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Biomedical subjects

A R Webster

Publications and source records attributed to A R Webster.

11 recordsLinked to original sources
PubMed1997

Chromosomal assignment of 311 sequences transcribed in human adult testis.

A total of 311 expressed sequence tags (ESTs) derived from human adult testis have been assigned to human chromosomes by Southern analysis of a monochromosome somatic cell hybrid panel. Over 70% of the ESTs show conservation to hamster and mouse DNA, and the overall distribution of transcripts correlates well with physical chromosome size and to a greater extent with male meiotic chromosome length. The notable exception is the X chromosome, for which the number of testis-derived ESTs is greatly underrepresented. This finding may reflect inactivation of the X chromosome during the meiotic phase of spermatogenesis and a consequent selection against large numbers of X-linked germ cell transcripts. Further analysis of the distribution of testis ESTs showed that the EST density remains significantly correlated with the recombination density of each autosome. Analysis of a comparable number (320) of brain EST autosome assignments showed no similar correlation. These data suggest a specific association between transcription in testis tissue and male meiotic recombination.

Adult↗
PubMed1997

Independent segregation of von Hippel-Lindau disease and cerebral cavernomas.

A probable diagnosis of von Hippel-Lindau disease was made in a two generation family in which the proband had a phaeochromocytoma, renal cysts, and multiple cerebral cavernomas. His sister had multiple similar cerebral vascular lesions and his father died from renal carcinoma aged 42. Although the family did not satisfy the conventional diagnostic criteria for von Hippel-Lindau disease, an underlying germline mutation in the von Hippel-Lindau disease tumour suppressor gene was identified in the proband. Molecular genetic analysis not only confirmed the putative diagnosis of the disease in the proband but also showed that the cerebral vascular lesions segregated independently from the von Hippel-Lindau disease mutation. This report exemplifies how molecular genetic investigations can enhance the diagnosis and management of families with suspected von Hippel-Lindau disease, particularly when the manifestations, as in this family, are not typical.

Adult↗
PubMed1997

Somatic inactivation of the VHL gene in Von Hippel-Lindau disease tumors.

Von Hippel-Lindau (VHL) disease is a dominantly inherited disorder predisposing to retinal and CNS hemangioblastomas, renal cell carcinoma (RCC), pheochromocytoma, and pancreatic tumors. Interfamilial differences in predisposition to pheochromocytoma reflect allelic heterogeneity such that there is a strong association between missense mutations and risk of pheochromocytoma. We investigated the mechanism of tumorigenesis in VHL disease tumors to determine whether there were differences between tumor types or classes of germ-line mutations. Fifty-three tumors (30 RCCs, 15 hemangioblastomas, 5 pheochromocytomas, and 3 pancreatic tumors) from 33 patients (27 kindreds) with VHL disease were analyzed. Overall, 51% of 45 informative tumors showed loss of heterozygosity (LOH) at the VHL locus. In 11 cases it was possible to distinguish between loss of the wild-type and mutant alleles, and in each case the wild-type allele was lost. LOH was detected in all tumor types and occurred in the presence of both germ-line missense mutations and other types of germline mutation associated with a low risk of pheochromocytoma. Intragenic somatic mutations were detected in three tumors (all hemangioblastomas) and in two of these could be shown to occur in the wild-type allele. This provides the first example of homozygous inactivation of the VHL by small intragenic mutations in this type of tumor. Hypermethylation of the VHL gene was detected in 33% (6/18) of tumors without LOH, including 2 RCCs and 4 hemangioblastomas. Although hypermethylation of the VHL gene has been reported previously in nonfamilial RCC and although methylation of tumor-suppressor genes has been implicated in the pathogenesis of other sporadic cancers, this is the first report of somatic methylation in a familial cancer syndrome.

Chromosome Deletion↗
PubMed1996

Thyroid function testing based on assay of thyroid-stimulating hormone: assessing an algorithm's reliability.

