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This position paper summarizes the current understanding of the medical management of chronic pancreatitis (CP) in children in light of the existing medical literature, incorporating recent advances in understanding of nutrition, pain, lifestyle considerations, and sequelae of CP. This article complements and is intended to integrate with parallel position papers on endoscopic and surgical aspects of CP in children. Concepts and controversies related to pancreatic enzyme replacement therapy (PERT), the use of antioxidants and other CP medical therapies are also reviewed. Highlights include inclusion of tools for medical decision-making for PERT, CP-related diabetes, and multimodal pain management (including an analgesia ladder). Gaps in our understanding of CP in children and avenues for further investigations are also reviewed.

PACAP was discovered 30 years ago in Dr. Akira Arimura's laboratory. In the past three decades since then, it has become evident that this peptide plays numerous crucial roles in mammalian organisms. The most important functions of PACAP are the following: 1. neurotransmitter, 2. neuromodulator, 3. hypophysiotropic hormone, 4. neuroprotector. This paper reviews the accumulated data regarding the distribution of PACAP and its receptors in the mammalian hypothalamus and pituitary gland, the role of PACAP in the gonadotropin hormone secretion of females and males. The review also summarizes the interaction between PACAP, GnRH, and sex steroids as well as hypothalamic peptides including kisspeptin. The possible role of PACAP in reproductive functions through the biological clock is also discussed. Finally, the significance of PACAP in the hypothalamo-hypophysial system is considered and the facts missing, that would help better understand the function of PACAP in this system, are also highlighted.

Background:Although the incidence of acute pancreatitis (AP) in children is increasing, management recommendations rely on adult published guidelines. Pediatric-specific recommendations are needed.Methods:The North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pan

Background. No licensed cholera vaccine is presently available in the United States. Cholera vaccines available in other countries require 2 spaced doses. A single-dose cholera vaccine that can rapidly protect short-notice travelers to high-risk areas and help control explosive outbreaks where logistics render 2-dose immunization regimens impractical would be a major advance. PXVX0200, based on live attenuated Vibrio cholerae O1 classical Inaba vaccine strain CVD 103-HgR, elicits seroconversion of vibriocidal antibodies (a correlate of protection) within 10 days of a single oral dose. We investigated the protection conferred by this vaccine in a human cholera challenge model. Methods. Consenting healthy adult volunteers, 18–45 years old, were randomly allocated 1:1 to receive 1 oral dose of vaccine (approximately 5 × 108 colony-forming units [CFU]) or placebo in double-blind fashion. Volunteers ingested approximately 1 × 105 CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961 10 days or 3 months after vaccination and were observed on an inpatient research ward for stool output measurement and management of hydration. Results. The vaccine was well tolerated, with no difference in adverse event frequency among 95 vaccinees vs 102 placebo recipients. The primary endpoint, moderate (≥3.0 L) to severe (≥5.0 L) diarrheal purge, occurred in 39 of 66 (59.1%) placebo controls but only 2 of 35 (5.7%) vaccinees at 10 days (vaccine efficacy, 90.3%; P < .0001) and 4 of 33 (12.1%) vaccinees at 3 months (vaccine efficacy, 79.5%; P < .0001). Conclusions. The significant vaccine efficacy documented 10 days and 3 months after 1 oral dose of PXVX0200 supports further development as a single-dose cholera vaccine. Clinical Trials Registration. {"type":"clinical-trial","attrs":{"text":"NCT01895855","term_id":"NCT01895855"}}NCT01895855

Background Pediatric pancreatitis is an underdiagnosed disease with variable etiology. In the past 10–15 years the incidence of pediatric pancreatitis has increased, it is now 3.6–13.3 cases per 100,000 children. Up-to-date evidence based management guidelines are lacking for the pediatric pancreatitis. The European Pancreatic Club, in collaboration with the Hungarian Pancreatic Study Group organized a consensus guideline meeting on the diagnosis and management of pancreatitis in the pediatric population. Methods Pediatric Pancreatitis was divided into three main clinical categories: acute pancreatitis, acute recurrent pancreatitis and chronic pancreatitis. Fifteen relevant topics (acute pancreatitis: diagnosis; etiology; prognosis; imaging; complications; therapy; biliary tract management; acute recurrent pancreatitis: diagnosis; chronic pancreatitis: diagnosis, etiology, treatment, imaging, intervention, pain, complications; enzyme replacement) were defined. Ten experts from the USA and Europe reviewed and summarized the available literature. Evidence was classified according to the GRADE classification system. Results Within fifteen topics, forty-seven relevant clinical questions were defined. The draft of the updated guideline was presented and discussed at the consensus meeting held during the 49th Meeting of European Pancreatic Club, in Budapest, on July 1, 2017. Conclusions These evidence-based guidelines provides the current state of the art of the diagnosis and management of pediatric pancreatitis.

