Insulinoma in childhood: clinical, radiological, molecular and histological aspects of nine patients.

BACKGROUND: Insulinomas are a rare cause of hyperinsulinaemic hypoglycaemia (HH) in children. The clinical features, investigations, management and histology of these rare pancreatic tumours in children have not been described in a large cohort of patients. METHODS: We conducted a retrospective review of cases diagnosed between 2000 and 2012, presenting to two referral centres in the United Kingdom. Clinical, biochemical, imaging (magnetic resonance imaging (MRI) and 6-L-¹8F-fluorodihydroxyphenylalanine (¹8F-DOPA) PET/CT scanning) and histological data were collected. RESULTS: Nine children (age range 2-14.5 years) were diagnosed during the study period at Great Ormond Street Hospital (n=5) and Royal Manchester Children's Hospital (n=4). The combination of abdominal MRI scan (7/8) and ¹8F-DOPA PET/CT scan (2/4) correctly localised the anatomical location of all insulinomas. Before surgery, diazoxide therapy was used to treat hypoglycaemia, but only four patients responded. After surgical resection of the insulinoma, hypoglycaemia resolved in all patients. The anatomical localisation of the insulinoma in each patient was head (n=4), uncinate process (n=4) and tail (n=2, one second lesion) of the pancreas. Histology confirmed the diagnosis of insulinoma with the presence of sheets and trabeculae of epithelioid and spindle cells staining strongly for insulin and proinsulin, but not for glucagon or somatostatin. Two children were positive for MEN1, one of whom had two separate insulinoma lesions within the pancreas. CONCLUSIONS: We describe a cohort of paediatric insulinoma patients. Although rare, insulinomas should be included in the differential diagnosis of HH, even in very young children. In the absence of a single imaging modality in the preoperative period, localisation of the tumour is achieved by combining imaging techniques, both conventional and functional.

Amniotic fluid stem cells improve survival and enhance repair of damaged intestine in necrotising enterocolitis via a COX-2 dependent mechanism.

OBJECTIVE: Necrotising enterocolitis (NEC) remains one of the primary causes of morbidity and mortality in neonates and alternative strategies are needed. Stem cells have become a therapeutic option for other intestinal diseases, which share some features with NEC. We tested the hypothesis that amniotic fluid stem (AFS) cells exerted a beneficial effect in a neonatal rat model of NEC. DESIGN: Rats intraperitoneally injected with AFS cells and their controls (bone marrow mesenchymal stem cells, myoblast) were analysed for survival, behaviour, bowel imaging (MRI scan), histology, bowel absorption and motility, immunofluorescence for AFS cell detection, degree of gut inflammation (myeloperoxidase and malondialdehyde), and enterocyte apoptosis and proliferation. RESULTS: AFS cells integrated in the bowel wall and improved rat survival and clinical conditions, decreased NEC incidence and macroscopic gut damage, improved intestinal function, decreased bowel inflammation, increased enterocyte proliferation and reduced apoptosis. The beneficial effect was achieved via modulation of stromal cells expressing cyclooxygenase 2 in the lamina propria, as shown by survival studies using selective and non-selective cyclooxygenase 2 inhibitors. Interestingly, AFS cells differentially expressed genes of the Wnt/ß-catenin pathway, which regulate intestinal epithelial stem cell function and cell migration and growth factors known to maintain gut epithelial integrity and reduce mucosal injury. CONCLUSIONS: We demonstrated here for the first time that AFS cells injected in an established model of NEC improve survival, clinical status, gut structure and function. Understanding the mechanism of this effect may help us to develop new cellular or pharmacological therapies for infants with NEC.

Severe resistance to weight gain, lack of stored triglycerides in adipose tissue, hypoglycaemia, and increased energy expenditure: a novel disorder of energy homeostasis.

