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).

[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.

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.

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.

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.

[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.

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.

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.

The role of circulating lipoprotein lipase and adiponectin on the particle size of remnant lipoproteins in patients with diabetes mellitus and metabolic syndrome.

BACKGROUND: The factors regulating particle size of remnant lipoproteins (RLPs) in type 2 diabetes (T2DM) and metabolic syndrome (MetS) cases have not been well elucidated. METHODS: T2DM, MetS and healthy controls with and without a fatty liver were studied. Remnant lipoprotein (RLP)-cholesterol (RLP-C) and RLP-triglyceride (RLP-TG), small dense LDL-cholesterol (sdLDL-C), lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL) and adiponectin concentrations were measured in the fasting pre-heparin plasma. The RLP particle size was estimated by the RLP-TG/RLP-C ratio. RESULTS: The serum TG, RLP-C, RLP-TG, RLP-TG/RLP-C ratio and sdLDL-C were significantly greater in T2DM and MetS than in controls. Fatty liver and high serum TG were significantly associated with an increased RLP-TG/RLP-C ratio which was used to estimate the particle size of RLP in controls, T2DM and MetS. LPL and adiponectin in the pre-heparin plasma were inversely correlated with RLP-TG/RLP-C ratio in normal, T2DM and MetS. LPL was also positively correlated with adiponectin in all three cases. CONCLUSIONS: RLP particle size in T2DM and MetS was significantly larger than in controls and was regulated by circulating LPL and adiponectin, but not HTGL. Fatty liver and high TG were significantly associated with the prevalence of the large RLP particle size.

Comparison of the effect of post-heparin and pre-heparin lipoprotein lipase and hepatic triglyceride lipase on remnant lipoprotein metabolism.

BACKGROUND: A comparison of post-heparin and pre-heparin plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) on the metabolism of remnant lipoproteins (RLPs) has not been reported yet. METHODS: Healthy volunteers were injected with heparin for LPL and HTGL determination in the fasting (8:00) and postprandial (20:00) plasma on the same day. Plasma total cholesterol (TC), triglycerides (TG), LDL-C, HDL-C, small dense LDL (sdLDL)-C, remnant lipoprotein (RLP)-C, RLP-TG, the RLP-TG/RLP-C ratio, adiponectin and apoCIII were measured. RESULTS: LPL activity and concentration in the post-heparin plasma exhibited a significant inverse correlation with TG, RLP-C, RLP-TG, and RLP particle size estimated as RLP-TG/RLP-C ratio and sdLDL-C, and positively correlated with HDL-C. HTGL was only inversely correlated with HDL-C. LPL concentration in the pre-heparin plasma was also inversely correlated with the RLP-TG/RLP-C ratio and other lipoprotein parameters. Adiponectin was inversely correlated with RLP-TG/RLP-C ratio and apoC III was positively correlated with RLP-TG/RLP-C ratio, but not correlated with LPL activity. CONCLUSION: LPL activity and concentration were inversely and significantly correlated with the particle size of RLP in both the post-heparin and pre-heparin plasma. Those results suggest that LPL concentration in pre-heparin plasma can take the place of LPL activity in the post-heparin plasma.

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.

[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.

Synthesis and evaluation of diarylthiazole derivatives that inhibit activation of sterol regulatory element-binding proteins.

Fatostatin, a recently discovered small molecule that inhibits activation of sterol regulatory element-binding protein (SREBP), blocks biosynthesis and accumulation of fat in obese mice. We synthesized and evaluated a series of fatostatin derivatives. Our structure-activity relationships led to the identification of N-(4-(2-(2-propylpyridin-4-yl)thiazol-4-yl)phenyl)methanesulfonamide (24, FGH10019) as the most potent druglike molecule among the analogues tested. Compound 24 has high aqueous solubility and membrane permeability and may serve as a seed molecule for further development.

Development of a novel rapid immunochromatographic test specific for the H5 influenza virus.

