History of WOFAPS (1963-2019).

The formation of the World Federation of Associations of Pediatric Surgery (WOFAPS) was an important unifying force in the emergence of pediatric surgery as a distinct specialty. Beginning with the formation of several national societies in the early '60s, an early, multinational effort was created. This was in large part fostered by the International Pediatric Association (IPA), which lent logistical support from the medical pediatric community to the pediatric surgeons. In 2001, the mission of the Federation was formalized to focus on the development and education of surgeons serving children, in all parts of the world. This was articulated in the famous Kyoto Declaration of Pediatric Surgery: "Every infant and child who suffers from an illness or disease has the right to be treated in an environment devoted to their care by a pediatric medical or surgical specialist". This vision was unique at the time and foreshadowed the major increase in advocacy activity which has emerged in recent years. While the mission has evolved with time, the present organization continues to hold true to the guiding principles of the original founders and seeks to improve the quality of "Surgical Care for the child, no matter where they live". Education and collaboration across borders underpins the organization's endeavors.

Pathophysiology, prevention, treatment, and outcomes of intestinal failure-associated liver disease.

BACKGROUND: Intestinal failure-associated liver disease (IFALD) remains a serious problem in the treatment of infants with nutritional problems and short bowel syndrome. METHODS: A review of the recent literature from 2010 to 2016, concentrating on articles related to the pathophysiology of IFALD and to outcomes of novel nutritional and pharmacological therapies for neonatal cholestasis in the post-surgical neonate. RESULTS: The pathophysiology of IFALD relates to an increase sensitivity of the neonatal liver to cholestasis in the non-fed state; prolonged cholestasis almost inevitably results in liver damage which will progress from fibrosis to cirrhosis. Clinically discerned risk factors include premature birth, inflammation, sepsis, disruption of the enterohepatic circulation by creation of a proximal stoma, and the duration and type of parenteral nutritional support. Within the hepatocyte, the regulatory enzyme farsanoid receptor X (FXR) appears to play a pivotal role in the development of cholestasis. Recent studies have shown that its activity is suppressed by sepsis, and by plant phytosterols found in soy-based lipid preparations. This paradigm is reflected in the emerging consensus for the care of post-surgical neonates, which is based around a multi-disciplinary team approach. Using an algorithm-driven approach, an appropriate balance between caloric support and prevention of IFALD can be achieved. CONCLUSIONS: Further prospective studies are required to further refine the optimal sequence of use of these therapies and the long-term effects on neurological development and hepatic function. However, with optimal care, the number of IF patients progressing to end-stage liver disease because of IFALD should be very low.

Animal models of gastrointestinal and liver diseases. Animal models of infant short bowel syndrome: translational relevance and challenges.

Intestinal failure (IF), due to short bowel syndrome (SBS), results from surgical resection of a major portion of the intestine, leading to reduced nutrient absorption and need for parenteral nutrition (PN). The incidence is highest in infants and relates to preterm birth, necrotizing enterocolitis, atresia, gastroschisis, volvulus, and aganglionosis. Patient outcomes have improved, but there is a need to develop new therapies for SBS and to understand intestinal adaptation after different diseases, resection types, and nutritional and pharmacological interventions. Animal studies are needed to carefully evaluate the cellular mechanisms, safety, and translational relevance of new procedures. Distal intestinal resection, without a functioning colon, results in the most severe complications and adaptation may depend on the age at resection (preterm, term, young, adult). Clinically relevant therapies have recently been suggested from studies in preterm and term PN-dependent SBS piglets, with or without a functional colon. Studies in rats and mice have specifically addressed the fundamental physiological processes underlying adaptation at the cellular level, such as regulation of mucosal proliferation, apoptosis, transport, and digestive enzyme expression, and easily allow exogenous or genetic manipulation of growth factors and their receptors (e.g., glucagon-like peptide 2, growth hormone, insulin-like growth factor 1, epidermal growth factor, keratinocyte growth factor). The greater size of rats, and especially young pigs, is an advantage for testing surgical procedures and nutritional interventions (e.g., PN, milk diets, long-/short-chain lipids, pre- and probiotics). Conversely, newborn pigs (preterm or term) and weanling rats provide better insights into the developmental aspects of treatment for SBS in infants owing to their immature intestines. The review shows that a balance among practical, economical, experimental, and ethical constraints will determine the choice of SBS model for each clinical or basic research question.

