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Title: A study of molecular forms of the cholinesterases with particular reference to Hirschsprung's disease and neural tube defects
Author: Bonham, James Robert
Awarding Body: Newcastle University
Current Institution: University of Newcastle upon Tyne
Date of Award: 1986
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Acetylcholinesterase [ACNE) and butyrylcholinesterase [EChE) were studied in amniotic fluid in relation to the detection of neural tube defects CNTD), and in rectal tissue in the diagnosis of Hirschsprung's disease. An automated assay is described for measurement of AChE and BChE activity in amniotic Fluid, and an increase in both is found in the presence of NTD. Analysis of AChE molecular forms by sucrose density sedimentation revealed three species with differing sedimentation coefficients and molecular masses: monomeric G1[4. OS, 78KOa), dimeric G2[5.5S, 126KOa) and tetrameric G4(10.35,256KDa). The tetramer, G4 is NTD specific and is largely responsible for the increase in activity seen in the quantitative assessment of'total AChE and for the abnormal band identifiable by polyacrylamide gel electrophoresis in pregnancies affected by NTO. Evidence is presented which indicates that G4 is a soluble species secreted from nerve trunks exposed as a result of the lesion. SChE activity, the likely source of which is fetal plasma is shown to be a less specific indicator of NTD. These results represent the first description of the structural molecular heterogeneity of AChE and SChE forms in amniotic fluid. AChE activity was measured in rectal biopsy specimens from 213 patients in whom a diagnosis of Hirschsprung's disease was suspected. The results from this, the largest study so far reported, indicate the value of AChE measurement in the detection of the disease. The molecular forms of AChE and SChE were investigated in resected bowel segments from patients with Hirschsprung's disease. Four species of AChE were identified: G1[3.55,74KOa), G2[S. OS, 131KDa), 64(9.23,275KOa] and the asymmetric form A12(16.83,811KDa). In all cases there was an increase (4-14 fold] in G4-AChE activity in the aganglionic cola-rectum. The evidence indicates that this is derived from hypertrophied nerve trunks present in the affected zone. The increase in G4-AChE was largely responsible for the increase in total AChE activity in rectal biopsy specimens from patients with Hirschsprung's disease. BChE molecular forms showed no consistent changes in Hirschsprung's disease. Characterisation of the molecular forms of AChE by gel filtration and with respect to their thermal stability, sensitivity to Triton X-100 and response to substrate inhibition is also investigated.
Supervisor: Not available Sponsor: Mr J Wagget, Fleming Memorial Hospital
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Biochemistry Biochemistry Medicine