OBJECTIVE: To assess the ability of an algorithm for thyroid-function testing (based on assay of thyroid-stimulating hormone [TSH]) to discern euthyroidism in patients with and without conditions affecting thyroid function. DESIGN: The Australian Health Insurance Commission (HIC) specifies clinical categories for which Medicare rebate is given for assay of both TSH and free thyroxine (FT4), but otherwise rebates for thyroid function testing are given for TSH assay only. A prospective study was made of paired TSH and FT4 results of 1000 consecutive assays categorised by indication for testing. An FT4 value within the reference range was accepted as indicating euthyroidism; the reliability of an initial TSH measurement as the sole indicator of thyroid disease was assessed against this criterion standard. SETTING: A large suburban teaching hospital. OUTCOME MEASURE: Success or failure of the algorithm, with failure defined as an abnormal FT4 level missed because the TSH level was normal. RESULTS: The algorithm failure rate both overall and in the patients not in the HIC clinical categories was 2.7%, and there was no significant difference in algorithm failure rate in the patients in the various HIC clinical categories. The categories and failure rates were: patients being monitored for thyroid disease, 3.4%; patients with the "sick euthyroid" syndrome, nil; patients with psychosis or dementia, 1.1%; patients taking drugs affecting thyroid function, 2.1%; and patients with pituitary dysfunction, one of six cases. The range of FT4 values in patients in whom the algorithm failed was 6.4-29.5 pmol/L in those without thyroid disease and 3.4-27.4 pmol/L in those with thyroid disease. In patients being monitored for thyroid disease, the proportion of abnormal values of TSH alone was significant (P<0.001). CONCLUSION: We have shown that the HIC's imposition of a TSH-based algorithm by financial fiat is also scientifically acceptable. Use of this algorithm in hospitals (including psychiatric hospitals) will result in substantial savings.

Algorithms↗
PubMed1996

Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan.

Germline mutation analysis was performed in 469 VHL families from North America, Europe, and Japan. Germline mutations were identified in 300/469 (63%) of the families tested; 137 distinct intragenic germline mutations were detected. Most of the germline VHL mutations (124/137) occurred in 1-2 families; a few occured in four or more families. The common germline VHL mutations were: delPhe76, Asn78Ser, Arg161Stop, Arg167Gln, Arg167Trp, and Leu178Pro. In this large series, it was possible to compare the effects of identical germline mutations in different populations. Germline VHL mutations produced similar cancer phenotypes in Caucasian and Japanese VHL families. Germline VHL mutations were identified that produced three distinct cancer phenotypes: (1) renal carcinoma without pheochromocytoma, (2) renal carcinoma with pheochromocytoma, and (3) pheochromocytoma alone. The catalog of VHL germline mutations with phenotype information should be useful for diagnostic and prognostic studies of VHL and for studies of genotype-phenotype correlations in VHL.

Adrenal Gland Neoplasms↗
PubMed1996

Phenotypic expression in von Hippel-Lindau disease: correlations with germline VHL gene mutations.

Von Hippel-Lindau disease is an autosomal dominantly inherited familial cancer syndrome predisposing to retinal and central nervous system haemangioblastomas, renal cell carcinoma, and phaeochromocytoma. VHL disease shows variable expression and interfamilial differences in predisposition to phaeochromocytoma. In a previous study of 65 VHL kindreds with defined VHL mutations we detected significant differences between VHL families with and without phaeochromocytoma such that missense mutations were more common and large deletions or protein truncating mutations less frequent in phaeochromocytoma positive families. To investigate the significance and cause of this association further, we studied 138 VHL kindreds for germline mutations and calculated the age related tumour risks for different classes of VHL gene mutations. Using SSCP, heteroduplex and Southern analysis we identified a germline VHL gene mutation in 101 families (73%). Direct sequencing of the VHL coding region further increased the mutation detection rate to 81%. In addition to precise presymptomatic diagnosis, identification of a VHL gene mutation can provide an indication of the likely phenotype. We found that large deletions and mutations predicted to cause a truncated protein were associated with a lower risk of phaeochromocytoma (6% and 9% at 30 and 50 years, respectively) than missense mutations (40% and 59%, respectively) and that missense mutations at codon 167 were associated with a high risk of phaeochromocytoma (53% and 82% at ages 30 and 50 years). Cumulative probabilities of renal cell carcinoma did not differ between the two groups (deletion/ truncation mutations: 8% and 60%, and missense mutations: 10% and 64% at ages 30 and 50 years, respectively). Age related risks for haemangioblastoma were similar in the two mutation groups, with the age related risks of cerebellar haemangioblastoma slightly less (35% and 64% v 38% and 75% at ages 30 and 50 years) and retinal haemangioblastoma slightly higher (45% and 72% v 37% and 64% at ages 30 and 50 years) in the missense mutation group than in the deletion/protein truncation group. These results provide valuable data for counselling VHL families and indicate that specific VHL mutations may be associated with different tumour susceptibility risks. There was no evidence of a generalised increase in age related tumour risks for missense mutations, suggesting that missense mutations predisposing to phaeochromocytoma have tissue specific effects, possibly because the VHL protein has several functions, the importance of which varies from tissue to tissue, or because the proteins which interact with VHL differ between different tissues.