Exogenous glucagon-like peptide-2 improves outcomes of intestinal adaptation in a distal-intestinal resection neonatal piglet model of short bowel syndrome.

BACKGROUND: Endogenous glucagon-like peptide-2 (GLP-2) levels and intestinal adaptation are reduced in distal-intestinal resection animal models of short bowel syndrome (SBS) that lack remnant ileum. We hypothesized that exogenous GLP-2 would improve intestinal adaptation in a distal-intestinal resection neonatal piglet model of SBS. METHODS: In all, 35 piglets were randomized to 2 treatment and 3 surgical groups: control (sham), 75% mid-intestinal resection (JI), and 75% distal-intestinal resection (JC). Parenteral nutrition (PN) commenced on day 1 and was weaned as enteral nutrition (EN) advanced. IV GLP-2 (11 nmol/kg/d) or saline was initiated on day 2. Piglets were maintained for 14 d. Clinical, functional, morphological, and histological outcomes were obtained. RESULTS: JC-GLP-2 piglets had fewer days on PN (10.0 ± 0.6 vs. 13.8 ± 0.2), more days on EN (4.0 ± 0.6 vs. 0.2 ± 0.2), a higher percentage of EN at termination (92 ± 5 vs. 52 ± 10%), fewer days of diarrhea (8.0 ± 0.7 vs. 12.3 ± 0.4), increased intestinal length (19 ± 4 vs. -5 ± 3%), and deeper jejunal crypts (248 ± 21 vs. 172 ± 12 µm), compared with saline piglets. CONCLUSION: GLP-2 therapy improves clinical, morphological, and histological outcomes of intestinal adaptation in a distal-intestinal resection model of SBS. Since this anatomical subtype represents the majority of clinical cases of neonatal SBS, these results support a potential role for GLP-2 therapy in pediatric SBS.

Role of glucagon-like peptide-2 deficiency in neonatal short-bowel syndrome using neonatal piglets.

BACKGROUND: Short-bowel syndrome (SBS) is the most common cause of neonatal intestinal failure. Recovery requires intestinal adaptation, dependent on enteral nutrition (EN) and growth factors such as glucagon-like peptide-2 (GLP-2), which is secreted from L cells in the ileum. Neonatal SBS often results in loss of ileum; therefore, we hypothesized that without ileum, endogenous GLP-2 production would be inadequate to promote adaptation. We compared endogenous GLP-2 production and adaptation in neonatal animals with SBS, with and without ileum. METHODS: Neonatal piglets (4-6 d) were randomized to 75% mid-intestinal resection, 75% distal-intestinal resection, or sham control without resection. Postoperatively, all piglets commenced parenteral nutrition (PN), tapering as EN was increased to maintain specific growth. RESULTS: The resected SBS piglets developed intestinal failure, requiring a longer duration of PN support and experiencing fat malabsorption. The piglets without ileum were not able to wean from PN during the study and did not show adaptation, specifically growth in intestinal length or crypt hyperplasia on histology of the jejunum. Adaptation was observed in the resected SBS piglets with ileum, and these piglets also had an increased plasma GLP-2 level that was not observed in piglets without ileum. CONCLUSION: SBS piglets with ileum undergo adaptation associated with increased endogenous GLP-2 production. SBS piglets without ileum undergo limited adaptation and severe intestinal failure, requiring prolonged PN support. This appears to be related to a deficiency in endogenous GLP-2 production.

From diarrhea to obesity in prohormone convertase 1/3 deficiency: age-dependent clinical, pathologic, and enteroendocrine characteristics.

