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V V Smith

Publications and source records attributed to V V Smith.

At least 37 records · Page 2Linked to original sources
PubMed2000

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↗
PubMed1999

Coordinated expression of 3' hox genes during murine embryonal gut development: an enteric Hox code.

BACKGROUND & AIMS: Hox genes are highly conserved developmental control genes that may be organized and expressed in the form of a code required for correct morphogenesis. Little is known about their control of the embryonal gut. However, Hox paralogues 4 and 5, which are expressed at the sites of origin of vagal neural crest cells and splanchnic mesoderm, are likely to be important. We have studied the expression domains of these genes in the gut both spatially and temporally. METHODS: CD1 mice embryos of embryonic days E8.5-E17.5 were studied. The spatial and temporal expression patterns of messenger RNA of Hoxa4, b4, c4, d4, a5, c5, and b5 homeoprotein were determined by in situ hybridization and immunohistochemistry in whole embryos, whole gastrointestinal tracts, and vibratome sections. RESULTS: There were different spatial, temporal, and combinatorial expression patterns in different morphological regions: foregut, prececal gut, cecum, and postcecal gut. Two dynamic gradients, rostral and caudal, were coordinated with nested expression domains along the gut primordium. Region-specific domains were present in the stomach and cecum. CONCLUSIONS: The expression patterns of genes in paralogous groups 4 and 5 suggest that they are organized to form a specific enteric Hox code required for correct enteric development.

Animals↗
PubMed1999

Chronic intestinal pseudo-obstruction: treatment and long term follow up of 44 patients.

AIMS: To document the long term course of chronic idiopathic intestinal pseudo-obstruction syndrome (CIIPS) in children with defined enteric neuromuscular disease, and the place and type of surgery used in their management; in addition, to identify prognostic factors. METHODS: Children with CIIPS were investigated and treated prospectively. RESULTS: Twenty four children presented congenitally, eight during the 1st year of life, and 10 later. Twenty two had myopathy and 16 neuropathy (11 familial). Malrotation was present in 16 patients, 10 had short small intestine, six had non-hypertrophic pyloric stenosis, and 16 had urinary tract involvement. Thirty two patients needed long term parenteral nutrition (TPN): for less than six months in 19 and for more than six months in 13, 10 of whom are TPN dependent; 14 are now enteral feeding. Prokinetic treatment improved six of 22. Intestinal decompression stomas were used in 36, colostomy relieved symptoms in five of 11, and ileostomy in 16 of 31. A poor outcome (death (14) or TPN dependence (10)) was seen with malrotation (13 of 16), short small bowel (eight of nine), urinary tract involvement (12 of 16), and myopathic histology (15 of 22). CONCLUSIONS: In CIIPS drugs are not helpful but decompression stomas are. Outcome was poor in 24 of 44 children (15 muscle disorder, 10 nerve disease).

Adolescent↗
PubMed1999

Intestinal ganglioneuromatosis and multiple endocrine neoplasia type 2B: implications for treatment.

Three infants, who presented with intestinal obstruction due to diffuse transmural intestinal ganglioneuromatosis, are described. Mutation analysis of exon 16 of the RET proto-oncogene revealed germline M918T and thus, a molecular diagnosis of multiple endocrine neoplasia type 2B (MEN 2B). Two infants developed medullary carcinoma of the thyroid. The third had a prophylactic thyroidectomy despite no obvious thyroid masses and normal calcitonin concentrations, but microscopic multifocal medullary carcinoma was found on histological examination. Early recognition of intestinal ganglioneuromatosis with germline RET M918T mutation in pseudo-Hirschsprung's disease is an indication for prophylactic thyroidectomy.

Female↗
PubMed1998

Altered contractile proteins and neural innervation in idiopathic megarectum and megacolon.

