01, respectively). The levels of hsp60 antibodies of IDDM (0.218 +/- 0.227) and rheumatoid arthritis patients (0.259 +/- 0.191) were significantly higher than those of healthy subjects (0.076 +/- 0.131, P0.001, P0.01, respectively). Patients with slowly progressive IDDM (n = 26), autoimmune thyroid disease (n = 42), or NIDDM (n = 40) had levels of hsp60 antibodies similar to those in healthy subjects. We found no relationship between the levels of hsp60 antibodies and islet cell antibodies (ICA) or antibodies to glutamic acid decarboxylase (GAD65) in IDDM patients. In conclusion, hsp60 antibodies were detected in Japanese IDDM as well as in rheumatoid arthritis patients. Although the positivity was low, the detection of hsp60 antibodies may be helpful for diagnosis of IDDM especially in GAD65 Ab- or JCA-negative Japanese patients.

C57BL/KsJ mice carrying homozygous db/db mutation (db/db mice) are characterized by extreme obesity and early onset of hyperglycemia. In an attempt to rectify diabetes of these mice, a pancreatic beta cell line MIN6, which retains glucose-inducible insulin secretion, was transplanted subcutaneously into the back of the mice. Glucose and insulin levels of individual mice were examined biweekly and their weight gain weekly. All mice were sacrificed at 100 days after the transplantation of MIN6 cells. In db/db mice that had received MIN6 cells, blood insulin levels were restored and blood glucose levels were reduced to those of non-diabetic mice, although they remained obese. Glucose tolerance test suggested that transplanted MIN6 cells responded to loaded glucose as beta cells of non-diabetic mice. Immunohistochemical study showed that transplanted MIN6 cells produced insulin. Fatty liver associated with diabetes mellitus observed in db/db mice was not found in the MIN6 cell-transplanted mice. Implication of the results is discussed with reference to potential therapies for severe diabetes.

We experienced two cases of cecal granular cell tumor. The site of occurrence and diagnosis are discussed in relation to the literature on granular cell tumor of the large intestine. Most granular cell tumors of the large intestine tend to remain constant in size, showing the morphology of a submucosal tumor. Endoscopic excision was considered a useful diagnostic procedure. S-100 protein was positive in most cases, supporting the hypothesis that the tumor is derived from Schwann cells.

We have generated transgenic mice, in either C57BL/6 or C3H background, expressing antisense glucokinase mRNA in β-cells. The glucose phosphorylating activity at 60 mM glucose in transgenic islets was significantly lower than that in controls, and the insulin secretory response to glucose was lower in transgenic islets than in those of controls in both strains. Following i.p. glucose challenge, higher blood glucose levels were observed in transgenic mice than in controls in the C57BL/6 nut not the C3H background. These data suggest that a β-cell secretory defect, in combination with other undefined genetic factors, causes impaired glucose homeostasis in mice.

原発性肺癌における新しい腫瘍マーカーであるサイトケラチン19フラグメント (CYFRA21-1) の臨床的意義を検討するため原発性肺癌患者52例と他の肺疾患患者38例, 健常者22例について血清CYFRA21-1を測定し, 他の腫瘍マ-カー (CEA, SCC, NSE) と比較検討した.cut-off値を3.5ng/mlとすると原発性肺癌における陽性率は65%, 他の肺疾患における偽陽性率は8%であった.組織型別では, 扁平上皮癌で88.9%と最も高い陽性率を示し, 腺癌でも61.5%の陽性率を示した.免疫組織学的検討では扁平上皮癌において細胞質内で均一に強陽性に染色された.臨床病期別検討では, 1期50%, II期50%, IIIA期40%, IIIB期71%, IV期72%と早期肺癌でも高い陽性率を認めた.ROC曲線の検討においてもCYFRA2Hは原発性肺癌全体及び肺扁平上皮癌でCEA, SCCに比較し感受性, 特異性でも優れていると考えられた.

