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Corticosteroid receptors are critical for homeostasis maintenance, but understanding of the principal roles of the glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) throughout vertebrates is limited. Lines of constitutive GR-knockout zebrafish and MR-knockout medaka have recently been generated as the first adult-viable corticosteroid receptor-knockout animals, in contrast to the lethality of these receptor knockouts in mice. Here, we describe behavioral and physiological modifications following disruption of corticosteroid receptor function in these animal models. We suggest these data point toward a potentially conserved function of corticosteroid receptors in integrating brain-behavior and visual responses in vertebrates. Finally, we discuss how future work in cartilaginous fishes (Chondrichthyes) will further advance understanding of the unity and diversity of corticosteroid receptor function, since distinct orthologs of GR and MR derived from an ancestral corticoid receptor appear in these basal jawed vertebrates.

We investigated progestin and corticosteroid activation of the progesterone receptor (PR) from elephant shark (Callorhinchus milii), a cartilaginous fish belonging to the oldest group of jawed vertebrates. Comparison with human PR experiments provides insights into the evolution of steroid activation of human PR. At 1 nM steroid, elephant shark PR is activated by progesterone, 17-hydroxy-progesterone, 20b-hydroxy-progesterone, 11-deoxycorticosterone (21-hydroxyprogesterone) and 11-deoxycortisol. At 1 nM steroid, human PR is activated only by progesterone and11-deoxycorticosterone indicating increased specificity for progestins and corticosteroids during the evolution of human PR. RU486, an important clinical antagonist of human PR, did not inhibit progesterone activation of elephant shark PR. Cys-528 in elephant shark PR corresponds to Gly-722 in human PR, which is essential for RU486 inhibition of human PR. Confirming the importance of this site on elephant shark PR, RU486 inhibited progesterone activation of the Cys528Gly mutant PR. There also was a decline in activation of elephant shark Cys528Gly PR by 11-deoxycortisol, 17-hydroxy-progesterone and 20b-hydroxy-progesterone and an increase in activation of human Gly722Cys PR by 11-deoxycortisol and decreased activation by corticosterone. One or more of these changes may have selected for the mutation corresponding to human glycine-722 PR that first evolved in platypus PR, a basal mammal.

Orthologs of human glucocorticoid receptor (GR) and human mineralocorticoid receptor (MR) first appear in cartilaginous fishes. Subsequently, the MR and GR diverged to respond to different steroids: the MR to aldosterone and the GR to cortisol and corticosterone. We report that cortisol, corticosterone and aldosterone activate full-length elephant shark GR, and progesterone, which activates elephant shark MR, does not activate elephant shark GR. However, progesterone inhibits steroid binding to elephant shark GR, but not to human GR. Together, this indicates partial functional divergence of elephant shark GR from the MR. Deletion of the N-terminal domain (NTD) from elephant shark GR (truncated GR) reduced the response to corticosteroids, while truncated and full-length elephant shark MR had similar responses to corticosteroids. Swapping of NTDs of elephant shark GR and MR yielded an elephant shark MR chimera with full-length GR-like increased activation by corticosteroids and progesterone compared to full-length elephant shark MR. Elephant shark MR NTD fused to GR DBD+LBD had similar activation as full-length MR, indicating that the MR NTD lacked GR-like NTD activity. We propose that NTD activation of human GR evolved early in GR divergence from the MR.

Background/Aims Electrohydraulic lithotripsy (EHL) under endoscopic retrograde cholangiopancreatography (ERCP) guidance can be an option to treat difficult stones. Recently, a digital, single-operator cholangioscope (SPY-DS) has become available. Peroral transluminal cholangioscopy (PTLC) using SPY-DS has also been reported. In this retrospective study, the technical feasibility and clinical effectiveness of EHL for difficult bile duct stones under ERCP guidance and under PTLC guidance was examined. Methods In this pilot study, patients with difficult bile duct stones between July 2016 and July 2017 were retrospectively enrolled. Results Forty-two consecutive patients underwent EHL using a SPY-DS; 34 patients underwent EHL under ERCP guidance, and the other 8 patients underwent EHL under PTLC guidance. Median procedure time was 31 minutes (range, 19 to 66 minutes). The median number of EHL sessions was 1 (range, 1 to 2), and that of ERCP sessions was also 1 (range, 1 to 3). The rate of complete stone clearance was 98% (41/42). Adverse events such as cholangitis and acute pancreatitis were seen in 14% (6/42), which could be treated conservatively. Conclusions EHL using SPY-DS was technically feasible, not only under ERCP guidance, but also PTLC guidance. A prospective clinical study of EHL using SPY-DS is needed.

