[Refractory Hypertension and Intermittent Claudication Caused by Distal Elephant Trunk Stenosis 10 Years After Total Arch Replacement for Stanford Type A Aortic Dissection;Report of a Case].

A 49-year-old man was admitted to our hospital because of intermittent claudication and refractory hypertension 10 years after surgery to Stanford type A acute aortic dissection. He underwent total arch replacement with an elephant trunk of 22 mm in diameter. Transesophageal echocardiography revealed that distal end of the elephant trunk was stenosed. Systolic blood pressure gradient over this portion reached to more than 100 mmHg. Folding of elephant trunk and thrombus formation were considered to be the cause. Thoracic endovascular aortic repair relieved stenosis and intermittent claudication, and enabled better blood pressure control.

Chemical structure of cichorinotoxin, a cyclic lipodepsipeptide that is produced by Pseudomonas cichorii and causes varnish spots on lettuce.

Pseudomonas cichorii, which causes varnish spots on lettuce and seriously damages lettuce production during the summer season in the highland areas of Japan (e.g., Nagano and Iwate prefectures) was isolated. The structure of a toxin produced by this organism was analyzed based on the detailed evaluation of its 2D NMR and FABMS spectra, and this compound has not been reported previously. We propose the name cichorinotoxin for this toxin. In conjunction with the D or L configurations of each amino acid, which were determined by Marfey's method, we propose the structure of cichorinotoxin to be as follows: 3-hydroxydecanoyl-(Z)-dhThr1-D-Pro2-D-Ala3-D-Ala4-D-Ala5-D-Val6-D-Ala7-(Z)-dhThr8-Ala9-Val10-D-Ile11-Ser12-Ala13-Val14-Ala15-Val16-(Z)-dhThr17-D-alloThr18-Ala19-L-Dab20-Ser21-Val22, and an ester linkage is present between D-alloThr18 and Val22 (dhThr: 2-aminobut-2-enoic acid; Dab: 2,4-diaminobutanoic acid). Thus, the toxin is a lipodepsipeptide with 22 amino acids. The mono- and tetraacetate derivatives and two alkaline hydrolysates, compounds A and B, were prepared. We discuss here the structure-activity relationships between the derivatives and their necrotic activities toward lettuce.

To what extent can 3D model replicate dimensions of individual mitral valve prolapse?

Determining the complex geometry of mitral valve prolapse is often difficult. We constructed 3D models of six prolapsed mitral valves for surgical assessment, and evaluated how accurately the models could replicate individual valve dimensions. 3D polygon data were constructed based on an original segmentation method for computed tomography images. The model's replication performance was confirmed via dimensional comparison between the actual hearts during surgery and those models. The results revealed that the prolapsed segments matched in all cases; however, torn chordae were replicated in four cases. The mean height differences were 0.0 mm (SD 1.6, range - 2 to + 2 mm) for the anterolateral side, 0.0 mm (SD 1.7, range - 2 to + 2 mm) for the prolapsed leaflet center, and - 1.5 mm (SD 0.6, range - 1 to - 2 mm) for the posteromedial side. Regression analysis showed a strong and positive correlation, and Bland-Altman plots indicated quantitative similarity of the models to the actual hearts. We concluded that our 3D valve models could replicate the actual mitral valve prolapses within acceptable dimensional differences. Our concepts are useful for better 3D valve creation and better surgical planning with reliable 3D valve models.

[Splenic Artery Left Common Iliac Artery Bypass for Hepatocellular Carcinoma with Celiac Artery Compression Syndrome - A Case Report].

Celiac artery compression syndrome(CACS)is a rare disorder characterized by postprandial intestinal angina caused by insufficient blood supply to the gastrointestinal organs. In this syndrome, the root of the celiac artery is compressed and narrowed by the median arcuate ligament of the diaphragm during expiration, sometimes causing difficulties in trans-arterial intervention. We report here a case that trans-hepatic arterial intervention was able to performed by splenic bypass. A 74- year-old man with multiple hepatocellular carcinoma(HCC)was performed the angiography, and diagnosed as CACS due to celiac artery root obstruction. The median arcuate ligament was incised in order to introduce trans-arterial intervention, but sufficient resumption of blood flow in the root of celiac artery could not be obtained, so bypass surgery was added from left common iliac artery to splenic artery with grafted right saphenous vein. One month later, trans hepatic arterial intervention is performed via graft, and treatment of HCC is ongoing. Splenic artery left common iliac artery bypass surgery was also considered to be an option for cases in which the resurgence of the blood flow in the root of the celiac artery was not obtained even in the median arcuate ligament dissection for CACS.

