Hiroki Toma

Nerve growth factor regulates VR-1 mRNA levels in cultures of adult dorsal root ganglion neurons.

&NA; Nerve growth factor (NGF) regulates the nociceptive properties including sensitivity to capsaicin of a subset of dorsal root ganglion neurons, which express the high‐affinity NGF receptor, trkA. Capsaicin sensitivity co‐localizes with the expression of a cloned capsaicin receptor, vanilloid receptor type 1 (VR‐1), which displays properties similar to the native capsaicin response. To determine whether VR‐1 mRNA levels are regulated by NGF, VR‐1 mRNA levels and the ability to respond to capsaicin by release of the neuropeptide calcitonin gene related peptide (CGRP) were measured as a function of NGF concentration in cultures of adult dorsal root ganglion neurons. NGF treatment increased both VR‐1 mRNA expression and capsaicin evoked release of CGRP. These effects were inhibited by treatment with the trkA inhibitor k252a.

Japan Pancreatic Cancer Registry; 30th year anniversary: Japan Pancreas Society.

Objectives Since 1981, the Japan Pancreas Society has been hosting a nationwide pancreatic cancer registry. To commemorate its 30th anniversary, we review its history and latest achievement. Methods During 3 decades, more than 350 leading institutions in Japan contributed voluntarily to register and periodic follow-up. The registry was modified to protect privacy by encrypting and hash algorithm. Results From 1981 to 2007, 32,619 cumulative records were analyzed. The overall survival of invasive cancer was improved significantly. More patients with earlier stage or with intraductal and cystic neoplasms underwent resection. The strongest prognostic factor of Union for International Cancer Control (UICC) stage IIA and IIB tubular adenocarcinoma in the pancreatic head was histological grade, followed by tumor size, extent of lymph node dissection, and postoperative chemotherapy. The 5-year survival rate of Union for International Cancer Control stage 0 reached 85%. The improvement of survival of patients with invasive cancer in Japan can be attributed to the introduction of effective chemotherapies, regionalization, and the earlier diagnosis and treatment. Simple definition of “early pancreatic cancer” is needed. Conclusions At the 30th year anniversary, the Japan Pancreas Society nationwide pancreatic cancer registry is more shining than ever for current perspectives and for future diagnostic and treatment tactics.

Acute pancreatitis results in referred mechanical hypersensitivity and neuropeptide up-regulation that can be suppressed by the protein kinase inhibitor k252a ☆

Although pain is a cardinal feature of pancreatitis, its pathogenesis is poorly understood and treatment remains difficult. Nociceptive sensitization in several somatic pain models has been associated with activation of protein kinases including trkA, protein kinase C, and protein kinase A. We therefore tested the hypothesis that systemic treatment with a kinase inhibitor, k252a, known to inhibit all of these kinases would alleviate pain in an animal model of pancreatitis. Von Frey filament testing of somatic referral regions was evaluated as a method to measure referred pain in a rat model of acute necrotizing pancreatitis induced by L-arginine. Rats with pancreatitis showed increased sensitivity to abdominal stimulation with Von Frey filament. This referred mechanical sensitivity was associated with an 8-fold increase in levels of phosphorylated trkA in the pancreas and with significant up-regulation of both calcitonin gene-related peptide and preprotachykinin mRNA expression in thoracic dorsal root ganglia and with increased calcitonin gene-related peptide and substance P immunoreactivity in spinal cord segment T10. Treatment with the kinase inhibitor k252a suppressed the phosphorylation of trkA in the pancreas as well as reversed both the behavioral changes and the increase in neuropeptide expression associated with pancreatitis.

Characterization of the neurotrophic response to acute pancreatitis.

