Genes and parkinsonism.
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Case-Control Studies↗
Biomedical subjects
N Wood
Publications and source records attributed to N Wood.
Trinucleotide (GAA)n repeat expansion in two families with Friedreich's ataxia with retained reflexes.
In occasional families in whom cases of classic Friedreich's ataxia (FRDA) coexist with affected cases with retained reflexes, linkage analysis has shown that both map to the FRDA locus on chromosome 9q13-21.1. A gene X25 has been identified within the critical region of the FRDA locus, and an intronic expanded GAA trinucleotide repeat has been found in most cases of FRDA. We report two further FRDA families in whom some patients with classic FRDA were areflexic whereas others had brisk reflexes. Molecular genetic analysis disclosed an abnormal trinucleotide repeat expansion within intron 1 of the FRDA gene in both phenotypes.
Adolescent↗
Do the homeless get a fair deal from general practitioners?
Many studies have indicated the health status of homeless people to be typically poorer than that of the general population, with various studies indicating a high prevalence of psychiatric illness, drug or alcohol misuse and associated socio-medical problems. The Bristol Primary Healthcare Project is an agency which was established to provide a local health care service tailored to the needs of people who are homeless. The present study was carried out as part of an evaluation of the service offered locally to homeless people by General Practitioners (GPs). A postal questionnaire survey of 155 general practices within the Avon FHSA area was carried out. Both fundholding and non-fundholding practices were included, within an area including inner city, urban and rural/semi-rural locations. One hundred and seventeen completed questionnaires were returned, providing a response rate of 75%. Twenty-seven percent of practices would fully register a homeless person who seeks to register at the practice, 24% would treat as immediate and necessary and 33% would treat as a temporary resident. Four percent of fundholding practices surveyed would fully register homeless persons and 55% of inner city practices would do so. Seventy-nine percent of doctors indicated that homeless patients were more difficult to treat than other patients. The most frequent problems associated with registering homeless persons were perceived to be the associated social problems (90% of respondents agreed), the lack of medical records (88% agreed), the complex health problems (79% agreed) and the associated alcohol or substance misuse (78% agreed). The study has highlighted a need for government to consider providing incentives to GPs to register homeless people without resulting in adverse effects on their contract targets. The reluctance of some practices to register these patients varied by area and type of practice with doctors at fundholding practices being the most reluctant. There is an identified need for further health education and promotion work and initiatives exemplified by the Bristol Primary Healthcare Project for people who are homeless.
Attitude of Health Personnel↗
Pharmacokinetics and pharmacodynamics of single and multiple doses of the MAO-B inhibitor lazabemide in healthy subjects.
AIMS: The objectives of this study were to assess the tolerability, pharmacokinetics and pharmacodynamics of the reversible monoamine oxidase B (MAO-B) inhibitor, lazabemide, in healthy subjects. METHODS: Single and multiple (1 week) twice daily oral doses (100-350 mg) of lazabemide were administered sequentially to five groups of six healthy male subjects in a placebo-controlled, double-blind design. Adverse events, vital signs, and clinical laboratory variables were recorded. Pharmacokinetic parameters of lazabemide were determined after single and multiple doses. Pharmacodynamics were assessed by determination of MAO-B activity in blood platelets and intravenous tyramine potentiation tests. RESULTS: Lazabemide was well tolerated at all dose levels, causing no clinically relevant changes in vital signs or laboratory parameters. Headache was the most frequent adverse event at higher doses. Lazabemide was rapidly absorbed and eliminated by mixed linear and non-linear pathway. Only minor accumulation occurred upon multiple dosing and steady-state plasma concentrations were achieved on the third day. Lazabemide caused a rapid and reversible inhibition of MAO-B activity in platelets. The twice daily dosing regimen resulted in complete inhibition at all dose levels. The duration of complete inhibition was dose-dependent and ranged from 16 h with 100 mg to 36 h with 350 mg. The sensitivity to i.v. tyramine did not change to a clinically relevant extent following single and multiple doses of lazabemide. CONCLUSIONS: The clinical pharmacology characteristics of lazabemide did not differ markedly after single and multiple oral doses. A dose regimen of lazebemide 100 mg twice daily is anticipated because it caused full and continuous MAO-B inhibition.
Administration, Oral↗
Genetic aspects of parkinsonism.
The genetic basis of many monogenic neurological diseases with parkinsonian features has been elucidated over the past few years. The clinical and genetic features are discussed for the diseases with prominent parkinsonian signs. There is also accumulating evidence for a role of genetic factors in the aetiology of idiopathic Parkinson's disease (PD); however, the approach to polygenic diseases is quite different from that to the simpler single-gene disorders. The role of epidemiology in not only establishing genetic susceptibility, but its impact on estimating the size of the problem, is also discussed. A number of candidate genes have been studied in PD but, to date, there is no conclusive proof for any of these. It therefore seems likely that a random genome search is required, and the technical and statistical methods are now available. It is hoped that knowledge of the genes involved will lead to better therapy for this incurable and common disorder.