Adolescent↗
PubMed1995

Ischaemic retinopathy occurring in patients receiving bone marrow allografts and campath-1G: a clinicopathological study.

AIMS/BACKGROUND: Ischaemic retinopathy is a well characterised complication of bone marrow transplantation (BMT). Although the aetiology is unclear, it is most probably multifactorial, and may be related to treatment such as radiation and cyclosporin A. The clinical findings are reported of two patients who developed such a retinopathy and the ocular histology from one of these cases is presented. METHODS: Two patients underwent BMT for acute lymphoblastic leukaemia, receiving campath-1G for prophylaxis against graft versus host disease, and showed fundal changes compatible with BMT retinopathy. The eyes from one patient were retrieved at post mortem and examined by both light and electron microscopy. RESULTS: The visual symptoms and fundal signs resolved spontaneously with no specific treatment in one patient. Light and electron microscopic examination of the eyes of the other patient was compatible with an ischaemic aetiology and showed evidence of retinal capillary endothelial loss. CONCLUSIONS: (i) Histopathology in one case of BMT retinopathy demonstrates a retinal endotheliopathy similar to that described in radiation retinopathy. (ii) BMT retinopathy may occur in the absence of cyclosporin A treatment. (iii) The retinopathy can recover spontaneously with no specific treatment.

Adult↗
PubMed1995

Clinical features and molecular genetics of Von Hippel-Lindau disease.

Although familial cancer syndromes are rare, a knowledge of these disorders is relevant to both clinicians and basic scientists. This is exemplified by Von Hippel-Lindau (VHL) disease which is caused by germline mutations in the VHL tumour suppressor gene. This multisystem disorder provides a complex clinical problem for ophthalmologists and other specialists. In addition, recent advances in the molecular genetics of this disorder are providing novel insights into the molecular mechanisms of tumourigenesis in VHL disease and in more common nonfamilial neoplasms such as clear cell renal carcinoma and central nervous system haemangioblastoma. In this review, we describe the clinical manifestations (with particular reference to the ocular complications) and the molecular genetics of VHL disease.

Angiomatosis↗
PubMed1993

The effect of pilocarpine on the glaucomatous visual field.

Patients with chronic open angle glaucoma are traditionally managed by medical therapy during the early stages of the disease. Pilocarpine is a well established topical agent, but suffers troublesome sequelae, the most apparent of which is pupillary constriction. This study assesses the effect of miosis (produced by one drop of 2% pilocarpine) on the static threshold perimetry of 20 subjects with chronic open angle glaucoma and documented visual field loss, using the 30-2 program of the Humphrey field analyser. Following miosis, the Statpac mean defect deteriorated by an average of -1.49 dB compared with baseline (p = 0.004). This dB deterioration is twice that reported in studies on younger normal subjects following miosis. The decrease in mean defect showed a positive correlation with the degree of pupillary constriction, the correlation being greater in those eyes with a miosed pupil diameter of 2 mm or less. There was no significant decrease in the other Statpac global indices following miosis. A parallel study using the fellow eye of the same glaucoma patients showed a high degree of intertest variability, but no significant learning or fatigue effect. We conclude that pilocarpine-induced miosis causes a significant deterioration in visual field in a population of patients with chronic open angle glaucoma: this factor should be considered when choosing therapy for glaucoma particularly in cases where field loss approaches the permitted legal minimum for driving.

Aged↗