Background Adipocyte fatty acid-binding protein (A-FABP) is expressed in both adipocytes and macrophages. Recent studies have shown that A-FABP is secreted by adipocytes and that the A-FABP concentration is associated with obesity, insulin resistance, and atherosclerosis. We have reported that the coronary atherosclerotic burden is associated with the serum A-FABP concentration. In the present study, we investigated whether the serum A-FABP concentration is associated with prognosis in patients with stable angina pectoris who have undergone percutaneous coronary intervention (PCI). Methods This was a prospective single-center trial. In total, 130 patients with stable angina pectoris undergoing their first PCI were enrolled from August 2008 to July 2010 at Kagawa Prefectural Central Hospital. The primary endpoints were cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, revascularization, and hospitalization for heart failure. Results During the follow-up (median, 50 months; interquartile range, 23–66 months), 49 cardiovascular events occurred. Kaplan–Meier analysis showed that the cumulative incidence of the primary endpoints in the high A-FABP group (median A-FABP concentration of ≥ 18.6 ng/ml) was greater than that in the low A-FABP group. Cox analysis showed that the A-FABP concentration was an independent predictor of cardiovascular events adjusted for age and the presence of multi-vessel disease (hazard ratio, 1.03; 95% confidence interval, 1.01–1.04; p = 0.01). Conclusion The serum A-FABP concentration is associated with prognosis in patients with stable angina undergoing PCI, suggesting that the serum A-FABP concentration could be useful for risk assessment of secondary prevention. Trial registration UMIN Clinical Trials Registry UMIN000029283 (registration date: September 25, 2017), retrospectively registered.

Background and Aim The clinical impact of catheter-based radiofrequency ablation (RFA) under endoscopic retrograde cholangiopancreatography (ERCP) guidance has recently been reported; however, severe adverse events have also been noted. If tumor is not present in the biliary tract, severe adverse events such as perforation or bleeding as a result of vessel injury around the biliary tract may occur. In addition, the effectiveness of RFA may not be sufficient based solely on radiographic guidance. The aim of the present study was to evaluate the actual feasibility of intraductal RFA by peroral cholangioscope (POCS) evaluation before/after RFA. Methods In this retrospective study carried out between July and September 2016, consecutive patients who underwent RFA for malignant biliary stricture and POCS evaluation before/after RFA were enrolled. Primary endpoint of this study was technical feasibility of RFA, which was evaluated by POCS. Secondary endpoints were rates and types of adverse event. Results A total of 12 consecutive patients were retrospectively enrolled in this study. Stent placement using uncovered metal stents had been previously done in six patients before RFA. Tumor was seen in the biliary tract in all patients. RFA was technically successful in all patients, and clinical success was confirmed in all patients by POCS imaging. Adverse events were seen in only one patient. Median stent patency was 154 days. Conclusions RFA for malignant biliary stricture may be safe. To confirm the feasibility and efficacy of RFA, additional cases, prospective studies, and a comparison study between with and without endobiliary RFA are needed.

Background and Aim On endoscopic ultrasound (EUS)-guided biliary drainage, fistula dilation may be accompanied by leakage of bile juice, potentially along with bacteria or air, so this procedure should be kept as simple and short as possible. To date, various techniques to dilate the fistula have been reported. This prospective, single-center, single-arm study evaluated the technical feasibility and safety of EUS-guided biliary drainage using novel balloon catheters. Methods Tip of novel balloon catheters is only 3 Fr and tapered, and the catheters also show favorable push ability. First, biliary tract was punctured using 19-G fine needle aspiration needle. Next, we immediately inserted the novel balloon catheter, and the biliary tract and intestinal wall were dilated. Then, we performed metallic stent placement without any dilation fistula. Results A total of 20 patients were prospectively enrolled in this study. Technical success rate was 100%. Eleven patients underwent EUS-guided choledochoduodenostomy, and nine patients underwent EUS-guided hepaticogastrostomy. Median procedure time was only 11 min (range, 8–16 min) for EUS-guided choledochoduodenostomy and 14 min (range, 11–18 min) for EUS-guided hepaticogastrostomy. Adverse events were seen in 15% (3/20; self-limited abdominal pain n = 2, peritonitis n = 1). Conclusions Although additional cases and a randomized controlled comparison with another dilation technique such as the graded dilation or cystotome dilation technique are needed, our technique may be helpful for EUS-guided biliary drainage.