Introduction Interesting preliminary data on changes in the neurotrophin system in various digestive diseases have recently begun to emerge. Aims To measure changes in messenger RNA (mRNA) levels of neurotrophins and to identify cell types expressing neurotrophins in the pancreas of rats with L-arginine-induced pancreatitis. Methodology Rats were killed at time points from 2 hours to 4 weeks after the induction of pancreatitis, and responses were measured by assay. Results By RNase protection assay, ciliary neurotrophic factor (CNTF) mRNA expression showed a rapid response (sixfold increase over control) in the inflamed pancreas at 2 hours. The levels of mRNA expression of brain-derived neurotrophic factor (BDNF), glial cell line–derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3), and neurotrophin-4 (NT-4) in the inflamed pancreas reached a peak at 1 week (2.5-fold, twofold, fourfold, and fivefold increase, respectively). By immunohistochemistry, immunoreactivity for all neurotrophins examined was observed in the islets of Langerhans in the control pancreas at all time points, but it was markedly reduced in the islets in the inflamed pancreas at 2 and 6 hours. Acinar and ductal cells, inflammatory cells, and neural elements were immunoreactive for those neurotrophins in the inflamed pancreas from 2 hours to 2 weeks. Conclusion The temporal and spatial expression of neurotrophins in the course of experimental pancreatitis suggests that their upregulation is a critical component of the response of the pancreas to injury in this model.

Effect of Local Injection of Botulinum Toxin on Sphincter of Oddi Cyclic Motility in Dogs

To study effects of intrasphincteric injectionsof botulinum toxin on the sphincter of Oddi cyclicmotility and responses to motilin and cholecystokinin,four conscious dogs with duodenal cannula underwent manometry of the common bile duct, sphincter ofOddi, and duodenum. After baseline recording, each doghad intrasphincteric injections of saline or botulinumtoxin. The injections of saline had no effect, whereas botulinum toxin significantly reducedmean basal pressure, amplitude, and motility index ofthe sphincter of Oddi. These effects took place in fourto seven days and reached a maximum in seven to 10 days. The basal pressure returned to thebaseline level in 28 weeks, but the amplitude andmotility index remained low. The pressure parameters ofmotilin-induced premature phase III-like activity also decreased, but action of cholecystokinin wasnot affected. These results indicate that the botulinumtoxin injections reduce sphincter of Oddi phasiccontractile activity for a prolonged period oftime.

Laparoscopic and endoscopic cooperative surgery for non-ampullary duodenal epithelial neoplasms

Aim: We herein describe our initial experience of laparoscopic and endoscopic cooperative surgery (LECS) for nonampullary duodenal epithelial neoplasms (NADENs) and reveal its clinical significance. Methods: This study included 5 consecutive patients treated by LECS for NADENs between April 2015 and January 2016 in our hospital. For surgery, R0-resection of NADENs was accomplished by endoscopic submucosal dissection (ESD), and the mucosal defect resulting from ESD was subsequently repaired by laparoscopic seromuscular suture and endoscopic clipping. Clinical records were reviewed retrospectively. Results: LECS was accomplished in four patients. There was a case of open conversion due to the relatively large mucosal defect resulting from ESD. In the postoperative course, no serious complications, including intraand postoperative bleeding and delayed perforation, were noted. The duodenal stenosis occurred in the case of open conversion but was treated by repeated endoscopic balloon dilatation. Of the five lesions of NADENs, there were three adenomas and two adenocarcinomas confined in the mucosa. To date, no tumor recurrence was observed during the postoperative course. Conclusion: LECS is a promising procedure of choice in the treatment of NADENs, facilitating early resumption of both food intake and full daily activity in the postoperative course.

Hyperalgesia and up-regulation of nociceptive genes in sensery neurons in pancreatitis is associated with up-regulation of nerve growth factor (NGF) and requires the activation of tyrosine kinase receptor

that the majority of distension-sensitive fibers were located in the cardia, up to 5 mm from the gastro-esophageal junction. Baclofen decreased both basal (P<0.001) and distension-evoked activity of vagal afferent fibres, over the full range of volumes (2, 5 and 10 mls of air) and maximally at 10 mls by 40% (P<0.05, n = 7). 3-APPiA dose-dependently inhibited distension-evoked afferent firing frequency (P<0.001, n = 5). The effects of baclofen were reversed following treatment with the GABAe receptor antagonist CGP 62349 (7 #M). Neither baclofen nor 3-APPiA treatment significantly altered gastric compliance during distension. Conclusion: These results demonstrate a direct inhibitory role for GABAe receptors on vagal afferent responses to gastric distension. This may be a contributing mechanism to the efficacy of GABAe receptor agonists in their capacity to modulate TLESRs and reflux episodes. Supported by AstraZeneca.