Histopathological features of gastrointestinal mucosal biopsy specimens in children with epidermolysis bullosa.
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Adolescent↗
Biomedical subjects
V V Smith
Publications and source records attributed to V V Smith.
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↗
Intestinal ischemia-reperfusion injury does not lead to acute central nervous system damage.
BACKGROUND: The detrimental effects of intestinal ischemia reperfusion (IIR) injury on secondary organs including the liver, lungs, heart, and kidney have been widely investigated in animal models. However, the effect of IIR on the central nervous system (CNS) is largely unknown. We investigated the effect of IIR on the CNS as it may be of clinical relevance to patients at high risk of neurological injury. MATERIALS AND METHODS: Adult male rats underwent IIR (60 min superior mesenteric artery occlusion followed by 120 min reperfusion, n = 7) or sham operation (n = 6) under anesthesia. Following the procedure, the cerebral hemispheres were removed for histological assessment and measurement of N-acetyl-aspartate (NAA), a marker of neuronal damage, by HPLC. Blood was taken for determination of plasma S100B concentration, a measure of glial cell damage by ELISA. Data are median (range). RESULTS: Cerebral tissue from all animals from both groups was macroscopically and microscopically normal with no evidence of inflammation. NAA in brain homogenate was similar in the IIR group (0.2 [0.1-0.32] nmol/mg protein) and sham-operated group (0.19 [0.12-0.34], P = 0.83). Plasma S100B levels were higher in the IIR group compared to sham-operated animals but this difference was not statistically significant (1.13 [0.24-7.26] versus 0.55 [0.23-2.84] mug/l, P = 0.18). CONCLUSIONS: In this model, IIR injury did not produce histological CNS changes nor biochemical changes suggestive of neuronal damage. Further work is required to elucidate any functional effect of IIR injury on the CNS.
Acute Disease↗
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↗
Histopathological features of chronic granulomatous disease (CGD) in childhood.
AIMS: To describe the spectrum of histopathological features encountered in children with chronic granulomatous disease (CGD) at a specialist centre. METHODS AND RESULTS: The histopathological findings of 88 surgical pathology requests from a range of organ systems including upper and lower gastrointestinal tract biopsy series, liver, bladder, bone, lung, skin, soft tissue, bone marrow and lymph node biopsy specimens, in 32 patients aged 4 months to 18 years (median 7 years) with CGD were reviewed. In most tissues the features were those of active chronic inflammation, with or without abscess or granuloma formation, often associated with fungal infection. In some tissues, more characteristic findings were identified, including the presence of pigmented macrophages, especially in hepatic sinusoids and colonic mucosa, where active chronic eosinophil predominant colitis was also observed. CONCLUSIONS: Chronic granulomatous disease may present to histopathologists in a wide range of tissue specimens most often demonstrating features of active chronic inflammation with or without granuloma formation. The presence of numerous pigmented macrophages in association with such inflammation should raise suspicion of the diagnosis. In addition, diffuse granulomatous inflammation of the lung and hepatic abscess formation should be regarded as suggestive of the diagnosis.
Adolescent↗
Blood film examination for vacuolated lymphocytes in the diagnosis of metabolic disorders; retrospective experience of more than 2,500 cases from a single centre.
BACKGROUND: A range of metabolic diseases can result in abnormal accumulation of metabolic byproducts, resulting in abnormal lymphocyte cytoplasmic vacuolation, identifiable on routine blood film examination. AIMS: This study retrospectively examines the usefulness of blood film examination for vacuolated lymphocytes in a specialist paediatric pathology department in relation to patient's age and presentation. It also describes specific diagnostic features in relation to specific classes of metabolic disease. METHODS: Retrospective review of a histopathology database to identify all blood films examined for the detection of vacuolated lymphocytes during a 15 year period (1989-2004). RESULTS: In total, 2,550 blood films were investigated. The median age at submission was 2 years (range, birth to 88), and>90% of samples were from children<18 years. The most common indications were developmental delay/regression, ataxia, seizures, and cardiomyopathy. Vacuolated lymphocytes were identified in 156 films (6.1%). The frequency of vacuolated lymphocytes varied with clinical presentation, with ophthalmic indications having the highest positive rate (40%). In cases with vacuolated lymphocytes, a wide range of underlying metabolic diagnoses was apparent, the most common being juvenile neuronal ceroid lipofuscinosis and acid maltase deficiency, which accounted for more than half of the diagnoses. CONCLUSIONS: The examination of blood films for lymphocyte vacuolation is clinically useful in patients with a history suggestive of metabolic disease. The test is cheap, rapid, minimally invasive, and provides first line screening, with some findings indicating clues to a specific underlying diagnosis.
