Histopathological features of gastrointestinal mucosal biopsy specimens in children with epidermolysis bullosa.
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Adolescent↗
Biomedical subjects
K J Lindley
Publications and source records attributed to K J Lindley.
Management of fulminating ulcerative colitis in childhood with chimeric anti-CD25 antibody.
Fulminating acute ulcerative colitis (UC) is a potentially life threatening medical emergency. Up to 30% of individuals respond poorly to corticosteroids alone and second line medical or surgical therapies are indicated. We describe the successful use of chimeric anti-CD25 therapy in 4 such children poorly responsive to combined therapy with intravenous steroids and calcineurin inhibitors with a pretreatment predictive risk of colectomy of 85-100%. Clinical disease activity scores normalized within 72 hours of anti-CD25 administration and colonic histology provided evidence of mucosal healing within 10-14 days. None required emergency colectomy. Anti-CD25 is efficacious in fulminating UC and randomized placebo controlled trials appear indicated.
Acute Disease↗
Systemic vasculitis: a cause of indeterminate intestinal inflammation.
OBJECTIVES: Indeterminate intestinal inflammation may result from a variety of inflammatory conditions in addition to ulcerative colitis and Crohn disease. The primary systemic vasculitides may present with intestinal inflammation and an indeterminate colitis. We set out to describe a series of children with primary systemic vasculitis who initially presented with clinical features suggestive of inflammatory bowel disease (IBD) to establish criteria that might help discriminate between IBD and primary systemic vasculitis. METHODS: Ten children (6 boys, median age at presentation 8.9 years, range 0.9-14.5 years) satisfied inclusion criteria. RESULTS: All had abdominal pain, weight loss, diarrhea (6 of 10 bloody) and laboratory evidence of a severe acute phase response. Extraintestinal clinical features included vasculitic rash, renal impairment, myalgia, testicular pain and polyarthritis. Endoscopy showed vascular changes or other macroscopic findings suggestive of vasculitis in 5 of 10 patients. Gut histology revealed indeterminate chronic inflammatory mucosal changes and one patient with small artery fibrinoid necrosis in the submucosal vessels. Extraintestinal biopsy was performed in 6 patients and had a higher yield for the demonstration of vasculitis than intestinal biopsy. The results of selective visceral angiography was suggestive of vasculitis in all patients, but was normal in 7 cases of treatment-unresponsive classic IBD. Treatment comprised corticosteroid and azathioprine in all patients. Cyclophosphamide was given to 7 of 10 patients. CONCLUSIONS: Extraintestinal manifestations and inflammatory responses that may be disproportionate to the degree of intestinal inflammation provide clues to the presence of an underlying primary systemic vasculitis, and these data suggest that selective visceral angiography plays a key role in the diagnosis of vasculitis in this context. It is important to identify and treat any vasculitic component because failure to do so may result in consequential morbidity or mortality.
Abdominal Pain↗
Treatment of multiple small bowel angiodysplasias causing severe life-threatening bleeding with thalidomide.
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Angiodysplasia↗
Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann syndrome due to defects in the function of pancreatic beta-cell adenosine triphosphate-sensitive potassium channels.
BACKGROUND: Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is clinically and genetically heterogeneous. Hyperinsulinemic hypoglycemia occurs in about 50% of children with BWS and, in the majority of infants, it resolves spontaneously. However, in a small group of patients the hypoglycemia can be persistent and may require pancreatectomy. The mechanism of persistent hyperinsulinemic hypoglycemia in this group of patients is unclear. PATIENTS AND METHODS: Using patch-clamp techniques on pancreatic tissue obtained at the time of surgery, we investigated the electrophysiological properties of ATP-sensitive K(+) (K(ATP)) channels in pancreatic beta-cells in a patient with BWS and severe medically-unresponsive hyperinsulinemic hypoglycemia. RESULTS: Persistent hyperinsulinism was found to be caused by abnormalities in K(ATP) channels of the pancreatic beta-cell. Immunofluorescence studies using a SUR1 antibody revealed perinuclear pattern of staining in the BWS cells, suggesting a trafficking defect of the SUR1 protein. No mutations were found in the genes ABCC8 and KCNJ11 encoding for the two subunits, SUR1 and KIR6.2, respectively, of the K(ATP) channel. Genetic analysis of this patients BWS showed evidence of mosaic paternal isodisomy. CONCLUSIONS: In this novel case of BWS with mosaic paternal uniparental disomy for 11p15, persistent hyperinsulinism was due to abnormalities in K(ATP) channels of the pancreatic beta-cell. The mechanism/s by which mosaic paternal uniparental disomy for 11p15 causes a trafficking defect in the SUR1 protein of the K(ATP) channel remains to be elucidated.
