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Biomedical subjects

F Crawford

Publications and source records attributed to F Crawford.

90 records · Page 5Linked to original sources
PubMed1992

Alzheimer's disease untangled.

The last year has seen major advances in the study of Alzheimer's disease (AD). Four mutations involving amino acid substitutions in exons 16 and 17 of the amyloid precursor protein (APP) gene, have been identified which co-segregate with the disease in some families multiply affected by early onset Alzheimer's disease. These mutations are strongly suggestive of a causative role for the amyloid precursor protein in Alzheimer's disease. Despite their rarity, these mutations are important because they represent the first known cause of Alzheimer's disease. Processing of APP must be central to the pathogenesis of the disease although the precise effects of these amino acid substitutions are not understood. Work is now being undertaken to characterise the processing pathways of APP and to identify other causes of AD. The development of models of AD using the APP mutations offers the possibility of identifying drug targets and developing more effective treatments than are presently available.

Alzheimer Disease↗
PubMed1992

A pathogenic mutation for probable Alzheimer's disease in the APP gene at the N-terminus of beta-amyloid.

Mutations at codon 717 in exon 17 of the beta-amyloid precursor protein (APP) gene have previously been shown to segregate with early onset Alzheimer's disease in some families. We have identified a double mutation at codons 670 and 671 (APP 770 transcript) in exon 16 which co-segregates with the disease in two large (probably related) early-onset Alzheimer's disease families from Sweden. Two base pair transversions (G to T, A to C) from the normal sequence predict Lys to Asn and Met to Leu amino acid substitutions at codons 670 and 671 of the APP transcript. This mutation occurs at the amino terminal of beta-amyloid and may be pathogenic because it occurs at or close to the endosomal/lysosomal cleavage site of the molecule. Thus, pathogenic mutations in APP frame the beta-amyloid sequence.

Alzheimer Disease↗
PubMed1991

Sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene in 14 families with early onset Alzheimer's disease fails to reveal mutations in the beta-amyloid sequence.

A mutation within exon 17 at codon 717 of the beta-amyloid protein precursor (APP) gene is one cause of early onset familial Alzheimer's disease. Direct sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene in 14 families with familial early onset Alzheimer's disease without the known pathogenic mutation (APP717) failed to reveal other mutations within the beta-amyloid sequence in this form of the disorder.

Adult↗
PubMed1991

Early-onset Alzheimer's disease caused by mutations at codon 717 of the beta-amyloid precursor protein gene.

A mutation at codon 717 of the beta-amyloid precursor protein gene has been found to cosegregate with familial Alzheimer's disease in a single family. This mutation has been reported in a further five out of approximately 100 families multiply affected by Alzheimer's disease. We have identified another family, F19, in which we have detected linkage between the beta-amyloid precursor protein gene and Alzheimer's disease. Direct sequencing of exon 17 in affected individuals from this family has revealed a base change producing a Val----Gly substitution, also at codon 717. The occurrence of a second allelic variant at codon 717 linked to the Alzheimer's phenotype supports the hypothesis that they are pathogenic mutations.

Alzheimer Disease↗
PubMed1991

Screening for the beta-amyloid precursor protein mutation (APP717: Val----Ile) in extended pedigrees with early onset Alzheimer's disease.

Screening for the APP717 mutation in 5 further families with early onset Alzheimer's disease failed to reveal further cases with this variant. Screening a further 100 normal individuals for this mutation also failed to reveal further occurrences of this variant in the general population. Sequencing of exons 16 and 17 of the beta-amyloid precursor protein gene (the exons which encode the beta-amyloid fragment) in pedigree FAD4 revealed them to be of normal sequence. The significance of these observations to the genetics of Alzheimer's disease is discussed.

Alzheimer Disease↗
PubMed1991

Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease.

A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene.

Alzheimer Disease↗
PubMed1989

Multiple neurotrophic factors from skeletal muscle: demonstration of effects of basic fibroblast growth factor and comparisons with the 22-kilodalton choline acetyltransferase development factor.