AIM: The aetiology of idiopathic megarectum and idiopathic megacolon is unknown. We postulated that biochemical or ultrastructural abnormalities may be pathologically important, as has been observed in patients with chronic idiopathic intestinal pseudo-obstruction. METHODS AND RESULTS: Resection specimens from five patients with idiopathic megarectum or megacolon were processed for paraffin wax-embedded tissue histology (haematoxylin and eosin, Gomori trichrome and picrosirius stains, phosphatase activity and periodic acid-Schiff staining), and frozen tissue for histochemistry and electron microscopy. The antibodies used in the immunohistochemistry were to myosin light chain kinase, smooth muscle myosin, alpha and beta actins, filamin, tropomyosin, phosphorylated and dephosphorylated neurofilaments and N-CAM. Variable hypertrophy of the muscularis mucosae and externa, no atrophy, and a variable nerve density decrease in longitudinal muscle and increase in the lamina propria was seen. In one patient beta actin and myosin light chain kinase immunoreactivity was reduced. CONCLUSION: Variable changes in innervation, and an abnormal contractile protein immunoreactivity pattern in one patient, may be of pathogenic importance. These clinically homogeneous conditions are likely to be due to a range of underlying pathogenic abnormalities. A search for further specific biochemical abnormalities is justified.

Actins↗
PubMed1997

Acquired intestinal aganglionosis and circulating autoantibodies without neoplasia or other neural involvement.

The clinical course, diagnosis, and treatment of 2 patients with acquired intestinal aganglionosis without other neurological involvement or neoplasia are described. They initially presented with constipation and abdominal pain in late childhood. They were found to have enteric ganglionitis with a loss of neurons together with vacuolated nerve cells surrounded by CD3- and CD4-positive T lymphocytes. This process initially affected only the colon but later the entire gastrointestinal tract was involved in 1 patient. Associated with this process there were circulating immunoglobulin G class enteric neuronal antibodies in high titer (1:5000-8000). The staining of central nervous system neuronal nuclei and Western blotting indicated the presence of antineuronal nuclear protein antibodies of the ANNA-1 (anti-Hu) type usually associated with paraneoplastic sensory neuropathy. However, the reaction pattern in enteric neurons was quite different with strong reaction to perikarya and only weak staining of nuclear antigens.

Adolescent↗
PubMed1997

Histological phenotypes of enteric smooth muscle disease causing functional intestinal obstruction in childhood.

AIMS: Functional intestinal obstruction or chronic idiopathic intestinal pseudo-obstruction is due to defects either in the enteric innervation or in intestinal smooth muscle. We have studied full-thickness intestinal biopsies from 27 patients with functional intestinal obstruction due to enteric smooth muscle disease by routine histology and electron microscopy together with histochemical and immunohistochemical techniques to detect changes in the intestinal smooth muscle. METHODS AND RESULTS: Two patients appeared to have an acquired intestinal myopathy as a result of an autoimmune process. In 25 the disorders were congenital, of these seven had segmental abnormalities limited to the rectum and distal colon and 18 had a diffuse disease affecting both the small and large bowel. We identified five apparent histological phenotypes of enteric muscle disease, three of which represent abnormalities in morphogenesis resulting in alterations in intestinal muscle layering and two exemplify intrinsic myocyte defects and/or changes in the extracellular matrix. CONCLUSIONS: Careful phenotyping of these patients is important in devising optimal treatment and in understanding the underlying defect as well as the possible genetic mechanisms resulting in these abnormalities. Recognition of autoimmune smooth muscle disease is helpful, since making the diagnosis influences the patient's management.

Child, Preschool↗
PubMed1997

An evaluation of the role of suction rectal biopsy in the diagnosis of intestinal neuronal dysplasia.

BACKGROUND: German pathologists have developed a consensus for histological features of intestinal neuronal dysplasia. METHODS: A blind reevaluation of ganglionic suction rectal biopsies from infants and children who initially presented with symptoms of intestinal dysmotility was made. RESULTS: 84 of 411 specimens had sufficient depth of submucosa for adequate assessment. Questionnaires or clinical interviews were employed 3-5 years after biopsy in these 84 patients to assess the relationship between histological changes and persistent symptomology. Eighteen children were lost to follow-up, 4 others had Hirschsprung's disease the study biopsy specimen having been taken from the pulled-through bowel after surgical resection of the aganglionic segment. The remaining 62 patients were divided into three groups. There were six patients in group A (both obligatory criteria) and 28 in group B (nonessential, or just one of the obligatory criteria), and 28 in group C (normal appearances). On follow-up, two of the 28 (7%) in group B, and six of the 28 (21%) in group C had persistent dysmotility symptoms. CONCLUSIONS: Histological criteria of the consensus of German Pathologists for intestinal neuronal dysplasia was unhelpful in predicting the clinical outcome and therefore, should not influence clinical management. As one of the obligatory criteria, hyperplasia of the submucosal plexus was significantly more common in neonates (< 4 weeks), it is concluded that this is an age-related variation.