Pediatric pancreatitis is a rare disease with variable etiology. In the past 10-15 years the incidence of pediatric pancreatitis has been increased. The management of pediatric pancreatitis requires up-to-date and evidence based management guidelines. The Hungarian Pancreatic Study Group proposed to prepare an evidence based guideline based on the available international guidelines and evidences. The preparatory and consultation task force appointed by the Hungarian Pancreatic Study Group translated and complemented and/or modified the international guidelines if it was necessary. In 8 clinical topics (diagnosis; etiology; prognosis; imaging; therapy; biliary tract management; complications; chronic pancreatitis) 50 relevant questions were defined. Evidence was classified according to the UpToDate(®) grading system. The draft of the guidelines was presented and discussed at the consensus meeting on September 12, 2014. All clinical statements were accepted with total (more than 95%) agreement. The present Hungarian Pancreatic Study Group guideline is the first evidence based pediatric pancreatitis guideline in Hungary. The present guideline is the first evidence-based pancreatic cancer guideline in Hungary that provides a solid ground for teaching purposes, offers quick reference for daily patient care in pediatric pancreatitis and guides financing options. The authors strongly believe that these guidelines will become a standard reference for pancreatic cancer treatment in Hungary.A hasnyálmirigy gyulladásos megbetegedése gyermekkorban ritka és etiológiája változatos. Az utóbbi 10–15 évben a gyermekkori pancreatitisek gyakorisága növekedést mutatott világszerte. A betegség korszerű és bizonyítékokon alapuló kezelési útmutatót igényel. A Magyar Hasnyálmirigy Munkacsoport célul tűzte ki, hogy a jelenleg elérhető nemzetközi irányvonalakat, illetve evidenciákat alapul véve a gyermekkori pancreatitis kezelésének kulcskérdései vonatkozásában bizonyítékalapú irányelveket fogalmazzon meg. A Magyar Hasnyálmirigy Munkacsoport által kijelölt előkészítő és konzulens munkacsoport lefordította, és ahol szükségesnek találta, kiegészítette és/vagy módosította a nemzetközi irányelveket. Összesen 8 témakörben (Diagnózis, Etiológia, Prognózis, Képalkotók, Kezelés, Epeúti beavatkozás, Szövődmények, Krónikus pancreatitis) 50 releváns kérdést állított össze. Az evidencia osztályozását az UpToDate® rendszere alapján határozta meg. Az összeállított irányelvek a 2014. szeptember 12-ei konszenzustalálkozón kerültek bemutatásra és megvitatásra. A résztvevők minden kérdést teljes (95% feletti) egyetértéssel fogadtak el. A Magyar Hasnyálmirigy Munkacsoport kezelési irányelvei az első, bizonyíték alapján készült gyermekkori pancreatitis kezelési útmutató hazánkban. A Magyar Hasnyálmirigy Munkacsoport gyermekkori pancreatitis kezelési irányelvei komoly segítséget nyújtanak a gyermekkori pancreatitis oktatásához, a mindennapi betegellátáshoz és a megfelelő finanszírozás kialakításához, ezért bízunk benne, hogy ezen irányelvek minél szélesebb körben alapreferenciaként fognak szolgálni Magyarországon. Orv. Hetil., 2015, 156(8), 308–325.

Acute pancreatitis (AP) is an emerging problem in pediatrics, with most cases resolving spontaneously. Approximately 10% to 30%, however, are believed to develop "severe acute pancreatitis" (SAP).This consensus statement on the classification of AP in pediatrics was developed through a working group that performed an evidence-based search for classification of AP in adult pancreatitis, definitions and criteria of systemic inflammatory response syndrome, and organ failure in pediatrics.Severity in pediatric AP is classified as mild, moderately severe, or severe. Mild AP is defined by AP without organ failure, local or systemic complications, and usually resolves in the first week. Moderately SAP is defined by the presence of transient organ failure that resolves in no48 hours, or local complications or exacerbation of co-morbid disease. SAP is defined by persistent organ failure that lasts48 hours. The presence of systemic inflammatory response syndrome is associated with increased risk for persistent organ dysfunction. Criteria to define organ failure must be pediatric- and age-based.Classifying AP in pediatrics in a uniform fashion will help define outcomes and encourage the development of future studies in the field of pediatric pancreatitis.