GOALS: The aim of this report is to delineate the clinical, pathologic, and enteroendocrine (EE) features of prohormone convertase 1/3 (PC1/3) deficiency in children. BACKGROUND: Prohormone convertases play a pivotal role in the activation of biologically inactive hormones. Congenital defects in the EE axis, such as PC1/3 deficiency, have been rarely reported and their pathophysiological mechanisms are largely unknown. STUDY: EE function and pathology was evaluated in 4 males (1, 2, 7, and 10 y old) from 2 families with PC1/3 deficiency at a university children's hospital. Clinical course, pathology analysis including immunohistochemistry for PC1/3, PC2, and glucagon-like peptide 1 (GLP-1) and electron microscopy, as well as EE function tests (GLP-1, GLP-2, oral glucose tolerance test) were performed. RESULTS: All (n=4) suffered from congenital severe diarrhea associated with malabsorption. The diarrhea improved during the first year of life and hyperphagia with excessive weight gain (BMI>97th percentile) became the predominant phenotype at an older age. Analysis of the enteroendocrine axis revealed high proinsulin levels (57 to 1116 pmol/L) in all patients, low serum GLP-2 levels, and impaired insulin and GLP-1 secretion after an oral glucose tolerance test at a young age, with improvement in 1 older child tested. Electron microscopy showed normal ultrastructure of enterocytes and EE cells. Immunohistochemistry revealed normal expression of chromogranin A, a marker of EE cells but markedly reduced immunostaining for PC1/3 and PC2 in all patients. CONCLUSIONS: PC1/3 deficiency is associated with an age dependent, variable clinical phenotype caused by severe abnormalities in intestinal and EE functions. Serum level of proinsulin can be used as an effective screening tool.

Nutritional support of infants with intestinal failure: something more than fishy is going on here!

BACKGROUND: This review will highlight recent advances in the care of infants with Intestinal Failure, focusing on the benefits of a multi-disciplinary team and the types of nutrition used. METHODS: Recent best "practices" from the literature are described, including strategies for promoting intestinal adaptation, the use of lipid sparing Parenteral Nutrition (PN) and the effects of the associated high glucose infusion rates. Special emphasis will be placed on lipid minimization and specialized lipid emulsions including fish oil, and blended lipid sources such as SMOF. Enteral nutritional therapy will be reviewed, including the rationale for the use of expressed breast milk or elemental formula in preference to partial milk hydrolysates. The utility and indications for the use of formula additives and the use of nutritional supplements and the timing and rate of advancement of feeds, and the optimal strategy for preserving oral feeding skills will be reviewed. Treatments to optimize intestinal adaptation such as the use of dietary supplements including vegetable oils, fat emulsions and medium-chain triglycerides will be discussed. Feeding strategies will be described. The rationale and effects of using rotating antibiotics to treat small intestinal bacterial overgrowth will be reviewed. RESULTS: The long-term consequences and complications of the different types of nutritional therapy will be examined, with a focus on growth and development. The potential and described effects of established and novel lipid therapies on neurological development will be reviewed in detail. CONCLUSION: Areas of interest for potential future research will be explored for all aspects of nutritional therapy with a discussion of future strategies which may enhance the intestinal adaptive process, and thus aid our goal of making the adaptation process occur more quickly and shortening the time of PN.

Glucagon-like peptide 2 induces vasoactive intestinal polypeptide expression in enteric neurons via phophatidylinositol 3-kinase-γ signaling.

Glucagon-like peptide 2 (GLP-2) is an enteroendocrine hormone trophic for intestinal mucosa; it has been shown to increase enteric neuronal expression of vasoactive intestinal polypeptide (VIP) in vivo. We hypothesized that GLP-2 would regulate VIP expression in enteric neurons via a phosphatidylinositol-3 kinase-γ (PI3Kγ) pathway. The mechanism of action of GLP-2 was investigated using primary cultures derived from the submucosal plexus (SMP) of the rat and mouse colon. GLP-2 (10(-8) M) stimulation for 24 h increased the proportion of enteric neurons expressing VIP (GLP-2: 40 ± 6% vs. control: 22 ± 5%). GLP-2 receptor expression was identified by immunohistochemistry on neurons (HuC/D+) and glial cells (GFAP+) but not on smooth muscle or fibroblasts in culture. Over 1-4 h, GLP-2 stimulation of SMP increased phosphorylated Akt/Akt ratios 6.1-fold, phosphorylated ERK/ERK 2.5-fold, and p70S6K 2.2-fold but did not affect intracellular cAMP. PI3Kγ gene deletion or pharmacological blockade of PI3Kγ, mammalian target of rapamycin (mTOR), and MEK/ERK pathways blocked the increase in VIP expression by GLP-2. GLP-2 increased the expression of growth factors and their receptors in SMP cells in culture [IGF-1r (3.2-fold increase), EGFr (5-fold), and ErbB-2-4r (6- to 7-fold)] and ligands [IGF-I (1.5-fold), amphiregulin (2.5-fold), epiregulin (3.2-fold), EGF (7.5-fold), heparin-bound EGF (2.0-fold), ß-cellulin (50-fold increase), and neuregulins 2-4 (300-fold increase) (by qRT-PCR)]. We conclude that GLP-2 acts on enteric neurons and glial cells in culture via a PI3Kγ/Akt pathway, stimulating neuronal differentiation via mTOR and ERK pathways, and expression of receptors and ligands for the IGF-I and ErbB pathways.

