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Abstract Background and Aim Post‐endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most serious adverse event of ERCP. Therefore, it is important to identify high‐risk patients who require prophylactic measures. The aim of this study was to develop a practical prediction model for PEP that identifies high‐risk patients. Methods Patients who underwent ERCP at three tertiary hospitals between April 2010 and September 2012 were enrolled. The dataset was divided into a training set (two centers) and validation set (one center). Using the training set, univariable and multivariable analyses were performed to identify predictive factors for PEP. We constructed a scoring system and evaluated reproducibility using the validation set. Results A total of 2719 ERCPs were analyzed. PEP developed in 133 cases (4.9%). Risk factors (adjusted odds ratios [OR]) in the training set were a history of PEP (OR: 4.2), intact papilla (OR: 2.4), difficult cannulation (OR: 1.9), pancreatic guidewire‐assisted biliary cannulation (OR: 2.2), pancreatic injection (OR: 2.1), pancreatic intraductal ultrasonography (IDUS)/sampling from the pancreatic duct (OR: 2.2), and biliary IDUS/sampling from the biliary tract (OR: 2.8). A scoring system was constructed using these seven clinical variables. The areas under the receiver‐operating characteristic curve of this model were 0.799 in the training set and 0.791 in the validation set. In the high‐risk group at a score of 3 or higher, the incidence of PEP was 13.4%, and all severe/fatal cases were in the high‐risk group. Conclusions This scoring system helps to predict each patient's risk and select preventive measures.

Abstract Background Although primary duodenal adenocarcinoma (DA) is a rare malignancy representing ~ 0.5% of all gastrointestinal cancers, the incidence of DA is more frequent in Lynch syndrome. Because of its rarity, treatment strategies or optimal chemotherapeutic regimens have not been clearly defined for advanced DA. Case presentation A 72-year-old woman with Lynch syndrome visited our hospital with a right upper abdominal pain. Computed tomography (CT) showed wall thickness with enhancement in the second portion of the duodenum and adjacent abdominal wall, which suggested direct tumor invasion to the abdominal wall. Upper gastrointestinal endoscopy (UGE) showed a large ulcerative tumor in the second portion of the duodenum, and histological analysis revealed a poorly differentiated adenocarcinoma. A cT4N0M0, cStage IIB (Union for International Control Cancer TNM staging) DA was diagnosed. After three courses of chemotherapy with S-1 and oxaliplatin (SOX), follow-up CT and UGE showed shrinkage of the duodenal tumor. Therefore, the patient underwent pancreaticoduodenectomy with lymph node dissection with curative intent. Histological examination showed a pathological complete response to SOX therapy. The postoperative course was uneventful, and the patient was discharged on postoperative day 29. The patient received no adjuvant chemotherapy, and there has been no evidence of recurrence 6 months after the operation. Conclusions SOX therapy provided a remarkable response and can be an optimal chemotherapeutic regimen for advanced DA in Lynch syndrome.

Abstract Background Skeletal muscle metastasis from gastric cancer is extremely rare and often accompanied with synchronous metastasis to any other organs. We herein report a case of rapidly developing multiple skeletal metastases from gastric cancer without any other organ metastases. Case presentation A 47-year-old man underwent distal gastrectomy for advanced gastric cancer. Pathological diagnosis was poorly differentiated adenocarcinoma, T2N1M0, Stage IIA. The patient presented with a history of left dorsal tenderness 12 months after the operation. A computed tomography (CT) revealed a solid mass in the left latissimus dorsi muscle. Pathological examination of the ultrasound guided needle biopsy specimen revealed poorly differentiated adenocarcinoma similar to the previously resected gastric cancer, and the tumor was diagnosed as metastasis of gastric cancer. Thereafter, the systemic chemotherapy was administrated. However, the metastases were extended to the paraspinal muscle and quadriceps, and the patient died 7 months after the recurrence. Conclusions The prognosis of patients with skeletal muscle metastasis may be extremely poor, even in patients without any other organ metastases. The development of further chemotherapeutic agents and regimens is therefore needed.