PACAP (ADCYAP1) was isolated from ovine hypothalami. PACAP activates three distinct receptor types: G-protein coupled PAC1, VPAC1, and VPAC2 with seven transmembrane domains. Eight splice variants of PAC1 receptor are described. A part of the hypothalamic PACAP is released into the hypophyseal portal circulation. Both hypothalamic and pituitary PACAP are involved in the dynamic control of gonadotropic hormone secretion. In female rats, PACAP in the paraventricular nucleus is upregulated in the morning and pituitary PACAP is upregulated in the late evening of the proestrus stage of the reproductive cycle. PACAP mRNA peak in the hypothalamic PVN precedes the LHRH release into the portal circulation. It is supposed that PACAP peak is evoked by the elevated estrogen on proestrous morning. At the beginning of the so-called critical period of the same day, PACAP level starts to decline allowing LHRH release into the portal circulation, resulting in the LH surge that evokes ovulation. Just before the critical period, icv-administered exogenous PACAP blocks the LH surge and ovulation. The blocking effect of PACAP is mediated through CRF and endogenous opioids. The effect of the pituitary-born PACAP depends on the intracellular cross-talk between PACAP and LHRH.

The aim of experiments was to characterize the neurons of the autonomic chain that innervates the nipple and the mammary gland of lactating rats using retrograde transynaptic virus labeling and neurotransmitter and neuropeptide immunohistochemistry. Two days after injection of green fluorescence protein labeled virus in two nipples and underlying mammary glands, labeling was observed in the ipsilateral paravertebral sympathetic trunk and the lateral horn. Three days after inoculation the labeling appeared in the brain stem and the hypothalamic paraventricular nucleus. Above the spinal cord the labeling was bilateral. A subpopulation of virus labeled cells in the paraventricular nuclei synthesized oxytocin. Labeled neurons in the lateral horn showed cholinergic immunoreactivity. These cholinergic neurons innervated the paravertebral ganglia where the virus labeled neurons were partially noradrenergic. The noradrenergic fibers in the mammary gland innervate the smooth muscle wall of vessels, but not the mammary gland in rats. The neurons in the lateral horn receive afferents from the brain stem, and paraventricular nucleus and these afferents are noradrenergic and oxytocinergic. New findings in our work: Some oxytocinergic fibers may descend to the neurons of the lateral horn which innervate noradrenergic neurons in the paravertebral sympathetic trunk, and in turn these noradrenergic neurons reach the vessels of the mammary gland.

Dopamine (DA) and enkephalin (ENK) release from the tuberoinfundibular dopaminergic neurons (TIDA) into the hypophysial portal circulation is fundamentally different under non-lactating and lactating conditions. The aim of this experiment was to compare the effect of a brief interruption then resumption of suckling on the temporal program of tyrosine hydroxylase (TH; rate-limiting enzyme of dopamine synthesis) and ENK regulation in dams. On post partum day 10, pups were removed for a 4-h period from a group of the dams then returned for 4- and 24-h periods. It was examined whether such a brief interruption of suckling provokes full up-regulation of TH and down-regulation of ENK, and whether reinitiation of suckling limits the extent to which TH up- and ENK down-regulate. At the end of experiment, the animals were decapitated. In situ hybridization was used to examine the expression of TH and ENK mRNA in the arcuate nucleus where TIDA neurons reside. The results showed that, on one hand, the removal of pups induced TH up-regulation, on the other hand, ENK expression also increased 8 h after removal of pups and then started to slowly decline. In dams whose sucklings were reinitiated both TH and ENK mRNAs were up-regulated at least for a day. ENK expression responded more slowly to the removal of pups than expression of TH, and after reinitiation of suckling, the temporal program of regulation of both TH and ENK expressions ran parallel in the first 24 h.