Background and aim Re-intervention after stent placement for malignant hepatic hilum obstruction (HBO) is challenging. endoscopic ultrasound-guided biliary drainage (EUS-BD) has been developed as an alternative method for failed endoscopic retrograde cholangiopancreatography (ERCP). In this retrospective study, the clinical utility of EUS-BD as a rescue drainage technique for HBO patients who failed re-intervention under ERCP guidance was evaluated. Methods Between April 2012 and August 2015, patients with HBO were enrolled. Patients' characteristics, kinds of metallic stents, configuration of stent placement, overall survival, stent patency, and results of re-intervention were reviewed, along with the re-intervention technical success rate. Results The biliary stricture type was Bismuth type IV in 59% (23/39) and types IIIa and b in 20.5% (8/39) each. Biliary metallic stent placement was bilateral in 38.5% (15/39), and unilateral in 61.5% (24/39). Primary stent dysfunction was observed in 71.8% (28/39) of cases. Planned re-intervention under ERCP guidance was attempted in 26 patients. The technical success rate was 62% (16/26). For the 10 patients who failed re-intervention under ERCP guidance, EUS-BD was planned. The technical success rate was 100% (10/10). The procedure time was 25.8 min. Adverse events were not seen in any patients. Stent patency after re-intervention was not significantly different between ERCP (165 days) guidance and EUS-BD (152 days) guidance (P = 0.463) CONCLUSIONS: In conclusion, EUS-BD as a re-intervention method for metallic stent obstruction was safe and feasible. If ERCP was failed, EUS-BD may be one of option as re-intervention method for high-grade hilar stricture.

There is no evidence that strict follow-up using cross-sectional imaging after curative gastrectomy benefits survival; however, nonperitoneal recurrence detected early might be treated with additional surgery. The present study examined whether early detection of recurrence by imaging modalities could increase survival, particularly in patients with nonperitoneal recurrence. We retrospectively analyzed 218 patients with recurrent gastric cancer after curative gastrectomy performed from 2002 to 2014. The patients were divided into an asymptomatic group (n = 117) and a symptomatic group (n = 101), according to the presence of symptoms at the time of recurrence, to compare clinicopathological characteristics and long-term survival. Peritoneal recurrence was less frequent in the asymptomatic group (22.2%) than in the symptomatic group (62.4%), the median time to recurrence was shorter (12.7 months vs 18.9 months; P

The mineralocorticoid receptor (MR) is a nuclear receptor and part of a large and diverse family of transcription factors that also includes receptors for glucocorticoids, progesterone, androgens, and estrogens. The corticosteroid aldosterone is the physiological activator of the MR in humans and other terrestrial vertebrates; however, its activator is not known in cartilaginous fish, the oldest group of extant jawed vertebrates. Here, we analyzed the ability of corticosteroids and progesterone to activate the full-length MR from the elephant shark (Callorhinchus milii). On the basis of their measured activities, aldosterone, cortisol, 11-deoxycorticosterone, corticosterone, 11-deoxcortisol, progesterone, and 19-norprogesterone are potential physiological mineralocorticoids. However, aldosterone, the physiological mineralocorticoid in humans and other terrestrial vertebrates, is not found in cartilaginous or ray-finned fish. Although progesterone activates MRs in ray-finned fish, progesterone does not activate MRs in humans, amphibians, or alligator, suggesting that during the transition to terrestrial vertebrates, progesterone lost the ability to activate the MR. Both elephant shark MR and human MR are expressed in the brain, heart, ovary, testis, and other nonepithelial tissues, suggesting that MR expression in diverse tissues evolved in the common ancestor of jawed vertebrates. Our data suggest that 19-norprogesterone- and progesterone-activated MR may have unappreciated functions in reproductive physiology.

Despite intensive lipid-lowering interventions, patients treated with statins develop atherosclerotic cardiovascular disease (ASCVD), and these patients have an increased risk of developing recurrent cardiovascular events during follow-up. Therefore, there is a need to focus on the residual risks in patients in statin therapy to further reduce ASCVD. The aim of this study was to retrospectively investigate the 10-year trend (2011&ndash, 2019) regarding changes in polyunsaturated fatty acids (PUFAs) in patients with acute coronary syndrome (ACS) in a single center. We included 686 men and 203 women with ACS admitted to Kagawa Prefectural Central Hospital. Plasma PUFAs, including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), arachidonic acid (AA), and dihomo-&gamma, linolenic acid (DGLA), were measured at admission for suspected ACS. A secular decreasing trend in the levels of EPA and DHA and the EPA/AA ratio, but not of AA and DGLA, was observed. The analyses based on age (&gt, 70 or &lt, 70 years) and sex showed that the decreasing trend in the levels of EPA and DHA did not depend on age and remained significant only in men. Further studies are needed to obtain robust evidence to justify that the administration of n-3 PUFA contributes to the secondary prevention of ACS.