Macrophages from recent onset non-obese diabetic (NOD) mice showed cytotoxicity against the NOD mouse derived beta-cell line, MIN6N-9a. In this report, we examined whether nitric oxide is associated with beta-cell destruction. Peritoneal exudate cells (PEC), obtained from cyclophosphamide treated NOD mice showed higher cytotoxicity against MIN6N-9a compared to PECs from saline injected NOD mice (P

To elucidate the roles of macrophages in the pathogenesis of NOD murine diabetes, peritoneal macrophages from NOD mice were injected into young NOD mice. We used 12 to 20 week-old NOD mice of both sexes as donors, and sex-matched 2-week-old NOD mice as recipients. Cyclophosphamide (CY), 200 mg/kg, was intraperitoneally injected into the donors. Two weeks later, peritoneal exudate cells (PEC) were collected from the diabetic donors. Macrophagerich fractions (MRF) were collected by adherence. Then PEC(5–8 × 10 6 ) or MRF(3–7 × 10 6 ) were transferred, intraperitoneally, to the recipients. Two weeks later, some of the recipients were killed in order to perform immunofluorescent analysis of splenocytes and to assess pancreatic histology. Mac 1 positive splenocytes were increased in PEC- and in MRF-injected recipient mice. Insulitis was seen in PEC- and MRF-injected mice, but not in controls. Some of the recipients were injected with CY, 200 mg/kg, intraperitoneally, at two weeks post cell transfer. Two weeks after CY injection, the animals were examined for the presence of diabetes. The incidences of diabetes were 67% in PEC-injected mice, 40% in the MRF-injected group, and 3% in the controls. These results suggest that peritoneal macrophages accelerate the disease process in NOD mice.

Transgenic expression of the MHC (major histocompatibility complex) class II I-Ak molecule was previously shown to effectively reduce the incidence of insulitis in non-obese diabetic (NOD) mice at the age of 20 weeks. We have further characterized the expression and function of the I-Ak molecule and examined its effects on the incidence of diabetes in NOD mice. The newly expressed I-Ak molecule was recognized as an alloantigen by the T lymphocytes of normal NOD mice as shown by mixed lymphocyte reaction (MLR). The levels of endogenous I-Ag7 expression on peripheral blood lymphocytes were not affected by the transgene expression. Transgenic NOD mice were completely resistant to spontaneous diabetes, but the treatment by cyclophosphamide, which effectively induces diabetes in normal NOD mice, caused diabetes, although at a much lower incidence than that of normal NOD mice. On the basis of these findings, we discuss the role of I-Ak in the prevention of diabetes in NOD mice.

Sparfloxacin, a new synthetic quinolone antimicrobial agent, was administered to 20 patients with mycoplasmal pneumonia to evaluate its clinical efficacy and adverse effects. The efficacy rate was 100%. In all cases, the subjective symptoms, chest x-ray findings and inflammatory response improved within 5 days after sparfloxacin administration. There were no adverse events including abnormal laboratory values in any of the patients during the treatment period, and no adverse effects that were thought to be due to sparfloxacin were encountered. Since sparfloxacin displays an excellent activity against Mycoplasma pneumoniae and has a broad spectrum of antimicrobial activity against not only Gram-negative bacteria but also Gram-positive bacteria, Legionella, Chlamydia and acid-fast bacteria, it appears to be useful as the drug of first choice in the treatment of respiratory tract infections.

Two cell lines have been established from insulinomas obtained by targeted expression of the simian virus 40 T antigen gene in transgenic mice. These cell lines, designated MIN6 and MIN7, produce insulin and T antigen and have morphological characteristics of pancreatic beta cells. MIN6 cells exhibit glucose-inducible insulin secretion comparable with cultured normal mouse islet cells, whereas MIN7 cells do not. Both cell lines produce liver-type glucose transporter (GT) mRNA at high level. Brain-type GT mRNA is also present at considerable level in MIN7 cells, but is barely detectable in MIN6 cells, suggesting that exclusive expression of the liver-type GT is related to glucose-inducible insulin secretion. MIN6 cells do not express either major histocompatibility (MHC) class I or class II antigens on the cell surface. However, treatment with interferon-gamma induces high levels of MHC class I antigens, and a combination of interferon-gamma and tumor necrosis factor-alpha induces a MHC class II antigen on the cell surface. These results emphasize that the MIN6 cell line retains physiological characteristics of normal beta cells. The MIN6 cell line will be especially useful to analyze the molecular mechanisms by which beta cells regulate insulin secretion in response to extracellular glucose concentrations. We discuss a possible role of GT isoforms in glucose sensing by beta cells.

Normalization of tumor vasculature is an emerging strategy to improve cytotoxic therapies. Here we show that eliminating nitric oxide (NO) production from tumor cells via neuronal NO synthase silencing or inhibition establishes perivascular gradients of NO in human glioma xenografts in mice and normalizes the tumor vasculature, resulting in improved tumor oxygenation and response to radiation treatment. Creation of perivascular NO gradients may be an effective strategy for normalizing abnormal vasculature.

