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Biomedical subjects

N Wood

Publications and source records attributed to N Wood.

At least 19 recordsLinked to original sources
PubMed1998

Fine mapping of de novo CMT1A and HNPP rearrangements within CMT1A-REPs evidences two distinct sex-dependent mechanisms and candidate sequences involved in recombination.

The molecular mechanism resulting in the duplication or deletion of a 1.5 Mb region of 17p11.2-p12, associated, respectively, with Charcot-Marie-Tooth type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP), has been proposed to be an unequal crossing-over during meiosis between the two chromosome 17 homologues generated by misalignment of the proximal and distal CMT1A-REP repeats, two homologous sequences flanking the 1.5 Mb CMT1A/HNPP monomer unit. In a recent study of a large series of de novo cases of CMT1A and HNPP, two distinct sex-dependent mechanisms were identified. Rearrangements of paternal origin, essentially duplications, were indeed generated by unequal meiotic crossing-over between the two chromosome 17 homologues, but duplications and deletions of maternal origin resulted from an intrachromosomal process, either unequal sister chromatid exchange or, in the case of deletion, excision of an intrachromatidal loop. In order to determine how these recombinations occur, 24 de novo crossover breakpoints were localized within the 1.7 kb rearrangement hot spot by comparing the sequences of the parental CMT1A-REPs with the chimeric copy in affected offspring. Nineteen out of 21 paternal crossovers were found in a 741 bp hot spot. All the breakpoints of maternal origin (n = 3), however, were located outside this interval, but in closely flanking sequences, supporting the hypothesis that two distinct sex-dependent mechanisms are involved. Several putative recombination promoting sequences in the hot spot, which are rare or absent in the surrounding 7.8 kb, were identified.

Charcot-Marie-Tooth Disease↗
PubMed1998

Symptomatic unilateral pleural effusion as a presentation of ovarian hyperstimulation syndrome.

Isolated acute unilateral pleural effusion has twice been reported as the only symptom of ovarian hyperstimulation syndrome (Kingsland et al, 1989; Jewelewicz and Vande Wiele, 1975). The pathogenesis of this disorder is not fully understood and the presence of an isolated pleural effusion lends support to the role of systemic factors rather than purely the transudation of fluid from grossly enlarged ovaries in the progression of this disease. This article describes a second case of an isolated pleural effusion following in-vitro fertilization and embryo transfer.

Adult↗
PubMed1997

Expression of alpha 2 macroglobulin receptor/low density lipoprotein receptor-related protein is cell culture density-dependent in human breast cancer cell line BT-20.

alpha 2Macroglobulin receptor/low density lipoprotein receptor-related protein (alpha 2MR/LRP) is a multifunctional cell plasma membrane receptor that binds and facilitates the endocytosis of a number of ligands involved in protease regulation and lipoprotein metabolism. In the invasive breast cancer cell line BT-20 we show that the expression of alpha 2MR/LRP can be strongly affected by cell culture density. By comparing measurements of mRNA, total cellular alpha 2MR/LRP antigen, and cell surface alpha 2MR/LRP expression we have demonstrated a marked cell density-dependent regulation of this receptor expression. Increasing the cell density results in a 3.4-fold increase in cell surface alpha 2MR/LRP expression. This corresponds to a marked increase in alpha 2MR/LRP mRNA in Northern blots of total RNA from cells cultured at high density and to consistent increases in alpha 2MR/LRP heavy chain in Western blots of cell lysates from high density cultures. These studies together demonstrate the significant up-regulation of alpha 2MR/LRP expression in BT-20 by increased cell density.

Blotting, Northern↗
PubMed1997

Expression of alpha2-macroglobulin receptor/low density lipoprotein receptor-related protein on surfaces of tumour cells: a study using flow cytometry.

alpha2-Macroglobulin receptor/low density lipoprotein receptor-related protein (alpha2 MR/LRP) is a multifunctional cell surface receptor that binds and endocytoses several structurally and functionally distinct ligands. Very little is known about the expression and function of alpha2 MR/LRP in tumour cells. The aim of this study was to quantify the number of alpha2 MR/LRP on surfaces of human tumour cells by flow cytometry. Using human alpha2 MR/LRP monoclonal antibody 8G1, human peripheral blood lymphocytes (negative control cells), monocytes (positive control cells), human neonatal foreskin fibroblast cells (NFF) (positive control cells), three human breast cancer cell lines (BT-20, T-47D, and MCF-7), two human ovarian tumour cell lines (JAM, and CI80-13S), and five human melanomas (MM418c1, MM253c1, A2058, MM138, MM370) were indirectly labelled with goat anti-mouse IgFITC. The fluorescent signals of stained cells were measured by flow cytometry. Using Quantum Simply Cellular bead standards, the number of alpha2 MR/LRP binding sites per cell was assessed. The flow cytometric method to quantify of alpha2 MR/LRP described here is simple and reliable. All the human tumour cell lines so far examined express alpha2 MR/LRP at different levels from approximately 300 to approximately 10000 sites per cell.

