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In laparoscopic surgery, low pneumoperitoneum pressure is reported to reduce pain, which suggests that easing abdominal expansion is crucial for less postoperative pain. However, although abdominal compliance (AC) is associated with the degree of abdominal expansion, the role of AC in pain by pneumoperitoneum is unknown. In this study, we devised a novel index as a surrogate of AC to evaluate the association between AC and postoperative pain in laparoscopic inguinal hernia repair.We reviewed 83 patients who underwent elective transabdominal preperitoneal repair from 2019 to 2021 at Heisei Memorial Hospital. Insufflation pressure was set to low pressure (8 mm Hg). The abdominal compliance index [ACI; insufflated intra-abdominal volume (L)/body surface area (m2)] was utilized to evaluate the association between AC and postoperative pain.ACI was evaluated in 30 patients. Median ACI was 1.53 (1.00 to 2.48) L/m2. Although there was no difference in the average body constitution, the high ACI group (n=15) had significantly higher intra-abdominal volume at 8 mm Hg pressure, compared with the low ACI group (n=15) (3.1 vs. 2.1 L, P0.0001). The high ACI group had significantly higher pain than the low ACI group on the day of surgery (2.0 vs. 1.0, P=0.006) and the day after (0.8 vs. 0.3, P=0.007). In addition, 46.7% of the patients in the high ACI group experienced pneumoperitoneum-associated pain, whereas patients in the low ACI group experienced incision pain only. Additional analgesics were administered in 53.3% of the high ACI group, compared with 33.3% in the low ACI group.AC was suggested to be a vital factor of postoperative pain after laparoscopic inguinal hernia repair. Patients with high AC may be susceptible to higher pain by pneumoperitoneum, even in low-pressure settings.

INTRODUCTION Laparoscopic inguinal hernia repair is reported to be associated with lower postoperative pain than open repair. However, in the actual clinical setting, some patients experience relatively severe pain. This study aimed to elucidate surgical factors that affect pain after transabdominal preperitoneal (TAPP) repair. METHODS We evaluated 199 patients who underwent elective TAPP for inguinal hernia from 2014 to 2019 in Heisei Memorial Hospital. The umbilical trocar size was changed from 12 to 5 mm from October 2017. The pneumoperitoneum intra-abdominal pressure was changed from 10 to 8 mmHg from 2019. Postoperative pain scores and analgesics were compared between patients who were grouped according to trocar size and intra-abdominal pressure, as well as 80 patients who received open repair. RESULTS Patients with a 12 mm trocar had significantly higher pain than open repair patients (P

[Image: see text] Tau prions feature in the brains of patients suffering from Alzheimer’s disease and other tauopathies. For the development of therapeutics that target the replication of tau prions, a high-content, fluorescence-based cell assay was developed. Using this high-content phenotypic screen for nascent tau prion formation, a 4-piperazine isoquinoline compound (1) was identified as a hit with an EC(50) value of 390 nM and 0.04 K(p,uu). Analogs were synthesized using a hypothesis-based approach to improve potency and in vivo brain penetration resulting in compound 25 (EC(50) = 15 nM; K(p,uu) = 0.63). We investigated the mechanism of action of this series and found that a small set of active compounds were also CDK8 inhibitors.

In the course of our screening, we discovered a novel compound, A-503451A, as a potent hypoxia-inducible factor (HIF) activator. In human hepatocarcinoma HepG2 cells, A-503451A induced HIF-mediated luciferase reporter gene expression and stabilized HIF-1α protein. A-503451A increased the mRNA expression levels and the protein secretion of HIF-dependent genes, vascular endothelial growth factor and erythropoietin. Addition of excess ferric chloride to the culture medium suppressed the HIF-induction activity of A-503451A. A-503451A did not have iron-chelating activity in vitro, but decreased the intracellular labile iron pool concentration. These data indicate that A-503451A is a unique HIF activator.

