Management of Acute Pancreatitis in the Pediatric Population: A Clinical Report From the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition Pancreas Committee

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 Pancreas committee performed a MEDLINE review using several preselected key terms relating to management considerations in adult and pediatric AP. The literature was summarized, quality of evidence reviewed, and statements of recommendations developed. The authorship met to discuss the evidence, statements, and voted on recommendations. A consensus of at least 75% was required to approve a recommendation. RESULTS:The diagnosis of pediatric AP should follow the published INternational Study Group of Pediatric Pancreatitis: In Search for a CuRE definitions (by meeting at least 2 out of 3 criteria: (1) abdominal pain compatible with AP, (2) serum amylase and/or lipase values ≥3 times upper limits of normal, (3) imaging findings consistent with AP). Adequate fluid resuscitation with crystalloid appears key especially within the first 24 hours. Analgesia may include opioid medications when opioid-sparing measures are inadequate. Pulmonary, cardiovascular, and renal status should be closely monitored particularly within the first 48 hours. Enteral nutrition should be started as early as tolerated, whether through oral, gastric, or jejunal route. Little evidence supports the use of prophylactic antibiotics, antioxidants, probiotics, and protease inhibitors. Esophago-gastro-duodenoscopy, endoscopic retrograde cholangiopancreatography, and endoscopic ultrasonography have limited roles in diagnosis and management. Children should be carefully followed for development of early or late complications and recurrent attacks of AP. CONCLUSIONS:This clinical report represents the first English-language recommendations for the management of pediatric AP. Future aims should include prospective multicenter pediatric studies to further validate these recommendations and optimize care for children with AP

In Vivo Delta Opioid Receptor Internalization Controls Behavioral Effects of Agonists

GPCRs regulate a remarkable diversity of biological functions, and are thus often targeted for drug therapies. Stimulation of a GPCR by an extracellular ligand triggers receptor signaling via G proteins, and this process is highly regulated. Receptor activation is typically accompanied by desensitization of receptor signaling, a complex feedback regulatory process of which receptor internalization is postulated as a key event. The in vivo significance of GPCR internalization is poorly understood. In fact, the majority of studies have been performed in transfected cell systems, which do not adequately model physiological environments and the complexity of integrated responses observed in the whole animal.In this study, we used knock-in mice expressing functional fluorescent delta opioid receptors (DOR-eGFP) in place of the native receptor to correlate receptor localization in neurons with behavioral responses. We analyzed the pain-relieving effects of two delta receptor agonists with similar signaling potencies and efficacies, but distinct internalizing properties. An initial treatment with the high (SNC80) or low (AR-M100390) internalizing agonist equally reduced CFA-induced inflammatory pain. However, subsequent drug treatment produced highly distinct responses. Animals initially treated with SNC80 showed no analgesic response to a second dose of either delta receptor agonist. Concomitant receptor internalization and G-protein uncoupling were observed throughout the nervous system. This loss of function was temporary, since full DOR-eGFP receptor responses were restored 24 hours after SNC80 administration. In contrast, treatment with AR-M100390 resulted in retained analgesic response to a subsequent agonist injection, and ex vivo analysis showed that DOR-eGFP receptor remained G protein-coupled on the cell surface. Finally SNC80 but not AR-M100390 produced DOR-eGFP phosphorylation, suggesting that the two agonists produce distinct active receptor conformations in vivo which likely lead to differential receptor trafficking.Together our data show that delta agonists retain full analgesic efficacy when receptors remain on the cell surface. In contrast, delta agonist-induced analgesia is abolished following receptor internalization, and complete behavioral desensitization is observed. Overall these results establish that, in the context of pain control, receptor localization fully controls receptor function in vivo. This finding has both fundamental and therapeutic implications for slow-recycling GPCRs

Trafficking of delta-opioid receptors and other G-protein-coupled receptors: implications for pain and analgesia.

A cell can regulate how it interacts with its external environment by controlling the number of plasma membrane receptors that are accessible for ligand stimulation. G-protein-coupled receptors (GPCRs) are the largest superfamily of cell surface receptors and have a significant role in physiological and pathological processes. Much research effort is now focused on understanding how GPCRs are delivered to the cell surface to enhance the number of 'bioavailable' receptors accessible for activation. Knowing how such processes are triggered or modified following induction of various pathological states will inevitably identify new therapeutic strategies for treating various diseases, including chronic pain. Here, we highlight recent advances in this field, and provide examples of the importance of such trafficking events in pain

FIERAsystem: a fire risk assessment tool to evaluate fire safety in industrial buildings and large spaces