BACKGROUND: Growth during childhood is a consequence of the equilibrium of energy balance. Obesity results from a shift of the equilibrium towards increased energy intake over expenditure. A clinical description of extreme leanness and failure to thrive secondary to a shift of the equilibrium towards increased energy expenditure over energy intake has not been previously described in the medical literature. SUBJECTS AND METHODS: We report the case of a female child born premature with a birth weight of 1.1 kg who presented with extreme failure to thrive, persistent hypoglycaemia, paucity of fat in the adipose tissue with increased brown fat and increased resting energy expenditure. RESULTS: Complete cessation of weight and height was noted between 3 months to 3.5 years of age. Hypoglycaemia was secondary to depleted energy stores and increased insulin sensitivity. Increased resting energy expenditure was demonstrated on indirect calorimetric assessment. Biopsy of adipose tissue demonstrated paucity of stored fat with increase in brown fat. No gain in weight and height was demonstrated despite high calorie intake of enteral and parenteral feeds. CONCLUSION: We describe a unique case of extreme failure to thrive with increased energy expenditure and severe hypoglycaemia. Unravelling the molecular basis of this novel disorder has the potential to provide insights into the prevention of obesity.

A rat decellularized small bowel scaffold that preserves villus-crypt architecture for intestinal regeneration.

Management of intestinal failure remains a clinical challenge and total parenteral nutrition, intestinal elongation and/or transplantation are partial solutions. In this study, using a detergent-enzymatic treatment (DET), we optimize in rats a new protocol that creates a natural intestinal scaffold, as a base for developing functional intestinal tissue. After 1 cycle of DET, histological examination and SEM and TEM analyses showed removal of cellular elements with preservation of the native architecture and connective tissue components. Maintenance of biomechanical, adhesion and angiogenic properties were also demonstrated strengthen the idea that matrices obtained using DET may represent a valid support for intestinal regeneration.

The heterogeneity of focal forms of congenital hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia due to unregulated insulin secretion from pancreatic ß-cells. Histologically, there are two major subgroups, focal and diffuse. Focal CHI is typically unresponsive to diazoxide and can be cured with surgical removal of the focal lesion. AIMS: We report on three patients with focal CHI to illustrate the marked clinical, genetic, radiological, and histological heterogeneity. METHODS AND RESULTS: The first two patients had focal CHI due to a paternal (c.3992-9G→A) ABCC8 mutation. One of these patients was fully responsive to a small dose (5 mg/kg · d) of diazoxide, whereas the other patient was medically unresponsive. In both patients, the focal lesions were accurately localized preoperatively by [(18)F]dihydroxyphenylalanine (DOPA) positron emission tomography (PET) and surgically resected. The third patient had a paternally inherited ABCC8 (A1493T) mutation, and the initial [(18)F]DOPA PET scan indicated extensive uptake of DOPA in the body and tail of the pancreas. However, despite surgical resection of the body and tail, this patient continued to have severe CHI. A subsequent [(18)F]DOPA PET scan now showed markedly increased DOPA uptake in the remaining body and head of the pancreas. This focal lesion occupied virtually the whole of the pancreas. conclusions: These three cases illustrate that focal lesions even with the same genotype (c.3992-9G→A) may have a different clinical presentation and that [(18)F]DOPA PET scans in very large focal lesions may be difficult to interpret.

The predictive value of preoperative fluorine-18-L-3,4-dihydroxyphenylalanine positron emission tomography-computed tomography scans in children with congenital hyperinsulinism of infancy.

BACKGROUND/PURPOSE: In congenital hyperinsulinism (CHI) of infancy, the use of preoperative fluorine-18-L-3,4-dihydroxyphenylalanine-positron emission tomography-computed tomography ((18)F-DOPA-PET-CT) scan has recently been reported. The aim of this study was to evaluate the accuracy of this technique in discriminating between diffuse and focal CHI and the anatomical localization of focal lesions. METHODS: Between 2006 and 2010, (18)F-DOPA-PET scan was performed in 19 children with CHI (median age, 2 months; range, 1-12 months) who were not responding to medical therapy and underwent laparoscopic or open surgery. The findings of (18)F-DOPA-PET scan were correlated with histology. RESULTS: In 5 children, (18)F-DOPA-PET scan showed diffuse pancreatic uptake, confirmed at histology and supporting the genetic suspicion of diffuse disease. In 14 children, (18)F-DOPA-PET scan indicated focal pancreatic uptake, which corresponded to histology. However, in 5 patients (36%), (18)F-DOPA-PET scan was inaccurate in defining the location of the lesion (n = 3), size of the lesion (n = 1), or both location and size (n = 1), leading to an inaccurate pancreatic resection. CONCLUSIONS: Fluorine-18-L-3,4-dihydroxyphenylalanine-positron emission tomography-computed tomography scan discriminates between diffuse and focal forms of CHI. In focal forms, (18)F-DOPA-PET scan is useful in 2/3 of patients in defining the site and dimension of the focal lesion. Intraoperative histologic confirmation of complete focal lesion resection is needed.

