Recurrent Acute Pancreatitis: International State-of-the-Science Conference With Recommendations

Recurrent acute pancreatitis (RAP) is a clinically significant problem globally. The etiology remains unclear in approximately 10% to 15% of patients despite a thorough workup. Data on natural history and efficacy of treatments are limited. We aimed to establish criteria for diagnosis, evaluate the causative factors, and arrive at a consensus on the appropriate workup and management of patients with RAP. The organizing committee was formed, and a set of questions was developed based on the current evidence, controversies, and topics that needed further research. After a vetting process, these topics were assigned to a group of experts from around the world with special interest in RAP. Data were presented as part of a workshop on RAP organized as a part of the annual meeting of the America Pancreatic Association. Pretest and Posttest questions were administered, and the responses were tabulated by the current Grades of Recommendation Assessment, Development and Evaluation system. The consensus guidelines were established in the format of a diagnostic algorithm. Several deficiencies were identified with respect to data on etiology, treatment efficacies, and areas that need immediate research

A novel gene delivery method transduces porcine pancreatic duct epithelial cells.

Gene therapy offers the possibility to treat pancreatic disease in cystic fibrosis (CF), caused by mutations in the CF transmembrane conductance regulator (CFTR) gene; however, gene transfer to the pancreas is untested in humans. The pancreatic disease phenotype is very similar between humans and pigs with CF; thus, CF pigs create an excellent opportunity to study gene transfer to the pancreas. There are no studies showing efficient transduction of pig pancreas with gene-transfer vectors. Our objective is to develop a safe and efficient method to transduce wild-type (WT) porcine pancreatic ducts that express CFTR. We catheterized the umbilical artery of WT newborn pigs and delivered an adeno-associated virus serotype 9 vector expressing green-fluorescent protein (AAV9CMV.sceGFP) or vehicle to the celiac artery, the vessel that supplies major branches to the pancreas. This technique resulted in stable and dose-dependent transduction of pancreatic duct epithelial cells that expressed CFTR. Intravenous (IV) injection of AAV9CMV.sceGFP did not transduce the pancreas. Our technique offers an opportunity to deliver the CFTR gene to the pancreas of CF pigs. The celiac artery can be accessed via the umbilical artery in newborns and via the femoral artery at older ages--delivery approaches that can be translated to humans.

Effect of peroxynitrite on motor function of the opossum esophagus.

Nitric oxide (NO*) is a mediator of esophageal motility. Esophageal dysmotility accompanies esophagitis. During inflammation, superoxide and NO* form peroxynitrite (ONOO-), a reactive molecule that alters cellular function. We tested the hypotheses that ONOO- affects esophageal motility and is produced in association with esophagitis. Transverse muscle strips from the opossum esophagus were stimulated by an electrical field, and nitrotyrosine immunoblots were performed. Peroxynitrite, its decomposed form, or NaNO2 relaxed the lower esophageal sphincter (LES) and attenuated the off response. These effects were inhibited by oxyhemoglobin (Hgb). An antagonist of guanylate cyclase, 1H[1,2,4]oxadiazole[4,3]quinoxalin-1-one (ODQ), inhibited the LES relaxation produced by ONOO-. Nitrotyrosine, a footprint for ONOO- production, was detected in inflamed esophagus. These studies support the hypotheses that ONOO alters esophageal motor function and is formed in association with esophagitis. It is possible that some of the esophageal motor dysfunction seen with esophagitis may be related to the formation of ONOO-.

Camphor hepatotoxicity.

We report a case of hepatotoxicity in a 2-month-old baby after a camphor-containing cold remedy was applied dermally. Liver function tests returned to normal after the application of the cold remedy was discontinued. Ingestion of camphor can cause severe liver and central nervous system injury, and neurotoxicity has been observed after exposure to camphor through the skin. Hepatotoxicity after dermal application of camphor has never been reported. This report emphasizes the common use of cold remedies that are usually not beneficial and may be potentially dangerous.

Biphasic relaxation of the opossum lower esophageal sphincter: roles of NO., VIP, and CGRP.

Vasoactive intestinal polypeptide (VIP) and nitric oxide (NO.) are thought to mediate lower esophageal sphincter (LES) relaxation. Transverse muscle strips from the opossum LES were used to test this hypothesis. Electrical field stimulation (EFS) produced a biphasic LES relaxation: a rapid component during the stimulus was more prominent at lower stimulus frequencies, and a sustained component was more prominent at higher frequencies. N(omega)-nitro-L-arginine and hemoglobin inhibited the rapid component but affected the sustained component less. Exogenous VIP decreased LES tone. A number of purported VIP antagonists blocked neither VIP-induced nor EFS-induced relaxation of the LES. The calcitonin gene-related peptide (CGRP) antagonist CGRP-(8-37) did not alter EFS-induced LES relaxation. EFS-induced relaxation of opossum LES muscle is biphasic, and the initial, rapid component of the relaxation is mediated primarily by NO. The mediator of the sustained component was not identified.

Gastric volvulus and wandering spleen.