Three anti-H5 influenza virus monoclonal antibody (mAb) clones, IFH5-26, IFH5-115 and IFH5-136, were obtained by immunising a BALB/C mouse with inactivated A/duck/Hokkaido/Vac-1/04 (H5N1). These mAbs were found to recognise specifically the haemagglutinin (HA) epitope of the influenza H5 subtypes by western blotting with recombinant HAs; however, these mAbs have no neutralising activity for A/duck/Hokkaido/84/02 (H5N3) or A/Puerto Ric/8/34 (H1N1). Each epitope of these mAbs was a conformational epitope that was formed from the regions located between 46 to 60 amino acids (aa) and 312 to 322 aa for IFH5-115, from 101 to 113 aa and 268 to 273 aa for IFH5-136 and from 61 to 80 aa and 290 to 300 aa for IFH5-26. The epitopes were located in the loop regions between the receptor region and alpha-helix structure in haemagglutinin 1 (HA1). Influenza A virus H5-specific rapid immunochromatographic test kits were tested as solid phase antibody/alkaline phosphate-conjugated mAb in the following three combinations: IFH5-26/IFH5-115, IFH5-136/IFH5-26 and IFH5-136/IFH5-115. In every combination, only influenza A H5 subtypes were detected. For effective clinical application, rapid dual discrimination immunochromatographic test kits in combination with H5 HA-specific mAb, IFA5-26 and IFA5-115 and the influenza A NP NP-specific mAb, FVA2-11, were developed. The dual discrimination immunochromatographic tests kits detected influenza A virus H5 subtypes as H5 line-positive and all influenza A subtypes as A line-positive simultaneously. The dual discrimination immunochromatographic test kits may be useful for discriminating highly pathogenic avian influenza A H5N1 viruses from seasonal influenza A virus, as well as for confirming influenza infection status in human, avian and mammalian hosts.

Marine natural product aurilide activates the OPA1-mediated apoptosis by binding to prohibitin.

Aurilide is a potent cytotoxic marine natural product that induces apoptosis in cultured human cells at the picomolar to nanomolar range; however, its mechanism of action has been unknown. Results of the present study showed that aurilide selectively binds to prohibitin 1 (PHB1) in the mitochondria, activating the proteolytic processing of optic atrophy 1 (OPA1) and resulting in mitochondria-induced apoptosis. The mechanism of aurilide cytotoxicity suggests that PHB1 is an apoptosis-regulating protein amenable to modulation by small molecules. Aurilide may serve as a small-molecule tool for studies of mitochondria-induced apoptosis.

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.

Expression of various glutamate receptors including N-methyl-D-aspartate receptor (NMDAR) in an ovarian teratoma removed from a young woman with anti-NMDAR encephalitis.

A 21-year-old woman developed psychiatric symptoms, progressive unresponsiveness, generalized seizures, severe dyskinesia, marked fluctuation of blood pressure, and hypersalivation after a flu-like episode. Anti-glutamate receptor (GluR)ε2 and anti-N-methyl-D-aspartate receptor (NMDAR) antibodies were positive in both her serum and CSF. After she recovered five months later she underwent surgery to remove a right ovarian teratoma. Immunohistochemical examinations of her teratoma disclosed abundant expression of various GluRs including NR2B subunit of NMDAR, GluR1, and GluR2/3. These immunoreactivities of GluRs were seen not only in small areas of neural tissue identified as anti-glial fibrillary acidic protein (GFAP)-immunoreactive areas but also in other large areas of undifferentiated neuroepithelial tissue without GFAP immunoreactivity. Our findings strongly support the recent idea that neural elements in ovarian teratoma play an important role in the production of antibodies to NMDARs in anti-NMDAR encephalitis. Additionally, the study of control ovaries clearly showed NR2B-related immunoreactivity in the cytoplasm of oocytes, indicating that the normal ovary itself has expression of NMDARs. This finding might provide a clue to understand the pathogenesis of this disease in female patients without ovarian teratoma.

Biochemical target isolation for novices: affinity-based strategies.

Although a number of genomic and biochemical technologies are now used to elucidate the mechanisms of action of bioactive small molecules, affinity-based isolation of molecular targets is a classic, but still powerful, approach. This review highlights recent cases where biochemical isolation of target proteins of bioactive small molecules highlighted general strategies for a successful isolation and identification of molecular targets. This review is intended to be both an update on the most recent findings for those already active in the field of forward chemical genetics and a guide for scientists entering this burgeoning field.