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Biomedical subjects

A Clarke

Publications and source records attributed to A Clarke.

At least 163 records · Page 9Linked to original sources
PubMed1994

Detection of de novo mutations and analysis of their origin in families with X linked hypohidrotic ectodermal dysplasia.

Hypohidrotic ectodermal dysplasia (EDA) has been localised to the q12-q13.1 region of the X chromosome by both physical and genetic mapping methods. Although linkage analysis using closely linked flanking markers can clarify the carrier status for many females at risk for the disorder, knowledge of the origin of the mutation in instances of possible de novo mutation is critical for accurate genetic counselling of families. Two methods have been used to confirm de novo mutation in families with EDA and to trace their origin. Direct detection of three de novo molecular deletions, one arising during oogenesis and the other two during spermatogenesis, was achieved by Southern analyses using cosmids isolated from the EDA region as probes. Seven de novo mutations arising during spermatogenesis, and two possible de novo mutations during oogenesis, were identified by an analysis of the cosegregation of the disorder with polymorphic markers closely linked to and flanking the EDA locus. The confirmation and analysis of the origin of the 10 de novo mutations greatly assisted genetic counselling in these families. The apparent 3.5:1 excess of male to female origin of mutation in families studied with unidentified types of mutation is similar to other studies of X linked disorders, and suggests that the majority of these mutations may involve single base pair substitutions.

Adult↗
PubMed1994

Tuberous sclerosis: how to recognise this challenging disorder.

Tuberous sclerosis is a multi-system genetic disorder affecting up to one in 6000 newborn infants. It is about one third as common as cystic fibrosis, and half as common as Duchennes muscular dystrophy, yet many doctors and health professionals are ill-acquainted with the condition. Parents who turn to medical text books for information find only a brief mention of a few, frequently out-dated facts. Antonia Clarke and John Osborne describe the symptoms of the disorder and the special needs of affected children and their families.

Child↗
PubMed1994

Support for families with children with special needs.

Families with children with special needs have to cope not only with their child's condition, but also with practical problems such as transport and opportunities for a break from their caring responsibilities. Anthea Clarke describes how 'Flexicare' helps these families in Oxfordshire, and calls for more such voluntary groups across the country.

Child↗
PubMed1994

Cholesterol and lipoprotein(a) as risk factors for coronary heart disease in elderly subjects.

The changes in lipoprotein(a) concentration that occur with age as a result of its association with an increased risk of coronary artery disease were investigated. Lipoprotein(a) concentrations were measured in serum samples from healthy volunteers, individuals with premature coronary artery disease, individuals with hyperlipidaemia but without evidence of premature coronary artery disease, and also in elderly men and women who had hyperlipidaemia. Concentrations in individuals with premature coronary artery disease were the same as those of the healthy volunteers, while in both these groups they were lower than those found in hyperlipidaemic elderly men and women, and those found in hyperlipidaemic women aged 36-68 years. No association between raised lipoprotein(a) concentration and mortality as a result of premature coronary artery disease was demonstrated. Raised lipoprotein(a) levels found in the hyperlipidaemic individuals also suggested that it may not be an independent risk factor.

Adult↗
PubMed1993

Titin folding energy and elasticity.

Molecules of the giant protein titin are responsible for the passive elasticity and central A-band location of muscle myofibrils. The molecular mechanism of titin elasticity is not known, but the I-band region of the molecule appears capable of approximately fourfold reversible extension. Such large extensions are likely to involve unfolding of titin domains. In the present experiments, equilibrium unfolding of titin from rabbit skeletal muscles was studied in vitro by fluorescence and circular dichroism spectroscopy, after addition of guanidinium chloride. The data suggest two unfolding transitions, both of which appear cooperative. The second transition is likely to involve complete unfolding of the immunoglobulin- and fibronectin-like domains from which the molecules is composed. The free energy associated with this transition is comparable with the energy required to extend titin molecules to the maximum amount seen in situ.

Animals↗
PubMed1993

In vivo analysis of Pim-1 deficiency.