Abstract The newt, a group of urodele amphibians, has outstanding ability to repeatedly regenerate various body parts, even in the terrestrial life-stage. In this animal, when the limb is amputated, a cell mass named the blastema appears on the stump and eventually gives rise to a new functional limb. Erythrocytes (red blood cells) in most non-mammalian vertebrates, including the newt, preserve their nucleus throughout their life-span, although physiological roles of such nucleated erythrocytes, other than oxygen delivery, are not known. Here we report novel behavior of erythrocytes in the newt. We identified an orphan gene Newtic1, whose transcripts significantly increased in the blastema. Newtic1 was expressed in a subset of erythrocytes that formed a novel clump (EryC). EryC formed a complex with monocytes and was circulating throughout the body. When the limb was amputated, EryCs were newly generated in the stump and accumulated into a distal portion of the growing blastema. Our data suggested that the newt erythrocytes carried multiple secretory molecules including growth factors and matrix metalloproteases, and were capable of delivering these molecules into the blastema as a form of EryCs. This study provides insight into regulations and roles of nucleated erythrocytes, that are independent of oxygen delivery.

Internal fertilization ensures successful reproduction of tetrapod vertebrates on land, although how this mode of reproduction evolved is unknown. Here, we identified a novel gene encoding sperm motility-initiating substance (SMIS), a key protein for the internal fertilization of the urodele Cynops pyrrhogaster by Edman degradation of an isolated protein and subsequent reverse transcription polymerase chain reaction. The SMIS gene encoded a 150 amino-acid sequence including the cysteine knot (CK) motif. No gene with substantial similarity to the SMIS was in the data bank of any model organisms. An active site of the SMIS was in the C-terminal region of the 2nd loop of CK motif. A synthetic peptide including the active site sequence bound to the midpiece and initiated/enhanced the circular motion of C. pyrrhogaster sperm, which allows penetration of the egg jelly specialized for the internal fertilization of this species. The synthetic peptide bound to whole sperm of Rhacophorus arboreus and enhanced the rotary motion, which is adapted to propel the sperm through egg coat matrix specialized for arboreal reproduction, while it bound to the tip of head and tail of Bufo japonicus sperm, and enhanced the vibratory motion, which is suited to sperm penetration through the egg jelly specialized for the reproduction of that species in freshwater. The polyclonal antibody against the active site of the SMIS specifically bound to egg coat matrix of R. arboreus. These findings suggest that diversification of amphibian reproductive modes accompanies the specialization of egg coat and the adaptation of sperm motility to penetrate the specialized egg coat, and SMIS acts as the sperm motility enhancer of anurans and urodeles that might facilitate to adaptively optimize sperm motility for allowing the establishment of internal fertilization.

Background: Nasal obstruction is considered the most serious problem for patients with allergic rhinitis. We have previously established a model of nasal obstruction in guinea pigs. In the present study, we tried to establish an allergic model of nasal obstruction using Brown Norway (BN) rats to evaluate the effects of phosphodiesterase (PDE) 4 inhibitors in this model. Methods: The volume of the nasal cavity was measured with an acoustic rhinometer. Decrease in the volume of the nasal cavity was taken as nasal obstruction. BN rats were actively sensitized with ovalbumin conjugated with aluminium hydroxide. Intranasal antigen instillation induced biphasic nasal obstruction in sensitized BN rats. Results: Early and late phase responses (EPR and LPR) were observed peaking at 0.5 and 6 hours after the antigen challenge, respectively. Chlorpheniramine did not inhibit EPR or LPR at 10 mg/kg, although the dose was sufficient for the compound to exert its anti-histamine activity. Prednisolone inhibited both responses at 30 mg/kg. Rolipram and CDP-840, PDE4 inhibitors, inhibited both responses at 100 mg/kg. KF19514, a PDE1/4 dual inhibitor, inhibited EPR at 0.1 mg/kg or more and inhibited LPR at 10 mg/kg. Conclusions: The present study provides a simple model of allergic biphasic nasal obstruction in BN rats, and also suggests that the PDE4 inhibitor may alleviate nasal obstruction in patients with allergic rhinitis.

We investigated sperm nuclear vacuolation in relation to acrosome reactions and the maintenance of sperm motility. Thirty male patients who visited our Male Infertility Clinic were enrolled. These patients underwent conventional semen analyses, Acrobeads tests, and high-magnification observation of the sperm head to evaluate the degree of nuclear vacuolation on the Acrobeads test scoring after 24 hours of incubation. The presence of acrosome reactions was evaluated using the Acrobeads test. The spermatozoa were classified into three groups: (I) those bound to MH61-beads, (II) motile spermatozoa that did not bind to MH61-beads, and (III) immotile spermatozoa that did not bind to MH61-beads. The percentage of spermatozoa with large nuclear vacuoles (%LNV) was compared between the three groups. The degree of sperm nuclear vacuolation was evaluated in 17,992 ejaculated spermatozoa. The mean %LNVs were 2.4% in group I, 5.8% in group II, and 9.8% in group III. These values were significantly different from each other (P