Adolescent↗
Light microscopic examination of scalp hair samples as an aid in the diagnosis of paediatric disorders: retrospective review of more than 300 cases from a single centre.
BACKGROUND: Microscopic examination of scalp hair can provide important diagnostic information in a range of paediatric conditions. It is a non-invasive and cost effective investigation, which is not widely performed. AIMS: To examine retrospectively the value of hair examination by light microscopy, including polarising microscopy, in a specialist paediatric pathology department during a 15 year period (1989-2004) and to describe the morphological abnormalities indicative of specific paediatric conditions. METHODS: Three hundred and twenty two hair samples were submitted. Microscopic changes were analysed in the light of clinical information categorised as: (1) erythroderma, (2) neurological impairment, (3) immunological/haematological defect, (4) ectodermal dysplasia, (5) abnormal hair only, and (6) non-specific/absent clinical details. RESULTS: Abnormalities were evident in 49% of the samples. In 25%, the changes were compatible with specific diagnoses including Menkes disease, Netherton's syndrome, trichothiodystrophy, Griscelli and Chediak-Higashi syndromes, monilethrix, uncombable hair, and loose anagen syndromes. In respect of the clinical presentation groups noted above, diagnostic changes were seen in 41%, 32%, 33%, 0%, 29%, and 0%, respectively. CONCLUSIONS: Morphological light microscopic examination of scalp hair is an inexpensive, rapid, and non-invasive investigation, which can provide valuable diagnostic information in a range of paediatric conditions.
Adolescent↗
LEKTI demonstrable by immunohistochemistry of the skin: a potential diagnostic skin test for Netherton syndrome.
BACKGROUND: Netherton syndrome (NS) is a rare autosomal recessive condition characterized by ichthyosiform erythroderma, trichorrhexis invaginata and atopic manifestations. Confirming the diagnosis may be difficult in the early stages. Mutations in the SPINK5 gene which encodes for the serine protease inhibitor LEKTI are associated with NS. These mutations create premature termination codons which result in absent or abnormal expression of LEKTI in patients with NS. OBJECTIVES: To investigate the expression of LEKTI in the skin of patients with NS in comparison with normal controls and patients with other skin conditions, namely atopic dermatitis, psoriasis and nonbullous ichthyosiform erythroderma. METHODS: Immunohistochemistry was performed on skin sections from four patients with NS, four normal controls, four with atopic dermatitis, two with psoriasis and two with nonbullous ichthyosiform erythroderma, using a primary rabbit polyclonal antibody against LEKTI. RESULTS: LEKTI was localized to the stratum granulosum in normal skin. All four skin sections from patients with NS showed absent or very reduced staining for LEKTI. Staining in the other disorders showed positive LEKTI expression in varying patterns. CONCLUSIONS: NS can be difficult to diagnose especially in the early stage, which can lead to inappropriate treatments particularly if it is misdiagnosed as atopic dermatitis. Immunohistochemistry of skin with an antibody against LEKTI is a potentially useful diagnostic test for NS.
Adolescent↗
The histological appearances of Nissen-type fundoplication in the ferret.
