Mediastinal hematoma due to traumatic injury to the azygous vein.

Rupture of the azygous vein may result from abrupt deceleration applied to the mobile azygous arch, which can initiate shearing forces within the thorax.

Two Cases of Atraumatic Chylous Ascites Characterized by Hypotriglyceridemia and Partially Managed with an Oral Fat-Free Elemental Diet.

Most cases of chylous ascites occur after surgery, but it also develops in nonoperative cases, although rarely. Such cases are often difficult to treat. In this study, we treated 2 cases of atraumatic chylous ascites, which were controlled by combining diuretic treatment with an oral fat-free elemental diet (Elental®, EA Pharma Co., Ltd., Tokyo, Japan). Elental can provide oral nutrition compatible with a lipid-restricted diet, which may be useful for control of chylous ascites. We report on these cases, including literature review-based considerations.

A case of large cell neuroendocrine carcinoma of the stomach with multiple liver metastases.

A 79-year-old man was admitted to our hospital to determine the cause of his melena. He underwent esophagogastric endoscopy and computed tomography, revealing a submucosal tumor on the anterior wall of the gastric antrum with multiple liver metastases. Endoscopic biopsy revealed a large cell neuroendocrine cell carcinoma. A subtotal gastrostomy was performed to prevent pyloric stenosis and anemia caused by tumor hemorrhage. Previous studies on gastric neuroendocrine carcinoma reported poor prognosis. Large- and small-cell types of gastric neuroendocrine carcinomas were differentiated for the first time in the 14th edition of the Japanese Classification of Gastric Carcinoma. It is expected that the number of reports of gastric neuroendocrine carcinomas classified as either the large-cell or small-cell type will increase. It is necessary to collect information on more cases to improve prognosis and to establish appropriate treatment guidelines.

Comparative Analysis of Biological Sphingolipids with Glycerophospholipids and Diacylglycerol by LC-MS/MS.

Liquid chromatography-electrospray ionization mass spectrometry (LC-MS) is an effective and popular technique used in lipid metabolomic studies. Although many LC-MS methods enabling the determination of sphingolipid molecular species have been reported, they do not cover a broad range of sphingolipid metabolites with expanding glycerophospholipids (GPLs) and diacylglycerol (DAG). In this study, we developed an approach for the comprehensive analysis of sphingolipids, GPLs and DAG molecular species in a biological sample, without alkaline hydrolysis. After validating the reliability of this approach, we analyzed tissue lipids of sphingomyelin synthase 2-knockout mice and found that changes in sphingolipid metabolism in the liver affect the level of docosahexaenoic acid-containing GPLs. Our method analyzes GPLs and DAG, as well as sphingolipids within biological samples and, thus, will facilitate more comprehensive studies of sphingolipid metabolism in pathology and diagnostics.

Difference in the emetic control among highly emetogenic chemotherapy regimens: Implementation for appropriate use of aprepitant.

Although antiemetic medication based on the emetogenicity of the cancer chemotherapy regimen is recommended, emetic control varies even among highly emetogenic chemotherapy (HEC). In the present study, we retrospectively investigated the rates of emetic control by a combination of granisetron, 5-HT3 antagonist and dexamethasone in various HEC regimens, including 5 single-day chemotherapy regimens such as gemcitabine/cisplatin (GEM/CDDP), epirubicin/cyclophosphamide (EPI/CPA), pemetrexed or vinorelbine/cisplatin (PEM or VNR/CDDP), doxorubicin/bleomycin/vinblastine/dacarbazine (ABVd) and rituximab/doxorubicin/cyclophosphamide/vincristine/prendisolone (R-CHOP21), and 2 multiple-day chemotherapy regimens such as 5-fluorouracil/cisplatin (5-FU/CDDP) and bleomycin/etoposide/cisplatin (BEP). Complete response (no emesis, no rescue treatment) during the overall period (days 1-5) was assessed as the primary endpoint. Chemotherapy-induced nausea and vomiting was well-controlled (complete response >70%) in GEM/CDDP and R-CHOP21, but not in other regimens. The effect of a triple antiemetic medication including aprepitant (APR) was subsequently examined in patients receiving EPI/CPA and 5-FU/CDDP. Complete response was significantly improved in patients receiving 5-FU/CDDP but not in those receiving EPI/CPA, although the complete protection from vomiting significantly increased in both cases. Of note, the administration of APR for 5 days, but not for 3 days, was required to completely block the incidence of vomiting during the 7 days of the observation period in patients receiving 5-FU/CDDP. These findings suggest that APR should be used appropriately based on the emetogenicity of HEC regimens.