FIERAsystem is a computer model for evaluating fire protection systems in industrial buildings. The model has been developed as a tool to assist fire protection engineers, building officials, fire service personnel and researchers in performing fire safety engineering calculations, and can be used to conduct hazard and risk analyses, as well as to evaluate whether a selected design satisfies established fire safety objectives. While the model is primarily designed for use in warehouses and aircraft hangars, it can be modified for application to other industrial buildings. This paper describes the framework for FIERAsystem, along with its capabilities and flexibility. Individual models used to perform calculations are discussed, particularly those that calculate fire development and life hazard. A hazard analysis of an aircraft hangar is then described in detail, as an example of the types of calculations this model can perform. Methods used by the model to conduct risk assessments are also briefly described.FIERAsystem est un mod\ue8le informatique con\ue7u pour \ue9valuer les syst\ue8mes de s\ue9curit\ue9-incendie dans les immeubles industriels. Le mod\ue8le est mis au point comme outil pour aider les ing\ue9nieurs en s\ue9curit\ue9-incendie, les responsables des b\ue2timents, le personnel des services d'incendie et les chercheurs \ue0 effectuer les calculs de l'ing\ue9nierie de la s\ue9curit\ue9-incendie, \ue0 effectuer des analyses des dangers et des risques et \ue0 d\ue9terminer si une conception donn\ue9e cadre ou non avec les objectifs arr\ueat\ue9s de la s\ue9curit\ue9-incendie. Bien que le mod\ue8le soit con\ue7u surtout pour les entrep\uf4ts et les hangars d'a\ue9rodromes, on peut le modifier et l'appliquer \ue0 d'autres immeubles industriels. Ce m\ue9moire d\ue9crit le cadre du FIERAsystem, ainsi que ses capacit\ue9s et sa souplesse. On d\ue9crit notamment des mod\ue8les particuliers servant \ue0 faire des calculs, surtout en rapport avec la propagation des incendies et le danger pour la vie. Ensuite, on pr\ue9sente une description d\ue9taill\ue9e de l'analyse des dangers qui peuvent se produire dans un hangar d'a\ue9rodrome, comme exemple des types de calculs que ce mod\ue8le peut permettre d'effectuer. On trouvera \ue9galement une br\ue8ve description des m\ue9thodes que le mod\ue8le emploie pour effectuer des analyses de risques.Peer reviewed: YesNRC publication: Ye

The Roles of Endoscopic Ultrasound and Endoscopic RetroNorthwell Healthe Cholangiopancreatography in the Evaluation and Treatment of Chronic Pancreatitis in Children: A Position Paper From the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Pancreas Committee.

INTRODUCTION:Pediatric chronic pancreatitis is increasingly diagnosed. Endoscopic methods [endoscopic ultrasound (EUS), endoscopic retroNorthwell Healthe cholangiopancreatography (ERCP)] are useful tools to diagnose and manage chronic pancreatitis. Pediatric knowledge and use of these modalities is limited and warrants dissemination. METHODS:Literature review of publications relating to use of ERCP and EUS for diagnosis and/or management of chronic pancreatitis with special attention to studies involving 0--18 years old subjects was conducted with summaries generated. Recommendations were developed and voted upon by authors. RESULTS:Both EUS and ERCP can be used even in small children to assist in diagnosis of chronic pancreatitis in cases where cross-sectional imaging is not sufficient to diagnose or characterize the disease. Children under 15 kg for EUS and 10 kg for ERCP can be technically challenging. These procedures should be done optimally by appropriately trained endoscopists and adult gastroenterology providers with appropriate experience treating children. EUS and ERCP-related risks both include perforation, bleeding and pancreatitis. EUS is the preferred diagnostic modality over ERCP because of lower complication rates overall. Both modalities can be used for management of chronic pancreatitis -related fluid collections. ERCP has successfully been used to manage pancreatic duct stones. CONCLUSION:EUS and ERCP can be safely used to diagnose chronic pancreatitis in pediatric patients and assist in management of chronic pancreatitis-related complications. Procedure-related risks are similar to those seen in adults, with EUS having a safer risk profile overall. The recent increase in pediatric-trained specialists will improve access of these modalities for children

Morphine-induced changes in delta opioid receptor trafficking are linked to somatosensory processing in the rat spinal cord.

An in vivo fluorescent deltorphin (Fluo-DLT) internalization assay was used to assess the distribution and regulation of pharmacologically available delta opioid receptors (deltaORs) in the rat lumbar (L4-5) spinal cord. Under basal conditions, intrathecal injection of Fluo-DLT resulted in the labeling of numerous deltaOR-internalizing neurons throughout dorsal and ventral horns. The distribution and number of Fluo-DLT-labeled perikaryal profiles were consistent with that of deltaOR-expressing neurons, as revealed by in situ hybridization and immunohistochemistry, suggesting that a large proportion of these cells was responsive to intrathecally administered deltaOR agonists. Pretreatment of rats with morphine for 48 hr resulted in a selective increase in Fluo-DLT-labeled perikaryal profiles within the dorsal horn. These changes were not accompanied by corresponding augmentations in either deltaOR mRNA or (125)I-deltorphin-II binding levels, suggesting that they were attributable to higher densities of cell surface deltaOR available for internalization rather than to enhanced production of the receptor. Unilateral dorsal rhizotomy also resulted in increased Fluo-DLT internalization in the ipsilateral dorsal horn when compared with the side contralateral to the deafferentation or to non-deafferented controls, suggesting that deltaOR trafficking in dorsal horn neurons may be regulated by afferent inputs. Furthermore, morphine treatment no longer increased Fluo-DLT internalization on either side of the spinal cord after unilateral dorsal rhizotomy, indicating that microOR-induced changes in the cell surface availability of deltaOR depend on the integrity of primary afferent inputs. Together, these results suggest that regulation of deltaOR responsiveness through microOR activation in this region is linked to somatosensory information processing