Genetic Linkage↗
Genetic screening and testing by induced heteroduplex formation.
Clustered point mutations and small deletions or insertions within DNA are amenable to rapid analysis using induced heteroduplex formation. A single synthetic molecule (universal heteroduplex generator, UHG) may detect any of a series of such mutations following amplification by the polymerase chain reaction. This paper illustrates the use of UHG-based DNA heteroduplex analysis by describing the construction, properties, and methods of use of five UHGs, designed for genetic screening and testing of the inherited metabolic diseases: phenylketonuria, sickle-cell disease, cystic fibrosis, von Willebrand's disease type 2B, and mamman-binding lectin deficiency. In all cases, identification of multiple disease-associated genotypes is possible using a single UHG.
Anemia, Sickle Cell↗
UHG-based mutation screening in type 2B von Willebrand's disease: detection of a candidate mutation Ser547Phe.
We have recently described a novel mutation screening technique for the diagnosis of type 2B von Willebrand's disease (vWD). Analysis involves the use of a synthetic universal heteroduplex generator (UHG). To test the validity of the technique, we have applied UHG screening to seven type 2B vWD patients of previously unknown genotype. Characteristic heteroduplex patterns for Arg543Trp and Val553Met mutations were found in three patients and one patient, respectively. A fifth patient gave a novel pattern and direct sequencing revealed a hitherto unreported candidate mutation (Ser547Phe) 8 bases downstream of an "identifier" deletion in the UHG molecule. The two remaining patients gave normal heteroduplex patterns; an Arg578Gln mutation was identified by PstI digestion in one individual and no mutation could be identified in the sequence covered by the UHG in the final patient. Using a combination of UHG technology and restriction analysis, over 85% of type 2B vWD patients can be rapidly diagnosed by genotype.
Amino Acid Sequence↗
The gene for autosomal dominant cerebellar ataxia type II is located in a 5-cM region in 3p12-p13: genetic and physical mapping of the SCA7 locus.
Two families with autosomal dominant cerebellar ataxia with pigmentary macular dystrophy (ADCA type II) were investigated. Analysis of 23 parent-child couples demonstrated the existence of marked anticipation, greater in paternal than in maternal transmissions, with earlier age at onset and a more rapid clinical course in successive generations. Clinical analysis revealed the presence of a great variability in age at onset, initial symptom, and associated signs, confirming the characteristic clinical heterogeneity of ADCA type II. The gene for ADCA type II previously was mapped to the spinocerebellar ataxia 7 (SCA7) locus on chromosome 3p12-p21.1. Linkage analysis of the two new families of different geographic origin confirmed the characteristic genetic homogeneity of ADCA type II, distinguishing it from ADCA type I. Haplotype analysis permitted refinement of the SCA7 region to the 5-cM interval between markers D3S1312 and D3S1600 on chromosome 3p12-p13. Eighteen sequence-tagged sites were used for the construction of an integrated map of the candidate region, based on a YACs contig. The entire candidate region is contained in a single nonchimeric YAC of 660 kb. The probable involvement of a CAG trinucleotide expansion, suggested by previous studies, should greatly facilitate the identification of the gene for ADCA type II.
Adolescent↗
Continued malignant cell proliferation in head and neck tumors during cytotoxic therapy.
The effect of cytotoxic therapy on the proliferation of squamous cell carcinoma of the head and neck in vivo in patients was evaluated before and 15-35 days after the start of therapy. To accomplish this, iododeoxyuridine was administered at t = 0, and bromodeoxyuridine was administered 15-35 days later during treatment with a tumor biopsy obtained for study immediately after each pyrimidine infusion. Monoclonal antibodies specific for the halogenated pyrimidines were used to identify cells that were in the S-phase at the time of the infusions. Eleven patients were studied prior to treatment. Of those, the intratreatment biopsy of eight patients contained tumor tissue. In the other three patients, tumor tissue was not present in the second biopsy. Continued precursor incorporation into DNA-synthesizing cells during treatment was detected in six of eight tumor specimens. In two tumor specimens, an increase in the percentage of S-phase cells was noted, in two specimens tumor cells synthesizing DNA were not detected, and in four specimens the percentage of S-phase tumor cells was lower than that in the pretherapy specimen. Patients in whom there were no S-phase cells detected during treatment or in whom no tumor was detected in the second biopsy had a favorable treatment outcome in comparison to those patients in whom continued tumor proliferation during treatment was detected. The number of cells in S-phase prior to the initiation of treatment was not predictive of whether or not proliferation would continue during cytotoxic therapy. Evidence for reentry of kinetically quiescent cells into the cycle during treatment was noted. Additionally, cytotoxic therapy altered the proliferation pattern of normal-appearing mucosa as well. The results of this study demonstrate that tumor cell proliferation does continue in some squamous cell carcinoma of the head and neck during intensive cytotoxic therapy.