Noncompetitive immunoassay detection system for haptens on the basis of antimetatype antibodies.

BACKGROUND: Small molecules classified as haptens are generally measured by competitive immunoassay, which is theoretically inferior to noncompetitive sandwich immunoassay in terms of sensitivity and specificity. We created a method for developing sandwich immunoassays to measure haptens on the basis of antimetatype antibodies. METHODS: We generated antimetatype monoclonal antibodies against a hapten-antibody immunocomplex using an ex vivo antibody development system, the Autonomously Diversifying Library (ADLib) system. We selected 2 haptens, estradiol (E2) and 25-hydroxyvitamin D [25(OH)D], as analytes. Sandwich immunoassays for these 2 haptens were developed by use of a 96-well microtiter plate and a fully automated chemiluminescence analyzer, and the performances of these immunoassays were investigated. RESULTS: The developed assays exhibited sensitivity high enough to detect target haptens in serum samples. The limit of detection of the ELISA for E2 was 3.13 pg/mL, and that of the fully automated chemiluminescent enzyme immunoassay (CLEIA) system was 2.1 ng/mL for 25(OH)D. The cross-reactivity with immunoreactive derivatives was effectively improved compared with the competitive assay. The CVs for the sandwich ELISA for E2 were 4.2%-12.6% (intraassay) and 6.2%-21.8% (total imprecision). The CVs for the sandwich CLEIA for 25(OH)D were 1.0%-2.3% (intraassay) and 1.9%-3.5% (total imprecision). In particular, the sandwich CLEIA for 25(OH)D showed correlations of r = 0.99 with both LC-MS/MS and a commercially available (125)I RIA. CONCLUSIONS: Our method represents a potentially simple and practical approach for routine assays of haptens, including vitamins, hormones, drugs, and toxins.

Mislocalization and inhibition of acetyl-CoA carboxylase 1 by a synthetic small molecule.

Chromeceptin is a synthetic small molecule that inhibits insulin-induced adipogenesis of 3T3-L1 cells and impairs the function of IGF2 (insulin-like growth factor 2). The molecular target of this benzochromene derivative is MFP-2 (multifunctional protein 2). The interaction between chromeceptin and MFP-2 activates STAT6 (signal transducer and activator of transcription 6), which subsequently induces IGF inhibitory genes. It was not previously known how the binding of chromeceptin with MFP-2 blocks adipogenesis and activates STAT6. The results of the present study show that the chromeceptin-MFP-2 complex binds to and inhibits ACC1 (acetyl-CoA carboxylase 1), an enzyme important for the de novo synthesis of malonyl-CoA and fatty acids. The formation of this ternary complex removes ACC1 from the cytosol and sequesters it in peroxisomes under the guidance of Pex5p (peroxisomal-targeting signal type 1 receptor). As a result, chromeceptin impairs fatty acid synthesis from acetate where ACC1 is a rate-limiting enzyme. Overexpression of malonyl-CoA decarboxylase or siRNA (small interfering RNA) knockdown of ACC1 results in STAT6 activation, suggesting a role for malonyl-CoA in STAT6 signalling. The molecular mechanism of chromeceptin may provide a new pharmacological approach to selective inhibition of ACC1 for biological studies and pharmaceutical development.

Deactivation of STAT6 through serine 707 phosphorylation by JNK.

Signal transducer and activator of transcription 6 (STAT6), which plays a critical role in immune responses, is activated by interleukin-4 (IL-4). Activity of STAT family members is regulated primarily by tyrosine phosphorylations and possibly also by serine phosphorylations. Here, we report a previously undescribed serine phosphorylation of STAT6, which is activated by cell stress or by the pro-inflammatory cytokine, interleukin-1ß (IL-1ß). Our analyses suggest that Ser-707 is phosphorylated by c-Jun N-terminal kinase (JNK). Phosphorylation decreases the DNA binding ability of IL-4-stimulated STAT6, thereby inhibiting the transcription of STAT6-responsive genes. Inactivation of STAT6 by JNK-dependent Ser-707 phosphorylation may be one mechanism of controlling the balance between IL-1ß and IL-4 signals.

[Evaluation of S-1 for stage IV gastric cancer].