A comparative study was conducted in elderly subjects with mild bronchial asthma to investigate the clinical usefulness of monotherapy with a leukotriene receptor antagonist in comparison to an inhaled corticosteroid. A total of 41 elderly patients aged 65 years or older with mild bronchial asthma, classified as being in severity step 1 and 2, were randomly assigned to the following two treatment groups: a pranlukast (CAS 103177-37-3, Onon) treatment group of 21 patients and an inhaled corticosteroid treatment group of 20 patients. Patients of the former group received pranlukast 450 mg daily and those of the latter group received fluticasone (CAS 90566-53-3) 200 microg daily for eight weeks. In the reference group, one patient was found to suffer from oral candidiasis 4 weeks after the start of the study. Therefore the evaluation was conducted on the remaining 19 participants. The evaluation parameters examined were obtained by keeping an asthma diary, determinations of PEF (peek expiratory flow), use frequency of beta2 stimulants, changes in symptom scores, and medication compliance. Further, measured before and after therapy were the ratio of peripheral blood eosinophils counts, serum ECP (eosinophils cationic protein), ECP levels induced sputum, and forced expiratory volume in one second (FEV1.0). As a result, in the time-course changes of symptoms scores and morning PEF, swift improvement was noted in the pranlukast group. Further, in the variables such as use frequency of beta2 stimulants, serum ECP levels, ECP levels induced sputum, and FEV1.0, an almost comparable level of improvement to the fluticasone group was demonstrated. From the above results, it was deemed that in elderly patients with mild bronchial asthma classified as steps 1 and 2, the pranlukast monotherapy, with superior medication compliance to inhaled therapy, would produce an equivalent level of clinical efficacy to the monotherapy with inhaled corticosteroid (fluticasone 200 microg daily).

Background: We investigated the possibility of preventing common cold-like symptoms as a previously unknown benefit of leukotriene receptor antagonists (LTRAs). Methods: A total of 279 adult patients with bronchial asthma referred to our hospital between June and December 2004 were retrospectively analyzed. Patients were divided into LTRA treated and untreated groups. Frequency of acute exacerbations and number of visits to emergency rooms and of hospital admissions were analyzed as indicators of frequency of infections and asthma exacerbation over the previous 12 months. Results: Irrespective of inhaled corticosteroid (ICS) use, frequency of infections was significantly lower in the LTRA treated group (0.3 ± 0.7 times/year) than in the LTRA untreated group (1.6 ± 4.2 times/year) (P < 0.05), suggesting that LTRA therapy prevents common cold-like symptoms. Frequency of acute exacerbations and number of hospital admissions were significantly lower in the LTRA treated versus LTRA untreated group (0.4 ± 0.8 versus 2.7 ± 4.3 times/year and 0.0 ± 0.2 versus 0.4 ± 0.7 times/year, respectively; both P < 0.01). When the patients were divided into ICS treated and untreated groups, none of the parameters analyzed differed significantly between the two groups, although all parameters tended to be lower in the ICS treated group. Conclusions: Adult asthma patients undergoing treatment with LTRAs exhibit lower incidence rates of common cold-like symptoms than those not receiving LTRAs. LTRAs play an important role in reducing the incidence of common cold-like symptoms among asthma patients and in suppressing exacerbation of asthma symptoms possibly associated with these symptoms.

A 52-year-old man suffering from a pure-type primary gastric small cell carcinoma was treated with surgery and combination chemotherapy. The small cell carcinoma, approximately 6.5 cm in diameter, was situated in the posterior wall of the antrum and there were no distant metasatses. Total gastrectomy and regional lymph node dissection was carried out. Histological examination revealed a solid pattern of proliferation of small cells with hyperchromatic, round nuclei and scant cytoplasm. Neoplastic cells infiltrated into the subserosal layer with severe lymphatic and vascular invasion. Regional lymph node cells were mostly replaced by tumor cells that stained positive for Grimelius, neuron-specific enolase (NSE), and synaptophysin. Accumulations of electron-dense core granules in the small neoplastic cells were seen by electron microscopy. Following surgery, the patient was treated with adjuvant chemotherapy consisting of cisplatin and etoposide. The patient is alive and recurrence free 3 years after surgical operation. We review 107 published cases of primary gastric small cell carcinoma, an extremely rare disease first reported in 1976. Small cell carcinoma is an aggressive, malignant tumor. Intensive chemotherapy is essential for patient survival even when curative surgical resection is carried out.