Objective. The clinical factors associated with sperm DNA fragmentation (SDF) were investigated in male patients with infertility. Materials and Methods. Fifty-four ejaculates from infertile Japanese males were used. Thirty-three and twenty-one were from the patients with varicoceles and idiopathic causes of infertility, respectively. We performed blood tests, including the serum sex hormone levels, and conventional and computer-assisted semen analyses. The sperm nuclear vacuolization (SNV) was evaluated using a high-magnification microscope. The SDF was evaluated using the sperm chromatin dispersion test (SCDt) to determine the SDF index (SDFI). The SDFI was compared with semen parameters and other clinical variables, including lifestyle factors. Results. The SDFI was 41.3 ± 22.2% (mean ± standard deviation) and did not depend on the cause of infertility. Chronic alcohol use increased the SDFI to 49.6 ± 23.3% compared with 33.9 ± 18.0% in nondrinkers. The SDFI was related to adverse conventional semen parameters and sperm motion characteristics and correlated with the serum FSH level. The SNV showed a tendency to increase with the SDFI. The multivariate analysis revealed that the sperm progressive motility and chronic alcohol use were significant predictors of the SDF. Conclusion. The SCDt should be offered to chronic alcohol users and those with decreased sperm progressive motility.

The effects of TYB-2285 and its metabolites (TC-286 and TC- 326) on the adhesion of eosinophils and neutrophils to cultured human umbilical vein endothelial cells (HUVEC) stimulated with tumour necrosis factor α (TNF-α) were investigated. The treatment of HUVEC with TNF-α enhanced eosinophil adhesion in a dose-dependent manner (1–100 U/mL). The adhesion of eosinophils to TNF-α (100U/mL)-stimulated HUVEC was inhibited by TYB-2285 and its metabolites in a dose-dependent manner (10−8–10−5mol/L). These compounds showed stronger inhibitory effects than any other anti-allergic drugs, such as disodium cromoglycat (DSCG), ketotifen and tranilast. TYB-2285, TC-286 and TC-326 did not inhibit the adhesion of neutrophils at the same range (10−8–l 0−5 mol/L). In our adhesion assay system, eosinophil adhesion to TNF-α-stimulated HUVEC was blocked by monoclonal antibody against VLA-4 (anti-VLA-4) but not by that against Mac-1 (anti-Mac-1). In contrast, neutrophil adhesion was blocked by anti-Mac-1, but not by anti-VLA-4. The results of the present study demonstrate that TYB-2285 and its metabolites selectively inhibit the adhesion of eosinophils to HUVECs stimulated with TNF-α and also suggest that TYB-2285, TC-286 and TC-326 might block the VLA-4/VCAM-1 pathway selectively.

Sperm intracellular Ca2+ is crucial for the induction of sperm-egg interaction, but little is known about the significance of Ca2+ maintenance prior to induction. In sperm of the newt Cynops pyrrhogaster, intracellular Ca2+ is localized to the midpiece during storage in the vas deferens, while extracellular Ca2+ is influxed in modified Steinberg's salt solution to promote a spontaneous acrosome reaction related to the decline of sperm quality. In the present study, sperm from the vas deferens were loaded with the Ca2+ indicator Fluo8H, and changes in Ca2+ localization in modified Steinberg's salt solution were examined. Calcium ions expanded from the cytoplasmic area of the midpiece to the entire tail in most sperm during a 1-h incubation and localized to the principal piece in some sperm within 24 h. Similar changes in Ca2+ localization were observed in reconstructed vas deferens solution that included ions and pH at equivalent levels to those in the vas deferens fluid. Sperm with Ca2+ localization in the entire tail or the principal piece weakened or lost responsiveness to sperm motility-initiating substances, which trigger sperm motility for fertilization, but responded to a trigger for acrosome reaction. The change in Ca2+ localization was delayed and transiently reversed by ethylene glycol tetraacetic acid or a mixture of Ca2+ channel blockers including Ni2+ and diltiazem. These results suggest that C. pyrrhogaster sperm localize intracellular Ca2+ to the midpiece through Ca2+ transport in the vas deferens to allow for responses to sperm motilityinitiating substances. [ABSTRACT FROM AUTHOR]