The Pim-1 proto-oncogene encodes a highly conserved serine/threonine phosphokinase which is predominantly expressed in hematopoietic organs and gonads in mammals. Overexpression of Pim-1 predisposes to lymphomagenesis in mice. To develop a further understanding of Pim-1 in molecular terms, as well as in terms of its potential role in hematopoietic development, we have generated mice deficient in Pim-1 function. Pim-1-deficient mice are ostensibly normal, healthy and fertile. Detailed comparative analyses of the hematopoietic systems of the mutant mice and their wild-type littermates showed that they are indistinguishable for most of the parameters studied. Our analyses revealed one unexpected phenotype that correlated with the level of Pim-1 expression: Pim-1 deficiency correlated with a erythrocyte microcytosis, whereas overexpression of Pim-1 in E mu-Pim-1-transgenic mice resulted in erythrocyte macrocytosis. In order to confirm that the observed decrease in erythrocyte Mean Cell Volume (MCV) was attributable to the Pim-1 deficiency, we developed mice transgenic for a Pim-1 gene construct with its own promoter and showed that this transgene could restore the low erythrocyte Mean Cell Volume observed in the Pim-1-deficient mice to near wild-type levels. These results might be relevant to the observed involvement of the Pim-1 gene in mouse erythroleukemogenesis. The surprising lack of a readily observed phenotype in the lymphoid compartment of the Pim-1-deficient mice, suggests a heretofore unrecognized degree of in vivo functional redundancy of this highly conserved proto-oncogene.

Animals↗
PubMed1993

Run for your money.

The DoH's efficiency index is criticised for being crude, biased and inaccurate. John Appleby, Trevor Sheldon and Aileen Clarke discuss NAHAT's consultation and suggest some improvements.

Abstracting and Indexing↗
PubMed1993

Decreased expression of Mac-2 (carbohydrate binding protein 35) and loss of its nuclear localization are associated with the neoplastic progression of colon carcinoma.

The Mac-2 lectin (carbohydrate binding protein 35) is a soluble, 32- to 35-kDa phosphoprotein that binds galactose-containing glycoconjugates. We report here that the colonic epithelium is a major site of Mac-2 expression in vivo based on immunohistochemistry of human tissue specimens. In this epithelium, proliferating cells at the base of the crypts do not express Mac-2 but its expression increases with differentiation along the crypt-to-surface axis. Mac-2 expression is concentrated in the nuclei of these differentiated epithelial cells. The progression from normal mucosa to adenoma to carcinoma is associated with significant changes in Mac-2 nuclear localization and expression. In all adenomas (9/9) and carcinomas (13/13) examined, Mac-2 was not present in the nucleus but was localized in the cytoplasm. Sequencing of Mac-2 cDNAs from normal mucosa and carcinoma revealed no specific mutations that could account for this loss of nuclear localization. We also observed a 5- to 10-fold decrease in Mac-2 mRNA levels in cancer compared to normal mucosa as well as a significant reduction in the amount of Mac-2 protein expressed. These observations suggest that Mac-2 exclusion from the nucleus and its decreased expression may be related to the neoplastic progression of colon cancer.

Adenocarcinoma↗
PubMed1993

Charcot-Marie-tooth disease 1A (CMT1A) associated with a maternal duplication of chromosome 17p11.2-->12.

We report here the second case of Charcot-Marie-Tooth disease 1A (CMT1A) with a cytogenetically visible de novo direct duplication of 17p11.1-->17p12. A male child who was initially referred for developmental delay and dysmorphism was subsequently shown to have significantly reduced motor nerve conduction velocities characteristic of CMT1A. This patient was not informative for the DNA markers mapping to the CMT1A region; however, with DNA markers pA10-41 and EW503 that map proximally and distally with respect to the disease locus, a dosage difference was observed between the two alleles. Comparison with parental genotypes indicated a de novo maternal duplication. Pulsed field gel analysis using probe VAW409R3a indicated that a 500-kb SacII junction fragment usually associated with CMT1A was absent in this patient. These findings confirm that the disease phenotype is probably caused by a gene dosage effect.

Charcot-Marie-Tooth Disease↗
PubMed1993

Immunohistological evidence for second or somatic mutations as the underlying cause of dystrophin expression by isolated fibres in Xp21 muscular dystrophy of Duchenne-type severity.

Using five monoclonal antibodies against different parts of the dystrophin molecule, we have studied the dystrophin composition of 17 dystrophin-positive fibres in a muscle biopsy from a boy with Xp21 muscular dystrophy of Duchenne-type severity. The fibres showed five distinct, reproducible, immunoreactive dystrophin profiles. All the profiles included both the N-terminal and the C-terminal domains, but between these domains, different fibres were negative for different antibodies, suggesting the somatic loss of certain exons. We interpret this as the first in situ evidence of an individual having different patterns of missing exons leading to restoration of the reading frame in various ways in the original germline frame-shifting deletion of exons 35-43. It follows that various somatic mutations had taken place in different fibres.

Antibodies, Monoclonal↗