Postoperative complications following colectomy for ulcerative colitis in children.

BACKGROUND AND AIMS: Colectomy rates for ulcerative colitis (UC) and data on postcolectomy complications in children are limited. Thus, we assessed colectomy rates, early postcolectomy complications, and clinical predictors in children with UC undergoing a colectomy. METHODS: Children (18 years old or older) with UC who underwent colectomy from 1983 to 2009 were identified (n=30). All of the medical charts were reviewed. The diagnostic accuracy of International Classification of Diseases codes for UC and colectomy were validated. The primary outcome was postoperative complications defined as Clavien-Dindo classification grade II or higher. The yearly incidence of colectomies for pediatric UC was calculated and temporal trends were evaluated. RESULTS: The sensitivity and positive predictive value of UC and colectomy International Classification of Diseases codes were 96% and 100%, respectively. The median ages at UC diagnosis and colectomy were 10.9 and 12.1 years, respectively. All of the children had pancolitis and 63% underwent emergent colectomy. Postoperatively, 33% experienced at least 1 complication. Patients with emergent colectomy were more likely to have a postoperative complication compared with patients with elective colectomy (90% vs 50%; P=0.03). For emergent colectomy, postoperative complications were associated with a disease flare of ≥2 weeks before admission (60% vs 0%; P=0.03) and >2 weeks from admission to colectomy (78% vs 22%; P=0.04). The average annual rate of pediatric colectomy was 0.059/100,000 person-years and stable from 1983 to 2009 (P>0.05). CONCLUSIONS: Colectomy UC was uncommon and rates have remained stable. Postcolectomy complications were common, especially in patients undergoing emergent colectomy. Optimizing timing of colectomy may reduce postoperative complications.

Temporal expression of cytokines in rat cutaneous, fascial, and intestinal wounds: a comparative study.

BACKGROUND: Previous studies have shown that healing in intestinal wounds is proportionally faster than skin. Cytokines and growth factors play a major role in these coordinated wound-healing events. We hypothesized that this more rapid intestinal healing is due to an early upregulation of proinflammatory cytokines (IL-1beta, TNF-alpha, and IFN-gamma), followed by increases in the expression of the anti-inflammatory cytokine IL-10 and growth factor TGF-beta. METHODS: Four wounds (skin, fascia, small intestinal, and colonic anastomosis) were created in each of 48 juvenile male Sprague Dawley rats; tissue samples of each site were harvested at 0, 1, 3, 5, 7, and 14 days postoperatively (n = 8/group) and levels of IL-1beta, IFN-gamma, TNF-alpha, IL-10 and TGF-beta expression from each site were measured using ELISA kits. RESULTS: IL-1beta expression peaked earlier in small-intestinal and colonic wounds when compared to skin or fascia (e.g., small intestine: day 3 and colon day 5, P < 0.05 by ANOVA). Post-wounding levels of TNF-alpha were elevated in fascial wounds, but decreased in small-intestinal and colonic wounds. IFN-gamma levels were not significantly altered in any wounds. IL-10 showed a similar downregulation pattern in all wounds, while TGF-B levels were decreased in colonic and fascial wounds, but relatively unchanged in SI and skin. CONCLUSIONS: An earlier peak in IL-1beta levels and a consistent decrease in TNF-alpha were seen in healing intestinal tissues; but no clear pattern of increased anti-inflammatory or regulatory cytokines was seen, which might explain the earlier healing of intestinal tissues. Additional studies are required to determine the role of individual cytokines, or the intrinsic reactivity of the tissues may explain the site specific differences of healing rates in different tissues.

Successful Establishment of the First Neonatal Respiratory Extracorporeal Membrane Oxygenation (ECMO) Program in the Middle East, in Collaboration With Pediatric Services.