Endoscopic retrograde cholangiopancreatography (ERCP) is the gold-standard modality for diagnosis and therapy of bilio-pancreatic disease. In particular, peroral cholangiography (POCS) is a useful modality not only for diagnosing biliary disease, but also for therapeutic procedures such as electrohydraulic lithotripsy. The SPY-DS single-operator cholangioscope has recently become available, and offers favorable visualization, a wide view, suction function and a larger accessory working channel. However, if the duodenoscope cannot be advanced into the ampulla of Vater for reasons such as surgical anatomy, POCS cannot be performed. On the other hand, percutaneous transhepatic cholangiodrainage (PTCD) has been developed as an alternative endoscopic ultrasound-guided approach to the biliary tract. Peroral transluminal cholangioscopy (PTLC) using SPY-DS is a novel approach. Because transluminal interventional procedures under endoscopic ultrasound guidance have recently been developed, our technique may have clinical impact for selected cases.

Background Pharyngolaryngectomy with total esophagectomy (PLTE) is an effective surgical treatment for synchronous or metachronous hypopharyngeal or laryngeal cancer and thoracic esophageal cancer, although it is more invasive than esophagectomy and total pharyngolaryngectomy. The aim of this study was to identify risk factors for complications after PLTE. Methods From November 2002 to December 2014, a total of 8 patients underwent PLTE at the Shizuoka Cancer Center Hospital, Shizuoka, Japan. We investigated the clinicopathological characteristics, surgical procedures, and postoperative complications of these patients. Results Of the 8 patients, 5 underwent one-stage PLTE and 3 underwent staged PLTE. There was no mortality in this study. Two cases of tracheal necrosis, two of anastomotic leakage, and one of ileus were observed as postoperative complications. Two patients who underwent one-stage PLTE with standard mediastinal lymph node dissection developed tracheal necrosis and severe anastomotic leakage. Conclusion One-stage PLTE and standard mediastinal lymph node dissection were identified as the risk factors for severe postoperative complications. Staged PLTE or transhiatal esophagectomy should be considered when PLTE is performed and standard mediastinal lymph node dissection should be avoided when one-stage PLTE is performed with transthoracic esophagectomy.

A 75-year-old Japanese man with type 2 diabetes mellitus suffered from unresectable pancreatic head cancer and was admitted to our institution due to acute cholangitis. A partially covered metal stent was placed at that time. 11 months later, he was readmitted for acute cholangitis. Upper endoscopy revealed complete stent distal migration and a small hole on the oral side of the ampulla. While attempting cannulation into the hole, an upstream biliary tract was revealed. Accordingly, we diagnosed the patient to have a choledochoduodenal fistula. After metal stent removal and balloon dilation, we placed two 7 Fr plastic stents, which successfully relieved the patient's cholangitis.

BACKGROUND AND STUDY AIM Despite high technical and functional success rates with endoscopic ultrasound-guided hepaticogastrostomy (EUS-HGS), rates of adverse events have also been high. No reports have focused on EUS-HGS alone with a large sample size about predictors of stent patency. The present study examined predictors of stent patency in patients who underwent EUS-HGS. PATIENTS AND METHODS The consecutive 51 patients who underwent EUS-HGS using one metallic stent were retrospectively enrolled in this study. Baseline characteristics, stent length from the hepatic portion and in the luminal portion, kinds of stent dysfunction, and stent patency were reviewed. RESULTS Median duration of stent patency was significantly shorter with stent length in the luminal portion

Batoidea (rays and skates) is a monophyletic subgroup of elasmobranchs that diverged from the common ancestor with Selachii (sharks) about 270 Mya. A larger number of batoids can adapt to low-salinity environments, in contrast to sharks, which are mostly stenohaline marine species. Among osmoregulatory organs of elasmobranchs, the kidney is known to be dedicated to urea retention in ureosmotic cartilaginous fishes. However, we know little regarding urea reabsorbing mechanisms in the kidney of batoids. Here, we performed physiological and histological investigations on the nephrons in the red stingray (Hemitrygon akajei) and two shark species. We found that the urine/plasma ratios of salt and urea concentrations in the stingray are significantly lower than those in cloudy catshark (Scyliorhinus torazame) under natural seawater, indicating that the kidney of stingray more strongly reabsorbs these osmolytes. By comparing the three-dimensional images of nephrons between stingray and banded houndshark (Triakis scyllium), we showed that the tubular bundle of stingray has a more compact configuration. In the compact tubular bundle of stingray kidney, the distal diluting tubule was highly developed and frequently coiled around the proximal and collecting tubules. Furthermore, co-expression of NKAα1 (Na+/K +-ATPase) and NKCC2 (Na+- K+-2Cl– cotransporter 2) mRNAs was prominent in the coiled diluting segment. These findings imply that NaCl reabsorption is greatly facilitated in the stingray kidney, resulting in a higher reabsorption rate of urea. Lowering the loss of osmolytes in the glomerular filtrate is likely favorable to the adaptability of batoids to a wide range of environmental salinity.