ATP-Binding Cassette Transporters↗
Hypertrophic eosinophilic gastroenteropathy is associated with reduced enterocyte apoptosis.
AIMS: To investigate the cause of grossly elongated villi in four children presenting with obstruction due to a novel form of eosinophilic gastroenteropathy in which there was profound hyperplasia of the intestinal villi with grossly increased villous/crypt ratio and prominent mucosal eosinophilia. Increased eosinophils were also present in the muscularis propria and submucosa. All had intermittent diarrhoea and signs of a protein-losing enteropathy. METHODS AND RESULTS: The cause of the grossly elongated villi was investigated by studying enterocyte proliferation (Ki67), survival factors (bcl-2) and apoptosis (TUNEL) in these patients (n = 4) and normal (jejunum n = 6, ileum n = 6) and disease (n = 6) controls. The most remarkable finding was that apoptotic enterocytes were undetectable in the elongated villi. CONCLUSIONS: It seems likely that a defect in the regulation of apoptosis of the epithelium occurs which could explain the remarkable hyperplasia of the villi seen.
Adolescent↗
Consumerism in healthcare can be detrimental to child health: lessons from children with functional abdominal pain.
AIMS: To determine prognostic indicators in children with severe functional abdominal pain (FAP) and to test the hypothesis that "healthcare consumerism" in these families might be deleterious to the child. METHODS: Retrospective analysis of a cohort of 23 children aged <16 years fulfilling the Rome II diagnostic criteria for FAP during the period December 1997 to February 2001. Poor outcome was defined as continued pain and failure to return to normal functioning >12 months after onset. RESULTS: Poor outcome was associated with refusal to engage with psychological services, involvement of more than three consultants, lodging of a manipulative complaint with hospital management by the child's family, and lack of development of insight into psychosocial influences on symptoms. Three of four adverse prognostic indicators reflected healthcare consumerism by the families. CONCLUSIONS: Actions of families who lack insight into their child's illness may perpetuate FAP in childhood. A culture of parental consumerism in healthcare, however well intentioned, needs to be accompanied by robust systems to protect the interests of the child.
Abdominal Pain↗
Eosinophilic myenteric ganglionitis is associated with functional intestinal obstruction.
The diagnostic features and clinical course of three children (aged 1 month to 15 years) with severe functional intestinal obstruction and inflammation of the colonic lamina propria and myenteric plexus are described. The myenteric inflammatory infiltrate was eosinophil predominant with none of the immunological characteristics of lymphocytic ganglionitis. Neurones in the myenteric ganglia expressed the potent eosinophil chemoattractant interleukin 5. None responded to dietary exclusion but all three responded symptomatically to immunosuppression/anti-inflammatory treatments. Eosinophilic ganglionitis is associated with a pseudo-obstructive syndrome which is amenable to anti-inflammatory treatment.
Adolescent↗
Faecal elastase 1 concentration is a marker of duodenal enteropathy.
BACKGROUND: Measurement of faecal elastase (FE1) is used widely to screen for pancreatic exocrine insufficiency (PI). FE1 does not allow differentiation of primary from secondary PI. AIMS: To investigate the relation between duodenal morphology and FE1 in children with secondary PI resulting from primary gastrointestinal diseases. METHODS: A group of 51 children underwent small intestinal biopsy and FE1 measurement. Villus to crypt ratio (VCR) and inflammation within the lamina propria of duodenal mucosal biopsy specimens were scored and compared with FE1 values. RESULTS: In 51 children from nine diagnostic categories, a highly significant correlation between FE1 and both duodenal morphology and inflammation was found. CONCLUSION: Small bowel enteropathy is associated with low FE1 concentrations, indicative of secondary exocrine pancreatic insufficiency.
Biomarkers↗
Uncontrolled insulin secretion from a childhood pancreatic beta-cell adenoma is not due to the functional loss of ATP-sensitive potassium channels.
We report the case of an 8-year-old child who presented with severe hyperinsulinaemic hypoglycaemia due to a pancreatic islet cell adenoma. In vivo, there was no beneficial response to the hyperglycaemia-inducing agent diazoxide and as a consequence the child underwent a subtotal pancreatectomy. In vitro studies of adenomatous beta-cells revealed no operational defects in ATP-sensitive potassium channel activity and appropriate responses to diazoxide. In comparison with patients with focal adenomatous hyperplasia, genetic analysis of the isolated adenoma showed no loss of heterozygosity for chromosome 11p15 and expression of the cyclin-dependent kinase inhibitor p57(kip2). This case illustrates that the excess insulin secretion from an infantile adenoma has an aetiology different from that observed in hyperinsulinism in infancy.