The retinoic acid-related orphan nuclear receptor γt (RORγt)/RORγ2 is well known as a master regulator of interleukin 17 (IL-17)-producing helper T (Th17) cell development. To develop a therapeutic agent against Th17-mediated autoimmune diseases, we screened chemical compounds and successfully found that digoxin inhibited IL-17 production. Further studies revealed that digoxin bound to the ligand binding domain of RORγt and suppressed Th17 differentiation without affecting Th1 differentiation. To better understand the structural basis for the inhibitory activity of digoxin, we determined the crystal structure of the RORγt ligand-binding domain in complex with digoxin at 2.2 Å resolution. The structure reveals that digoxin binds to the ligand-binding pocket protruding between helices H3 and H11 from the pocket. In addition, digoxin disrupts the key interaction important for the agonistic activity, resulting in preventing the positioning of helix H12 in the active conformation, thus antagonizing coactivator interaction. Functional studies demonstrated that digoxin inhibited RORγt activity and decreased IL-17 production but not RORα activity. Digoxin inhibited IL-17 production in CD4(+) T cells from experimental autoimmune encephalomyelitis mice. Our data indicates that RORγt is a promising therapeutic target for Th17-derived autoimmune diseases and our structural data will help to design novel RORγt antagonists.

Formyl peptide receptor 1 (FPR1) and FPR2/ALX are known to control neutrophil chemotaxis in response to various ligands. In this study, we investigated the inhibitory mechanism of compound 43 (Cpd43), an FPR1 and FPR2/ALX dual agonist, on human neutrophil chemotaxis. Precedent stimulation of human peripheral blood neutrophils with Cpd43 rendered the cells unresponsive in calcium mobilization induced by interleukin-8, C5a, or leukotriene B4. In addition, neutrophils pretreated with Cpd43 lost their chemotactic responses against these chemoattractants, wherein the expressions of chemoattractant receptors CXCR1, CXCR2, C5a receptor, and leukotriene B4 receptor 1 on the surface of neutrophils were all diminished significantly by treatment with Cpd43. By evaluating its pharmacological effect on 341 molecules, including receptors and enzymes, we also confirmed that Cpd43 has a highly specific affinity to FPR1 and FPR2/ALX and does not show binding affinity to the other chemoattractant receptors. These results indicate a previously unrecognized inhibitory mechanism of Cpd43 on neutrophil chemotaxis: the induction of cross-desensitization of multiple chemoattractant receptors in human neutrophils through its FPR1 and FPR2/ALX dual agonism. Keywords:: formyl peptide receptor, neutrophil, chemotaxis, cross-desensitization

Summary It has been reported that the stimulation of neutrophils with N-formyl-Met-Leu-Phe (fMLF), an agonist for formyl peptide receptor (Fpr) 1, renders cells unresponsive to other chemoattractants in vitro. This is known as cross-desensitization, but its functional relevance in neutrophil migration in vivo has not been investigated. Here, we show that precedent stimulation of mouse neutrophils with compound 43, a non-peptidyl agonist for mouse Fpr1 and Fpr2, rendered the cells unresponsive to a second stimulation with C5a, leukotriene B4, or keratinocyte-derived cytokine (KC) in calcium mobilization and chemotaxis assays in vitro. The expression of chemokine (C-X-C motif) receptor 2 (CXCR2) on the surface of neutrophils was concomitantly diminished by stimulating the cells with the compound. Moreover, oral administration of the compound to mice before they were exposed to lipopolysaccharide (LPS) aerosol resulted in a dose-dependent reduction in the neutrophil count in bronchoalveolar lavage fluid. The expression of CXCR2 on blood neutrophils was also reduced in the compound-administered mice. The recipient mice that underwent adoptive transfer of fluorescence-labelled neutrophils that had been incubated with the compound showed a substantial decrease in neutrophil counts in bronchoalveolar lavage fluid after they were exposed to LPS, when compared with the control mice to which vehicle-treated neutrophils had been transferred. These results are consistent with the idea that the agonist for Fpr1 and Fpr2 induced cross-desensitization in neutrophils and attenuated neutrophil migration into the airways. Our results also revealed the unpredicted effect of an Fpr1 and Fpr2 dual agonist, which may act as a functional antagonist for multiple chemoattractant receptors in vivo.