The pathogenesis of Crohn's disease (CD) is not known. However, monocytes and macrophages are thought to play important roles in the development of mucosal inflammation. Therefore, in this study, we examined the role of monocyte-endothelial cell interactions in senescence-accelerated mouse P1 (SAMP1)/Yit mice, a murine model of spontaneous ileitis. Fluorescence-labeled CD14+ monocytic cells isolated from the spleen and mesenteric lymph nodes of AKR/J (control) mice were injected into the tail veins of recipient (AKR/J and SAMP1/Yit) mice, and migration in the postcapillary venules (PCV) of Peyer's patches, submucosal venules, and villus microvessels of the terminal ileum was monitored by using an intravital microscope. Rolling and adhesion of CD14+ monocytic cells in the PCV of Peyer's patches and microvessels of the terminal ileum were increased in SAMP1/Yit mice. An imunohistochemical study showed increased expression of P-selectin glycoprotein-1 (PSGL-1), P-selectin, and vascular cell adhesion molecule-1 in the terminal ileum of SAMP1/Yit mice. Antibodies against these three adhesion molecules significantly inhibited adhesion of CD14+ monocytic cells to the PCV of Peyer's patches and microvessels of the terminal ileum, treatment with an anti-PSGL-1 monoclonal antibody (mAb) showing the strongest suppressive effect. Anti-PSGL-1 mAb also attenuated T cell adhesion in microvessels of intestinal mucosa. In addition, periodical administration of an anti-PSGL-1 mAb for 7 weeks significantly ameliorated ileitis of SAMP1/Yit mice. The results suggest that PSGL-1-P-selectin interaction plays an important role in monocyte-endothelial cell interactions and the development of ileitis in a murine model of CD and that the blockade of this adhesion molecule may be a novel strategy for treating CD.

A number of in vitro studies have suggested potential pathophysiological roles of human (h-) chymase. However, the lack of an appropriate animal model has left the in vivo roles of chymase unclear. To approach this problem, a transgenic mouse (TGM) model carrying the h-chymase gene was established. The h-chymase cDNA transgene was constructed with the chicken βactin promoter and cytomegalovirus immediate early gene enhancer, and injected into mouse oocytes. Homozygous mice with a high copy number of the h-chymase gene suffered from intrauterine death. In three heterozygous TGM lines, h-chymase transgene expression was detected in entire organs, including the heart, vessels, skin, liver, lung, and brain. The h-chymase immunoreactivity was localized in the extracellular matrices of each organ, especially on the basement membranes of vessels. Aortic and hepatic chymase-dependent angiotensin II formations were significantly higher than those in the wild-type littermates. Three independent TGM lines showed the same phenotypic changes: elevation of blood pressure, left ventricular hypertrophy, emaciation with reduction in the lipid tissue, leukocytosis, and oligotrichia. The angiotensin II subtype 1 (AT1) receptor antagonist valsartan suppressed the elevated blood pressure completely and left ventricular hypertrophy incompletely, but did not affect the other phenotypes. These data suggested that in vivo expression of h-chymase caused mild hypertension (AT1 receptor-dependent) with left ventricular hypertrophy (partially AT1 receptor-dependent), and also chronic inflammatory changes (AT1 receptor-independent). (Hypertens Res 2003; 26: 759-768)

Galectin-3, a multifunctional beta-galactocide binding lectin possibly participates in a variety of biological events including cell proliferation, differentiation, and apoptosis. The implication of galectin-3 during malignancy progression has been suggested in several cancers, including colon, prostate, thyroid, and breast cancer, however, scarce data are available in gastric cancer. We examined the expression of galectin-3 in 86 primary gastric cancers and the 40 metastatic lymph nodes by immunohistochemistry to explore whether it is related to the malignant progression. Positive galectin-3 expression was observed in 84% of the gastric cancer cases. In enhanced cells of cancerous lesions, 48% showed stronger nuclear immunoreactivity than cytoplasmic one, whereas adjacent epithelial cells showed little or weak nuclear immunoreactivity. When galectin-3 expression in gastric carcinoma was compared with that in gastric tissues adjacent to the cancers, there was a significant difference. The degree of enhancement of immunoreactivity was different corresponding to various histopathological subtypes in cancer tissues. A significantly stronger expression of galectin-3 in cancer tissues was only observed in papillary and poorly differentiated adenocarcinoma. When galectin-3 expression and tumor progression (TNM staging) was compared, a significant correlation was observed in overall cases, and only in poorly differentiated adenocarcinoma the galectin-3 expression correlated with tumor progression among various subtypes. Galectin-3 expression was observed significantly stronger in metastatic lymph nodes than in the primary gastric cancers, and also in these cases among histological subtypes, only in poorly differentiated adenocarcinoma, the expression of galectin-3 in metastatic lymph nodes was stronger than the primary cancer. In conclusion galectin-3 might be a useful tumor marker for gastric cancers with respects to tumor progression and potentiality of lymph node metastasis especially in certain histological types of gastric cancer.

