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Biomedical subjects

C Williamson

Publications and source records attributed to C Williamson.

At least 73 records · Page 4Linked to original sources
PubMed1997

Analysis of the preS1 gene of hepatitis B virus (HBV) to define epidemiologically linked and un-linked infections in South Africa.

Analysis of the preS1 gene of hepatitis B virus was used to define two nosocomial outbreaks of HBV infection. In an outbreak in an oncology unit we had previously shown by single stranded conformational polymorphism (SSCP) analysis of a 189 bp fragment of the preS1 gene, that 52 children were infected with HBV strains that displayed only 5 different SSCP profiles. Sequencing of a 383 bp fragment encompassing the entire preS1 gene, revealed that isolates with same SSCP profile were identical in sequence across the entire preS1 gene, confirming that those patients with the same SSCP pattern had epidemiologically linked infections. A second outbreak involved 8 liver transplant patients from two different hospitals, 5 of whom were from the same hospital at which the oncology outbreak had occurred. Two of these 5 patients had HBV strains that were identical to strains from the oncology unit and nosocomial transmission probably accounted for the infections in these two, while diversity of both SSCP profiles and sequence data of remaining 6 patients supported the conclusion that they had not been infected from a common source. The donor liver is believed to be the most likely source of infection in these patients. HBV isolates from patients infected in the community were used as a standard for the general degree of preS1 sequence variation of local HBV strains. Phylogenetic analysis and comparison with reference HBV clones revealed that of 27 local HBV strains, genotypes A and D occurred most frequently and were identified in 14 and 12 patients respectively, while genotype C was detected in one patient.

Base Sequence↗
PubMed1997

Metastatic parathyroid carcinoma in the MEN2A syndrome.

We report a patient with a metastatic parathyroid carcinoma and medullary carcinoma of the thyroid. This patient represents a variation of the multiple endocrine neoplasia syndrome (MEN) type 2A. There was no evidence of a phaeochromocytoma. The case illustrates the difficulties that may be encountered in localising the source of PTH secretion; the patient underwent four unsuccessful exploratory operations of the neck and mediastinum before further investigations revealed a single metastatic deposit of parathyroid carcinoma involving the first thoracic vertebra. PCR amplification and sequencing of the RET oncogene from the metastatic parathyroid carcinoma and genomic DNA revealed a heterozygous mutation (Cys634Tyr) in exon 11, as has previously been described to occur in MEN 2A. In addition, loss of tumour heterozygosity was demonstrated at loci from chromosomes 1, 2, 3p, 13q and 16p. This represents the first report of a parathyroid carcinoma in a MEN2A patient, in which the multiple allelic deletions are consistent with the generalised losses observed in aggressive tumours.

Carcinoma↗
PubMed1997

An association between HIV-1 subtypes and mode of transmission in Cape Town, South Africa.

OBJECTIVES: To determine HIV-1 env and gag subtypes in male homosexual and heterosexual populations in Cape Town, South Africa. DESIGN: DNA was isolated from blood originating from 61 patients attending local clinics. Samples were divided according to presumed mode of transmission: male homosexual (n = 26), heterosexual/vertical (n = 32), blood transfusion (n = 1) and unknown (n = 2). METHODS: Proviral HIV-1 DNA was subtyped by heteroduplex mobility assay (HMA) based on the 799 base-pair V3-V5 region of the env gene (n = 47) or by sequence analysis of the p17 region of the gag gene (n = 33), or both. For HMA, reference plasmids were constructed containing the V1-V5 env region sequences (1.2-kb) representative of local subtypes. Subtype designation of reference subtypes was confirmed by sequence analysis of the V3-loop region. RESULTS: Analysis of the partial gag sequences and HMA of the V3-V5 env region identified three subtypes: B, C and D. A fourth env subtype, subtype E, was also identified by HMA. Subtypes were found to segregate according to mode of transmission, with subtype B viruses found in 96% (25 out of 26) of the male homosexual group and subtype C viruses found in 81% (26 out of 32) of the heterosexual/vertical transmission group. Subtype B viruses were also found in four heterosexual patients, one patient infected by blood transfusion and in two patients with unknown mode of transmission. Subtype D viruses were found in one male homosexual patient and one heterosexual patient. A subtype E virus was identified in a heterosexual patient. No discrepancy was found in subtype designation in samples analysed in both between the gag and env regions (n = 19). CONCLUSIONS: Subtype B viruses were associated with male homosexual transmission and subtype C viruses with heterosexual transmission, suggesting two independent epidemics. This data may have implications in the selection of appropriate vaccines for different risk groups in the country.

Adult↗
PubMed1997

Localisation of a gene causing endocrine neoplasia to a 4 cM region on chromosome 1p35-p36.