The clinical outcome of malignant biliary obstruction caused by metastatic gastric cancer remains unclear. This study was designed to evaluate the clinical outcome and predictive factors of survival in patients who underwent percutaneous transhepatic biliary drainage (PTBD) for malignant biliary obstruction caused by metastatic gastric cancer. Between April 1997 and March 2006, 38 consecutive patients with malignant biliary obstruction caused by metastatic gastric cancer were retrospectively analyzed. All patients underwent PTBD. After PTBD, serum bilirubin levels significantly decreased in 29 (76%) of 38 patients. Pruritus, fever, jaundice, anorexia, abdominal pain, and general fatigue improved significantly in 100%, 100%, 78%, 64%, 53%, and 48% of patients, respectively. Early complications related to the intervention occurred in ten patients. Seven patients developed symptoms of recurrent jaundice or cholangitis. Overall median survival was 79 days, and 6-month and 1-year survival rates after PTBD were 39.5% and 13.2%, respectively. Serum bilirubin level after PTBD (P

A pyrazolone compound acting as a formyl peptide receptor (FPR) 2/ALX–selective agonist has been reported, but its pharmacological activities on human FPRs (hFPRs) and mouse FPRs (mFprs) have not been well demonstrated. In this study, we found that this compound, designated as compound A, induced concentration-dependent calcium flux not only in Chinese hamster ovary (CHO) cells expressing hFPR2/ALX but also in cells expressing hFPR1, mFpr1, or mFpr2. It also induced the receptor internalization of hFPR1 and hFPR2/ALX and, accordingly, induced calcium influx and chemotactic responses in both human and mouse neutrophils. Our study revealed that compound A is in fact an FPR1 and FPR2/ALX dual agonist. Keywords:: formyl peptide receptor, neutrophil, chemotaxis

はじめに:胃癌骨転移の頻度は少ないが，quality of lifeを著しく悪化させるため，その特徴を知ることは重要である．対象と方法:1991年から2007年までに当科で経験した初発胃癌で，手術あるいは化学療法を施行した1,084例のうち骨転移を呈した16例を対象とした．16例の臨床像と予後因子，骨転移単独症例の臨床像，本邦報告例について検討した．結果:骨転移症例は比較的若年の女性，U領域，4型，未分化型，脈管侵襲やリンパ節転移の高度な進行癌が多かった．骨転移発症までの期間は中央値266日（23～1,579日）であった．骨転移発症からの生存期間は中央値102日（8～310日），6カ月生存率は42％と不良であったが，1980年代の報告と比較すると良好であった．骨転移発症後の予後因子として単変量解析で女性，66歳以上の高齢，PS不良例，化学療法非施行例が挙げられた．多変量解析では年齢，PS，化学療法の有無が独立した予後因子となった．骨転移単独症例は4例で原発巣の悪性度が低いにもかかわらず，リンパ節転移の高度な症例が多かった．骨転移後の治療法では9例に化学療法が施行され，TS-1を中心として多剤を投与できた症例の生存期間は比較的良好であった．結語:骨転移症例の特徴を十分に理解し，早期発見から化学療法を施行することにより，予後が改善する可能性が示唆された．

症例は50歳代の男性. 上腹部痛を主訴に近医を受診し下部消化管内視鏡検査にて横行結腸肝彎曲に腫瘤を指摘された. 精査加療目的に平成17年4月当科に入院した. 腹部CTにて傍大動脈リンパ節の腫大を認め, 傍大動脈周囲リンパ節転移を伴う横行結腸癌の診断にて横行結腸切除術, リンパ節郭清を施行した. 腫瘍は境界不明瞭で潰瘍形成を伴わない5型を呈していた. 病理組織診断では腺扁平上皮癌であり, 郭清したすべてのリンパ節に転移を認めstageIV (SE, H0, P0, M1) であった. 術後は早期より一日20行以上の下痢を認め, 縫合不全から消化管皮膚瘻を形成したが保存的に軽快し, 術後75日目に退院した. 現在は外来にて化学療法を施行中である. 腺扁平上皮癌は結腸での発生は稀であり, 悪性度が高く予後不良であるとされる. 若干の文献的考察を加えて報告する.

症例は70歳代, 男性. 前立腺癌に対し内分泌療法を受けている. 2006年12月, 下腹部痛のため当科を受診した. 下腹部に著明な圧痛と反跳痛を認め, 血液検査で炎症所見を認めた. 腹部造影CT検査で骨盤腔内に腹水の貯留と大網に帯状の肥厚像を認めた. 保存的加療を行うも改善せず, 急性腹膜炎の原因精査のため, 全身麻酔下に腹腔鏡検査を施行した. 肥厚した大網が広汎に腹壁に癒着し, 壁側腹膜は発赤し, 骨盤内に淡血性腹水を認めた. 大網を剥離した後, 小切開を加え大網を部分切除した. 切除した大網に4cm大の腫瘤を4個認め, 病理組織検査で腺癌の転移と診断された. 術後の上部消化管内視鏡検査でBorrmann4型胃癌を認め, 胃癌の大網転移と診断した.