Familial focal congenital hyperinsulinism.

BACKGROUND: Congenital hyperinsulinism (CHI) is a cause of persistent hypoglycemia. Histologically, there are two subgroups, diffuse and focal. Focal CHI is a consequence of two independent events, inheritance of a paternal mutation in ABCC8/KCNJ11 and paternal uniparental isodisomy of chromosome 11p15 within the embryonic pancreas, leading to an imbalance in the expression of imprinted genes. The probability of both events occurring within siblings is rare. AIM: We describe the first familial form of focal CHI in two siblings. PATIENTS AND METHODS: The proband presented with medically unresponsive CHI. He underwent pancreatic venous sampling and Fluorine-18-L-dihydroxyphenylalanine positron emission tomography scan, which localized a 5-mm focal lesion in the isthmus of the pancreas. The sibling presented 8 yr later also with medically unresponsive CHI. An Fluorine-18-L-dihydroxyphenylalanine positron emission-computerised tomography scan showed a 7-mm focal lesion in the posterior section of the head of the pancreas. Both siblings were found to be heterozygous for two paternally inherited ABCC8 mutations, A355T and R1494W. Surgical removal of the focal lesions in both siblings cured the Hyperinsulinaemic hypoglycaemia. CONCLUSION: This is the first report of focal CHI occurring in siblings. Genetic counseling for families of patients with focal CHI should be recommended, despite the rare risk of recurrence of this disease.

The London Classification of gastrointestinal neuromuscular pathology: report on behalf of the Gastro 2009 International Working Group.

OBJECTIVE: Guidelines on histopathological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology have been produced recently by an international working group (IWG). These addressed the important but relatively neglected areas of histopathological practice of the general pathologist, including suction rectal biopsy and full-thickness intestinal tissue. Recommendations were presented for the indications, safe acquisition of tissue, histological techniques, reporting and referral of such histological material. DESIGN: Consensual processes undertaken by the IWG and following established guideline decision group methodologies. RESULTS AND CONCLUSION: This report presents a contemporary and structured classification of gastrointestinal neuromuscular pathology based on defined histopathological criteria derived from the existing guidelines. In recognition of its origins and first presentation in London at the World Congress of Gastroenterology 2009, this has been named 'The London Classification'. The implementation of this classification should allow some diagnostic standardisation, but should necessarily be viewed as a starting point for future modification as new data become available.

Does intestinal permeability lead to organ failure in experimental necrotizing enterocolitis?

PURPOSE: The rat gavage model is used to explore the pathogenesis and treatment of necrotizing enterocolitis (NEC). Although intestinal histological damage is seen in this model, intestinal perforation is rarely observed. Whether organ failure occurs in this model is largely unknown. We hypothesised that increased intestinal permeability leads to organ failure in experimental NEC. METHODS: NEC was induced in neonatal rats by gavage feeding of hypertonic formula plus exposure to hypoxia plus oral lipopolysaccharide (4 mg/kg per day daily). Breast-fed rats were used for comparison. At 92 h, lactulose (3 mg) and mannitol (2 mg) were administered orally in 0.1 ml water. Four hours later, rats were killed and blood samples collected. Lactulose and mannitol were measured by gas chromatography-mass spectrometry and lactulose/mannitol ratio calculated as index of intestinal permeability. Plasma cardiac troponin-I was measured by ELISA as a marker of cardiac damage and plasma creatinine measured spectrophotometrically as a marker of renal failure. RESULTS: Experimental NEC induced an increase in intestinal permeability (P = 0.0002). This was associated with cardiac damage (P < 0.0001), and renal failure (P = 0.004). CONCLUSION: Intestinal permeability is increased in experimental NEC in association with increased cardiac damage. Rat mortality may be due to cardiac failure secondary to an inflammatory response caused by increased intestinal permeability.