Acetylcholinesterase↗
PubMed1996

Infantile chronic idiopathic intestinal pseudo-obstruction: the role of small intestinal manometry as a diagnostic tool and prognostic indicator.

BACKGROUND: Chronic idiopathic intestinal pseudo-obstruction (CIIP) presenting in infancy is a rare but serious condition of heterogeneous aetiology often with an uncertain outcome. AIM: To assess whether intestinal manometry in the first two years of life can help define a neuropathic or myopathic aetiology or clinical outcome, or both, in cases of infantile CIIP. SUBJECTS AND METHODS: 14 consecutive children who presented in the first year of life with CIIP were studied histologically and by small intestinal manometry. RESULTS: Five had a myopathic disorder, four were neuropathic, and five unclassified following histological investigation of full thickness intestinal biopsy specimens. Analysis of fasting phase III activity showed four patterns: (1) (n = 4) no detectable motor activity, (2) (n = 5) low amplitude phase III activity, (3) (n = 3) poorly formed phase III complexes of short duration, (4) (n = 2) well formed cyclical phase III activity with abnormal propagation. The seven children with low amplitude phase III: motility index (MI) < 10 KPa/min, all had a poor outcome (death or dependence on parenteral nutrition) after 1-10 years follow up, compared with two of seven of those with a MI > 10 KPa/min. Of the five with myopathic histology, four had a MI < 10 KPa/min. CONCLUSION: These results show that small intestinal manometry is useful not only as an aid in diagnosing the aetiology of CIIP presenting in infancy, but also in predicting outcome.

Chronic Disease↗
PubMed1996

The locus for a novel syndromic form of neuronal intestinal pseudoobstruction maps to Xq28.

The neuronal type of primary chronic idiopathic intestinal pseudoobstruction (CIIP) results from the developmental failure of enteric neurons to migrate or differentiate correctly. This leads to intestinal motility disorders, which are characterized by symptoms and signs of bowel obstruction in the absence of a mechanical obstacle. Most of these conditions are congenital, and among them some are inherited. One syndromic condition characterized by intestinal pseudoobstruction with morphological abnormalities of the argyrophil neurons in the myenteric plexus, associated with short small bowel, malrotation, and pyloric hypertrophy, has been previously described. We have studied a family affected by this disorder, in which the disease appeared to segregate as an X-linked recessive trait. In order to map the CIIP locus in this family, we performed linkage analysis in 26 family members by use of highly polymorphic microsatellite markers from the X chromosome. One of these markers, DXYS154, located in the distal part of Xq28, shows no recombination with a maximum lod score of 2.32. Multipoint analysis excluded linkage with markers spanning other regions of the X chromosome. Our results, integrated with the current genetic and physical map of Xq28, determine the order of loci as cen-DXS15-(CIIPX)-DXS1108/DXYS154-tel. This study establishes, for the first time, the mapping assignment of a neuropathic form of CIIP other than Hirschsprung disease.

Chromosome Mapping↗
PubMed1996

Argyrophilia in the developing human myenteric plexus.