78???, ??????. 2001???2????????????????????????????????????????????????????????????????????????. ?????????????????????????????????????????????????????????. ??????????????????????????????, c-kit, CD34???????????????gastrointestinal stromal tumor??????????????????. 2002???12?????????CT??????S2??????????????????, ?????????????????????????????????. 2005???1??????S3????????????????????????????????????, ??????????????????????????????????????????????????? (400mg/???). ????????????1???????????????CT??????, ?????????????????????????????????????????????, ?????????????????????????????????. ????????????3???????????????CT??????, 1????????????CT??????????????????, ????????????????????????????????????. ????????????????????????, Grade1???????????????????????????, ??????, ????????????????????????. 2005???6?????????????????????????????????????????????. ?????????????????????????????????????????????, ????????????????????????????????????????????????????????????????????????????????????, ?????????????????????????????????????????????. ???????????????????????????????????????.

In the course of our screening for activators of hypoxia-inducible factor (HIF), A-503451 A and virantmycin were isolated from the cultured broth of an actinomycete strain, Streptomyces sp. SANK 60101. From the same culture, the non-active homologs A-503451 B and D were also isolated. A-503451 A and virantmycin activated HIF-dependent reporter gene expression with EC

© 2015, National Academy of Sciences. All rights reserved. Increasingly, evidence argues that many neurodegenerative diseases, including progressive supranuclear palsy (PSP), are caused by prions, which are alternatively folded proteins undergoing self-propagation. In earlier studies, PSP prions were detected by infecting human embryonic kidney (HEK) cells expressing a tau fragment [TauRD(LM)] fused to yellow fluorescent protein (YFP). Here, we report on an improved bioassay using selective precipitation of tau prions from human PSP brain homogenates before infection of the HEK cells. Tau prions were measured by counting the number of cells with TauRD(LM)-YFP aggregates using confocal fluorescence microscopy. In parallel studies, we fused α-synuclein to YFP to bioassay α-synuclein prions in the brains of patients who died of multiple system atrophy (MSA). Previously, MSA prion detection required ∼120 d for transmission into transgenic mice, whereas our cultured cell assay needed only 4 d. Variation in MSA prion levels in four different brain regions from three patients provided evidence for three different MSA prion strains. Attempts to demonstrate α-synuclein prions in brain homogenates from Parkinson's disease patients were unsuccessful, identifying an important biological difference between the two synucleinopathies. Partial purification of tau and α-synuclein prions facilitated measuring the levels of these protein pathogens in human brains. Our studies should facilitate investigations of the pathogenesis of both tau and α-synuclein prion disorders as well as help decipher the basic biology of those prions that attack the CNS.

Objective Chemokine-like receptor 1 (CMKLR1) is expressed by human antigen presenting cells and binds to chemerin, a proteolytically activatable chemoattractant. Here we assessed the expression of mCMKLR1 on mouse leukocytes, focusing on ex vivo dendritic cells (DC) and macrophages. mCMKLR1-expressing cells were evaluated for functional responses to chemerin. We examined the regulation of mCMKLR1 expression by exposure to toll-like receptor (TLR) ligands and cytokines. Finally, we evaluated ex vivo human ascites macrophages for huCMKLR1 expression and chemerin responsiveness. Methods A novel anti-mCMKLR1 monoclonal antibody was generated to assess mCMKLR1 expression by mouse leukocytes using flow cytometry. Mouse bone marrow–derived DC precursors, mouse peritoneal macrophages, and human ascites leukocytes were examined in functional assays (in vitro chemotaxis and intracellular calcium mobilization). Results During DC differentiation from bone marrow, mCMKLR1 is upregulated early and then diminishes with time in culture. Most DC in vivo do not detectably express the receptor. In contrast, freshly isolated F4/80 + CD11b + mouse serosal macrophages express mCMKLR1, bind a fluorescently labeled chemerin peptide, and display calcium signaling and migration to the active ligand. Interestingly, macrophage mCMKLR1 is suppressed by proinflammatory cytokines and TLR ligands, whereas treatment with TGF-β upregulates the receptor. A small population of blood-borne F4/80 + CD11b + macrophages also expresses mCMKLR1. Freshly isolated macrophages from human ascites fluid express CMKLR1 and are chemerin responsive, as well. Conclusion The conserved expression of CMKLR1 by macrophages in mouse and man, coupled with the stimuli-specific regulation of CMKLR1, may reflect a critical role for CMKLR1:chemerin in shaping the nature (either proinflammatory or suppressive) in macrophage-mediated immune responses.