Jawed vertebrates have inner ears with three semicircular canals, the presence of which has been used as a key to understanding evolutionary relationships. Ostracoderms, the jawless stem gnathostomes, had only two canals and lacked the lateral canal1–3. Lampreys, which are modern cyclostomes, are generally thought to possess two semicircular canals whereas the hagfishes—which are also cyclostomes—have only a single canal, which used to be regarded as a more primitive trait1,4. However, recent molecular and developmental analyses have strongly supported the monophyly of cyclostomes5–7, which has left the evolutionary trajectory of the vertebrate inner ear unclear8. Here we show the differentiation of the otic vesicle of the lamprey Lethenteron camtschaticum and inshore hagfish Eptatretus burgeri. This is the first time, to our knowledge, that the development of the hagfish inner ear is reported. We found that canal development in the lamprey starts with two depressions—which is reminiscent of the early developmental pattern of the inner ear in modern gnathostomes. These cyclostome otic vesicles show a pattern of expression of regulatory genes, including OTX genes, that is comparable to that of gnathosomes. Although two depressions appear in the lamprey vesicle, they subsequently fuse to form a single canal that is similar to that of hagfishes. Complete separation of the depressions results in anterior and posterior canals in gnathostomes. The single depression of the vesicle in hagfishes thus appears to be a secondarily derived trait. Furthermore, the lateral canal in crown gnathostomes was acquired secondarily—not by de novo acquisition of an OTX expression domain, but by the evolution of a developmental program downstream of the OTX genes. The differentiation of the inner ear in the lamprey Lethenteron camtschaticum and hagfish Eptatretus burgeri sheds light on the evolution of the semicircular canals of jawed vertebrates.

Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has been established as a method to obtain tissues of various organs. To obtain sufficient tissue has clinical impact to facilitate the diagnosis by clinical pathologists, the assessment and subtyping of various neoplasms, and for further immunohistochemical investigations of tumor type. Recently, a novel 20G core trap with a forward-cutting beveled FNA needle (ProC-F) has become available. The aim of this prospective study was to evaluate the feasibility and diagnostic yield of EUS-FNA for pancreatic lesions using this needle. In this study, the first puncture was performed using the ProC-F. Only tissue obtained with the first puncture using the ProC-F was used to evaluate diagnostic yield of ProC-F. The second puncture was performed using a 22G standard FNA needle using the same technique as for the first puncture. Second puncture was performed if the endosonographer did not feel that sufficient tissue had not been obtained by first puncture. Fifty-three consecutive patients who underwent EUS-FNA for pancreatic lesions were prospectively enrolled. The technical success rate of EUS-FNA using the ProC-F was 98.1% (52/53). The rate of adequate tissue obtained by ProC-F was 96.2% (50/52). On the other hand, the rate of adequate tissue obtained by the standard needle was 71.1%. The sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy of the ProC-F and the standard needle were 92.5, 100, 100, 76.9, and 94.0%, and 85.2, 100, 100, 55.6, and 87.5%, respectively. Diagnostic yield of ProC-F about sensitivity (P = 0.027), NPV (P = 0.035), and accuracy (P = 0.004) was significantly higher than of standard needle. Adverse events were not seen in any patients. Although only tissue obtained by the first puncture was evaluated, the rate of adequate tissue and the histologic diagnostic yield for pancreatic lesions were extremely high using the ProC-F.

Laparoscopic gastrectomy is a widely used minimally invasive surgery for gastric cancer. However, skillful techniques are required to perform lymph node dissection using straight shaped forceps, particularly for D2 dissection. Robotic surgery using the da Vinci surgical system is anticipated to be a powerful tool for performing difficult techniques using high-resolution three-dimensional (3D) images and the EndoWrist equipped with seven degrees of freedom. Attempts are being made to apply robotic surgery in gastrectomy procedures mainly in Japan, South Korea, and Europe. Although definite superiority to laparoscopic gastrectomy is yet to be proven, robotic surgery has been reported to have a shorter learning curve and offer more precise dissection for total gastrectomy. Hence, its oncological efficacy needs to be verified in a clinical trial.