TNF-α is associated with loss of lean body mass only in already cachectic COPD patients.

BACKGROUND: Systemic inflammation may contribute to cachexia in patients with chronic obstructive pulmonary disease (COPD). In this longitudinal study we assessed the association between circulating C-reactive protein (CRP), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 levels and subsequent loss of fat free mass and fat mass in more than 400 COPD patients over three years. METHODS: The patients, aged 40-76, GOLD stage II-IV, were enrolled in 2006/07, and followed annually. Fat free mass and fat mass indexes (FFMI & FMI) were calculated using bioelectrical impedance, and CRP, TNF-α, IL-1ß, and IL-6 were measured using enzyme immunoassays. Associations with mean change in FFMI and FMI of the four inflammatory plasma markers, sex, age, smoking, FEV1, inhaled steroids, arterial hypoxemia, and Charlson comorbidity score were analyzed with linear mixed models. RESULTS: At baseline, only CRP was significantly (but weakly) associated with FFMI (r = 0.18, p < 0.01) and FMI (r = 0.27, p < 0.01). Univariately, higher age, lower FEV1, and use of beta2-agonists were the only significant predictors of decline in FFMI, whereas smoking, hypoxemia, Charlson score, and use of inhaled steroids predicted increased loss in FMI. Multivariately, high levels of TNF-α (but not CRP, IL-1ß or IL-6) significantly predicted loss of FFMI, however only in patients with established cachexia at entry. CONCLUSION: This study does not support the hypothesis that systemic inflammation is the cause of accelerated loss of fat free mass in COPD patients, but suggests a role for TNF-α in already cachectic COPD patients.

Inhibition of allergic bronchial asthma by thrombomodulin is mediated by dendritic cells.

RATIONALE: bronchial asthma is caused by inappropriate acquired immune responses to environmental allergens. It is a major health problem, with a prevalence that is rapidly increasing. Curative therapy is not currently available. OBJECTIVES: to test the hypothesis that thrombomodulin (TM) inhibits allergic bronchial asthma by inducing tolerogenic dendritic cells (DCs). METHODS: the protective effect of TM was evaluated using a murine asthma model. Asthma was induced in mice by exposure to chicken egg ovalbumin, and the effects of inhaled TM or TM-treated DCs were assessed by administering before ovalbumin exposure. MEASUREMENTS AND MAIN RESULTS: treatment with TM protects against bronchial asthma measured as improved lung function and reduced IgE and cells in alveolar lavage fluid by inducing tolerogenic dendritic dells. These are characterized by high expression of surface TM (CD141/TM(+)) and low expression of maturation markers and possess reduced T-cell costimulatory activity. The CD141/TM(+) DCs migrate less toward chemokines, and after TM treatment there are fewer DCs in the draining lymph node and more in the lungs. The TM effect is independent of its role in coagulation. Rather, it is mediated via the TM lectin domain directly interacting with the DCs. CONCLUSIONS: the results of this study show that TM is a modulator of DC immunostimulatory properties and a novel candidate drug for the prevention of bronchial asthma in atopic patients.

Stepped assessment of gastric emptying of a solid meal using the (13)C-octanoic acid breath test.

The (13)C-octanoic acid breath test is widely used for evaluating gastric emptying of solids. Since the results of this test are influenced by multiple factors such as the time required to grind the solid meal into smaller particles, the gastroduodenal transport time of the ground meal, and the time required for bowel drug absorption and drug dispersion, the administration of a test meal by the oral route alone cannot result in an accurate measurement of the complicated process of emptying the stomach of solids. The aim of the present study was to evaluate each phase of gastric emptying of solids by varying the administration route of the test meal. Six healthy male volunteers (mean age: 33.2 yr) participated in the study. The test meal consisted of a bowl of rice topped with a mixture of boiled chicken and eggs admixed with 100 mg of (13)C-octanoic acid (total: 273 kcal). All subjects were given the test meal by each of the following three methods: 1. Normal oral intake of the test meal, 2. Feeding of the ground test meal through a nasogastric tube, 3. Feeding of the ground test meal through a duodenal tube. For each set of examinations, the mean residence time (MRT), half-emptying time (T(1/2)), gastric emptying coefficient (GEC), lag phase (L-breath), and measured maximum (13)C excretion time (Tmax-measured) were calculated. The data was analyzed to determine the time for each phase of gastric emptying as follows: mean grinding time (MGT) = MRT(oral) - MRT(nasogastric), mean gastroduodenal transport time (MGDTT) = MRT(nasogastric) - MRT (nasoduodenal). Data was expressed as the mean +/- SE. The values of the parameters of MGT were 0.82 +/- 0.50 hr (MRT), 0.64 +/- 0.18 hr (T(1/2)), 0.51 +/- 0.24 hr (L-breath), -0.45 +/- 0.30 hr (GEC), and 49.2 +/- 8.0 min (Tmax-measured). The values of the parameters of MGDTT were 0.87 +/- 0.38 hr (MRT), 0.26 +/- 0.29 hr (T(1/2)), 0.92 +/- 0.36 hr (L-breath), 0.55 +/- 0.23 hr (GEC), and 63.33 +/- 8.16 min (Tmax-measured). The times required for the drug absorption and disposition were 1.60 0.20 hr (MRT), 1.03 +/- 0.24 hr (T(1/2)), 0.10 +/- 0.08 hr (L-breath), 3.72 +/- 0.46 hr (GEC), and 19.67 +/- 2.11 min (Tmax-measured). By varying the administration route of a test meal containing (13)C-octanoic acid, we may be able to assess each phase of the emptying of gastric solids in detail, thus leading to a better understanding of gastroduodenal motility.