Silver staining is a useful means of demonstrating enteric neurons, and an absence of argyrophilic neurons has been proposed as a cause of functional intestinal obstruction in infants. No systematic data are available about the origin and development of argyrophilia, or of normal neuronal appearances. Specimens of colon from 48 infants and children (pre-term to 14 years) who had died of nongastrointestinal causes were studied by silver staining. Inter-sample variations in neuronal size, morphology and intensity of staining (strong, faint or absent) were seen: strong argyrophilia (n = 17), age range three days to eight years (median seven months); no argyrophilia (n = 19), pre-term to one year (median eight weeks); weak argyrophilia (n = 12) one day to 14 years (median eight weeks). Neurons in every preterm infant were argyrophobic, and argyrophilic neurons were always found in babies aged over one year. Where argyrophilic neurons were seen, argyrophobes outnumbered them (median ratio of 9:1). This study demonstrated considerable variability in the appearance and argyrophilia of colonic myenteric neurons in the first year of life. The data were consistent with the continuing post-natal development of the enteric nervous system in a manner analogous to the brain, and show the importance of age in the interpretation of silver-stained material from infants with pseudo-obstruction.

Adolescent↗
PubMed1992

Intestinal pseudo-obstruction with deficient smooth muscle alpha-actin.

We describe a 48-year-old woman with chronic constipation since early childhood who has an intestinal myopathy associated with a hitherto undescribed absence by immunostaining of smooth muscle alpha-actin confined to the intestinal circular muscle. There were no abnormalities in other contractile proteins (myosin, tropomyosin, filamin, caldesmon or desmin) and despite the abnormality of a contractile protein isoform in the circular muscle, no significant morphological changes were identified by light microscopy or ultrastructural examination. A possible developmental mechanism for the observed change is proposed. The use of specific antibodies to isoforms of contractile proteins may have potential value in the study of intestinal myopathies.

Actins↗
PubMed1992

Persistent gastrointestinal symptoms after correction of malrotation.

Persistent vomiting, diarrhoea, or intolerance of feeding, are well recognised problems in children after surgical correction of intestinal malrotation. Conversely, intestinal malrotation is a common accompaniment of chronic idiopathic intestinal pseudo-obstruction. We investigated motor activity of the small intestine during fasting in eight children who had persistent vomiting, intolerance of full enteral feeding, or severe diarrhoea after surgical correction of intestinal malrotation. Abnormality of motor function similar to that found in neuropathic pseudo-obstruction was found in seven of the eight patients. Persistence of symptoms after surgical correction of a malrotation is associated with a motility disturbance which seems to be due to a defect of intrinsic enteric innervation. Such a defect may be important in the aetiology of the malrotation.

Child, Preschool↗
PubMed1992

Gastric antral dysrhythmias in children with chronic idiopathic intestinal pseudoobstruction.

Chronic idiopathic intestinal pseudoobstruction is a serious disorder of intestinal neuromuscular function resulting in recurrent episodes of intestinal obstruction, and is caused by primary disease of the enteric nerves or enteric smooth muscle. Gastric electrical control activity detected by the non-invasive technique of surface electrogastrography was investigated in 11 children (0.1-16 years) with proven chronic idiopathic intestinal pseudoobstruction (four with known disease of the enteric nerves, three with disease of smooth muscle cells, and four without defined pathology), to determine whether abnormalities were present and whether these were useful in detecting the underlying pathology. Abnormalities were present in eight of 11 patients. Persistent tachygastria (electrical control activity frequency > 5 cycles/minute) was found in three patients, all with a proven neuropathy. A continuously irregular frequency was found in five patients, three with a proven myopathy and two with undefined pathology. A normal electrical control activity frequency was present in three patients, one with a proven neuropathy and two with undefined pathology. It is suggested that this non-invasive technique may provide a useful screening test of the pathophysiological basis of the functional obstruction in children with chronic idiopathic intestinal pseudoobstruction.

Adolescent↗
PubMed1990

Depletion of alcohol (hexanol) dehydrogenase activity in the epidermis and jejunal mucosa in Sjögren-Larsson syndrome.

Using a histochemical technique, we have demonstrated a consistent deficiency of alcohol (hexanol) dehydrogenase activity within the epidermis and jejunal mucosa of patients with Sjögren-Larsson syndrome. Biochemical assay of the fatty alcohol: NAD oxidoreductase activity in cultured fibroblasts and leukocytes from these patients showed deficient activities compared with controls. The histochemical and biochemical results are complementary, and the simpler histochemical method can be used reliably for initial screening of patients with ichthyosis in whom a diagnosis of Sjögren-Larsson syndrome is suspected.

Alcohol Dehydrogenase↗