The host response to tissue injury and/or infection is dependent on the action of numerous extracellular proteases. Proteolytic cascades trigger blood clotting, fibrinolysis, and complement activation, while proteases released upon leukocyte degranulation are integral to the processes of inflammation and immunity. Modulation of effector protein activity by proteases provides a critical layer of posttranslational control that enables rapid enzymatic regulation of target proteins. This report reviews the emerging literature describing a novel class of proteolytic targets, leukocyte chemoattractants, and, in particular, chemerin, a dendritic cell and macrophage chemoattractant activated by serine proteases of the coagulation, fibrinolytic, and inflammatory cascades. As chemoattractants are critical for both systemic leukocyte positioning by triggering integrin activation and subsequent recruitment from circulation, and local intratissue leukocyte positioning via chemotaxis, modulation of attractant activities by proteases may have profound effects on the immune response.

症例は57歳女性.人間ドックで胃癌の診断を受け,手術目的で来院した.胃X線・内視鏡検査で胃幽門部小彎後壁のIIc型早期胃癌と診断した. AFP値は正常範囲で,腹部エコー, CT検査では異常を認めなかった.腹腔鏡補助下幽門側胃切除を施行した11カ月後に肝外側区域に巨大な転移を認めたため,再手術を施行した.摘出した肝転移巣,リンパ節の免疫組織学的検索で, AFP染色が強陽性であった.また血清AFP値は226,000U/mlと異常高値を示した. TS-1による全身化学療法と,残存肝転移巣にラジオ波焼灼術および肝動注を用いた集学的治療がQOLの改善に貢献した. AFP産生胃癌は進行癌に多いが早期胃癌でも稀に認められ,予後は悪い.術前および術後のAFP測定は転移・再発の早期発見に寄与するものと思われた.

症例は59歳,女性.平成13年11月,下痢を主訴に近医を受診したところ,右側腹部腫瘤を指摘され当院に紹介された.当院受診時,右側腹部に弾性軟,小児頭大の腫瘤を触知した.腹部CTでは右後腹膜腔に12×7 cmのlow density massとして描出され,注腸造影検査において,上行結腸は著名に左側に圧排されていた.後腹膜漿液性嚢胞の診断のもと,腫瘍摘出術を施行した.腫瘤は非常に薄い嚢胞壁を有し,その内容物は無色透明の液体であった.内溶液のCA19-9, CEA値はそれぞれ10,000U/ml以上, 344.5ng/mlと高値を示したが,細胞診は陰性であり,嚢胞壁にも悪性所見は認めなかった.後腹膜嚢腫は稀な疾患であり,若干の文献的考察を加え報告する.

The authors have designed a microcapsule composed of agarose and polystyrene sulfonic acid (PSSa) mixed gel that provides a protective barrier against complement attack. Xenografts of islets, encapsulated in an agarose-PSSa microcapsule, have been shown to normalize blood glucose in rodents with chemically induced diabetes for extended periods of time without immunosuppression.To investigate the efficacy of agarose-PSSa microencapsulated pig islets in reversing diabetes in a large animal model.Diabetes was induced in beagle recipients by total pancreatectomy. Each recipient received three to five intraperitoneal injections of either encapsulated (n = 5) or nonencapsulated pig islets (n = 2).In all dogs receiving microencapsulated islets, the graft function was achieved for 7.4 +/- 3.1 weeks (mean +/- standard error), as determined by elimination or reduction of exogenous insulin requirement. In three recipients, the fasting blood glucose levels were maintained ator = 200 mg/dL without any exogenous insulin for a period of 6, 50, and 119 days. Circulating porcine C-peptide was detected in the sera of all dogs after transplantation of encapsulated islets. Immunohistologic examination revealed the presence of insulin-positive cells in the microcapsules. In contrast, in two dogs receiving nonencapsulated islets there was no graft function.This preliminary study demonstrates that agarose-PSSa microencapsulated pig islets can survive and function for weeks or months in totally pancreatectomized diabetic dogs without immunosuppression.