Adenoma, Islet Cell↗
Colitis in chronic granulomatous disease.
BACKGROUND: Involvement of the gut in chronic granulomatous disease (CGD) has been previously described and colitis highlighted. However, the nature and histopathology of the colitis are unclear and have been thought to be non-specific or similar to Crohn's disease. METHODS: Seven patients with CGD, suffering from gastrointestinal symptoms were prospectively studied. RESULTS: All patients had anaemia; other symptoms were failure to thrive (5/7) and diarrhoea (5/7). Most had microcytic anaemia (5/7), increased platelets (7/7), and increased erythrocyte sedimentation rate (6/6). Endoscopically there was a friable erythematous mucosa in 6/7. The histological features present in all patients consisted of a colitis with paucity of neutrophils, increased numbers of eosinophils, eosinophilic crypt abscesses, pigmented macrophages, and nuclear debris. In some granulomas were present (2/7). CONCLUSIONS: Colitis is a common cause of gastrointestinal symptoms in CGD and is caused by a non-infective inflammatory process. The histology has specific features, which are distinctive from those seen in Crohn's disease.
Anemia↗
p57(KIP2) expression in normal islet cells and in hyperinsulinism of infancy.
Most cases of hyperinsulinism of infancy (HI) are caused by mutations in either the sulfonylurea receptor-1 (SUR1) or the inward rectifying K(+) channel Kir6.2, two subunits of the beta-cell ATP-sensitive K(+) channel (K(ATP) channel). Histologically, HI can be divided into two major subtypes. The diffuse form is recessively inherited and involves all beta-cells within the pancreas. Focal HI consists of adenomatous hyperplasia within a limited region of the pancreas, and it is caused by somatic loss of heterozygosity (LOH), including maternal Ch11p15-ter in a beta-cell precursor carrying a germ-line mutation in the paternal allele of SUR1 or Kir6.2. Several imprinted genes are located within this chromosomal region, some of which, including p57(KIP2) and IGF-II, have been associated with the regulation of cell proliferation. Using double immunostaining, we examined p57(KIP2) expression in different islet cell types, in control pancreases from different developmental stages (n = 15), and in pancreases from patients with both diffuse (n = 4) and focal HI (n = 9). Using immunofluorescence and computerized image analysis, we quantified IGF-II expression in beta-cells from patients with focal HI (n = 8). Within the pancreas, p57(KIP2) was specifically localized to the endocrine portion. beta-Cells demonstrated the highest frequency of expression (34.9 +/- 2.7%) compared with approximately 1-3% in other cell types. The fraction of beta-cells expressing p57(KIP2) did not vary significantly during development. beta-Cells within the focal lesions did not express p57(KIP2), whereas IGF-II staining inside focal lesions was mildly increased compared with unaffected surrounding tissue. In conclusion, we demonstrate that p57(KIP2) is expressed and is paternally imprinted in human pancreatic beta-cells. Loss of expression in focal HI is caused by LOH and is associated with increased proliferation and increased IGF-II expression. Manipulation of p57(KIP2) expression in beta-cells may provide a mechanism by which proliferation can be modulated, and thus this gene is a potential therapeutic target for reversing the beta-cell failure observed in diabetes.
Cell Nucleus↗
Hyperinsulinism of infancy: the regulated release of insulin by KATP channel-independent pathways.
Hyperinsulinism of infancy (HI) is a congenital defect in the regulated release of insulin from pancreatic beta-cells. Here we describe stimulus-secretion coupling mechanisms in beta-cells and intact islets of Langerhans isolated from three patients with a novel SUR1 gene defect. 2154+3 A to G SUR1 (GenBank accession number L78207) is the first report of familial HI among nonconsanguineous Caucasians identified in the U.K. Using patch-clamp methodologies, we have shown that this mutation is associated with both a decrease in the number of operational ATP-sensitive K+ channels (KATP channels) in beta-cells and impaired ADP-dependent regulation. There were no apparent defects in the regulation of Ca2+- and voltage-gated K+ channels or delayed rectifier K+ channels. Intact HI beta-cells were spontaneously electrically active and generating Ca2+ action currents that were largely insensitive to diazoxide and somatostatin. As a consequence, when intact HI islets were challenged with glucose and tolbutamide, there was no rise in intracellular free calcium ion concentration ([Ca2+]i) over basal values. Capacitance measurements used to monitor exocytosis in control and HI beta-cells revealed that there were no defects in Ca2+-dependent exocytotic events. Finally, insulin release studies documented that whereas tolbutamide failed to cause insulin secretion as a consequence of impaired [Ca2+]i signaling, glucose readily promoted insulin release. Glucose was also found to augment the actions of protein kinase C- and protein kinase A-dependent agonists in the absence of extracellular Ca2+. These findings document the relationship between SUR1 gene defects and insulin secretion in vivo and in vitro and describe for the first time KATP channel-independent pathways of regulated insulin secretion in diseased human beta-cells.