Background/Objectives Approximately 15–20% of pediatric patients with acute pancreatitis (AP) develop severe disease. Severity scoring tools were developed for adult patients, but have limitations when applied in children. We aimed to identify early predictors of severe acute pancreatitis (SAP) on hospital admission for early risk stratification of patients. Methods Retrospective review of AP admissions was conducted. The derivation cohort included cases at Cincinnati Children's Hospital Medical Center (CCHMC) between 2009 and 2013. Clinical data collected during the first 24 h of admission were analyzed and a predictive model was derived through statistical analysis. The performance of the model was evaluated in a validation cohort from 2 more institutions other than CCHMC. Results In the derivation cohort 19% of the 284 admissions were SAP. A generalized linear mixed effect model analysis revealed that lipase, albumin and white blood count (WBC) play a role in the development of SAP (area under the receiver operating curve (AUROC 0.76)). In the validation cohort of 165 AP cases, SAP ranged from 8 to 20% at the three institutions. Performance of the model in this cohort was comparable to the derivation model (AUROC 0.77). There were 369 encounters in the combined derivation and validation pool (AUROC 0.76). Conclusions The prognostic severity tool with 3 variables (lipase, albumin, and WBC) obtained within 24 h of admission can be applied to predict SAP in pediatric patients.

Objectives To determine whether recommendations for treatment of acute pancreatitis (AP) in adults impact the outcomes of pediatric AP. Study design Adult guidelines regarding early management of AP were implemented through an admission order set at Cincinnati Children's Hospital Medical Center at the beginning of the year 2014. Recommendations included administering high rates of intravenous fluid (IVF) within 24 hours of admission and enteral nutrition within 48 hours of admission. A retrospective chart review of AP admissions before and after the implementation of the recommendations was undertaken. Outcomes studied were: hospital length of stay, intensive care unit transfer rates, development of severe AP, pulmonary complications, and readmission rates post discharge from the hospital. Results The study included 201 patients. Children who received feeds within the first 48 hours and received greater than maintenance IVF within 24 hours had a shorter length of stay, less intensive care unit admissions and severe AP rates compared with the patients who remained nil per os during the first 48 hours and received lower rates of IVF. Conclusion Our data support that early enteral nutrition and early aggressive IVF improve outcomes of pediatric AP.

The onset of puberty is a concerted action of many factors which leads to cyclic LHRH release in rats. It has been demonstrated that; in common with vasoactive intestinal polypeptide (VIP), pituitary adenylate cyclase activating polypeptide (PACAP) is also involved in the differentiation of the central nervous system. In our previous work, it was shown that a single PACAP injection into neonatal female rats delayed puberty. In the present work, neonatal administration of PACAP delayed the vaginal opening and decreased the weight of anterior pituitaries, the number of expelled ova at the first ovulation and the intensity of LHRH immunostaining in the septo-preoptico-infundibular system. PACAP antiserum had a reverse effect on LHRH immunoreactivity. The other studied parameters in the latter group remained unchanged compared to control rats. It was concluded that neonatal PACAP administration delayed the onset of puberty through the influence of the LHRH neuronal system.

The presence of pituitary adenylate cyclase-activating polypeptide (PACAP) and its mRNA in the three levels of the hypothalamo-hypophyseal-ovarian axis was previously demonstrated using immunohistochemistry, in situ hybridization, and reverse transcriptase polymerase chain reaction (RT-PCR). In the hypothalamus, PACAP is present in neuroendocrine effector cells and in the median eminence. In the anterior pituitary and ovary, PACAP is transiently present during the proestrous stage of the estrous cycle. In the pituitary, PACAP was observed in gonadotropes. In the ovary, PACAP was demonstrated in the granulosa cells of the preovulatory ovarian follicles. The effect of PACAP on luteinizing hormone (LH) secretion was demonstrated in in vivo and in vitro models. In our work we have studied the role of PACAP in gonadotropic hormone secretion at hypothalamic and pituitary levels. At the hypothalamic level, PACAP, administered intracerebroventricularly to female rats before the critical period of the proestrus stage, can inhibit LH release and ovulation. Its inhibiting effect is mediated through corticotropin-releasing factor (CRF) and endogenous opioids. PACAP administered to neonatal female rats delayed the onset of puberty by influencing the luteinizing hormone-releasing hormone (LHRH) neuronal system. In the pituitary gland, the release of PACAP depended on the stage of the estrous cycle and on the time of day the animals were sacrificed. On the day of proestrus, the number of PACAP-releasing cells showed a diurnal change with two peaks (in the morning and in the evening). The peak was much higher in the evening at the end of the LH surge than in the morning.