To evaluate the efficacy of S-1 for Stage IV gastric cancer, we retrospectively examined 124 patients with Stage IV gastric cancer. We classified patients into two groups based on the presence or absence of S-1 administration: the S-1 therapy group (n= 56) and the non-S-1 therapy group (n=68). Basically, patients received S-1 orally at 40 mg per square meter of body surface area twice daily for 4 weeks, followed by 2 weeks without chemotherapy. When side effects appeared, we tried dose reduction or cut short the administering period according to the dose modification criteria. Major patient characteristics were as follows: gender (male/female: 76/48), and age (median[range]: 63[24-83]). The median S-1 dosage was about 5 courses, and the median of the S-1 total dosage was 10. 08 g, based on the amount of tegafur. The relative dose intensity (RDI) was well maintained (average: 74. 9%). The survival rate in the S-1 therapy group was significantly higher than in the non-S-1 therapy group. The median survival time (MST) was 308 days in the S-1 group and 157 days in the non-S-1 group. In the S-1 therapy group, the MST was 629 days for those receiving 10 g or more, while that of those receiving less than 10 g was 209 days. The MST of patients administered 10 g or more was significantly longer than that of those receiving less than 10 g (p<0. 0001). Therefore, we consider that S-1 therapy improves survival in patients with Stage IV gastric cancer.

Towards a Clinical Implementation of Measuring the Elastic Modulus of the Aorta From Cardiac Computed Tomography Images.

OBJECTIVE: The elasticity of the aortic wall varies depending on age, vessel location, and the presence of aortic diseases. Noninvasive measurement will be a powerful tool to understand the mechanical state of the aorta in a living human body. This study aimed to determine the elastic modulus of the aorta using computed tomography images. METHODS: We constructed our original formulae based on mechanics of materials. Then, we performed computed tomography scans of a silicon rubber tube by applying four pressure conditions to the lumen. The segment elastic modulus was calculated from the scanned images using our formulae. The actual modulus was measured using a tensile loading test for comparison. RESULTS: The segment moduli of elasticity from the images were 0.525 [0.524, 0.527], 0.524 [0.520, 0.524], 0.520 [0.515, 0.523], and 0.522 [0.516, 0.532] (unit: MPa, median [25%, 75% quantiles]) for the four pressure conditions, respectively. The corresponding measurements in the tensile test were 0.548 [0.539, 0.566], 0.535 [0.528, 0.553], 0.526 [0.513, 0.543], and 0.523 [0.508, 0.530], respectively. These results indicated errors of 4.2%, 2.1%, 1.1%, and 0.2%, respectively. CONCLUSION: Our formulae provided good estimations of the segment elastic moduli of a silicon rubber tube under physiological pressure conditions using the computed tomography images. SIGNIFICANCE: In addition to the elasticity, the formulae provide the strain energy as well. These properties can be better predictors of aortic diseases. The formulae consist of clinical parameters commonly used in medical settings (pressure, diameter, and wall thickness).

A case of extrahepatic bile duct wall recurrence of gastric carcinoma that was treated with pancreaticoduodenectomy.

We report on a patient with obstructive jaundice caused by recurrence of gastric carcinoma in the wall of an extrahepatic bile duct more than 5 years after gastrectomy who was treated with pancreaticoduodenectomy. Histopathologic examination of the surgically resected specimen revealed a poorly differentiated adenocarcinoma with focal signet ring cells in the wall of the common bile duct which was histologically similar to the primary gastric carcinoma. To confirm the diagnosis, immunohistochemical staining was performed with antibodies against cytokeratins (CK7, CK20) and mucin peptide core antigens (MUC5AC, MUC6, MUC2). Based on the expression patterns of this monoclonal antibody panel, the final diagnosis of the common bile duct tumor was an isolated local recurrence of the gastric carcinoma. The patient has survived for more than 26 months after pancreaticoduodenectomy without recurrence.

[Antitumor effect of paclitaxel for gastric cancer is AUC dependent].

Paclitaxel (PTX), which is used for ovarian cancer, lung cancer, breast cancer and gastric cancer, is administered at a dose of 210 mg/m(2) once every three weeks. However, WHO grade 3-4 hematological and non-hematological toxicity occurred frequently in this manner. In recent studies about ovarian cancer and lung cancer, a schedule in which PTX was given weekly could have the same or better efficacy, with fewer side effects. The response rate of PTX administered every three weeks for gastric cancer, was 23.3 to approximately 28.0%, while that of PTX administered weekly was 24.0 to approximately 25.8%. Because of fewer adverse events, weekly PTX is widely used for gastric cancer in Japan. To prove the validity of PTX weekly administration, we performed a study using six specimens removed surgically and one specimen collected from ascites. A chemosensitivity test was performed on the basis of two assumptions: a high concentration for a short time, and a low concentration for a long time. A similar PTX effect was obtained when the AUC was equal. In this study, we demonstrated that the effect of low-dose PTX was equal to the effect of high-dose PTX in gastric cancer.