Involvement of sphingosine 1-phosphate, a platelet-derived bioactive lipid, in contraction of mesangium cells.

Platelet-derived mediators may play an important role in the development of renal diseases through interaction with glomerular mesangial cells (MCs), and we, in this study, examined the effect of sphingosine 1-phosphate (Sph-1-P), a bioactive lipid released from activated platelets, on the contraction of MCs. Sph-1-P was found to induce MC contraction through mediation of Rho kinase both in cell shape change and collagen gel contraction assays. The specific antagonist of the Sph-1-P receptor S1P(2) inhibited the response. Similar results were obtained when the supernatant from activated platelet suspensions were used instead of Sph-1-P. Our findings suggest that platelet-derived Sph-1-P may be involved in MC contraction via S1P(2) and that regulation of this receptor might be useful therapeutically.

Fluid shear stress enhances the sphingosine 1-phosphate responses in cell-cell interactions between platelets and endothelial cells.

Fluid shear stress modulates the functional responses of platelets and vascular cells, and plays an important role in the pathogenesis of vascular disorders, including atherosclerosis and restenosis. Since shear stress induces activation of platelets, which abundantly store sphingosine 1-phosphate (Sph-1-P), and upregulates the mRNA expression of S1P(1), the most important Sph-1-P receptor expressed on the endothelial cells, we examined the effects of shear stress on the Sph-1-P-related responses involving these cells. Shear stress was found to induce Sph-1-P release from the platelets in a shear intensity- and time-dependent manner. Inhibitors of protein kinase C suppressed this mechanical force-induced Sph-1-P release, suggesting involvement of this kinase. On the other hand, in vascular endothelial cells, shear stress increased S1P(1) protein expression, as revealed by flow-cytometric analysis, and the responsiveness to Sph-1-P, which was assessed by monitoring the intracellular Ca(2+) concentration. These results indicate that shear stress enhances the Sph-1-P responses in cell-cell interactions between platelets and endothelial cells.

Measurement of lysophospholipase D/autotaxin activity in human serum samples.

OBJECTIVES: Lysophospholipase D (lysoPLD)/autotaxin regulates the blood levels of lysophosphatidic acid (LPA), and we designed a serum lysoPLD assay for use in clinical laboratory testing. DESIGN AND METHODS: LysoPLD activity was assessed based on the amount of choline released with lysophosphatidylcholine as the substrate. RESULTS AND CONCLUSIONS: It was confirmed that the lysoPLD assay can be applied to clinical laboratory testing. The serum lysoPLD activity in healthy female subjects was significantly higher than that in the male subjects.

Sphingosine 1-phosphate receptor expression profile in human gastric cancer cells: differential regulation on the migration and proliferation.