総胆管コレステローシスは非常に稀で術前診断が困難な疾患である.われわれは術前胆嚢・総胆管結石と診断され,術中胆道ファイバーにて総胆管ポリープ,病理組織診断にてポリープ型コレステローシスと診断された1例を経験したので,若干の文献的考察を加え報告した.症例は48歳,女性.嘔気,心窩部痛を主訴に当院内科受診.軽度の肝機能異常を認め,腹部超音波検査にて胆嚢結石, ERCPにて膵胆管合流異常症,胆嚢管低位合流,胆嚢総胆管結石と診断され,手術目的に当科紹介となった.手術は,胆嚢摘出術,総胆管切開術を施行した.総胆管内に結石を認めず,下部胆管に多数の黄白色のポリープ様病変を認めた.総胆管コレステローシスは,ほとんどが下部胆管の腫瘍性病変と診断され手術を施行されるが,病的意義は少ないとされており,胆道鏡での確診が容易なため,今後経内視鏡的胆道ファイバーの普及により,不要な手術を避けられるものと考えられた.

Arborcandins A, B, C, D, E and F, which possess potent 1,3-beta-glucan synthase inhibitory activity, were isolated from the culture broth of a filamentous fungus, strain SANK 17397. Arborcandins are novel cyclic peptides, that are structurally different from known glucan synthase inhibitors such as echinocandins. The 1,3-beta-glucan synthases of Candida albicans and Aspergillus fumigatus were inhibited by arborcandins with IC50 ranging from 0.012 to 3 microg/ml. The apparent Ki value of arborcandin C for C. albicans and A. fumigatus were 0.12 microM and 0.016 microM, respectively. The inhibition against these two 1,3-beta-glucan synthases by arborcandin C was noncompetitive. These compounds exhibited potent fungicidal activity against Candida spp. with MIC ranging from 0.25 to 8 microg/ml. The growth of A. fumigatus was suppressed by arborcandins with concentrations ranging from 0.063 to 4 microg/ml.

A convergent procedure for the preparation of optically active twelve-membered diketodiyne derivatives with C2 symmetry possessing four hydroxy functionalities was developed starting from the commercially available diethyl L-tartrate. The key step for the construction of the twelve-membered diyne framework involved an intramolecular chromous chloride-mediated coupling reaction between the aldehyde functionality and the alkyne moiety having an iodine atom at its terminus.

We examined the gene expression of the Escherichia coli cad operon, which consisted of the genes cadB and cadA (lysine decarboxylase), using cells possessing cadB-lacZ fusion gene. The cad operon was expressed when O2 was limited, and the expression was optimal at pH 6.3. The beta-galactosidase activity was lowered by the addition of sodium carbonate to the medium. The expression of the cad operon was reduced in cells containing the plasmid-encoding ornithine decarboxylase, which produced carbon dioxide, indicating that the gene expression of the cad operon was regulated by carbon dioxide (or its derivatives). It is known that the Krebs cycle is a major pathway for producing carbon dioxide, and that its activity is repressed when O2 is limited. Thus, our present results suggested that the physiological role of the cad operon is to supply carbon dioxide when its internal level is lowered under O2-limiting conditions at a low pH.

The clinical outcome of ureteral obstruction secondary to gastric cancer remains unclear. The present study was designed to evaluate the clinical outcome and predictive factors of survival in patients with ureteral obstruction secondary to gastric cancer.Twenty-five consecutive patients with ureteral obstruction secondary to gastric cancer between January 1998 and December 2007 were retrospectively analyzed. All patients had hydronephrosis; 13 patients had bilateral hydronephrosis, and 12 patients had unilateral hydronephrosis.Ten patients presented with pain, 3 patients with urinary tract infection, and 2 patients with acute renal failure. Seven (58%) of 12 patients with unilateral ureteral obstruction experienced progression to bilateral ureteral obstruction during the follow-up period. Eighteen patients (61%) were eventually managed with urinary diversion. In total, 5 patients were managed with percutaneous nephrostomy, and 15 patients with retrograde ureteral stenting. All symptomatic patients responded to urinary diversion. The overall median survival was 5.8 months, and the 6-month and 1-year survival rates were 48 and 32%, respectively. Chemotherapy was found to be the only independent predictor of survival (p=0.0498). Median survival in patients who received chemotherapy was 11.2 months, in comparison to 3.1 months in patients who did not receive chemotherapy (p=0.0002).The prognosis of ureteral obstruction secondary to gastric cancer was extremely poor, particularly when chemotherapy was not administered. The indications for palliative urinary diversion should be determined after considering the patient's symptoms, the expected survival time, the possibility of further chemotherapeutic options, and the current quality of life.

