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Sphingosine 1-phosphate (S1P), an inflammatory mediator, is abundantly contained in red blood cells and platelets. We hypothesized that the S1P concentration in the peritoneal cavity would increase especially during the menstrual phase due to the reflux of menstrual blood, and investigated the S1P concentration in the human peritoneal fluid (PF) from 14 non-endometriosis and 19 endometriosis patients. Although the relatively small number of samples requires caution in interpreting the results, S1P concentration in the PF during the menstrual phase was predominantly increased compared to the non-menstrual phase, regardless of the presence or absence of endometriosis. During the non-menstrual phase, patients with endometriosis showed a significant increase in S1P concentration compared to controls. In vitro experiments using human intra-peritoneal macrophages (MΦ) showed that S1P stimulation biased them toward an M2MΦ-dominant condition and increased the expression of IL-6 and COX-2. An in vivo study showed that administration of S1P increased the size of the endometriotic-like lesion in a mouse model of endometriosis.

Background: Relaxin (RLX)-2, produced by the corpus luteum and placenta, is known to be potentially effective in fibrotic diseases of the heart, lungs, kidneys, and bladder, however, its effectiveness in endometriosis has not yet been investigated. In the present study, we conducted a comprehensive study on the effect of RLX-2 on endometriosis. We checked the expressions of LGR-7, a primary receptor of RLX-2, in endometriomas using immunohistochemistry. Endometriotic stromal cells (ESCs) purified from surgical specimens were used in in vitro experiments. The effects of RLX-2 on ESCs were evaluated by quantitative-PCR, ELISA, and Western blotting. Gel contraction assay was used to assess the contraction suppressive effect of RLX-2. The effect of RLX-2 was also examined in the endometriosis mouse model. LGR-7 was expressed in endometriotic lesions. In ESCs, RLX-2 increased the production of cAMP and suppressed the secretion of interleukin-8, an inflammatory cytokine, by 15% and mRNA expression of fibrosis-related molecules, plasminogen activator inhibitor-1 (PAI-1), and collagen-I by approximately 50% (p &lt, 0.05). In the gel contraction assay, RLX-2 significantly suppressed the contraction of ESCs, which was cancelled by removing RLX-2 from the medium or by adding H89, a Protein Kinase A (PKA) inhibitor. In ESCs stimulated with RLX-2, p38 MAPK phosphorylation was significantly suppressed. In the endometriosis mouse model, administration of RLX-2 significantly decreased the area of the endometriotic-like lesion with decreasing fibrotic component compared to non-treated control (p = 0.01). RLX-2 may contribute to the control of endometriotic lesion by suppressing fibrosis, scar formation, and inflammation.

Neuroimmune interactions are involved in the development of endometriosis. Here, we examined the role of a neuropeptide, calcitonin gene–related peptide (CGRP), and its receptor, receptor activity–modifying protein (RAMP) 1, in growth of endometrial tissues and the formation of blood and lymphatic vessels in a mouse ectopic endometrial transplantation model. Endometrial fragments from donor wild‐type (WT) mice transplanted into the peritoneal wall of recipient WT mice grew with increased density of blood and lymphatic vessels. When tissues from RAMP1‐deficient (RAMP1−/−) mice were transplanted into RAMP1−/− mice, implant growth and angiogenesis/lymphangiogenesis were decreased. CGRP was up‐regulated in dorsal root ganglia, and CGRP+ nerve fibres were distributed into the implants from the peritoneum. RAMP1 was co‐expressed with CD11b (macrophages) and S100A4 (fibroblasts), but did not co‐localize with blood vessel endothelial cell marker CD31 or lymphatic vessel endothelial hyaluronan receptor (LYVE)‐1. Cultured with CGRP, macrophages up‐regulated vascular endothelial growth factor (VEGF)‐A, VEGF‐C and VEGF‐D, whereas fibroblasts up‐regulated VEGF‐C, but not VEGF‐A or VEGF‐D, in a RAMP1‐dependent manner. CGRP receptor antagonist CGRP8‐37 inhibited growth of and angiogenesis/lymphangiogenesis within endometrial tissue implants. These results suggest that RAMP1 signalling is crucial for growth and angiogenesis/lymphangiogenesis in endometrial tissue. Blockade of RAMP1 is a potential tool for the treatment of endometriosis.