Insulin-dependent diabetes mellitus is characterized by the infiltration of lymphocytes into the islets of Langerhans of the pancreas (insulitis) followed by destruction of insulin-secreting beta-cells leading to overt diabetes. The best model for the disease is the non-obese diabetic (NOD) mouse. Two unusual features of the class II major histocompatibility complex (MHC) of the NOD mouse are the absence of I-E and the presence of unique I-A molecules (I-ANOD), in which aspartic acid at position 57 of the beta-chain is replaced by serine. This feature is also found in the HLA-DQ chain of many Caucasians with insulin-dependent diabetes mellitus. We have previously reported that the expression of I-E prevents the development of insulitis in NOD mouse. Here we report that the expression of I-Ak (A alpha kA beta k) in transgenic NOD mice can also prevent insulitis, and that this protection is seen not only when the I-A beta-chain has aspartic acid as residue 57, but also when this residue is serine. These results show that the single amino-acid substitution at position 57 of the I-A beta-chain from aspartic acid to serine is not sufficient for the development of the disease.

The biohybrid artificial pancreas is designed to enclose pancreatic endocrine tissues with a selectively permeable membrane that immunoisolates the graft from the host immune system, allowing those endocrine tissues to survive and control glucose metabolism for an extended period of time. The pancreatic B cell line MIN6 is established from a pancreas B cell tumor occurring in transgenic mice harboring the human insulin promoter gene connected to the SV40 T-antigen hybrid gene. It has been proven that glucose-stimulated insulin secretion in MIN6 cells retains a concentration-dependent response similar to that of normal islets. In this study, we performed the histological and functional examination of three-layer microbeads employing MIN6 cells after subcutaneous xenotransplantation to evaluate this device as bioartificial pancreas. MIN6 cells were microencapsulated in three-layer microbeads formulated with agarose, polystyrene sulfonic acid, polybrene, and carboxymethyl cellulose. Microbeads were xenogenically implanted in the subcutaneous tissue of the back of Lewis rats with streptozotocin-induced diabetes. One week after implantation, microbeads were retrieved and cultured for 24 h before the static incubation. There was no evidence of adhesion to the graft and the fibrosis in the transplantation site as determined by gross visual inspection. Microscopic examination demonstrated that retrieved microbeads maintained normal shape, containing intact MIN6 cells. Histological study showed that these MIN6 cells in the microbeads appeared to be viable without cellular infiltration within or around the microbeads. Immunohistochemical analysis of the microbeads clearly revealed the intense staining of insulin in the cytoplasm of encapsulated MIN6 cells. Insulin productivity of MIN6 cells in the microbeads is strongly suggested to be preserved. In response to 16.7 mM glucose stimulation, static incubation of microbeads 1 wk after implantation caused the 2.3 times increase in insulin secretion seen after 3.3 mM glucose stimulation (84.3 ± 10.0 vs. 37.4 ± 10.7 μU/3 × 106 cells/hr, n = 5 each, p < 0.01). This study demonstrates that three-layer microbeads encapsulating MIN6 cells retain excellent biocompatibility and maintain good insulin secretion even after subcutaneous xenotransplantation, suggesting the possible future clinical application of this unique bioartificial pancreas to subcutaneous xenotransplantation.

Embedded-culture of pancreatic β-cells derived from a transgenic mouse insulinoma (MIN6 cells) was studied in vitro and in vivo. The MIN6 cells were enmeshed in an agarose-PVMA-collagen matrix for long-term maintenance. The cells formed islet-like cell clusters (ICCs) in the mixed matrix. When 10 mmol/L nicotinamide was added to these cultures the cells secreted insulin in response to various concentrations of glucose, whereas the untreated control cells were unresponsive. Both control and nicotinamide-treated MIN6 cells exhibited normal β-cell function for up to 35 days in the mixed matrix, and the cells were much better preserved with nicotinamide than without it. MIN6 cells were suspended in the mixed matrix with nicotinamide and transferred into diffusion chambers to create a bio-artificial endocrine pancreas (Bio-AEP). In streptozotocine-induced diabetic rats with implanted Bio-AEP but without any immunosuppressants, a return to normoglycaemia was observed for up to 12 wk or more after transplantation. Our results indicate that nicotinamide-treated MIN6 cells embedded in a mixed matrix should be useful for the study of xenotransplantation and the development of a bioartificial endocrine pancreas.