Lymphocytic leiomyositis and myenteric ganglionitis are intrinsic features of cystic fibrosis: studies in distal intestinal obstruction syndrome and meconium ileus.

BACKGROUND: Cystic fibrosis (CF) is a multisystem disorder intrinsically associated with inflammation of mucosal surfaces. Because inflammation can result in enteric neuromuscular dysfunction we hypothesized that terminal ileitis in patients with CF may predispose to distal ileal obstruction syndrome (DIOS). METHODS AND PATIENTS: Full-thickness terminal ileal tissues from 6 children with CF and severe DIOS, 6 infants with complicated meconium ileus (MI), and 6 children with non-CF intestinal atresia were studied. RESULTS: Lymphocyte-predominant mucosal and transmural ileal inflammation was present in 6 of 6 patients with DIOS. Lymphocytic ganglionitis was present in 4 of 6 although numbers of myenteric neurons were not decreased (5/5). Myocyte proteins were preserved (6/6). Mild submucosal fibrosis was common in DIOS (5/6) and transformation of submucosal fibroblasts to a myofibroblastic phenotype was noted in 4 of 6. Inflammatory changes were distinct from those described in fibrosing colonopathy. Antroduodenal manometry in an individual who had experienced MI/DIOS was consistent with a neuropathic pseudo-obstructive process. Submucosal or transmural lymphocyte predominant inflammation was also present in 6 of 6 infants with complicated MI, which, when coupled with submucosal myofibroblast proliferation (5/6), appeared highly predictive of CF rather than non-CF atresia. Histological findings at birth were similar, although milder, than those seen in DIOS, suggesting that these changes are a primary abnormality in CF. CONCLUSIONS: Submucosal or transmural inflammation of the ileum is common in newborns with CF and MI and older children with DIOS. Severe recurrent DIOS should be investigated with seromuscular and mucosal biopsy of the ileum to seek a transmural ileitis potentially amenable to anti-inflammatory therapies.

Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group.

The term gastrointestinal neuromuscular disease describes a clinically heterogeneous group of disorders of children and adults in which symptoms are presumed or proven to arise as a result of neuromuscular, including interstitial cell of Cajal, dysfunction. Such disorders commonly have impaired motor activity, i.e. slowed or obstructed transit with radiological evidence of transient or persistent visceral dilatation. Whilst sensorimotor abnormalities have been demonstrated by a variety of methods in these conditions, standards for histopathological reporting remain relatively neglected. Significant differences in methodologies and expertise continue to confound the reliable delineation of normality and specificity of particular pathological changes for disease. Such issues require urgent clarification to standardize acquisition and handling of tissue specimens, interpretation of findings and make informed decisions on risk-benefit of full-thickness tissue biopsy of bowel or other diagnostic procedures. Such information will also allow increased certainty of diagnosis, facilitating factual discussion between patients and caregivers, as well as giving prognostic and therapeutic information. The following report, produced by an international working group, using established consensus methodology, presents proposed guidelines on histological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology. The report addresses the main areas of histopathological practice as confronted by the pathologist, including suction rectal biopsy and full-thickness tissue obtained with diagnostic or therapeutic intent. For each, indications, safe acquisition of tissue, histological techniques, reporting and referral recommendations are presented.

Ciliopathy spectrum expanded? Jeune syndrome associated with foregut dysmotility and malrotation.

We report the association and surgical management of gastrointestinal dysmotility and malrotation with Jeune asphyxiating thoracic dystrophy (JATD), an autosomal recessive condition that often results in respiratory failure due to a small rib cage. A 4-month-old male with JATD presented with vomiting and aspiration pneumonitis compounding already severe respiratory morbidity. A contrast study revealed esophageal and gastric dysmotility with associated malrotation. This was treated surgically with good results. Some cases of JATD are caused by missense mutations in the gene IFT80, which encodes a protein implicated in the process of intraflagellar transport of primary cilia. We speculate that these abdominal complications might also be part of the extending spectrum of ciliopathy.

Mast cell-nerve interactions in children with functional dyspepsia.