Lymphangiogenesis is related to the growth of endometriosis. Here, we examined whether vascular endothelial growth factor (VEGF) receptor 1 (VEGFR1) signaling plays a role in lymphangiogenesis during endometriosis. Endometrial fragments from wild-type (WT) mice transplanted into the peritoneal wall of host WT mice (WT→WT) developed well and displayed enhanced lymphangiogenesis associated with increases in mRNA levels of VEGF-C and VEGF-D. Compared with WT mice, the implant size and lymphangiogenesis were reduced, when endometrial fragments from mice lacking the VEGFR1 tyrosine kinase (TK) domain (TK-/-) were transplanted into host TK-/- mice (TK-/-→TK-/-). Treatment of WT→WT mice with the VEGFR3 kinase inhibitor suppressed the size of implants and lymphangiogenesis. Immunofluorescence analyses demonstrated that VEGF-C and VEGF-D were expressed in both CD11b+ and S100A4+ cells. TK-/-→TK-/- mice had lower numbers of CD11b+ and S100A4+ cells than WT→WT mice. When isolated bone marrow (BM)-derived macrophages or culture murine fibroblasts were stimulated with placental growth factor (PlGF), a specific agonist of VEGFR1, the levels of VEGF-C and VEGF-D were increased in a VEGFR1-dependent manner. These results suggest that VEGFR1 signaling in macrophages and fibroblasts contributes to the growth of endometrial implants and lymphangiogenesis.

Background The purpose of this study was to evaluate the lymph function of the lower extremities and to identify early symptoms of lymph dysfunction in secondary lymphedema by observing lymph flow with indocyanine green (ICG) fluorescence lymphography (LG). Methods We retrospectively evaluated the lymph flow of 108 limbs in 54 female patients with leg lymphedema secondary to pelvic lymphadenectomy for gynecological carcinoma and 14 limbs in 7 female controls without a history of pelvic lymphadenectomy or radiotherapy. ICG was injected into four points at the distal part of the lower extremity. Lymph flow was evaluated by measuring the proximal point where the ICG could be observed 5 minutes after rest and 15 minutes after a walking exercise. Results In the controls, lymph flow was stable at rest and was well enhanced by exercise. In patients with early-stage lymphedema, lymph flow was already enhanced at rest (p = 0.005) and was further enhanced by exercise. In advanced-stage lymphedema, lymph flow was not enhanced, even by exercise (p = 0.001). Conclusion ICG-LG could evaluate lymph flow and functions of lymph systems and detect accelerated lymph flow in early-stage secondary lymphedema. Detecting accelerated lymph flow may facilitate early detection and treatment of secondary lymphedema.

Angiogenesis is critical in maintenance of endometrial tissues. Here, we examined the role of VEGF receptor 1 (VEGFR1) signaling in angiogenesis and tissue growth in an endometriosis model. Endometrial fragments were implanted into the peritoneal wall of mice, and endometrial tissue growth and microvessel density (MVD) were determined. Endometrial fragments from wild-type (WT) mice grew slowly with increased angiogenesis determined by CD31+ MVD, peaking on Day 14. When tissues from WT mice were transplanted into VEGFR1 tyrosine kinase-knockout mice, implant growth and angiogenesis were suppressed on Day 14 compared with growth of WT implants in a WT host. The blood vessels in the implants were not derived from the host peritoneum. Immunostaining for VEGFR1 suggested that high numbers of VEGFR1+ cells such as macrophages were infiltrated into the endometrial tissues. When macrophages were deleted with Clophosome N, both endometrial tissue growth and angiogenesis were significantly suppressed. Bone marrow chimera experiments revealed that growth and angiogenesis in endometrial implants were promoted by host bone marrow-derived VEGFR1+/CD11b+ macrophages that accumulated in the implants, and secreted basic fibroblast growth factor (bFGF). A FGF receptor kinase inhibitor, PD173047 significantly reduced size of endometrial tissues and angiogenesis. VEGFR1 signaling in host-derived cells is crucial for growth and angiogenesis in endometrial tissue. Thus, VEGFR1 blockade is a potential treatment for endometriosis.