Adult↗
Effects of mechanical signaling on plant cell cytosolic calcium.
Mechanical signals are important influences on the development and morphology of higher plants. Using tobacco transformed with the Ca(2+)-sensitive luminescent protein aequorin, we recently reported the effects of mechanical signals of touch and wind on the luminescence and thus intracellular calcium of young seedlings. When mesophyll protoplasts are isolated from these transgenic tobacco plants and mechanically stimulated by swirling them in solution, cytoplasmic Ca2+ increases immediately and transiently up to 10 microM, and these transients are unaffected by an excess of EGTA in the medium. The size of the transient effect is related to the strength of swirling. Epidermal strips isolated from transgenic tobacco leaves and containing only viable guard cells and trichomes also respond to the strength of swirling in solution and can increase their cytoplasmic Ca2+ transiently up to 10 microM. Finally, the moss Physcomitrella patens containing recombinant aequorin exhibits transient increases in cytoplasmic Ca2+ up to 5 microM when swirled in solution. This effect is strongly inhibited by ruthenium red. Our data indicate that the effect of mechanical stimulation can be found in a number of different cell types and in a lower plant as well as tobacco and suggest that mechanoperception and the resulting increase in cytoplasmic Ca2+ may be widespread.
Aequorin↗
Optimisation and properties of a UHG for genotyping of hemoglobins S and C.
The use of universal heteroduplex generators (UHG) as an effective means of screening for specific mutations has been previously reported. Here, we report the optimisation of a UHG system used for the rapid and simple detection of sickle cell hemoglobinopathies, HbS and HbC. The test involves heteroduplex formation between between polymerase chain reaction (PCR)-amplified beta-globin gene first exon sequences, and a UHG. The UHG is a synthetic DNA molecule homologous to HbA but which contains a small deletion adjacent to the HbS and HbC mutation sites in codons 5 and 6. Heteroduplexes are resolved on nondenaturing polyacrylamide minigels and are diagnostic of HbS and HbC in homozygous and heterozygous individuals. A blind trial of UHG genotyping involving eleven previously sequenced DNAs showed complete concordance between methods. In addition, we identified a characteristic heteroduplex banding pattern for the H2H silent mutation (CAC-->CAT) in codon 2.
Anemia, Sickle Cell↗
The cocktail party phenomenon revisited: how frequent are attention shifts to one's name in an irrelevant auditory channel?
N. Moray's (1959) well-known study of the "cocktail party phenomenon" suggested that participants sometimes notice their name embedded in an ignored auditory channel. However, the empirical finding was preliminary in nature and never has been directly replicated. This was done with improved methodological controls, and the relationship between on-line attention shifts to one's name and subsequent recollection of the name in a sample of 34 undergraduates was examined. Similar to N. Moray, only 34.6% of the participants recalled hearing their name in the channel to be ignored. Only those participants showed on-line evidence of attention shifts, and those shifts occurred only for the two items following the name. The results suggest that participants who detected their name monitored the irrelevant channel for a short time afterward.
Affect↗
Rapid genotype analysis in type 2B von Willebrand's disease using a universal heteroduplex generator.
A new diagnostic technique based on DNA heteroduplex analysis has been used to identify specific point mutations in the von Willebrand's factor (vWF) gene of patients with von Willebrand's disease type 2B. Molecular analysis in these patients has shown previously that their mutations are clustered in a short region of sequence in exon 28 of the vWF gene. The principle of the method involves heteroduplex formation between amplified genomic sequence containing the defect and an exon 28 vWF gene universal heteroduplex generator (UHG). The UHG is a synthetic vWF gene exon 28 homologue which contains a number of sequence mismatches designed to generate allele specific heteroduplexes for each type 2B mutation. Individual mutant genotypes are identified by characteristic banding patterns following polyacrylamide minigel electrophoresis. The technique is rapid, simple, inexpensive, and is ideally suited for adoption by non-specialist haematology laboratories for screening purposes.
Base Sequence↗
The pathogenesis of demyelinating disease.
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Animals↗
A review of primary health-care organization.