INTRODUCTION: Sphingosine 1-phosphate (S1P) is a bioactive lysophospholipid, derived from activated platelet, that is known to induce diverse cellular responses through at least five G-protein-coupled receptors on various cell types. Abnormal platelet and coagulation activation is often seen in patients with gastric cancer. However, neither the effects of this platelet-derived mediator S1P nor the distribution of S1P receptors on the gastric cancer cell are fully understood. The aim of this study was to examine the possible role of S1P and its receptors in the progression of gastric cancer. MATERIALS AND METHODS: We characterized the expression profiles of S1P receptors in nine human gastric cancer cell lines and evaluated the relationship between the responses to S1P and its receptor expression on cell migration by modified Boyden chamber and cell proliferation by MTS assay. RESULTS: Northern blotting analysis has revealed that S1P2 was expressed in all gastric cancer cell lines to varying degrees, and S1P3 was expressed in four cell lines. S1P1 expression was weak, and no significant expression of either S1P4 or S1P5 was detected. The addition of S1P markedly stimulated the migration of MKN1 and HCG-27 that dominantly expressed S1P3, and the effect was potently inhibited by pertussis toxin or wortmannin. In contrast, SIP significantly inhibited the migration of AZ-521 that expressed S1P2 exclusively. This indicates that the balance between S1P2- and S1P3-mediated signals might be critical in determining the metastatic response of gastric cancer cells to S1P. S1P elicited weak but significant antiproliferative effects on all of the three cell lines, although the effects were not major. In these cells, S1P induced extracellular signal-regulated kinase (ERK) phosphorylation with transient Akt dephosphorylation that may cause the weak effects on proliferation. CONCLUSIONS: Our results suggest that the S1P receptor expression may critically determine the biological behavior of gastric cancers and thus therapeutic interventions directed at each S1P receptor might be clinically effective in preventing metastasis in gastric cancer.

Sphingosine 1-phosphate-related metabolism in the blood vessel.

Sphingosine 1-phosphate (Sph-1-P) is a bioactive lipid released from activated platelets and plays an important role in vascular biology. In this study, we investigated Sph-1-P-related metabolism in the blood vessel, mainly using radio-labeled Sph and Sph-1-P. Sph was metabolically stable in the plasma, while it was converted into Sph-1-P in the presence of activated platelets. When the mixture of Sph-1-P and plasma was fractionated on a gel-filtration column, all Sph-1-P co-eluted with protein fractions that coincide with lipoproteins and albumin by agarose gel electrophoresis. When evaluated by polyacrylamide gel electrophoresis, 7.2 +/- 3.8%, 53.3 +/- 6.4%, and 39.5 +/- 7.9% of the radioactivity of Sph-1-P added to plasma was recovered in the low-density lipoprotein (LDL), high-density lipoprotein (HDL), and albumin fractions, respectively. On the other hand, 5.2 +/- 3.2%, 38.4 +/- 5.5%, and 56.3 +/- 5.7% of the radioactivity of Sph-1-P converted from Sph in collagen-stimulated platelets and released into the plasma was recovered in the LDL, HDL, and albumin fractions, respectively. When Sph-1-P release from activated platelets was examined, a stronger response was observed in the presence of albumin than lipoproteins, suggesting efficient Sph-1-P extraction from platelets by albumin. Finally, Sph-1-P, which is stable in the plasma, was markedly degraded by an ectophosphatase activity in the presence of vascular endothelial cells or in whole blood. Although Sph-1-P is stable in the plasma, it is likely that the level of this bioactive lipid is dynamically controlled by various factors including release from platelets, distribution among plasma proteins, and degradation by ectophosphatase.

Synergistic effect of sphingosine 1-phosphate on thrombin-induced tissue factor expression in endothelial cells.

Sphingosine 1-phosphate (S1P), a bioactive lipid, is produced and stored in platelets and is released from activated platelets during blood coagulation activation. Thrombin, which is also generated during blood coagulation, has been shown to induce tissue factor (TF), the initiator of blood coagulation, in endothelial cells (ECs); however, the effect of S1P on this process is not evaluated. Here we demonstrated that S1P strongly potentiated thrombin-induced TF expression in ECs and that S1P itself did not induce TF expression. Among signaling lipids, platelet-activating factor slightly enhanced thrombin-induced TF expression; other lipids, including lysophosphatidic acid, lysophosphatidylcholine, sphingosine, and C2-ceramide exert no effect on TF expression. S1P enhanced TF expression at the transcriptional level, possibly via promoting the activation of transcription factors nuclear factor-kappaB (NF-kappaB) and Egr-1. Thrombin weakly and S1P strongly activated extracellular signal-regulated kinase 1/2 (ERK1/2) mitogen-activated protein (MAP) kinase and, in the presence of both stimulants, enhanced and sustained activation of this kinase was observed. The ERK1/2-specific inhibitor PD98059 significantly inhibited enhanced TF expression induced by both stimulants but only weakly inhibited thrombin-induced TF expression, thus indicating the requirement of the ERK1/2 pathway in synergistic induction of TF expression. In addition, we found that thrombin and S1P rapidly up-regulated the expression of S1P receptors, endothelial differentiation gene-1 (EDG-1) and EDG-3, thereby suggesting that the effect of S1P on TF expression and other EC functions may be enhanced by thrombin and S1P itself. The present data reveal the synergistic effect of S1P on thrombin-induced TF expression in ECs, which may promote further thrombin and S1P generation, thus propagating a positive feedback reaction.