We herein describe a fetal case of arrhythmogenic right ventricular cardiomyopathy (ARVC) with double mutations in transmembrane protein 43 (TMEM43). RV aneurysm and ventricular arrhythmia were detected during the fetal period. After birth, electrocardiogram showed frequent premature ventricular contractions (PVC) of left bundle branch block morphology and epsilon waves in the right-sided chest leads. Echocardiography also indicated RV aneurysm with regionally decreased systolic function. PVC disappeared after treatment with amiodarone and mexiletin. Mutations in TMEM43, which was recently identified as the causative gene of ARVC type 5, were also confirmed in the present patient and in the patient's mother, and they were therefore diagnosed with ARVC. The present case confirms that symptoms of ARVC can emerge during the fetal period. Pediatricians need to keep in mind the possibility of ARVC when they encounter patients with RV aneurysm and arrhythmia.

In two previous articles, I presented two case studies on conflicts between trade unions and employers in EU member countries: one in Sweden and the other in the U.K. Both case studies indicate these conflicts originate in the EU's two important but partly conflicting aims, namely, ensuring complete economic freedom within the EU, and guaranteeing full social democratic rights which have been long established in EU member countries. Conflicts over these issues have become more intense since the fifth enlargement of the EU. To establish an appropriate balance between economic freedoms and social democratic rights is an urgent and challenging task for the EU. Presented here is a third case study to complete this series of studies. It introduces the conflict between the Finnish shipping company "Viking" and the Finnish trade union, and examines public debate after the preliminary ruling of the ECJ concerning the Viking Case. I argue that it is vital for the EU to find a fair balance between the abovementioned two aims.

The European Union is attempting to create a single market where goods, capital, services and people move freely as if they were in a domestic market. Both goods and capital markets of the EU have been integrated to a great degree, respectively. However, European labour markets are not yet well integrated, nor are markets of services which include movement of natural persons. Due to the lack of sufficient coordination in national labour market policies, EU law concerning posted workers has caused conflicts in several EU member countries. In a previous article, I performed a case study on the conflict between a Latvian company and the Swedish Trade Union and analyzed reasons why a single European labour market can not be smoothly realized. This article presents another case study on the conflict between an Italian company and the British Trade Union in order to reinforce the evidence provided in the previous article.

This study examined the neurobehavioral changes and alteration in gene expression in the brains of metallothionein (MT)-I/II null mice exposed to low-levels of mercury vapor (Hg(0)) during postnatal development. MT-I/II null and wild-type mice were repeatedly exposed to Hg(0) at 0.030 mg/m(3) (range: 0.023-0.043 mg/m(3)), which was similar to the current threshold value (TLV), for 6 hr per day until the 20th day postpartum. The behavioral effects were evaluated with locomotor activity in the open field (OPF), learning ability in the passive avoidance response (PA) and spatial learning ability in the Morris water maze (MM) at 12 weeks of age. Hg(0)-exposed MT-I/II null mice showed a significant decrease in total locomotor activity in females, though learning ability and spatial learning ability were not affected. Immediately after Hg(0) exposure, mercury concentrations in the brain did not exceed 0.5 µg/g in any animals. Hg(0) exposure resulted in significant alterations in gene expression in the brains of both strains using DNA microarray analysis. The number of altered genes in MT-I/II null mice was higher than that in wild-type mice and calcium-calmodulin kinase II (Camk2a) involved in learning and memory in down-regulated genes was detected. These results provide useful information to elucidate the development of behavioral toxicity following low-level exposure to Hg(0).

Ten countries in 2004 and two countries in 2007 have newly become members of the European Union. Those twelve countries are much poorer than old member states and Latvia is the third poorest of the twelve. Economic theory of international migration tells us that labour will move from a country with low income to a country with high income, if barriers between the two countries are eliminated, so that the wage rate of both countries will converge to the same level, but the theory does not describe what will happen in the process of such a convergence. This article is a case study on the conflict between a Latvian Company "Laval"and Swedish Trade Unions in order to provide an example of what conflict would be like when a poor country has become a member in the EU enlargement process, and to consider what it implies regarding EU integration.