The acrosome reaction is induced in the sperm of Cynops pyrrhogaster immediately in response to a ligand protein called acrosome reaction-inducing substance (ARIS) in the egg jelly at fertilization, whereas a spontaneous acrosome reaction occurs time-dependently in correlation with the decline of sperm quality for fertilization. The ARIS-induced acrosome reaction was recently found to be mediated by TRPV4 in association with the NMDA type glutamate receptor, although the intracellular mediators for the acrosome reaction are largely unclear. In the present study, spontaneous acrosome reaction was significantly inhibited by Ni2+, RN1734, and diltiazem, which blocks Cav3.2, TRPV4 or TRPM8, and the cyclic nucleotide-gated channel, respectively. In contrast, expression of Ca2+-activated transmembrane and soluble adenylyl cyclases was detected in the sperm of C. pyrrhogaster by reverse transcription-polymerase chain reaction. Activator of transmembrane or soluble adenylyl cyclases (forskolin or HCO3 -) independently promoted spontaneous acrosome reaction, while an inhibitor of each enzyme (MD12330A or KH7) inhibited it only in the sperm with high potential for spontaneous acrosome reaction. An inhibitor of protein kinase A (H89) inhibited spontaneous acrosome reaction in a manner independent of sperm potential for spontaneous acrosome reaction. Surprisingly, KH7 significantly inhibited ARIS-induced acrosome reaction, but its effect was seen in a small percentage of sperm. H89 had no effect on ARIS-induced acrosome reaction. These results suggest that C. pyrrhogaster sperm possess multiple intracellular pathways for acrosome reaction, involving Ca2+ permeable channels, adenylyl cyclases and PKA, and that two pathways having distinct dependencies on adenylyl cyclases may contribute to ARISinduced acrosome reaction at fertilization. [ABSTRACT FROM AUTHOR]

The present study reports a rare case of bladder cancer that caused Trousseau's syndrome, a malignancy-associated hypercoagulative state leading to venous or arterial thrombosis. A 38-year-old Japanese female patient experienced a sudden onset of visual field defects and lower limb weakness. Cerebral magnetic resonance imaging revealed multi-regional hypointense areas compatible with acute cerebral infarction. Despite the repeated administration of anticoagulant treatment with heparin, the condition could not be adequately controlled and thromboembolic events occasionally recurred. Several tumor markers, including carbohydrate antigen 19-9, cancer antigen 125, carcinoembryonic antigen, cytokeratin 19 fragment and squamous cell carcinoma antigen levels, were elevated. Consequently, computed tomography scans were performed, which revealed a massive bladder tumor with multiple bone and lymph node metastases. The patient also exhibited other paraneoplastic disorders, including leukocytosis due to granulocyte colony-stimulating factor (G-CSF) production, and hypercalcemia due to parathyroid hormone-related protein (PTHrP) production. Transurethral resection of the bladder tumor was performed, and the tumor was pathologically confirmed as urothelial cell carcinoma. Immunohistochemical testing revealed positive staining for G-CSF and PTHrP. Despite undergoing gemcitabine/cisplatin-based systemic chemotherapy, the disease developed rapidly and the patient succumbed to the disease within 3 months of initial symptoms. The present case indicates that occult visceral malignancy should be considered in patients with unexplained thromboembolism. [ABSTRACT FROM AUTHOR]

A 26-year-old Japanese man was admitted to our unit with exacerbated paranoid schizophrenia. Prior to his admission, daily administration of olanzapine had been sufficient to maintain a partial remission of his schizophrenia, but due to an exacerbation of his delusions, he had then also been prescribed aripiprazole, which had been followed by no improvement in symptoms and a gradual further exacerbation of auditory delusions. Physical examinations, brain MRI and neurophysiological assessment were unremarkable. Blood analysis, however, revealed extremely low thyroid-stimulating hormone (TSH) and prolactin-releasing hormone (PRL) concentration. Interestingly, after aripiprazole discontinuation, he returned to partial remission with an increase in plasma TSH and PRL concentration. [ABSTRACT FROM AUTHOR]

A specific sperm-egg interaction in the oviductal matrix is crucial for internal fertilization of the red-bellied newt, Cynops pyrrhogaster. An understanding of the molecular basis of this interaction is expected to elucidate the evolutionary history of internal fertilization in amphibians. Recently, deep sequencing technology has provided global gene information even in nonmodel animals, allowing us to understand specific features of the molecular mechanisms underlying fertilization in C. pyrrhogaster. In the present study, we screened de novo assembled RNAseq from ovary, testis, and oviduct samples in C. pyrrhogaster and identified the base sequences encoding zona pellucida (ZP) proteins, voltage-dependent Caz+channels, and cysteine-rich secretory proteins (CRISPs), which respectively are sperm receptors for egg envelopes, major mediators of sperm intracellular signaling, and expected extracellular modulators for sperm function in the female reproductive tract. In the ovary, ZP homologues of all six subgroups were found, including a ZP1 homologue that was newly found in amphibians, a ZP4 homologue, and six ZPC homologues. The unique combination of ZP proteins suggests a new mechanism for sperm binding to egg envelopes in the internal fertilization of C. pyrrhogaster. In the testis, CaVI.1,1.2, and 3.2, which are L- andT-type voltage-dependent Ca2+ channels, were found as potential mediators for the internal fertilization-specific sperm-egg interaction. We also found CRISP 2 in the oviduct, which is speculated to participate in the sperm-egg interaction.These results indicate that the de novo assembled RIMAseq is a powerful tool allowing analysis of the specific sperm-egg interactions in C. pyrrhogaster. [ABSTRACT FROM AUTHOR]