We examined whether early loading of eicosapentaenoic acid (EPA) reduces clinical adverse events by 1 month, accompanied by a decrease in C-reactive protein (CRP) values in patients with acute myocardial infarction (MI).Acute MI triggers an inflammatory reaction, which plays an important role in myocardial injury. EPA could attenuate the inflammatory response.This prospective, open-label, blinded endpoint, randomized trial consisted of 115 patients with acute MI. They were randomly assigned to the EPA group (57 patients) and the control group (58 patients). After percutaneous coronary intervention (PCI), 1800 mg/day of EPA was initiated within 24h. The primary endpoint was composite events, including cardiac death, stroke, re-infarction, ventricular arrhythmias, and paroxysmal atrial fibrillation within 1 month.Administration of EPA significantly reduced the primary endpoint within 1 month (10.5 vs 29.3%, p=0.01), especially the incidence of ventricular arrhythmias (7.0 vs 20.6%, p=0.03). Peak CRP values after PCI in the EPA group were significantly lower than those in the control group (median [interquartile range], 8.2 [5.6-10.2] mg/dl vs 9.7 [7.6-13.9] mg/dl, p0.01). Logistic regression analysis showed that EPA use was an independent factor related to ventricular arrhythmia until 1 month, with an odds ratio of 0.29 (95% confidence interval, 0.09 to 0.96, p=0.04).Early EPA treatment after PCI in the acute stage of MI reduces the incidence of ventricular arrhythmias, and lowers CRP values.

The nuclear protein CCCTC-binding factor (CTCF) contributes as an insulator to chromatin organization in animal genomes. Currently, our knowledge of its binding property is confined mainly to mammals. In this study, we identified CTCF homologs in extant jawless fishes and performed ChIP-seq for the CTCF protein in the Arctic lamprey. Our phylogenetic analysis suggests that the lamprey lineage experienced gene duplication that gave rise to its unique paralog, designated CTCF2, which is independent from the previously recognized duplication between CTCF and CTCFL. The ChIP-seq analysis detected comparable numbers of CTCF binding sites between lamprey, chicken, and human, and revealed that the lamprey CTCF protein binds to the two-part motif, consisting of core and upstream motifs previously reported for mammals. These findings suggest that this mode of CTCF binding was established in the last common ancestor of extant vertebrates (more than 500 million years ago). We analyzed CTCF binding inside Hox clusters, which revealed a reinforcement of CTCF binding in the region spanning Hox1-4 genes that is unique to lamprey. Our study provides not only biological insights into the antiquity of CTCF-based epigenomic regulation known in mammals but also a technical basis for comparative epigenomic studies encompassing the whole taxon Vertebrata.

Urea is an essential osmolyte for marine cartilaginous fishes. Adult elasmobranchs and holocephalans are known to actively produce urea in the liver, muscle and other extrahepatic organs; however, osmoregulatory mechanisms in the developing cartilaginous fish embryo with an undeveloped urea-producing organ are poorly understood. We recently described the contribution of extraembryonic yolk sac membranes (YSM) to embryonic urea synthesis during the early developmental period of the oviparous holocephalan elephant fish (Callorhinchus milii). In the present study, to test whether urea production in the YSM is a general phenomenon among oviparous Chondrichthyes, we investigated gene expression and activities of ornithine urea cycle (OUC) enzymes together with urea concentrations in embryos of the elasmobranch cloudy catshark (Scyliorhinus torazame). The intracapsular fluid, in which the catshark embryo develops, had a similar osmolality to seawater, and embryos maintained a high concentration of urea at levels similar to that of adult plasma throughout development. Relative mRNA expressions and activities of catshark OUC enzymes were significantly higher in YSM than in embryos until stage 32. Concomitant with the development of the embryonic liver, the expression levels and activities of OUC enzymes were markedly increased in the embryo from stage 33, while those of the YSM decreased from stage 32. The present study provides further evidence that the YSM contributes to embryonic urea homeostasis until the liver and other extrahepatic organs become fully functional, and that urea-producing tissue shifts from the YSM to the embryonic liver in the late developmental period of oviparous marine cartilaginous fishes.