Extracts of skeletal muscle contain chromatographically distinct molecules that enhance the cholinergic development of cultured embryonic rat spinal cord neurons. We have recently purified a 20-22 kilodalton anionic polypeptide choline acetyltransferase (ChAT) development factor (CDF) from rat skeletal muscle extracts that stimulates the development of ChAT activity in rat spinal cord cultures. The maximum increase in the level of ChAT activity achieved by this factor, however, is less than that achieved by the addition of the crude extract. We now show that muscle extract also contains mitogenic activity that is immunologically related to basic fibroblast growth factor (bFGF) and also that recombinant bFGF stimulates ChAT development in rat spinal cord cultures. bFGF, however, differs from CDF in its physiochemical, chromatographic, and immunological properties and by its action on nonneuronal cells. Individually, CDF and bFGF each enhance the level of ChAT activity in rat spinal cord cultures two- to threefold after 2 days of treatment. However, their combined actions result in a five- to sixfold enhancement of ChAT activity, suggesting that they are affecting cholinergic development through different means. The demonstration that extracts of rat skeletal muscle contain two biochemically and immunologically distinct polypeptides, with additive effects on cultured embryonic spinal cord neurons, provides additional evidence for the involvement of multiple target-derived neurotrophic factors in the regulation of cholinergic development.

Animals↗
PubMed1988

Immunoglobulins from amyotrophic lateral sclerosis patients enhance spontaneous transmitter release from motor-nerve terminals.

Amyotrophic lateral sclerosis (ALS) is an incapacitating neuromuscular disease of unknown etiology. Although laboratory evidence is lacking, circumstantial evidence supports the importance of immune factors in the pathogenesis of ALS. In the present study immunoglobulins from 4 of 8 ALS patients induced a significant increase in spontaneous quantal transmitter release as monitored by miniature end-plate potential (MEPP) frequency in mouse phrenic nerve-diaphragm preparations at 23 degrees C, whereas immunoglobulins from normal individuals and from patients with other neuromuscular diseases had no effect. At 32 degrees C neither normal nor disease control immunoglobulins influenced MEPP frequency, but 8 of 11 ALS immunoglobulin samples produced a significant increase in spontaneous quantal transmitter release. The enhancing effect could be prevented by 10 mM Mg2+. No effects were noted on MEPP amplitude and muscle resting potential. These findings suggest that the presynaptic terminal of the motor neuron may be an early target and that immunological factors may play an important role in the disease process.

Amyotrophic Lateral Sclerosis↗
PubMed1985

Hepatitis A in day care centers.

A dramatic increase in the number of preschool children in US day care facilities has presented new problems in infectious disease control, particularly with agents transmitted through the fecal-oral route. As the school health field broadens to encompass the day care setting, such issues are becoming increasingly important for school health practitioners. Hepatitis A has attributes favoring day care-related reservoirs and outbreaks. The anicteric course of infection in young children usually does not alert the school health practitioner to infectious hepatitis. This article reviews epidemiologic and clinical features of hepatitis A in day care centers. Control measures including immunoglobulin prophylaxis for contacts of infected individuals and rigid attention to hygienic standards are examined, and suggestions for designing day care systems in communities are discussed.

Adolescent↗
PubMed1980

Influence of environmental chemicals on drug therapy in humans: studies with contraceptive steroids.

The effects have been studied of various environmental factors on the variability in response to oral contraceptive steroid therapy in women. Ten- to thirty-fold variations in plasma concentrations of norethisterone, L-norgestrel and ethinyloestradiol have been shown in samples taken 12 h after administration of oral contraceptives in mid-menstrual cycle. Factors shown to be responsible for this variation include passage into the enterohepatic circulation, a variable first-pass effect, and changes in metabolism in the gut wall or liver due to diet, disease, smoking or administration of drugs. Phenobarbitone and the antibiotic rifampicin increase both oestrogen and progestogen metabolism in women and in experimental animals by increasing hepatic and gut wall metabolism. In animals, other antibiotics (ampicillin, neomycin and lincomycin) suppress the gut flora that normally hydrolyse steroid conjugates excreted in bile; enterohepatic circulation or oral contraceptive steroids is thus reduced and their plasma concentrations lowered by up to 90%. In the human, ampicillin has a variable but less dramatic effect on elimination of oral contraceptives. Samples of gut wall mucosa obtained from patients with coeliac disease are defective in their ability to metabolize oral contraceptives. Cigarette smokers eliminate ethinyloestradiol more rapidly than non-smokers; an increased production of reactive steroid metabolites may thus be a cause of vascular disease in women who smoke and take contraceptive steroids.