It has been reported that the stimulation of neutrophils with N-formyl-Met-Leu-Phe (fMLF), an agonist for formyl peptide receptor (Fpr) 1, renders cells unresponsive to other chemoattractants in vitro. This is known as cross-desensitization, but its functional relevance in neutrophil migration in vivo has not been investigated. Here, we show that precedent stimulation of mouse neutrophils with compound 43, a non-peptidyl agonist for mouse Fpr1 and Fpr2, rendered the cells unresponsive to a second stimulation with C5a, leukotriene B4, or keratinocyte-derived cytokine (KC) in calcium mobilization and chemotaxis assays in vitro. The expression of chemokine (C-X-C motif) receptor 2 (CXCR2) on the surface of neutrophils was concomitantly diminished by stimulating the cells with the compound. Moreover, oral administration of the compound to mice before they were exposed to lipopolysaccharide (LPS) aerosol resulted in a dose-dependent reduction in the neutrophil count in bronchoalveolar lavage fluid. The expression of CXCR2 on blood neutrophils was also reduced in the compound-administered mice. The recipient mice that underwent adoptive transfer of fluorescence-labelled neutrophils that had been incubated with the compound showed a substantial decrease in neutrophil counts in bronchoalveolar lavage fluid after they were exposed to LPS, when compared with the control mice to which vehicle-treated neutrophils had been transferred. These results are consistent with the idea that the agonist for Fpr1 and Fpr2 induced cross-desensitization in neutrophils and attenuated neutrophil migration into the airways. Our results also revealed the unpredicted effect of an Fpr1 and Fpr2 dual agonist, which may act as a functional antagonist for multiple chemoattractant receptors in vivo.

A convergent procedure for the preparation of optically active twelve-membered diketodiyne derivatives with C2 symmetry possessing four hydroxy functionalities was developed starting from the commercially available diethyl L-tartrate. The key step for the construction of the twelve-membered diyne framework involved an intramolecular chromous chloride-mediated coupling reaction between the aldehyde functionality and the alkyne moiety having an iodine atom at its terminus.

Solitary fibrous tumors (SFTs) are uncommon neoplasms of mesenchymal origin that usually arise from the pleura. SFTs of the abdominal wall are extremely rare, and only 12 cases have been reported in the English language literature. This report presents a new case of SFT of the abdominal wall in a 74-year-old female. Positron emission tomography demonstrated the heterogeneous 18F-fluorodeoxyglucose uptake of the tumor (the maximum standardized uptake value was 2.8). Histologically, the mitotic count was 1 to 2/10 high-power fields. The patient is alive without recurrence at 10 months after undergoing a surgical excision. We discuss the clinicopathological features and differential diagnosis and present a review of the pertinent literature.

Mast cells contribute importantly to both protective and pathological IgE-dependent immune responses. We show that the mast cell–expressed orphan serpentine receptor mCCRL2 is not required for expression of IgE-mediated mast cell–dependent passive cutaneous anaphylaxis but can enhance the tissue swelling and leukocyte infiltrates associated with such reactions in mice. We further identify chemerin as a natural nonsignaling protein ligand for both human and mouse CCRL2. In contrast to other “silent” or professional chemokine interreceptors, chemerin binding does not trigger ligand internalization. Rather, CCRL2 is able to bind the chemoattractant and increase local concentrations of bioactive chemerin, thus providing a link between CCRL2 expression and inflammation via the cell-signaling chemerin receptor CMKLR1.

Aim: To investigate the role of angiotensin type 1 (AT1) and type 2 (AT2) receptors in hypoxia-induced retinal vascular hyperpermeability. Methods: Brown-Norway rat pups were exposed to hyperoxic conditions from postnatal day 7 (P7) to P12, and to subsequent normal air for 5 days [oxygen-induced retinopathy (OIR) model]. Olmesartan medoxomil (AT1 receptor antagonist; administered orally), PD123319 (AT2 receptor antagonist; administered subcutaneously) or a vehicle was administered once daily during the last 5 days. At P16, the retinal permeability was determined by measuring the leaked fluorescein-conjugated dextran concentration in the retina. The vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1) α proteins in the retina were assessed by an ELISA and western blotting, respectively. Results: Olmesartan medoxomil partially, but significantly, inhibited the retinal vascular hyperpermeability induced by hypoxia. In contrast, PD123319 did not show a significant effect. The VEGF and HIF-1α protein levels were significantly elevated in the OIR retina; however, there was no significant effect of olmesartan medoxomil on the expression of either protein. Conclusions: These results suggest that the AT1 receptor is, at least partly, responsible for hyperpermeability in the OIR rat retina via a mechanism independent of HIF-1 and VEGF expression.

