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Biomedical subjects

C Shaw-Smith

Publications and source records attributed to C Shaw-Smith.

8 recordsLinked to original sources
PubMed2005

Oesophageal atresia, tracheo-oesophageal fistula, and the VACTERL association: review of genetics and epidemiology.

Oesophageal atresia and/or tracheo-oesophageal fistula are relatively common malformations occurring in approximately 1 in 3500 births. In around half of the cases (syndromic oesophageal atresia), there are associated anomalies, with cardiac malformations being the most common. In the remainder (non-syndromic cases), oesophageal atresia/tracheo-oesophageal fistula occur in isolation. Data from twin and family studies suggest that genetic factors do not play a major role, and yet there are well-defined instances of this malformation where genetic factors clearly are important. This is highlighted by the recent identification of no fewer than three separate genes with a role in the aetiology of oesophageal atresia: those for Feingold syndrome (N-MYC), anophthalmia-oesophageal-genital (AEG) syndrome (SOX2), and CHARGE syndrome (CHD7). Additional support for genetic factors in this malformation comes from chromosomal studies and mouse models. This paper reviews current knowledge of the genetics and epidemiology of the different oesophageal atresia/tracheo-oesophageal fistula syndromes and associations.

Animals↗
PubMed2005

Prenatal detection of unbalanced chromosomal rearrangements by array CGH.

BACKGROUND: Karyotype analysis has been the standard method for prenatal cytogenetic diagnosis since the 1970s. Although highly reliable, the major limitation remains the requirement for cell culture, resulting in a delay of as much as 14 days to obtaining test results. Fluorescent in situ hybridisation (FISH) and quantitative fluorescent PCR (QF-PCR) rapidly detect common chromosomal abnormalities but do not provide a genome wide screen for unexpected imbalances. Array comparative genomic hybridisation (CGH) has the potential to combine the speed of DNA analysis with a large capacity to scan for genomic abnormalities. We have developed a genomic microarray of approximately 600 large insert clones designed to detect aneuploidy, known microdeletion syndromes, and large unbalanced chromosomal rearrangements. METHODS: This array was tested alongside an array with an approximate resolution of 1 Mb in a blind study of 30 cultured prenatal and postnatal samples with microscopically confirmed unbalanced rearrangements. RESULTS: At 1 Mb resolution, 22/30 rearrangements were identified, whereas 29/30 aberrations were detected using the custom designed array, owing to the inclusion of specifically chosen clones to give increased resolution at genomic loci clinically implicated in known microdeletion syndromes. Both arrays failed to identify a triploid karyotype. Thirty normal control samples produced no false positive results. CONCLUSIONS: Analysis of 30 uncultured prenatal samples showed that array CGH is capable of detecting aneuploidy in DNA isolated from as little as 1 ml of uncultured amniotic fluid; 29/30 samples were correctly diagnosed, the exception being another case of triploidy. These studies demonstrate the potential for array CGH to replace conventional cytogenetics in the great majority of prenatal diagnosis cases.

Chromosome Aberrations↗
PubMed2004

Learning and behavioural difficulties but not microcephaly in three brothers resulting from undiagnosed maternal phenylketonuria.

Universal screening introduced in the 1960s has reduced the incidence of learning disability resulting from phenylketonuria (PKU), which is a treatable condition. Nonetheless, PKU may still be having an impact on the paediatric-age population. We report a woman with previously undiagnosed PKU who was born before the onset of universal screening. She is of normal intelligence, and so the diagnosis was not suspected until after the birth of her three children. Her serum phenylalanine concentration was found to be in excess of 1 mmol/L, well into the toxic range. She has had three sons, all of whom have a significant degree of learning disability resulting from intrauterine exposure to toxic levels of phenylalanine. None of the sons had microcephaly, a physical sign that, if present, might have helped to point towards the correct diagnosis. We suggest that maternal PKU should be suspected where there is sibling recurrence of cognitive impairment, particularly where the mother was born before the initiation of the neonatal screening programme for PKU.

Adult↗
PubMed2004

Microarray based comparative genomic hybridisation (array-CGH) detects submicroscopic chromosomal deletions and duplications in patients with learning disability/mental retardation and dysmorphic features.

The underlying causes of learning disability and dysmorphic features in many patients remain unidentified despite extensive investigation. Routine karyotype analysis is not sensitive enough to detect subtle chromosome rearrangements (less than 5 Mb). The presence of subtle DNA copy number changes was investigated by array-CGH in 50 patients with learning disability and dysmorphism, employing a DNA microarray constructed from large insert clones spaced at approximately 1 Mb intervals across the genome. Twelve copy number abnormalities were identified in 12 patients (24% of the total): seven deletions (six apparently de novo and one inherited from a phenotypically normal parent) and five duplications (one de novo and four inherited from phenotypically normal parents). Altered segments ranged in size from those involving a single clone to regions as large as 14 Mb. No recurrent deletion or duplication was identified within this cohort of patients. On the basis of these results, we anticipate that array-CGH will become a routine method of genome-wide screening for imbalanced rearrangements in children with learning disability.

Adolescent↗
PubMed1996

Growth factors and ulcerative gastrointestinal disease.

A huge variety of peptides and cytokines are involved in the maintenance of mucosal integrity and in the inflammatory response at sites of ulceration. Most studies have focused on the effects of an individual factor in this complex process. However, it is becoming increasingly apparent that, to fully understand their importance in vivo, we should consider their function as part of a highly integrated system. It is also becoming clear that a relatively small number of common pathways are brought into play by the host in response to a wide variety of intestinal insults.

Cytokines↗
PubMed1996

Characterization of DRP2, a novel human dystrophin homologue.

The currently recognised dystrophin protein family comprises the archetype, dystrophin, its close relative, utrophin or dystrophin-related protein (DRP), and a distantly related protein known as the 87K tyrosine kinase substrate. During the course of a phylogenetic study of sequences encoding the characteristic C-terminal domains of dystrophin-related proteins, we identified an unexpected novel class of vertebrate dystrophin-related sequences. We term this class dystrophin-related protein 2 (DRP2), and suggest that utrophin/DRP be renamed DRP1 to simplify future nomenclature. DRP2 is a relatively small protein, encoded in man by a 45 kb gene localized to Xq22. It is expressed principally in the brain and spinal cord, and is similar in overall structure to the Dp116 dystrophin isoform. The discovery of a novel relative of dystrophin substantially broadens the scope for study of this interesting group of proteins and their associated glycoprotein complexes.

Amino Acid Sequence↗
PubMed1994

Non-steroidal anti-inflammatory drugs: how do they damage the gut?

NSAIDs are widely prescribed for the treatment of musculoskeletal disorders. The gastrointestinal tract, predominantly the stomach, bears the brunt of their side-effects. The basis of this toxicity is certainly multifactorial, with a wide range of local effects and mucosal defences being implicated. This review will highlight: (1) the epidemiology of NSAID-induced gastrointestinal toxicity; (2) their effects on prostaglandins, and the phenomenon of cytoprotection; (3) effects on neutrophil function; (4) effects on mucosal blood flow; (5) responses of the mucosa to damage (restitution, adaptation, and regenerative repair); (6) the relevance of growth factors; (7) interactions with Helicobacter pylori in ulcerogenesis, and finally (8) the effects of NSAIDs on the small intestine and colon.

Anti-Inflammatory Agents, Non-Steroidal↗