ATP-Binding Cassette Transporters↗
Glucose regulates islet amyloid polypeptide gene transcription in a PDX1- and calcium-dependent manner.
Islet amyloid polypeptide (IAPP) and insulin are expressed in the beta-cells of the islets of Langerhans. They are co-secreted in response to changes in glucose concentration, and their mRNA levels are also regulated by glucose. The promoters of both genes share similar cis-acting sequence elements, and both bind the homeodomain transcription factor PDX1, which plays an important role in the regulation of the insulin promoter and insulin mRNA levels by glucose. Here we examine the role of PDX1 in the regulation of the human IAPP promoter by glucose. The experiments were facilitated by the availability of a human beta-cell line (NES2Y) that lacks PDX1. NES2Y cells also lack operational K(ATP) channels, resulting in a loss of control of calcium signaling. We have previously used these cells to show that glucose regulation of the insulin gene is dependent on PDX1, but not calcium. In the mouse beta-cell line Min6, glucose (16 mm) stimulated a 3.5-4-fold increase in the activity of a -222 to +450 IAPP promoter construct compared with values observed in 0.5 mm glucose. In NES2Y cells, glucose failed to stimulate transcriptional activation of the IAPP promoter. Overexpression of PDX1 in NES2Y cells failed to reinstate glucose-responsive control of the IAPP promoter. Glucose effects on the IAPP promoter were observed only in the presence of PDX1 when normal calcium signaling was restored by overexpression of the two K(ATP) channel subunits SUR1 and Kir6.2. The importance of calcium was further emphasized by an experiment in which glucose-stimulated IAPP promoter activity was inhibited by the calcium channel blocker verapamil (50 microm). Verapamil was further shown to inhibit the stimulatory effect of glucose on IAPP mRNA levels. These results demonstrate that like the insulin promoter, glucose regulation of the IAPP promoter is dependent on the activity of PDX1, but unlike the insulin promoter, it additionally requires the activity of another, as yet uncharacterized factor(s), the activity of which is calcium-dependent.
Amyloid↗
A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene.
Usher syndrome type 1 describes the association of profound, congenital sensorineural deafness, vestibular hypofunction and childhood onset retinitis pigmentosa. It is an autosomal recessive condition and is subdivided on the basis of linkage analysis into types 1A through 1E. Usher type 1C maps to the region containing the genes ABCC8 and KCNJ11 (encoding components of ATP-sensitive K + (KATP) channels), which may be mutated in patients with hyperinsulinism. We identified three individuals from two consanguineous families with severe hyperinsulinism, profound congenital sensorineural deafness, enteropathy and renal tubular dysfunction. The molecular basis of the disorder is a homozygous 122-kb deletion of 11p14-15, which includes part of ABCC8 and overlaps with the locus for Usher syndrome type 1C and DFNB18. The centromeric boundary of this deletion includes part of a gene shown to be mutated in families with type 1C Usher syndrome, and is hence assigned the name USH1C. The pattern of expression of the USH1C protein is consistent with the clinical features exhibited by individuals with the contiguous gene deletion and with isolated Usher type 1C.
Adaptor Proteins, Signal Transducing↗
Practical management of hyperinsulinism in infancy.
Hyperinsulinism in infancy is one of the most difficult problems to manage in contemporary paediatric endocrinology. Although the diagnosis can usually be achieved without difficulty, it presents the paediatrician with formidable day to day management problems. Despite recent advances in understanding the pathophysiology of hyperinsulinism, the neurological outcome remains poor, and there is often a choice of unsatisfactory treatments, with life long sequelae for the child and his or her family. This paper presents a state of the art overview on management derived from a consensus workshop held by the European network for research into hyperinsulinism (ENRHI). The consensus is presented as an educational aid for paediatricians and children's nurses. It offers a practical guide to management based on the most up to date knowledge. It presents a proposed management cascade and focuses on the clinical recognition of the disease, the immediate steps that should be taken to stabilise the infant during diagnostic investigations, and the principles of definitive treatment.
Genetic Therapy↗
Persistent hyperinsulinaemic hyperglycaemia of infancy-derived cells; implications for beta-cells that replicate in vitro.
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Animals↗