OBJECTIVE To examine whether immunocytochemistry can distinguish pulmonary large cell neuroendocrine carcinoma (LCNEC) among non-small cell lung cancers (NSCLCs). STUDY DESIGN Tumor touch imprint cytologic specimens of 109 lung cancers were studied. Immunocytochemistry was done using a total of 8 primary antibodies: chromogranin A, synaptophysin, neural cell adhesion molecule, neuron specific enolase, CK34betaE12, thyroid transcription factor-1, cytokeratin 18 and E-cadherin. RESULTS If 2 or 3 antibodies of chromogranin A, synaptophysin and neural cell adhesion molecule were stained positive and CK34betaE12 was not stained, pulmonary LCNEC can be selected accurately among other NSCLCs with 100% sensitivity and 100% specificity. CONCLUSION This study reveals that immunocytochemistry can help distinguish LCNEC of the lung from other NSCLCs.

書誌情報のみ, Bibliographic data Only

書誌情報のみ, Bibliographic data Only

書誌情報のみ, Bibliographic data Only

FBXW7 is reported to be a tumor suppressor gene, and the functional inactivation of FBXW7 has been reported in various human tumors. In this study, we investigated the FBXW7 gene in human thymoma; although no mutations were evident, a significantly high frequency of methylation in the FBXW7 beta-form promoter was observed in types B1 or higher (P=0.014). We propose a novel mechanism for the pathogenesis of thymoma by FBXW7 beta-form and hypothesize that expressional suppression plays an important role in the malignant potential of thymoma.

The objective of this study was to analyze the spiritual pain from persistent chemotherapy-induced peripheral neuropathy (PCIPN) in colon cancer patients receiving long-term oxaliplatin therapy. The subjects were 20 colon

To examine the effects of the Kobe, Japan, earthquake, a life-threatening event, on stress and glycemic control in diabetic patients.Hemoglobin A1c levels before and after the earthquake were evaluated in diabetic patients in Kobe (N = 157; magnitude, 7.2) and in Osaka, Japan, as a control (N = 277; magnitude, 4.2), where little damage to houses and traffic facilities occurred. Glycosylated hemoglobin levels were also compared with those of 2 years before and 1 year after the earthquake. The General Health Questionnaire (GHQ) and a self-administered questionnaire regarding damage to houses and relatives killed or injured were used to assess psychological and mental stresses on earthquake survivors.Glycemic control was aggravated in diabetic patients after the earthquake in Kobe but not in Osaka. THe GHQ scores were significantly higher in the patients in Kobe than those in Osaka. Increased hemoglobin A1c concentrations and high scores on the GHQ were especially evident in diabetic patients with severe damage to houses and/or with relatives killed or injured.These results suggest an association between chronic, life-threatening stress and the worsening of metabolic control in patients with diabetes mellitus.

The earthquake 1 that hit the city of Kobe, Japan, January 17, 1995, caused health problems in Kobe citizens, some of whom had hypertension, 2 diabetes mellitus, or chronic renal failure with hemodialysis. 3 After the earthquake, people began to consume foods that were higher in fat and energy; therefore, control of blood glucose levels in patients with diabetes mellitus became more difficult (A.I., H. Kitaoka, MD, PhD, M. Majima, MD, PhD, et al, unpublished data, 1995). Since the earthquake was a life-threatening stress, we decided to study its impact on patients with anorexia nervosa, most of whom had distorted cognition toward food and their health status. Ten patients with anorexia who fulfilled the diagnostic criteria for Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised 4 and who lived in the most severely destroyed areas of Kobe were included in our study. We examined change in body weight

The crystal structure of (DMtTSF)2ReO4 (2 C11H12Se41⁄2+·ReO4−) was determined at room temperature. The structure is monoclinic, space group C2/c, with cell dimensions a=28.518(2), b=7.327(1), c=14.364(1) A β=109.84(1)°, Z=4. The DMtTSF molecules stack along the b axis to form a zigzag column. The interstack contacts between Se atoms are shorter than those in (TMTSF)2X. These contacts indicate that (DMtTSF)2ReO4 has a higher two-dimensional character than (TMTSF)2X.