We report a case of multiple bone metastases from gastric cancer treated with combination chemotherapy of S-1 and CDDP. A 54-year-old man underwent distal gastrectomy for gastric cancer (Stage II) in March 2003. Multiple bone metastases complicated with DIC were diagnosed in September 2005. The patient was treated with combination chemotherapy of S-1 and CDDP. S-1 (80 mg/m2/day) was administered for 21 days followed by 14 days rest as one course. CDDP (60 mg/m2) administration was begun 8 days after the start of S-1. After one course of the treatment, DIC was resolved. The abnormal uptake at the bone metastases was found to have decreased by bone scintigraphy. Bone metastases recurred in April 2006. Although combination chemotherapy of S-1 and DOC was administered, the patient died of DIC in August 2006. Combination chemotherapy of S-1 and CDDP is considered effective treatment for prolonging survival in cases of gastric cancer with bone metastases.

Chemerin is an attractant for cells that express the serpentine receptor CMKLR1, which include immature plasmacytoid dendritic cells (pDC) and macrophages. Chemerin circulates in the blood where it exhibits low biological activity, but upon proteolytic cleavage of its C terminus, it is converted to a potent chemoattractant. Enzymes that contribute to this conversion include host serine proteases of the coagulation, fibrinolytic, and inflammatory cascades, and it has been postulated that recruitment of pDC and macrophages by chemerin may serve to balance local tissue immune and inflammatory responses. In this work, we describe a potent, pathogen-derived proteolytic activity capable of chemerin activation. This activity is mediated by staphopain B (SspB), a cysteine protease secreted by Staphylococcus aureus. Chemerin activation is triggered by growth medium of clinical isolates of SspB-positive S. aureus, but not by that of a SspBnull mutant. C-terminal processing by SspB generates a chemerin isoform identical with the active endogenous attractant isolated from human ascites fluid. Interestingly, SspB is a potent trigger of chemerin even in the presence of plasma inhibitors. SspB may help direct the recruitment of specialized host cells, including immunoregulatory pDC and/or macrophages, contributing to the ability of S. aureus to elicit and maintain a chronic inflammatory state.

Case 1: A 62-year-old man was introduced to our hospital for Type 1 cardiac gastric cancer. On the abdominal CT, there was evidence of multiple liver metastases. The patient was treated with daily oral administration of TS-1 (120 mg/day) for 3 weeks followed by 2 weeks' rest and infusion of CDDP (60 mg/m2) on day 8 as 1 course. After completion of 1 course, partial response in the primary tumor, and complete responses in the liver and lymph node metastases had been assessed, although the primary tumor increased during the 2 months' rest after 4 courses. Case 2: A 67-year-old man was hospitalized for Type 3 cardiac gastric cancer with multiple liver and lymph node metastases. A combination of TS-1 (100 mg/day), and CDDP (60 mg/m2), and TS-1 (80-50 mg/ day) was used. After 2 courses of TS-1/CDDP and 4 courses of TS-1, the primary tumor decreased significantly in size, and complete responses in the liver and lymph node metastases had been assessed, although the primary tumor, liver and lymph node metastases increased after 6 courses of TS-1. The two cases under study suggest that the combination systemic chemotherapy of TS-1 and CDDP is an effective treatment for advanced gastric cancer with multiple liver metastases in terms of its antitumor effect and QOL of the patients.

Arborcandins A, B, C, D, E and F, which possess potent 1,3-beta-glucan synthase inhibitory activity, were isolated from the cultured broth of a filamentous fungus, strain SANK 17397. The structures of arborcandins A, B, C, D, E and F were elucidated by a combination of NMR and mass spectrometry, and established to be novel cyclic peptides containing uncommon amino acid residues.

Arborcandin C is a novel antibiotic with potent antifungal activity that inhibits 1,3-β-glucan synthase in fungi. We examined spontaneous Saccharomyces cerevisiae mutants which are selectively resistant to arborcandin C and revealed that a single amino acid replacement in Fks1p of Asn 470 with Lys or of Leu 642 with Ser confers selective resistance on Fks1p mutants.