Background and Aim Recently, the digital single-operator cholangioscope (SPY-DS) has become available. This system may allow diagnosis by direct visualization and allow performance of various therapeutic procedures. The aim of the present study was to prospectively evaluate the clinical utility of DSOCS for diagnostic and therapeutic procedures for biliary disease. Methods Technical success was defined as successful visualization of target lesions in the biliary tract and carrying out forceps biopsy as a diagnostic procedure, and successfully carrying out treatment such as guidewire insertion for the area of interest, electrohydraulic lithotripsy (EHL), or migrated stent removal. Also, the present study aimed at investigating diagnostic yield of the cholangioscopic findings and biopsy specimens. Results A total of 55 consecutive patients were prospectively enrolled in this study; a diagnostic procedure was done in 33 patients, and a therapeutic procedure was done in 22 patients. Overall accuracy of visual findings was 93%, with a sensitivity of 83%, a specificity of 89%, positive predictive value (PPV) of 83%, and negative predictive value (NPV) of 100%. However, the overall accuracy of forceps biopsy was 89%, with a sensitivity, specificity, and PPV of 100%, and NPV of 90%. Overall technical success rate of therapeutic procedures such as selective guidewire insertion, EHL or migrated stent removal was 91% (20/22). Finally, adverse events were seen in two cases in the diagnostic group, but were not seen in the therapeutic group. Conclusion Although additional cases and a randomized, controlled study with another cholangioscope are needed, diagnostic and therapeutic procedures using SPY-DS appear to be feasible and safe.

Background: Temporary stent placement is widely performed for pancreatic duct stenosis due to chronic pancreatitis. A fully covered self-expandable metal stent (FCSEMS) has a larger diameter, and therefore longer stent patency, and the effect of expansion of the main pancreatic duct stricture may be obtained. However, if stent migration upstream occurs, stent removal is extremely difficult. In addition, because of the diameter gap between the FCSEMS and the main pancreatic duct, stent-induced ductal change may occur. To prevent these adverse events, the technical feasibility, safety and efficacy of the placement of a novel 6 mm diameter FCSEMS with a long suture, to facilitate its removal in cases of stent migration upstream, were evaluated in a pilot study. Methods: Between December 2014 and August 2015, symptomatic chronic pancreatitis patients with abdominal pain and a main pancreatic head duct stricture were enrolled. Stent placement for main pancreatic duct stricture was performed under endoscopic retrograde cholangiopancreatography (ERCP) guidance and stent removal was performed within 6 months. Results: A total of 13 patients were retrospectively enrolled in this study. Metal stent insertion was successfully performed in all patients and clinical success was high (12/13, 92%). As adverse events, stent migration upstream was seen in two patients. Another 11 patients successfully underwent stent removal without any adverse events. During follow up (median 258 days), 2 patients still underwent pancreatic duct stenting because of continuing main pancreatic duct stricture. Conclusion: In conclusion, this novel FCSEMS is acceptable for stent placement in cases of chronic pancreatitis with a main pancreatic duct stricture.

Most vertebrates, including cartilaginous fishes, maintain their plasma SO42−concentration ([SO42−]) within a narrow range of 0.2–1 mM. As seawater has a [SO42−] about 40 times higher than that of the plasma, SO42−excretion is the major role of kidneys in marine teleost fishes. It has been suggested that cartilaginous fishes also excrete excess SO42−via the kidney. However, little is known about the underlying mechanisms for SO42−transport in cartilaginous fish, largely due to the extraordinarily elaborate four-loop configuration of the nephron, which consists of at least 10 morphologically distinguishable segments. In the present study, we determined cDNA sequences from the kidney of holocephalan elephant fish ( Callorhinchus milii) that encoded solute carrier family 26 member 1 (Slc26a1) and member 6 (Slc26a6), which are SO42−transporters that are expressed in mammalian and teleost kidneys. Elephant fish Slc26a1 (cmSlc26a1) and cmSlc26a6 mRNAs were coexpressed in the proximal II (PII) segment of the nephron, which comprises the second loop in the sinus zone. Functional analyses using Xenopus oocytes and the results of immunohistochemistry revealed that cmSlc26a1 is a basolaterally located electroneutral SO42−transporter, while cmSlc26a6 is an apically located, electrogenic Cl−/SO42−exchanger. In addition, we found that both cmSlc26a1 and cmSlc26a6 were abundantly expressed in the kidney of embryos; SO42−was concentrated in a bladder-like structure of elephant fish embryos. Our results demonstrated that the PII segment of the nephron contributes to the secretion of excess SO42−by the kidney of elephant fish. Possible mechanisms for SO42−secretion in the PII segment are discussed.