Our recent IR study demonstrated that hydrogen-bond structure in cellulose I drastically changes around 220 °C (Watanabe et al. Biomacromolecules2006, 7, 3164). In the present study, temperature-dependent IR spectra of cellulose I from 30 to 260 °C were analyzed by use of perturbation-correlation moving-window two-dimensional correlation spectroscopy. It was observed that as in the case of cellulose I abrupt changes in the hydrogen-bond structure occur around 220 °C in cellulose I. It was also revealed that although weakly hydrogen-bonded OH groups in I are stable below 230 °C thermal oxidation of those in I is accelerated around 220 °C. In this way, the present study has clarified a difference between the thermal behavior of I and that of I at the functional group level. Our result suggests that the drastic change in the hydrogen-bond structure around 220 °C makes cellulose I much more unstable than I. [ABSTRACT FROM AUTHOR]

The objective of this study is to provide additional data regarding morphological changes that occur to dentin matrices following demineralization with etchants. Our understanding of the mechanism of diffusion of comonomers into the demineralized substrate is very limited. It has been hypothesized that certain water-soluble polyelectrolytes (acidic proteins) and neutral proteins in dentin can influence the collapse of demineralized dentin when it is air dried. Some of these solubilized substances are thought to aggregate by the action of Ca cations, which become dissolved during H3PO4 etching, ultimately resulting in some degree of collapse. In the current study, dentin surfaces were examined by atomic force microscopy (AFM) before and after treatment by 10% H3PO4containing increasing concentrations of CaHPO4. Reversal of matrix collapse by aqueous 30% 2-hydroxyethyl methacrylate (HEMA) was evaluated by AMF for 60 min. The results demonstrate two forms of matrix collapse; we speculate that one form is induced by acidic noncollagenous polyelectrolytes and the other by neutral peptides. Our data indicate that further evaluation of the influence of endogenous noncollagenous proteins must be studied to understand the mechanism of the collapse and reexpansion dynamics of demineralized dentin networks. © 2003 Wiley Periodicals, Inc. J Biomed Mater Res 68A: 558–565, 2004 [ABSTRACT FROM AUTHOR]

Aim: To evaluate the efficacy of technical modifications of total hepatic vascular exclusion (THVE) for hepatectomy involving inferior vena cava (IVC)., Methods: Of 301 patients who underwent hepatectomy during the immediate previous 5-year period, 8 (2.7%) required THVE or modified methods of IVC cross-clamping for resection of liver tumors with massive involvement of the IVC. Seven of the patients had diagnosis of colorectal liver metastases and 1 had diagnosis of hepatocellular carcinoma. All tumors involved the IVC, and THVE was unavoidable for combined resection of the IVC in all 8 of the patients. Technical modifications of THVE were applied to minimize the extent and duration of vascular occlusion, thereby reducing the risk of damage., Results: Broad dissection of the space behind the IVC coupled with lifting up of the liver from the retrocaval space was effective for controlling bleeding around the IVC before and during THVE. The procedures facilitate modification of the positioning of the cranial IVC cross-clamp. Switching the cranial IVC cross-clamp from supra- to retrohepatic IVC or to the confluence of hepatic vein decreased duration of the THVE while restoring hepatic blood flow or systemic circulation via the IVC. Oblique cranial IVC cross-clamping avoided ischemia of the remnant hemi-liver. With these technical modifications, the mean duration of THVE was 13.4 ± 8.4 min, which was extremely shorter than that previously reported in the literature. Recovery of liver function was smooth and uneventful for all 8 patients. There was no case of mortality, re-operation, or severe complication (i.e., Clavien-Dindo grade of III or more)., Conclusion: The retrocaval liver lifting maneuver and modifications of cranial cross-clamping were useful for minimizing duration of THVE.