The development of some endocrine tumours, such as medullary thyroid carcinomas, phaeochromocytomas, anterior pituitary adenomas, and parathyroid adenomas involve a putative tumour suppressor gene located on chromosome 1p32-pter, a region that represents 111 cM. In order to refine the location of this gene, 93 endocrine tumours (39 parathyroid adenomas, 40 anterior pituitary adenomas, seven pancreatic islet cell adenomas, and seven carcinoids) were investigated for loss of tumour heterozygosity (LOH) using the seven polymorphic loci 1pter-D1S228-D1S507-D1S234-D1S476-D1S22 0-D1S207-D1S206-1cen. LOH was detected in 27% of the parathyroid tumours and in 7.5% of the pituitary tumours, but in none of the pancreatic islet cell or carcinoid tumours. In addition, seven of the 10 parathyroid tumours that showed LOH of chromosome 1p facilitated a more precise mapping of this putative tumour suppressor gene; five tumours involved a loss only of the telomeric locus D1S228, whereas two other tumours showed LOH at the centromeric loci D1S507, D1S234, D1S476, and D1S220, but not D1S228. Thus, our results have mapped this tumour suppressor gene implicated in endocrine tumours to a 4 cM region flanked by D1S228 and D1S507 on chromosome 1p35-p36.

Alleles↗
PubMed1996

Definition of the minimal MEN1 candidate area based on a 5-Mb integrated map of proximal 11q13. The European Consortium on Men1, (GENEM 1; Groupe d'Etude des Néoplasies Endocriniennes Multiples de type 1).

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder with a high penetrance characterized by tumors of the parathyroid glands, the endocrine pancreas, and the anterior pituitary. The MEN1 gene, a putative tumor suppressor gene, has been mapped to a 3- to 8-cM region in chromosome 11q13 but it remains elusive as yet. We have combined the efforts and resources from four laboratories to form the European Consortium on MEN1 with the aims of establishing the genetic and the physical maps of 11q13 and of further narrowing the MEN1 region. A 5-Mb integrated map of the region was established by fluorescence in situ hybridization on both metaphase chromosomes and DNA fibers, by hybridization to DNA from somatic cell hybrids containing various parts of human chromosome 11, by long-range restriction mapping, and by characterization of YACs and cosmids. Polymorphic markers were positioned and ordered by physical mapping and genetic linkage in 86 MEN1 families with 452 affected individuals. Two critical recombinants identified in two affected cases placed the MEN1 gene in an approximately 2-Mb region around PYGM, flanked by D11S1883 and D11S449.

Animals↗
PubMed1996

Definition of the Minimal MEN1 Candidate Area Based on a 5-Mb Integrated Map of Proximal 11q13

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder with a high penetrance characterized by tumors of the parathyroid glands, the endocrine pancreas, and the anterior pituitary. The MEN1 gene, a putative tumor suppressor gene, has been mapped to a 3- to 8-cM region in chromosome 11q13 but it remains elusive as yet. We have combined the efforts and resources from four laboratories to form the European Consortium on MEN1 with the aims of establishing the genetic and the physical maps of 11q13 and of further narrowing the MEN1 region. A 5-Mb integrated map of the region was established by fluorescence in situ hybridization on both metaphase chromosomes and DNA fibers, by hybridization to DNA from somatic cell hybrids containing various parts of human chromosome 11, by long-range restriction mapping, and by characterization of YACs and cosmids. Polymorphic markers were positioned and ordered by physical mapping and genetic linkage in 86 MEN1 families with 452 affected individuals. Two critical recombinants identified in two affected cases placed the MEN1 gene in an approximately 2-Mb region around PYGM, flanked by D11S1883 and D11S449.

Journal Article↗
PubMed1996

A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.

BACKGROUND: The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria. METHODS: We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293). RESULTS: Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required for the wild-type receptor. CONCLUSIONS: Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.

Adolescent↗
PubMed1996

An in vitro study of blast cell metabolism in acute myeloid leukaemia using the MTT assay.

We have utilized the MTT assay to measure the metabolic activity of cells from the bone marrow of 55 patients with acute myeloid leukaemia (AML), myelodysplastic syndrome (MDS) and non-clonal disease. Doubling dilutions of cells were exposed to MTT for 3-4 h. The mean optical density of the formazan produced by each cell dilution was plotted and the gradient of the line produced was calculated, higher gradients indicating more metabolically active cells. Results showed that the median activity of mononuclear cells from seven patients with non-clonal disease was 0.202 (range 0.175-0.253); blast cells from 27 patients with de novo AML had a median activity of 0.187 (range 0.079-0.345) and 13 patients with MDS a median of 0.155 (range 0.062-0.311). Seven assays on mononuclear cells from five patients in remission had a median activity of 0.203 (range 0.190-0.248), indicating no significant difference between these and normal patients. There was no correlation between the metabolic activity of cells when compared with their proliferative capacity, cell size and expression of P-glycoprotein. Following exposure of the AML patients' blast cells to the anthracyclines, cytosine arabinoside, 6-thioguanine and etoposide, cell survival was measured using the MTT assay. While there was no correlation between the in vitro sensitivity of these cells to the anthracyclines or etoposide, less metabolically active cells showed significantly greater sensitivity to 6-thioguanine. Conversely, the more active cells appeared to be more sensitive to cytosine arabinoside. Patients whose blasts cells showed higher metabolic activity appeared to achieve remission and had a longer mean survival time. Therefore, by using a simple technique we were able to establish that some patients were more likely to respond to certain cytotoxic regimes. Our preliminary study reflected the multifactorial nature of clinical response in AML and MDS, so providing further information on the relationship between cellular metabolic activity and treatment failure.

ATP Binding Cassette Transporter, Subfamily B, Mem↗