Background: Few reports have described endoscopic ultrasound (EUS)-guided fine needle aspiration (FNA) for biliary lesions. In addition, adverse events were not completely examined in previous reports, due to the inclusion of cases in which biliary stents had already been placed. The present study aimed to investigate the diagnostic yield and adverse events of EUS-FNA for biliary lesions as the first-line diagnostic modality for consecutive prospectively registered patients. Methods: Inclusion criteria were as follows: (1) patients with suspected cholangiocarcinoma (CCA) based on computed tomography or other imaging modalities; (2) patients who had not previously undergone endoscopic retrograde cholangiopancreatography or EUS-FNA; (3) absence of surgically altered anatomy, such as Roux-en-Y anastomosis or duodenal obstruction caused by tumor invasion, through which an endoscope could not pass; and (4) provision of written informed consent to all procedures associated with the study. Results: A total of 47 consecutive patients with suspected CCA were registered to this study. Sensitivity and accuracy were 89% and 87%, respectively. On multivariate analysis, puncture site was the only factor associated with reduced diagnostic yield (hazard ration, 6.879; 95% confidence interval, 1.172–40.374; P = 0.033). Remarkably, no adverse events such as bleeding or bile leakage were associated with EUS-FNA in any of the 47 patients. Conclusions: Our results suggest that EUS-FNA can be safely performed for biliary disease without biliary stenting. Furthermore, this procedure may warrant use as the first-line diagnostic method, although our results need to be validated in future prospective studies.

Background: Recently, endoscopic ultrasound-guided gall bladder drainage (EUS-GBD) has been reported using a self-expandable metallic stent. To prevent stent migration and food flowing into the common bile duct through the cystic duct, we perform a novel EUS-guided cholecystoduodenostomy. The aim of our study was to evaluate the safety and feasibility of EUS-guided cholecystoduodenostomy with an anti-stent migration and anti-food impaction system. Methods: A total of 16 consecutive patients who underwent EUS-guided cholecystoduodenostomy for acute cholecystitis were included in this study. Results: Technical and clinical success was obtained in all patients. The median procedure time was 26.9 min (range 19–42 min). Median follow-up time was 181.5 days (range 18–604 days), and in this time, recurrence of acute cholecystitis was not seen in all patients. Adverse events such as stent migration and cholangitis were not seen in any patients, although pneumoperitoneum was seen in one patient. Conclusion: Our technique may be favorable and effective for the prevention of adverse events on EUS-GBD.

We herein describe the case of a 67-year-old woman with a duodenal ulcer thought to be caused by elevated pancreatic ductal pressure. The patient complained of continuous upper abdominal pain. Her medical history included idiopathic chronic pancreatitis. Endoscopy revealed a huge duodenal ulcer located on the inferior duodenal angle, which had not been seen on endoscopic retrograde pancreatography two months previously. A combination study using endoscopy and contrast imaging confirmed the relationship between the duodenal ulcer and the pancreatic branch duct. To our knowledge, this is the first case of duodenal ulcer thought to be caused by elevated pancreatic ductal pressure.

Duodenal stent placement has been developed as an alternative to surgical gastrojejunostomy [1]. Compared with uncovered metallic stents, duodenal fully covered metallic stents offer advantages, such as the prevention of tumor ingrowth, and thus lower occlusion rates [2]. However, duodenal fully covered metallic stents also have several disadvantages, such as stent migration [3]. Acute pancreatitis is another adverse event associated with duodenal stent placement, occurring at a frequency of approximately 4% [4,5]. In previous reports, acute pancreatitis has been treated conservatively. If a fully covered metallic stent is placed in the duodenum, the frequency of acute pancreatitis may be increased, and the treatment of acute pancreatitis may prove difficult. We report herein a novel treatment for acute pancreatitis due to duodenal placement of a fully covered metallic stent. A 78-year-old man was admitted to our hospital because of vomiting and obstructive jaundice. He was undergoing chemotherapy for bladder cancer. Computed tomography showed a duodenal stenosis, attributed to lymph node metastasis. No other site of stenosis was detected, so we attempted duodenal stent placement. First, we advanced the endoscope into the duodenum, and contrast medium was injected. The second part of the duodenum was obstructed (●" Fig.1). Then, we placed a fully covered metallic stent (ComVi, 20mm×12 cm; TaeWoong Medical, Seoul, South Korea) in the duodenum (●" Fig.2). Although the vomiting resolved completely, acute pancreatitis developed. Computed tomography showed dilatation of the Fig.1 A duodenal stenosis is apparent (arrows) in a 78-year-oldmanadmittedwith vomitingand obstructive jaundice.