BACKGROUND AND AIMS: Functional dyspepsia in childhood is commonly triggered by food allergen in sensitised individuals. We investigated the topography of eosinophils and mast cells in gastric antral lamina propria, the interaction of mast cell products with mucosal nerve fibres, and changes in gastric antral muscle slow wave activity in children with atopy and non-atopy-related functional dyspepsia. PATIENTS AND METHODS: Open label study of gastric mucosal cow's milk challenge in 10 atopic and 6 nonatopic children (ages 2-12 years) investigated consecutively with gastroscopy for functional dyspepsia. Simultaneous surface electrogastrography and milk challenge were undertaken and laser scanning fluorescence microscopy used to examine the association of mast cell tryptase with mucosal nerves in the gastric mucosa before and after challenge. RESULTS: Eosinophils and mast cells within the lamina propria were increased in number in children with atopic functional dyspepsia and degranulated rapidly after cow's milk challenge in the atopic group. For degranulating eosinophils, median = 13.0% (interquartile range = 3.7-31.0) premilk versus 32.0% (12.0-42.0) after milk biopsies (P < 0.05); for degranulating mast cells, 5.35% (2.7-10.9) premilk biopsies versus 18.75% (12.9-22.1) after milk biopsies (P < 0.05). No such differences were seen in nonatopic patients. Mast cells were closely associated with mucosal nerve fibres and released tryptase, which colocalised with proteinase-activated receptors on mucosal nerve fibres. The gastric antral slow wave became abnormal within 2 minutes of antigen challenge in atopics with an increase in dominant frequency instability coefficient (P < 0.005), decrease in 3 cycles per minute myoelectrical activity (P < 0.01), and increase in bradygastria (P < 0.01). CONCLUSIONS: Early-onset neuroimmune interactions induced by cow's milk in the gastric mucosa of atopic children are associated with rapid disturbance of gastric myoelectrical activity and dyspeptic symptoms.

Moderate hypothermia as a rescue therapy against intestinal ischemia and reperfusion injury in the rat.

OBJECTIVE: Moderate hypothermia is protective when applied throughout experimental intestinal ischemia and reperfusion (I/R). However, therapeutic intervention is usually possible only after ischemia has occurred. The aim of this study was to evaluate moderate hypothermia when applied at reperfusion as a rescue therapy for intestinal I/R. DESIGN: Prospective, randomized, controlled experiment. SETTING: University research laboratory. SUBJECTS: Adult male Sprague-Dawley rats (240-300 g). INTERVENTIONS: In experiment I, rats underwent 60 mins of normothermic intestinal ischemia (36-38 degrees C) plus 300 mins of reperfusion at either normothermia or moderate hypothermia (30-32 degrees C) with or without rewarming. Hemodynamics were measured invasively and survival was assessed. In experiment II, rats underwent 60 mins of normothermic ischemia plus 120 mins of reperfusion at either normothermia or moderate hypothermia. At kill, organs and a blood sample were collected. MEASUREMENTS AND MAIN RESULTS: In experiment I, all normothermic I/R rats died within 197 mins of reperfusion after developing severe tachycardia and hypotension, whereas hypothermic rats, with or without rewarming, were alive at 300 mins of reperfusion (p < .001 vs. I/R normothermia) and were hemodynamically stable. In experiment II, normothermic reperfusion caused histologic and biochemical damage to the gut, hepatic energy failure, and inflammatory infiltration of the lung. However, hypothermia reduced injury to the reperfused ileum and prevented distant organ injury by counteracting energy failure in the liver, systemic overproduction of nitric oxide, altered cardiac fatty acid metabolism, and infiltration of inflammatory cells in the lungs. CONCLUSIONS: Hypothermia applied as a rescue therapy for intestinal I/R abolishes mortality even after rewarming. Hypothermic protection during early reperfusion appears to be mediated by several pathways, including prevention of intestinal and pulmonary neutrophil infiltration, reduction of oxidative stress in the ileum, and preservation of cardiac and hepatic energy metabolism. Moderate hypothermia may improve outcome in clinical conditions associated with intestinal I/R.

Captopril reduces the severity of bowel damage in a neonatal rat model of necrotizing enterocolitis.