Although rare in childhood, gastric volvulus and wandering spleen share a common etiology: congenital absence of intraperitoneal visceral attachments. We report an unusual case of a patient who presented with three episodes of intractable vomiting and abdominal mass but no abdominal pain. A diagnosis could not be made until the third episode because the gastric volvulus resolved each time on placement of a nasogastric (NG) tube before any further tests could be done. During the third episode, diagnostic imaging was performed before inserting an NG tube, and the diagnosis of a mesenteroaxial gastric volvulus and an abnormally positioned spleen was made. Although both conditions are caused by abnormalities of fixation, the association of gastric volvulus and wandering spleen has been reported only once before.

Effects of calcitonin gene-related peptide on opossum esophageal smooth muscle.

BACKGROUND & AIMS: Peristaltic contraction of the esophagus and relaxation of the lower esophageal sphincter (LES) are mediated by nitric oxide (NO.)-producing myenteric nerves. NO synthase immunoreactivity and calcitonin gene-related peptide (CGRP) immunoreactivity colocalize in these nerves. CGRP relaxes the LES and decreases the amplitude of esophageal peristalsis. The aim of this study was to test the hypothesis that CGRP plays a role in nerve-induced responses of the esophagus. METHODS: Smooth muscle strips from the LES and the body of the esophagus were stimulated by an electrical field to evoke nerve-mediated responses. RESULTS: CGRP decreased the amplitude and lengthened the latency of the off-response, and it relaxed the LES. Tetrodotoxin did not block the CGRP-induced LES relaxation. The CGRP antagonist CGRP 8-37 inhibited the effects of exogenous CGRP. It increased the amplitude and shortened the latency of the off-response, and it increased the resting tone of the LES. CGRP 8-37 did not inhibit LES relaxation or esophageal contraction. N omega-nitro-L-arginine abolished nerve-induced relaxation of the LES muscle and the esophageal off-response but not the relaxation produced by CGRP. CONCLUSIONS: These data support the hypothesis that CGRP may decrease the LES basal tone and modulate the timing and amplitude of the esophageal off-responses.

Antroduodenal manometry in children with no upper gastrointestinal symptoms.

BACKGROUND: The interpretation of antroduodenal manometry in children with gastrointestinal motility disorder has been limited by a paucity of data from normal children. The purpose of this study was to define antroduodenal manometry findings in children with no upper gastrointestinal symptoms. METHODS: We reviewed 260 consecutive antroduodenal manometries and selected 18 studies from subjects aged 2-12 years with no symptoms referable to a gastrointestinal motility disorder involving the stomach and/or the small bowel. RESULTS: During fasting, phase 3 of the migrating motor complex (MMC) was present in 14 of 18 children, and it was induced by erythromycin in 4 who failed to have a spontaneous phase 3. Phase 3 propagation velocity increased significantly with age. The cycle length between MMCs showed no age-dependent variation. Phase 3 occupied 3%; phase 1, 10%; and phase 2, 87% of the fasting recording time. CONCLUSIONS: Antroduodenal manometry findings in children with no upper gastrointestinal symptoms are similar to those in adults.

Chronic intestinal pseudoobstruction associated with fetal alcohol syndrome.

Alcohol acts as a teratogen in the fetus, resulting in prenatal or postnatal growth failure, characteristic facial dysmorphic features, and central nervous system dysfunction. The toxic effects of alcohol on the developing brain are well recognized, but gastrointestinal neuropathy has not been described in fetal alcohol syndrome (FAS). Five children with FAS presented in infancy with signs and symptoms suggestive of chronic intestinal pseudoobstruction. They were not able to sustain adequate caloric intake by mouth, and all required prolonged special methods of alimentation. We performed antroduodenal manometry in these children to determine whether their symptoms were associated with a gastrointestinal motility disorder. All patients had abnormally propagating phase III-like episodes during fasting (retrograde in four, simultaneous in two). Persistent clusters of stationary contractions were a prominent feature in two patients. In utero neurotoxicity of alcohol may not be limited to the central nervous system, but may also cause an enteric neuropathy presenting in infancy as chronic intestinal pseudoobstruction.

Analysis of fasting antroduodenal manometry in children.

Antroduodenal manometry has been used to determine the pathophysiology associated with signs and symptoms of gastrointestinal motility disorders. The diagnostic value of antroduodenal manomentry has been limited by the paucity of data from normal children. In this study, we compared antroduodenal manometry findings from 95 patients with symptoms suggesting a gastrointestinal motility disorder to 20 control children. Phase III of the migrating motor complex (MMC) was less frequent in patients (P < 0.05), especially in those who required total parenteral nutrition (P < 0.001), than in controls. Abnormal migration of phase III and short intervals between phase IIIs were more frequent in patients than in controls (P < 0.01 and P < 0.05, respectively). During phase II, persistent low-amplitude contractions and sustained tonic-phasic contraction were found only in parenteral-nutrition-dependent children. Short or prolonged duration of phase III, absence of phase I following phase III, tonic contractions during phase III, low amplitude of phase III contractions in a single recording site and clusters of contractions or prolonged propagating contractions during phase II were not more frequent in patients than in controls. We conclude that there are five manometric features having a clear association with pediatric gastrointestinal motility disorders: (1) absence of phase III of the MMC, (2) abnormal migration of phase III, (3) short intervals between phase III episodes, (4) persistent low-amplitude contractions, and (5) sustained tonic-phasic contractions.