Background: Extracorporeal membrane oxygenation (ECMO) is a complex life-saving support for acute cardio-respiratory failure, unresponsive to medical treatment. Starting a new ECMO program requires synergizing different aspects of organizational infrastructures and appropriate extensive training of core team members to deliver the care successfully and safely. Objectives: To describe the process of establishing a new neonatal ECMO program and to evaluate the program by benchmarking the ECMO respiratory outcomes and mechanical complications to the well-established Extracorporeal Life Support Organization (ELSO) registry data. Materials and Methods: We reviewed the processes and steps involved in planning and setting up the new ECMO program. To assess the success of the ECMO implementation program, we retrospectively reviewed data of clinical outcomes and technical complications for the first 11 patients who have received ECMO therapy for respiratory indications since program activation (July 2018-May 2020). We analyzed mechanical complications as a tool to measure infrastructures and our effective training for the core team of ECMO specialists. We also looked at all clinical complications and benchmarked these numbers with the last 10 years of ELSO registry data (2009-2019) in the corresponding categories for comparison. Chi-square test was used to compare, and outcomes are presented in percentage; a p-value of <0.05 is considered significant. Results: A total of 27 patients underwent ECMO in the hospital, out of which 11 (six neonatal and five pediatric) patients had acute respiratory failure treated with venovenous (VV) ECMO or veno-arterial (VA) ECMO over a 22-month period. We had a total of 3,360 h of ECMO run with a range from 1 day to 7 weeks on ECMO. Clinical outcomes and mechanical complications are comparable to ELSO registry data (no significant difference); there were no pump failure, oxygenator failure, or pump clots. Conclusions: Establishing the ECMO program involved a multisystem approach with particular attention to the training of ECMO team members. The unified protocols, equipment, and multistep ECMO team training increased staff knowledge, technical skills, and teamwork, allowing the successful development of a neonatal respiratory ECMO program with minimal mechanical complications during ECMO runs, showing a comparable patient flow and mechanical complications.

Ileal Transposition in Rats Reduces Energy Intake, Body Weight, and Body Fat Most Efficaciously When Ingesting a High-Protein Diet.

PURPOSE: Ileal transposition (IT) allows exploration of hindgut effects of bariatric procedures in inducing weight loss and reducing adiposity. Here we investigated the role of dietary macronutrient content on IT effects in rats. METHODS: Male Lewis rats consuming one of three isocaloric liquid diets enriched with fat (HF), carbohydrates (HC), or protein (HP) underwent IT or sham surgery. Body weight, energy intake, energy efficiency, body composition, and (meal-induced) changes in plasma GIP, GLP-1, PYY, neurotensin, and insulin levels were measured. RESULTS: Following IT, HC intake remained highest leading to smallest weight loss among dietary groups. IT in HF rats caused high initial weight loss and profound hypophagia, but the rats caught up later, and finally had the highest body fat content among IT rats. HP diet most efficaciously supported IT-induced reduction in body weight and adiposity, but (as opposed to other diet groups) lean mass was also reduced. Energy efficiency decreased immediately after IT irrespective of diet, but normalized later. Energy intake alone explained variation in post-operative weight change by 80%. GLP-1, neurotensin, and PYY were upregulated by IT, particularly during (0-60 min) and following 17-h post-ingestive intake, with marginal diet effects. Thirty-day post-operative cumulative energy intake was negatively correlated to 17-h post-ingestive PYY levels, explaining 47% of its variation. CONCLUSION: Reduction in energy intake underlies IT-induced weight loss, with highest efficacy of the HP diet. PYY, GLP-1, and neurotensin levels are upregulated by IT, of which PYY may be most specifically related to reduced intake and weight loss after IT.

Meal patterns, satiety, and food choice in a rat model of Roux-en-Y gastric bypass surgery.