Animals↗
PubMed1979

The effect of rifampicin on norethisterone pharmacokinetics.

The pharmacokinetics of norethisterone have been studied in 8 women during and one month after treatment with rifampicin (450--600 mg/day). Rifampicin caused a significant reduction in the A.U.C. of a single dose of 1 mg norethisterone from 37.8 +/- 13.1 to 21.9 +/- 5.9 ng/ml X h (p less than 0.01). The plasma norethisterone half life (beta-phase) was also reduced from 6.2 +/- 1.7 to 3.2 +/- 1.0 h (p less than 0.0025). In one additional woman on long term oral contraceptive therapy the 12 hour plasma norethisterone concentration was reduced by rifampicin from 12.3 ng/ml to 2.3 ng/ml. Rifampicin caused a significant increase in antipyrine clearance, 6 beta-hydroxycortisol excretion and plasma gamma-glutamyltranspeptidase activity but there was no significant correlations between changes in these indices of liver microsomal enzyme induction. There was a significant correlation between the percentage increase in antipyrine clearance and the percentage decrease in norethisterone A.U.C. during rifampicin. The changes in norethisterone pharmacokinetics during rifampicin therapy are compatible with the known enzyme inducing effect of rifampicin.

Adolescent↗
PubMed1977

Two-dimensional echocardiographic assessment of vegetative endocarditis.

Real-time, two-dimensional echocardiography was used to document the presence and assess the size and location of vegetative lesions of the cardiac valves and chambers in seven patients with bacterial endocarditis. Anatomic correlation (surgical or autopsy) was accurate in all patients. Two-dimensional echocardiography was shown to be of particular value in determining morphologic characteristics of the lesions since this technique provides spatial information concerning moving cardiac structures. The results of two-dimensional echocardiography were most helpful in determining selected aspects of the clinical care provided for each patient. These data demonstrate that real-time, two-dimensional echocardiography, in combination with M-mode imaging techniques, may be of great potential value in the detection of vegetative endocarditis. Furthermore, reliable assessment of lesion size and location may, in time, become a valuable method for following the morphologic changes that occur in vegetative lesions, and thus determine the efficacy of antibiotic therapy. This information may also provide a means for evaluating certain patients for surgical intervention.

Adolescent↗
PubMedDate not supplied

The molecular genetics of Alzheimer's disease.

The major pathological characteristic of Alzheimer's disease (AD) is the abnormal deposition of beta-amyloid peptide (A beta) in the brain. In some early onset cases, the disease develops because of mutations in the gene coding for beta-amyloid precursor protein (beta APP). However, the majority of AD families in the early onset subgroup are linked to a locus on chromosome 14. The genetic analysis and age of onset correlates of both the beta APP gene and the chromosome 14 locus are discussed. We speculate on the mechanisms by which the beta APP mutations cause the disease and discuss recent advances in beta APP processing that may be relevant to the pathogenesis of the late-onset (common) form of the disease. In addition, we review the association of the APOE locus with late-onset familial and nonfamilial disease. Further work is required to establish the effects of this locus on disease occurrence, age of onset, and progression. The molecular pathology of ApoE in relation to AD development and the identification of the chromosome 14 gene will greatly contribute to a general pathogenic model of AD, and will clarify the role of beta APP and its derivatives.

Age of Onset↗
PubMedDate not supplied

Providing support for qualified nurses.

In this article, the authors examine workforce issues in nursing. From their discussion, they recommend that qualified nurses should sanction the further training of support workers to enable them to spend more time in direct patient care.

Clinical Competence↗