The effects of transforming growth factor-beta (TGF-beta) on insulin secretion were investigated using a glucose-responsive clonal cell line, MIN6. One hundred pM TGF-beta stimulated insulin release during 0.5-24 h of incubation in the presence of 5.5 mM glucose, but not after 48 h; 1 nM TGF-beta also stimulated insulin release up to 2 h of exposure, but the effect was not seen after 6 h of exposure. When cells were incubated with 25 mM glucose for 24 h, 100 pM TGF-beta significantly inhibited glucose-stimulated insulin release, whereas insulin release was not altered at 0 or 2.8 mM glucose. On the contrary, forskolin- (10 microM) and tolbutamide- (40 microM) induced insulin release were not affected by TGF-beta. TGF-beta affected neither the cell growth nor the cellular insulin content. An addition of 1 microM nitrendipine abolished TGF-beta-induced insulin secretion at 5.5 mM glucose. The presence study shows that TGF-beta exerts a bimodal effect on glucose-induced insulin secretion from MIN6 cells, depending on dose, time of exposure and concentrations of coexisting glucose. These effects might be mediated by the Ca(2+)-dependent mechanism.

A 72-year-old woman was admitted to our hospital complaining of loss of weight, general fatigue, and upper abdominal pain. Barium studies suggested that a fistula was present between the proximal transverse colon and the stomach which originated from a carcinoma of the colon. A plain computed tomography (CT) scan confirmed the presence of a gastrocolic fistula. A two-thirds distal gastrectomy and right hemicolectomy with a resection of a bulky tumor in the mesocolon were performed en bloc. Histological examination revealed a well-differentiated adenocarcinoma of the transverse colon which was involved with the wall of the stomach. We were able to obtain information on 14 previous cases of gastrocolic fistula originating from transverse colon cancer in the Japanese literature, including the present case. The most common symptom was abdominal pain (64%). A preoperative diagnosis of fistula was confirmed in 10 of the 11 cases examined by barium studies. A plain CT and a CT scan after the barium studies may also be helpful in detecting fistula formation. A fistula between the carcinoma of the middle or distal transverse colon and the stomach was found in 13 of 14 cases, but not in our case. Only one case lived longer than 9 years, even though a surgical resection was possible in 9 of 11 cases.

We report a case of intracystic carcinoma of the breast in which a correct preoperative diagnosis was achieved on the basis of an increased level of carcinoembryonic antigen (CEA) in the aspirated cystic fluid. A 62-year-old woman was admitted with a 10 × 10 cm painful mass occupying the right breast. Ultrasonography revealed a cystic lesion with papillary projections arising from the cyst wall. Cytological examinations showed no malignant cells in the hemorrhagic aspirated fluid. However, the CEA level in the fluid was 5.5 times higher than the serum CEA level using a murine anti-CEA monoclonal antibody. The high level of CEA led to the preoperative diagnosis of intracystic carcinoma. Histological examinations confirmed the diagnosis of intracystic carcinoma after a modified radical mastectomy. Immunohistochemical staining by an anti-CEA monoclonal antibody elicited a strong positivity with diffuse intracytoplasmic distribution in the carcinoma cells, although heterogeneity of staining was observed. It is suggested that the measurement of the CEA value by anti-CEA monoclonal antibody in the aspirated fluid is easy, safe, and helpful for the definitive diagnosis of intracystic carcinoma of the breast.

Several important conclusions can be drawn from these experiments and are as follows. First, not only the lack of I-E but also the presence of unique I-A are involved in the development of autoimmune insulitis in a NOD mouse. Second, the mechanism of prevention in I-Ak transgenic mice might be different from that in I-E transgenic mice, although the negative selection of autoreactive T cells in thymus has been suggested in I-E transgenic mice. Third, the single amino acid substitution from Asp to Ser at position 57 of the Aβ chain is not sufficient for development of insulitis. Other amino acids including residue 56 of the Aβ chain as well as Aα chain are important in the development of insulitis and diabetes. However, the amino acid at position 57 may be involved in the conformational change of I-A molecule in such a way as to alter the interaction with the T cell receptor, leading to the positive or negative selection of autoreactive T cells. Fourth, the ectopic expression of class II molecules on β cells may not be the initial event for the generation of insulitis.