Gastric bypass surgery efficiently and lastingly reduces excess body weight and reverses type 2 diabetes in obese patients. Although increased energy expenditure may also play a role, decreased energy intake is thought to be the main reason for weight loss, but the mechanisms involved are poorly understood. Therefore, the aim of this study was to characterize the changes in ingestive behavior in a rat model of Roux-en-Y gastric bypass surgery (RYGB). Obese (24% body fat compared with 18% in chow-fed controls), male Sprague-Dawley rats maintained for 15 wk before and 4 mo after RYGB or sham-surgery on a two-choice low-fat/high-fat diet, were subjected to a series of tests assessing energy intake, meal patterning, and food choice. Although sham-operated rats gained an additional 100 g body wt during the postoperative period, RYGB rats lost approximately 100 g. Intake of a nutritionally complete and palatable liquid diet (Ensure) was significantly reduced by approximately 50% during the first 2 wk after RYGB compared with sham surgery. Decreased intake was the result of greatly reduced meal size with only partial compensation by meal frequency, and a corresponding increase in the satiety ratio. Similar results were obtained with solid food (regular or high-fat chow) 6 wk after surgery. In 12- to 24-h two-choice liquid or solid diet paradigms with nutritionally complete low- and high-fat diets, RYGB rats preferred the low-fat choice (solid) or showed decreased acceptance for the high-fat choice (liquid), whereas sham-operated rats preferred the high-fat choices. A separate group of rats offered chow only before surgery completely avoided the solid high-fat diet in a choice paradigm. The results confirm anecdotal reports of "nibbling" behavior and fat avoidance in RYGB patients and provide a basis for more mechanistic studies in this rat model.

Temporal changes in the intestinal growth promoting effects of glucagon-like peptide 2 following intestinal resection.

BACKGROUND: We investigated the effects of variations in the postresection timing of glucagon-like peptide-2 (GLP-2) administration on intestinal morphology and activity. METHODS: A rat model of 90% intestinal resection (SBR) with exclusively parenteral nutritional (TPN) was used. Early versus late postresection GLP-2 stimulation was compared between SBR + TPN alone, SBR + TPN + GLP-2 (first wk), and SBR + TPN + GLP-2 (second wk) (n = 8/group). On d 14, animals were sacrificed and remnant ileum analyzed for morphology, crypt cell proliferation index (CPI), apoptosis index (API), and nutrient transporter expression (SGLT-1, GLUT-2, GLUT-5). In a separate study, the resection-induced effect on acute GLP-2 responsiveness was studied at d 3 and 10, in control or SBR animals, both supported with TPN. (n = 6). RESULTS: Bowel length, weight, and width were increased in SBR + TPN + GLP-2 (first wk) compared with the SBR + TPN alone and SBR + TPN + GLP-2 (second wk) groups. Animal weight, villus height, total mucosal surface area, and CPI increased in both GLP-2 treated groups compared with the SBR + TPN group. Villus height and crypt depth effects were most pronounced in the SBR + TPN + GLP-2 (second wk) group. Increased expression of mRNA for the GLP-2 receptor was noted at d 3, declining below baseline by d 10, however this was not correlated with GLP-2 activation of enteric neurons. Exogenous GLP-2 increased the activation of submucosal neurons at d 3 in controls; resected animals had a higher baseline activity, but exogenous GLP-2 did not activate this further at either d 3 or 10 postresection. CONCLUSIONS: GLP-2 effects on intestinal growth are maximal in the early postresection period and are associated with an apparent increase in expression of the receptor but no increase in neuronal activation. This suggests that the intestinal adaptive and growth promoting actions of GLP-2 may be mediated by non-neuronal effector pathways. Although further studies are required, early treatment with GLP-2 following resection may maximize intestinal growth.

The effects of variations in dose and method of administration on glucagon like peptide-2 activity in the rat.

Glucagon-like peptide-2 (GLP-2) is a potent, intestinal-specific trophic hormone. However, the relationship between the dose and timing of GLP-2 administration and these trophic effects is not clear. We investigated the effects of variations in the dose and timing of GLP-2 administration on its intestinal trophic activity. A rodent model of total parenteral nutrition (TPN) mucosal atrophy was used, examining intestinal morphology in the adult male rat after 5 days. Groups were: controls, maintained with TPN alone and GLP-2 treated groups (high dose; 240 microg/kg/day, low dose; 24 microg/kg/day) given by continuous or intermittent (over 1 h, twice daily) intravenous infusion. Body weight and total small bowel length were significantly increased in the high dose, continuous infusion group. Both high dose infusion methods increased total small bowel weight, villus height, crypt depth, and total mucosal surface area. Both high dose infusion and low dose intermittent infusion routes increased crypt cell proliferation (P<0.05 for all comparisons). Both high dose routes gave nearly equivalent exposures; low dose continuous infusion gave higher exposure but intermittent low dose infusion resulted in an increase in crypt proliferation; neither low dose method resulted in morphologic changes. There were no differences in transporter protein expression or apoptosis rates. High dose continuous infusion appears to maximally induce intestinal growth, and also increases weight gain, while high dose GLP-2 intermittent infusion results in similar morphologic effects. A threshold level for the induction of proliferative and morphologic effects was seen in the low dose groups. These observations may be relevant for planning therapeutic trials.