Nissen fundoplication is of proven effectiveness in the surgical control of gastro-oesophageal reflux. However, our understanding of the effects of fundoplication upon foregut physiology is incomplete and post-operative symptoms are often poorly understood. This experimental study aimed systematically to characterize the tissue response to fundoplication in an animal model, to improve understanding of the effects of anti-reflux surgery upon foregut physiology. Nissen-type fundoplication was performed in the ferret, and the tissue response at 3 months examined histologically. Sham-operated animals that underwent laparotomy but no dissection or wrap, acted as controls. In fundoplicated animals, serosal fibrosis was observed in the gut wall, with patchy replacement of muscle by fibrous tissue. The ventral and dorsal vagal nerve trunks were identified intact within the wrap. In cases where the wrap had spontaneously disrupted, fibrosis was more extensive and there was evidence of nerve damage. This is the first systematic description of the histopathological response to Nissen fundoplication. In the intact wrap, the vagal trunks appear spared, but there is fibrosis in the serosa, extending into the muscularis of the distal oesophagus and region of the cardia. These findings are discussed in relation to the effects of Nissen fundoplication upon gastric physiology and postoperative symptoms.
Animals↗
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↗
Embryonic gut anomalies in a mouse model of retinoic Acid-induced caudal regression syndrome: delayed gut looping, rudimentary cecum, and anorectal anomalies.
Vitamin A and its derivatives such as retinoic acid (RA) are important signaling molecules for morphogenesis of vertebrate embryos. Little is known, however, about morphogenetic factors controlling the development of the gastrointestinal tract and RA is likely to be involved. In the mouse, teratogenic doses of RA cause truncation of the embryonic caudal body axis that parallel the caudal regression syndrome as described in humans. These changes are often associated with anomalies of the lower digestive tract. Overlapping spatiotemporal expression of retinoic acid receptor-beta (RAR beta) and cellular retinol-binding protein I, CRBPI, with Hoxb5 and c-ret in the gut mesoderm imply possible cooperation required for proper neuromuscular development. To determine susceptibility and responsiveness of the developing gut and its neuromusculature to exogenous retinoids we used a mouse model of RA-induced caudal regression syndrome. The results showed that stage-specific RA treatment both in vivo and in vitro affected gut looping/rotation morphogenesis and growth of asymmetrical structures such as the cecum together with delayed differentiation of the gut mesoderm and colonization of the postcecal gut by neural crest-derived enteric neuronal precursors. These observations demonstrate that RA has a direct effect on gut morphogenesis and innervation.
Animals↗
Symptomatic diffuse colonic lipomatosis in Proteus syndrome.
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Child↗
Chronic intestinal pseudo-obstruction: the pathologist's perspective.
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Child↗
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↗
Paraffin wax embedded muscle is suitable for the diagnosis of muscular dystrophy.
AIM: At present, the diagnosis of muscular dystrophy is made by means of immunohistochemistry on frozen sections. The aim of this study was to develop a sensitive and reproducible immunohistochemical method for use on formalin fixed, paraffin wax embedded sections for the demonstration of dystrophin associated proteins and other muscle associated antigens. METHODS: All the cases studied were from the files of the department of histopathology, Great Ormond Street Hospital for Children NHS Trust. Immunohistochemistry was performed on paraffin wax embedded sections with heat mediated antigen retrieval and overnight incubation with the antibodies at room temperature. Four different pretreatment buffers were tested in the attempt to optimise the immunostaining. Frozen sections were run in parallel for direct comparison. RESULTS: All the antibodies except delta sarcoglycan gave strong, consistent immunostaining in paraffin wax embedded sections, comparable with the frozen sections. The most consistent results were obtained using citrate/EDTA as the pretreatment buffer. CONCLUSION: A reliable and reproducible technique has been established, using a heat mediated citrate/EDTA buffer antigen retrieval method, which works well for most of the antibodies needed to make the diagnosis of muscular dystrophy in formalin fixed, paraffin wax embedded sections. This technique overcomes some of the inherent problems encountered using frozen muscle tissue and it could become a valuable tool for the diagnosis of muscular dystrophy.
Biomarkers↗