Stent grafting simulation using a three-dimensional printed model for extensive aortic arch repair combined with coarctation.

Stent grafting for complex aortic anatomy remains a challenge. In particular, stent graft collapse (i.e. infolding) is possible when an excessive oversized device is needed. We describe a case of preoperative stent grafting simulation using a three-dimensional (3D) printed model for extensive aortic arch repair in a 69-year-old woman with multiple aneurysms combined with coarctation. The patient was scheduled to undergo staged hybrid repair. A stent graft larger than 28 mm in diameter was needed to deploy into a coarctation of 15 mm in diameter during the 2nd stage of the operation. Preoperative, experimental stent grafting using a 3D printed model indicated that infolding would likely not occur. Therefore, we proceeded with surgery, which was successful. This technology could be a useful application for planning complicated stent grafting.

3D-printed aortic stenosis model with fragile and crushable calcifications for off-the-job training and surgical simulation.

Surgical simulation devices can be helpful and cost-effective adjuncts to on-the-job training. In this tutorial we present our method for creating an aortic stenosis model with realistically fragile and crushable calcifications, using modern 3D-printing techniques.  The model can be used for training and surgical simulation and is an effective aid to learning for young cardiovascular surgeons.

Regulation of Notch1 and Dll4 by vascular endothelial growth factor in arterial endothelial cells: implications for modulating arteriogenesis and angiogenesis.

Notch and its ligands play critical roles in cell fate determination. Expression of Notch and ligand in vascular endothelium and defects in vascular phenotypes of targeted mutants in the Notch pathway have suggested a critical role for Notch signaling in vasculogenesis and angiogenesis. However, the angiogenic signaling that controls Notch and ligand gene expression is unknown. We show here that vascular endothelial growth factor (VEGF) but not basic fibroblast growth factor can induce gene expression of Notch1 and its ligand, Delta-like 4 (Dll4), in human arterial endothelial cells. The VEGF-induced specific signaling is mediated through VEGF receptors 1 and 2 and is transmitted via the phosphatidylinositol 3-kinase/Akt pathway but is independent of mitogen-activated protein kinase and Src tyrosine kinase. Constitutive activation of Notch signaling stabilizes network formation of endothelial cells on Matrigel and enhances formation of vessel-like structures in a three-dimensional angiogenesis model, whereas blocking Notch signaling can partially inhibit network formation. This study provides the first evidence for regulation of Notch/Delta gene expression by an angiogenic growth factor and insight into the critical role of Notch signaling in arteriogenesis and angiogenesis.

[Substance P and anticancer drug-induced emesis].

BACKGROUND: Cytotoxic drug-induced emesis is the side effect most feared by cancer patients. The Acute emesis has become well controlled by the emergence appearance of 5-HT3 receptor antagonist, but control of delayed emesis (DE) is insufficient. The mechanism of DE is different from acute emesis,and the existence of a mediator different from serotonin is contemplated. There were some reports suggesting the role of substance P (SP) and its receptor, neurokinin receptor 1 (NK 1), in the development of emesis. AIM: We investigated the relationship between DE and SP in patients treated with anticancer agents. PATIENTS AND METHOD: Digestive cancer and breast cancer patients, who were administered cytotoxic agents, were the objects of this study. We measured plasma levels of SP for 20 cases on the day before administration of anticancer agents and for five days after administration. RESULT: Plasma levels of SP increased significantly on the first and third days after administration. In the patient who experienced DE, the difference in plasma levels on the day before and the first day after chemotherapy was higher than that of who never experienced. CONCLUSION: The plasma levels of SP were transiently increased by chemotherapy. The difference in plasma levels between the day before and the first day after chemotherapy is important.

[Three advanced gastric cancer patients successfully treated by combination therapy of paclitaxel and cisplatin].

We report 3 gastric cancer patients with peritoneal dissemination who were successfully treated with weekly paclitaxel and cisplatin. The patients were 2 men and 1 woman from 57 to 70 years in age. The histological types were 2 poorly-differentiated adenocarcinomas and 1 moderately-differentiated adenocarcinoma. Intravenous infusion of PTX (80 mg/m(2)) and CDDP (25 mg/m(2)) after short premedication was continued for 3 weeks followed by 1 week rest. Ascites improved only after administration of 1 course in all patients.PTX/CDDP is thought to be an effective chemotherapy showing acceptable toxicity against advanced gastric cancer with ascites.

[Correlation between clinical pathologic factors and enzymatic activity of orotate Phosphoribosyl transferase (OPRT), Dihydropyrimidine dehydrogenase (DPD) and Thymidylate synthase (TS) in colorectal cancer].