X-Ray and optical reflection measurements of (DBTTF)2-(Cu2Cl6) single crystals were carried out. The single crystal of the complex consists of stacking columns of the cation molecules DBTTF+. The analysis of the reflection spectra of (DBTTF)2-(Cu2Cl6) single crystals shows that the electronic structure of DBTTF+ cation molecules is typical of the dimer type configuration.

Hexacyanobutadiene(HCBD) forms two kinds of molecular complexes with tetramethyltetrathiafulvalene(TMTTF) one kind with tetramethylthiotetrathiafulvalene(TTMTTF). The crystal structures of these complexes and neutral TTMTTF are determined by X-ray analyses. (TMTTF)2·HCBD is composed of 2:1 donor and acceptor, and TMTTF exists as a dimer cation stacked along the c axis. HCBD anions are included in the cavity of the dimer stack directing their molecular planes parallel to the stacking axis. TMTTF·HCBD is composed of 1:1 donor and acceptor, and has segregated cation and anion stacks with the interplanar spacing of 3.61 A in TMTTF and 3.43 A in HCBD columns. TTMTTF·HCBD is shown to have a regular segregated column with a partial charge transfer. Neutral TTMTTF has a non-planar conformation. The C=C and C–S bond lengths of the donors in free and complexed states are correlated with the degree of the charge transfer in these four complexes, and linear relationships are found between these two quantities.

The single crystal of (HMTTeF)4(PF6)2 was first prepared by the electrochemical method. The X-ray crystal structure analysis revealed that among four HMTTeF molecules in the unit cell, three are stacked to form trimeric molecular column along the a-axis and the remaining one is located between the HMTTeF columns, having very short intermolecular Te–Te distances with the HMTTeF column.

Summary Smoke condensate obtained by pyrolysis of proteins, such as lysozyme and histone, was shown to be mutagenic to Salmonella typhimurium TA100 and TA98. In vitro metabolic activation by a mammalian postmitochondrial enzyme preparation (S-9 Mix) was required. Smoke condensates obtained by pyrolysis of DNA, RNA, starch and vegetable oil were slightly mutagenic, whereas those from pyrolysis of L- and D-tryptophan and 5-hydroxy-D,L-tryptophan were very strongly mutagenic with metabolic activation by S-9 Mix. Because of the high correlation between mutagenicity and carcinogenicity, it is theorized that the cooking of proteinaceous foods might be an important cause of human cancers.

Blood level profiles of flunitrazepam and its N-desmethyl-metabolite were in vestigated after single and multiple administrations of flunitrazepam to groups of 5 healthy male adult volunteers. Urinary excretion of some major metabolites of flunitrazepam was also examined following oral doses of a single 4 mg.Following the oral administration, the absorption of flunitrazepam was fairly rapid: the peak times were attained within 1-2 hr with peak levels of 9.6-16.0 ng/ml for 2 mg dose and 20.6-30.3 ng/ml for 4 mg dose. The drug then disappear ed from the blood biphasically. The rate of disappearance was independent of the doses, while the AUC for the unaltered drug was dose-related. Blood levels of N-desmethyl flunitrazepam were always lower than those of the unal tered drug. 7-Amino-flunitrazepam and 3-hydroxy-flunitrazepam were major urinary metabolites, comprising about 9% and 5% of the dose, respectively, in the initial 72-hr urine. During repeated administration of the drug at a daily oral dose of 2 mg, the blood level profiles showed gradual elevation during the first few days, and then the steady-state was attained within 3-5 days.After i. v. injection of 2 mg, flunitrazepam was eliminated from the blood triphasically. The mean AUC for the unaltered drug obtained after the i. v. injection was about twice as much as that obtained after the oral administration of the identical dose.