A contract for the provision of community nursing and associated services was drawn up between the Plymouth Community Unit and general practitioners associated with a fundholding practice at a health centre in Devon in October 1991. This project, which aimed at applying purchaser/provider principles, contained some novel features and was subject to evaluation and review after 6 months. An evaluation which had four main aspects was carried out, consisting of interviews and questionnaire assessment of staff attitudes, patients' views of the effectiveness of aspects of the practice health-promotion activity, an analysis of staff activity data before and during the pilot phase and an examination of the documentation concerned with critical issues which had arisen. Questionnaire data indicated that staff motivation and enthusiasm for the project was high and that patients' views on the practice facilities were generally positive. The role of the Macmillan nursing service at this practice was greatly enhanced during the pilot project with a fourfold increase in the number of visits carried out. Over 120 h were spent by health visiting and district nursing staff on issues surrounding the pilot project including attending additional meetings. The results are discussed in relation to service benefits to patients, the effect on the cohesion of the primary health-care team and issues of fundholding and are considered in the context of models put forward for the future development of community-based nursing care.
Adult↗
Multiple sclerosis.
Differences in the risk of multiple sclerosis depending on racial background, and the high clinical concordance rates in monozygotic compared with dizygotic twins, have stimulated attempts to identify and locate genes that confer susceptibility to the disease. The risk of multiple sclerosis is increased from 1 in 800 in northern European Caucasians to 1 in 3 in the monozygotic co-twins of affected individuals, with intermediate rates for siblings, offspring and more distant relatives. Concordance rates in monozygotic and dizygotic co-twins of affected individuals rise to 35% and 15%, respectively when magnetic resonance imaging is used to supplement clinical evidence for disease status. The increased recurrence risk in relatives of patients with multiple sclerosis is consistent with a model in which more than one gene contributes to susceptibility. Population studies have demonstrated an association with the class 2 major histocompatibility complex (MHC) phenotypes DR15 and DQw6 and their corresponding genotypes DRB1.1501, DRB5.0101 and DQA1.0102, DQB2.0602. An extensive search, using population studies, for other polymorphic alleles involved in restriction of the immune response may have yielded an additional candidate gene in the VH2-5 immunoglobulin heavy-chain variable region. Identity by descent analysis of candidate genes encoded within the alpha-chain of the T-cell receptor and the gene for myelin basic protein has failed to demonstrate linkage; paradoxically, this is also true for the MHC class 2 region, despite the population association. However, studies involving a large number of sibling pairs have reported a bias in the distribution of T-cell receptor beta-chain variable region haplotype sharing, favouring linkage. This becomes more marked when stratification is made for the presence of DR2 in both affected siblings, suggesting an interaction between genetic polymorphisms encoded within the MHC and T-cell receptor genes, as expected from their known functional co-operation in antigen presentation. The same is true for the immunoglobulin heavy chain, providing provisional evidence for linkage to a gene encoded within the immunoglobulin heavy-chain variable region in families reported from the UK. Taken together, these findings demonstrate the importance of family studies in elucidating the genetic basis of multiple sclerosis, and confirm that several genes are involved, one or more of which regulates genetic restriction of the immune response. The contribution made by the susceptibility genes that have provisionally been identified, occurring in isolation or together, can account for only a proportion of the increased risk of multiple sclerosis implicated by family studies.(ABSTRACT TRUNCATED AT 250 WORDS)
Genes↗
Rapid classification of phenylketonuria genotypes by analysis of heteroduplexes generated by PCR-amplifiable synthetic DNA.
We describe a rapid and simple method for phenylketonuria genotyping which identifies five point mutations within exon 12 of the human phenylalanine hydroxylase gene. The method involves PCR amplification of the target exon and hybridization with a PCR-amplifiable synthetic DNA (universal heteroduplex generator, UHG). The UHG contains identifiers consisting of nucleotide substitutions and/or deletions, contiguous with known mutation sites within the target exon. DNA heteroduplexes are resolved by nondenaturing polyacrylamide minigel electrophoresis. Individual mutant genotypes are identified by characteristic banding patterns, in either homozygous or heterozygous states. The method may potentially be applied to rapid genotyping of any mutation or series of mutations within PCR-amplifiable genetic material.
Base Sequence↗
Perceptions and reactions of the public to diarrhoea.
A questionnaire about diarrhoea and how people react to it was answered by 400 people aged 16-70 years, most of whom were in employment (77% of respondents). There was wide variation in perceptions and reactions. Older persons and people in skilled trades were more likely to consider any increased bowel looseness or frequency of their usual bowel habit as diarrhoea, compared to younger persons and people in professional and managerial positions. Over half the respondents rated a single soft stool as diarrhoea, and almost a third accepted likewise an increased frequency of defaecation. The most unpleasant aspect of diarrhoea was considered to be incontinence with soiling of underclothes. At the onset of diarrhoea, 16% of respondents would not wait even a day or two but would go straight to a pharmacist, and 8% would go direct to a doctor. Persons in professional and managerial positions were less likely to attend their doctor straight away than people in other occupational groups. The findings show that for improved clinical management and public health surveillance, health professionals should not accept the term when it is used by patients, but seek details of their defaecation patterns and the form of their stools. Improved public education is needed as to self-help, appropriate treatment and when to seek pharmaceutical and medical advice.
Adolescent↗