The bone marrow as a potential receptor site for pancreatic islet grafts.

BACKGROUND: Pancreatic islet transplantation in the human liver is being performed with increasing success to treat diabetes. However, the liver as a receptor site has many drawbacks due to immunological and non-immunological factors as well as important technical limitations. Bone marrow offers an easily accessible extrahepatic receptor site. Therefore, we attempted to explore the survival of pancreatic islets transplanted into the bone marrow of rats. METHODS: Pancreatic islets islografts and allografts were implanted into the bone marrow of rats. No immunosuppression was used. Morphology, presence of insulin, and glucagon and signs of apoptosis and rejection were explored. RESULTS: Pancreatic islets can be successfully engrafted into the bone marrow of rats, maintaining a normal histological appearance in insulin and glucagon content and no signs of apoptosis or rejection. CONCLUSIONS: These preliminary findings suggest that the bone marrow is capable of maintaining pancreatic islets in the absence of immunosuppression and, thus, can constitute an immunoprivileged environment for engraftment.

Intestinal permeability and glucagon-like peptide-2 in children with autism: a controlled pilot study.

We measured small intestinal permeability using a lactulose:mannitol sugar permeability test in a group of children with autism, with current or previous gastrointestinal complaints. Secondly, we examined whether children with autism had an abnormal glucagon-like peptide-2 (GLP-2) response to feeding. Results were compared with sibling controls and children without developmental disabilities. We enrolled 14 children with autism, 7 developmentally normal siblings of these children and 8 healthy, developmentally normal, unrelated children. Our study did not detect differences in these measures of gastrointestinal function in a group of children with autism.

Updating the Surgical Preference List.

Surgical procedure 'preference lists' are used worldwide, but their practice varies widely. Despite being positioned at a critical point in a surgical care pathway, they are often underemphasized, poorly maintained, and substandard. The following editorial material is gleaned from our experience in the set-up of a tertiary hospital on a green field site in Qatar. We comment on the use of preference lists, and contend that focus on standardizing and maintaining preference lists within an electronic record affords substantial opportunities for cost containment, whilst adding efficiency, safety, and value. We believe this approach represents an 'easy win' which would be applicable elsewhere.

The glucagon like peptide-2 'axis': Capacity for production and response following intestinal resection or repair of gastroschisis in infants.

PURPOSE: This study investigates the relationship between the enteric hormone glucagon-like peptide 2 (GLP-2) production, sensitivity, and intestinal adaptation in infants following resection or repair of gastroschisis. METHODS: With IRB approval (UCalgary #10656), consent was obtained from families of infants undergoing surgery for prospective monitoring of nutritional status, GLP-2 levels, and where possible, tissue sampling. RESULTS: Infants who adapted and weaned from parenteral nutrition (PN) had increased GLP-2 (86±32) n=24 vs. controls: 45±20 n=10 and vs. patients on prolonged PN: 42±6 pM, n=10). This was maintained to one year: weaned patients: 72±49 vs. non-weaned: 35±15 pM (p<0.05). Infants with gastroschisis (n=33) had decreased GLP-2 levels until enteral function was achieved and then became elevated: (21±15 with first feeding vs. 102±60 at full feeds and 60±19 pM at one year). There were no changes in the density or distribution of GLP-2 producing L-cells related to gestational age, nor in the expression of the GLP-2 receptor. CONCLUSION: GLP-2 levels correlate with intestinal adaptation in infants, and with recovery of intestinal function in gastroschisis. GLP-2 productive capacity (L-cell expression) and GLP-2 receptor expression do not vary with maturity. The findings support a role for GLP-2 in regulating intestinal function. Further study is suggested.