Summary 4-Dimethylaminoazobenzene is only a weak mutagen on Salmonella typhimurium strains TA100 and TA98, although it is a fairly strong carcinogen. Norharman, which is present in tobacco smoke and tryptophan pyrolysate, enhanced the mutagenicity of 4-dimethylaminoazobenzene on strain TA98 about 40-fold. Norharman alone had no mutagenic activity on TA98 and so it is a ‘Comutagen’. The mutagenicities of 4-methylaminoazobenzene, 3′-methyl-4-dimethylaminoazobenzene, 4-aminoazobenzene and 4′-methoxycarbonyl-N-hydroxy-4-methylaminoazobenzene were all potentiated by norharman. Presence of a metabolic activation system was essential for comutagenic action of norharman with these compounds. Dihydronorharman, tetrahydronorharman, 9-methyl-β-carboline, harman and tetrahydroharman did not enhance the mutagenicity of 4-dimethylaminoazobenzene.

胸部X線無所見で気管支鏡無所見のTX肺癌例のうち, 病変が気管支鏡の可視範囲外に存在した5例 (扁平上皮癌4例, 腺癌1例) を対象として局在部位同定に至る過程を分析した.部位別に採取した細胞診の標本上に出現した癌を疑いうる異型を有する単個細胞数を計数し, またシート状に出現してくる異型細胞集団は前記の細胞数のなかには加えず細胞集団の数として計数比較検討した. その結果病巣を擦過した場合には多数の癌細胞が採取され, なおかつ主としてライトグリーン好性に染色される結合性の強いシート状細胞集団が多数出現していた. このライトグリーン好性で結合性の強い集団の存在が局在部位を同定するうえでの強い根拠となり得た. 全体を通してみてみると癌細胞が全く採取されないことがあり, また部位別に採取した吸引物中の癌細胞の分布が必ずしも常に病巣の存在部位と一致するとは限らない. また多数の検体を一度に扱うことによる検体の取り違えや喀痰の気管支内移動に伴う部位診断の誤りの可能性もあり, 十分注意する必要がある. したがって局在部位同定のためには, 擦過細胞診によって前記のように多数の異型細胞が結合性の強いシート状集団で, 同一気管支から繰り返し2回以上採取されるまで根気強く検査を繰り返すことが必要である.

C9H17N~-. C10~ (orange form), Mr = 252.71, monoclinic, P21/a, a=13.671(3), b=14.899(2), c= 6.186(2)/~, fl =97-27(2) °, V= 1249.9(5) A, 3, Z=4, Dx = 1.343 g cm -3, graphite-monochromated Mo Ka radiation, h = 0.71073 A,, /z = 2.606 cm -1, F(000) = 536, T = 140 K, R = 0.045 for 4331 independent data. A slight alternation is found in the bond lengths of the conjugated system of the polymethine cyanine dye [C-C distances 1.376(2), 1.399(2), 1.378(2) and 1.394(2) A at 140 K]. The charge distribution is estimated by the method of Coppens, Guru Row, Leung, Stevens, Becker & Yang [Acta Cryst. (1979), A35, 63-72] and the result is in good agreement with the ab initio MO calculation. In particular, positive charges are found at the methyl groups [except C(11)] and the odd-numbered C atoms in the chain; negative charges are observed at C(4), C(11) and the N atoms.

Smoke condensates obtained from broiling fish showed mutagenic activity for Salmonella typhimurium TA100 and TA98. Metabolic activation was required to induce mutagenic activity of smoke condensates of some species of fish. The smoke condensate obtained during charcoal broiling of beefsteak was far less mutagenic than that of fish, with or without metabolic activation. Extracts of the charred surface of broiled fish and meat also contained mutagenic substances. These extracts needed metabolic activation to exhibit mutagenicities on TA98. The mutagenic activity of the smoke condensate obtained from one sardine weighing 100 g was equivalent to that of 132 micrograms benzo(a)pyrene and that of the charred surface of the sardine was equivalent to 358 micrograms benzo(a)pyrene. One piece of beefsteak weighing 190 g, contained mutagenic activity equivalent to that of 855 micrograns benzo(a)pyrene.