BACKGROUND/PURPOSE: Selective mesenteric ischemia may result from activation of the renin-angiotensin system during periods of shock and is implicated in the pathogenesis of neonatal necrotizing enterocolitis (NEC). We investigated the effectiveness of captopril, an angiotensin-converting enzyme inhibitor, in reducing the severity of bowel damage in a neonatal rat model of NEC. METHODS: Necrotizing enterocolitis was induced by a combination of gavage feeding of hypertonic formula, hypoxia, and oral lipopolysaccharide (LPS). Rats were randomly divided into 3 groups: group A, control (breast fed; n = 20); group B, NEC (gavage/hypoxia/LPS; n = 31); group C, NEC with captopril 20 mg/kg per dose with the formula for 4 days (gavage/hypoxia/LPS/captopril; n = 35). Pups were killed after 4 days. Incidence of NEC was evaluated microscopically. RESULTS: Severity of bowel damage was higher in the NEC group compared to controls and was reduced by administration of captopril. Dilatation of the intestinal vasculature was observed in the captopril group. There were no cases of NEC in the controls; the incidence increased to 55% in NEC group and reduced to 29% by captopril. CONCLUSIONS: In this model of neonatal NEC, captopril supplementation of formula reduces the severity of intestinal damage and the incidence of NEC, presumably by affecting mesenteric blood flow.

An ABCC8 gene mutation and mosaic uniparental isodisomy resulting in atypical diffuse congenital hyperinsulinism.

OBJECTIVE: Congenital hyperinsulinism (CHI) may be due to diffuse or focal pancreatic disease. The diffuse form is associated with an increase in the size of beta-cell nuclei throughout the whole of the pancreas and most commonly results from recessive ATP-sensitive K(+) channel (K(ATP) channel) mutations. Focal lesions are the consequence of somatic uniparental disomy for a paternally inherited K(ATP) channel mutation with enlargement of the beta-cell nuclei confined to the focal lesion. Some "atypical" cases defy classification and show pancreatic beta-cell nuclear enlargement confined to discrete regions of the pancreas. We investigated an atypical case with normal morphology within the tail of the pancreas but occasional enlarged endocrine nuclei in parts of the body and head. RESEARCH DESIGN AND METHODS: The KCNJ11 and ABCC8 genes encoding the K(ATP) channel subunits and microsatellite markers on chromosome 11 were analyzed in DNA samples from the patient and her parents. RESULTS: A mosaic ABCC8 nonsense mutation (Q54X) was identified in the proband. The paternally inherited mutation was present at 90% in lymphocytes and 50% in normal pancreatic sections but between 64 and 74% in abnormal sections. Microsatellite analysis showed mosaic interstitial paternal uniparental isodisomy (UPD) for chromosome 11p15.1. CONCLUSIONS: We report a novel genetic mechanism to explain atypical histological diffuse forms of CHI due to mosaic UPD in patients with dominantly inherited ABCC8 (or KCNJ11) gene mutations.

Voltage-gated ion channel Nav1.7 innervation in patients with idiopathic rectal hypersensitivity and paroxysmal extreme pain disorder (familial rectal pain).

Faecal urgency and incontinence with rectal hypersensitivity is a chronic, unexplained condition that is difficult to treat. The aim of this study was to determine if there was an altered level of the voltage gated tetrodotoxin-sensitive (TTX-s) sodium channel Na(v)1.7 in rectal sensory fibres, since this channel has been implicated in clinical nociceptive disorders. Full thickness rectal biopsies from patients with physiologically characterised rectal hypersensitivity (n=7) were compared with control tissues (n=10). Formalin fixed specimens were studied by immunohistochemistry using affinity purified antibodies to Na(v)1.7 and the pan-neuronal structural marker PGP9.5, and the immunoreactive nerve fibres quantified by computerised image analysis. In rectal hypersensitivity, Na(v)1.7 immunoreactive nerve fibres were significantly increased in mucosal (P=0.0004), sub-mucosal (P=0.019), and muscle layers (P=0.0076), while PGP9.5 immunoreactive nerve fibres were increased significantly only in the mucosa (P=0.04); ratios of Na(v)1.7:PGP9.5 showed a significant increase in all layers, suggesting increased expression of Na(v)1.7, and nerve sprouting in the mucosa. The cause of this increase remains uncertain, but may be due to increase of nerve growth factor (NGF), which regulates the expression of both Na(v)1.7 and TRPV1, which we have previously reported to be increased in this condition. In paroxysmal extreme pain disorder (familial rectal pain), where the gene that encodes Na(v)1.7 is mutated, Na(v)1.7 protein was undetectable in the rectum (n=2), which suggests reduced Na(v)1.7 immunoreactivity or expression. Drugs that target Na(v)1.7-expressing nerve terminals may be useful for treating rectal hypersensitivity, and combining these with TRPV1 antagonists may enhance efficacy.