Orotate Phosphoribosyl Transferase (OPRT), Dihydropyrimidine dehydrogenase (DPD) and Thymidylate synthase (TS) are initial key enzymes in the 5-FU metabolic pathway. In this study, we measured the activities of OPRT, DPD and TS. We also investigated the correlation between these 3 enzymatic activities and the clinical pathologic factors (Histological typing, extent of tumor invasion,extent of metastasis to the lymph nodes,stage, lymphatic invasion and venous invasion). We had surveyed 79 cases of colorectal cancers surgically removed. Poorly-differentiated adenocarcinoma showed a tendency to lower OPRT and higher DPD, as compared to moderately or well-differentiated adenocarcinomas. In case with metastasis to lymph nodes, OPRT showed a tendency to lower activities, but a significant difference was not noticed. TS showed no relation to any of these pathologic factors. In each application of 5-FU, measuring the activities of these three enzymes is important for estimation of the antitumoral effect. With poorly-differentiated adenocarcinoma, it is estimated that many cases would show high DPD and if the enzyme activities can not be measured, so administration of TS-1, which includes DPD inhibitor, may be considered.

[A case of advanced gastric cancer successfully treated by TS-1 and CDDP after jejunostomy].

A 65-year-old female with unresectable advanced gastric cancer accompanied by multiple lung metastases underwent jejunostomy and was treated with TS-1 and CDDP. One course consisted of TS-1 (80 mg/day) via an intestinal fistula tube from days 1 to 14 followed by 14 days rest and CDDP (80 mg/day) was administered by 24-hour continuous intravenous infusion on day 8. After 3 courses, the primary tumor and lymph node metastases decreased in size (PR), and CT scan showed the multiple lung metastases had disappeared. Total gastrectomy (D 2) and splenectomy were performed after chemotherapy. The final diagnosis was Stage IIIA and the pathological response to chemotherapy was Grade 2. The patient has survived for over 14 months after surgery and has presented no signs of recurrence.

[Prediction of sensitivity to 5-fluorouracil (5-fu) by metabolic and target enzyme activities in colon cancer].

BACKGROUND: 5-Fluorouracil (5-FU) and its derivatives are widely known as some of the most commonly prescribed anticancer drugs, especially for gastrointestinal cancer. Orotate phosphoribosyl transferase (OPRT), dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) are initial key enzymes in the 5-FU metabolic pathway. The activities of these enzymes may have the potential to affect the chemosensitivity of 5-FU. PURPOSE: This study was designed to investigate the effect of OPRT, DPD and TS in sensitivity to 5-FU. METHOD: We measured OPRT, DPD and TS activities in 11 colonic cancer tissues. The Collagen Gel Droplet Embedded Culture Drug Sensitivity Test (CD-DST) was used in an in vitro chemosensitivity assay. In these samples, the correlation between sensitivity to 5-FU and enzyme activities was investigated. RESULTS: There were no correlations among OPRT, TS activities and sensitivity to 5-FU. In contrast, there was a significant inverse correlation (r=-0.738) between DPD activity and 5-FU sensitivity. With regression analysis, the coefficient of determination of the activity of the three enzymes versus the sensitivity to 5-FU was 0.61. CONCLUSION: Though measuring OPRT, DPD, TS activities is valuable for prediction of sensitivity to 5-FU, DPD is considered to be the most important predictive factor of 5-FU sensitivity. To improve its accuracy, the finding of a fourth factor such as P-glycoprotein and multidrug resistance-associated proteins (MRP), to be added to OPRT, DPD and TS, is desired.

Morphological analysis and preoperative simulation of a double-chambered right ventricle using 3-dimensional printing technology.

We present a case of a double-chambered right ventricle in adulthood, in which we tried a detailed morphological assessment and preoperative simulation using 3-dimensional (3D) heart models for improved surgical planning. Polygonal object data for the heart were constructed from computed tomography images of this patient, and transferred to a desktop 3D printer to print out models in actual size. Medical staff completed all of the work processes. Because the 3D heart models were examined by hand, observed from various viewpoints and measured by callipers with ease, we were able to create an image of the complete form of the heart. The anatomical structure of an anomalous bundle was clearly observed, and surgical approaches to the lesion were simulated accurately. During surgery, we used an incision on the pulmonary infundibulum and resected three muscular components of the stenosis. The similarity between the models and the actual heart was excellent. As a result, the operation for this rare defect was performed safely and successfully. We concluded that the custom-made model was useful for morphological analysis and preoperative simulation.