Peroxynitrite decomposition catalyst FeTMPyP provides partial protection against intestinal ischemia and reperfusion injury in infant rats.

Free radicals are important in development of intestinal ischemia-reperfusion (I/R) injury, leading to intestinal and pulmonary damage. We evaluated the effects of peroxynitrite decomposition catalyst FeTMPyP in infant intestinal I/R. Suckling rats underwent 40 min intestinal ischemia + 90 min reperfusion. At reperfusion, animals received saline or FeTMPyP. Groups were (n = 11 per group): 1) control+saline; 2) I/R+saline; 3) I/R+FeTMPyP. Increased histologic injury and ICAM-1 expression were observed in ileum of both I/R+saline and I/R+FeTMPyP rats, but P-selectin expression was increased in I/R+saline animals only versus controls. Myeloperoxidase (neutrophil infiltration marker) was increased in ileum and lungs of I/R+saline rats, but FeTMPyP prevented this in the ileum. I/R+saline animals showed higher malondialdehyde (lipid peroxidation marker) in ileum and lungs versus both control+saline and I/R+FeTMPyP rats. Glutathione was decreased in all I/R animals, but oxidized and total glutathione were higher in I/R+FeTMPyP than the I/R+saline group. Nitrate+nitrite concentration (systemic nitric oxide production) was elevated in I/R+saline but not in I/R+FeTMPyP animals. FeTMPyP provides limited protection against intestinal I/R in neonatal rats by reducing ileal P-selectin expression, systemic nitric oxide production, neutrophil infiltration in ileum and lipid peroxidation in both lungs and ileum; and preserving intestinal antioxidant capacity.

Pathology of paediatric gastrointestinal neuromuscular disease.

Congenital and acquired disorders of the enteric neuromusculature are relatively uncommon in childhood, with the exception of Hirschsprung disease. Despite this, a number of histologically well-defined phenotypes of enteric neuromuscular disease are now recognised in paediatric populations, essentially comprising enteric neuropathies and enteric myopathies. This classification is briefly discussed.

P-selectin expression, neutrophil infiltration, and histologic injury in neonates with necrotizing enterocolitis.

BACKGROUND/PURPOSE: P-selectin promotes adherence of leukocytes to the endothelium in inflammatory processes. The aim of this study was to investigate the expression of P-selectin and its role in the development of inflammation in neonates with necrotizing enterocolitis (NEC). METHODS: Twenty-nine intestinal specimens from 13 neonates with NEC and 7 control neonates with congenital gastrointestinal abnormalities were studied. Histologic damage, immunohistochemical expression of P-selectin, and polymorphonuclear cell infiltrate were graded blindly. Mann-Whitney U and Spearman rank tests were used to compare grades. RESULTS: Expression of P-selectin was increased in NEC compared with controls in both medium-sized vessels (P = .03) and in the microcirculation (P = .03). P-selectin expression on medium-sized vessels correlated with the degree of histologic injury (P = .02, r = 0.425). P-selectin expression was greatest in areas of active inflammation but markedly lower in necrotic areas. The degree of polymorphonuclear cell infiltration strongly correlated with P-selectin expression on both medium-sized vessels (P = .004, r = 0.513) and the microcirculation (P = .001, r = 0.578). CONCLUSIONS: Expression of P-selectin is increased in medium-sized vessels and in the microcirculation in intestinal specimens of neonates with NEC compared with neonatal controls. Expression of P-selectin is associated with the recruitment of polymorphonuclear cells and the severity of histologic injury, although P-selectin expression is lost in necrotic tissue.