Fibroblasts↗
PubMed1997

Simultaneous genotyping for all three known structural mutations in the human mannose-binding lectin gene.

We describe a rapid and simple method for genotyping the three known structural mutations within exon 1 of the mannan-binding lectin (MBL) gene. A PCR-amplifiable synthetic DNA (Universal Heteroduplex Generator) was annealed to genomic PCR product from exon 1 to generate unique DNA heteroduplexes for each mutation. Heteroduplexes were then resolved by non-denaturing polyacrylamide gel electrophoresis. The technique was initially validated with previously typed samples and then applied to previously untyped samples with the results confirmed by DNA sequencing.

Amino Acid Sequence↗
PubMed1997

Patient satisfaction: a review of issues and concepts.

This review presents issues arising from an analysis of over 100 papers published in the field of patient satisfaction. The published output appearing in the medical and nursing literature which incorporated the term "patient satisfaction" rose to a peak of over 1000 papers annually in 1994, reflecting changes in service management especially in the U.K. and U.S.A. over the past decade. An introductory section discusses the setting and measurement of patient satisfaction within this wider context of changes in service delivery. Various models are examined that have attempted to define and interpret the idea of determining individual perceptions of the quality of health care delivered. Determinants of satisfaction are examined in relation to the literature on expectations, and demographic and psychosocial variables. These are distinguished from the multidimensional components of satisfaction as aspects of the delivery of care, identified by many authors. The review highlights the complexity and breadth of the literature in this field, the existence of which is often not acknowledged by researchers presenting the findings of studies.

Humans↗
PubMed1997

Cloning of the SCA7 gene reveals a highly unstable CAG repeat expansion.

The gene for spinocerebellar ataxia 7 (SCA7) has been mapped to chromosome 3p12-13. By positional cloning, we have identified a new gene of unknown function containing a CAG repeat that is expanded in SCA7 patients. On mutated alleles, CAG repeat size is highly variable, ranging from 38 to 130 repeats, whereas on normal alleles it ranges from 7 to 17 repeats. Gonadal instability in SCA7 is greater than that observed in any of the seven known neuro-degenerative diseases caused by translated CAG repeat expansions, and is markedly associated with paternal transmissions. SCA7 is the first such disorder in which the degenerative process also affects the retina.

Adult↗
PubMed1997

Rapid mutation screening in type 2A von Willebrand's disease using universal heteroduplex generators.

Patients with type 2A von Willebrand's disease (VWD) commonly have missense mutations in the A2 domain of the von Willebrand factor (VWF) protein. This domain is encoded by the 3' region of VWF gene exon 2 8 and the large majority of patients have heterozygous mutations clustered in the sequence between codons 742 and 909. We describe a DNA-based diagnostic technique which enables at least 10 previously described mutations to be rapidly identified. The method involves polymerase chain reaction (PCR) amplification of two exon 28 gene segments between codons 717-788 and 803-893, respectively. Each fragment is then hybridized with a synthetic complementary DNA molecule of similar size, termed a Universal Heteroduplex Generator (UHG). The UHG contains base deletions contiguous to the sites of known mutations and, following hybridization, allele-specific heteroduplexes are generated which can be detected by simple polyacrylamide gel electrophoresis and ethidium bromide staining. A small panel of UHG molecules covering the 3' region of exon 28 should enable the large majority of type 2A VWD patients to be rapidly diagnosed by genotype.

Base Sequence↗
PubMed1997

Chorea-acanthocytosis: genetic linkage to chromosome 9q21.

Chorea-acanthocytosis (CHAC) is a rare autosomal recessive disorder characterized by progressive neurodegeneration and unusual red-cell morphology (acanthocytosis), with onset in the third to fifth decade of life. Neurological impairment with acanthocytosis (neuroacanthocytosis) also is seen in abetalipoproteinemia and X-linked McLeod syndrome. Whereas the molecular etiology of McLeod syndrome has been defined (Ho et al. 1994), that of CHAC is still unknown. In the absence of cytogenetic rearrangements, we initiated a genomewide scan for linkage in 11 families, segregating for CHAC, who are of diverse geographical origin. We report here that the disease is linked, in all families, to a 6-cM region of chromosome 9q21 that is flanked by the recombinant markers GATA89a11 and D9S1843. A maximum two-point LOD score of 7.1 (theta = .00) for D9S1867 was achieved, and the linked region has been confirmed by homozygosity-by-descent, in offspring from inbred families. These findings provide strong evidence for the involvement of a single locus for CHAC and are the first step in positional cloning of the disease gene.

Acanthocytes↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1997

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↗
PubMed1996

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↗
PubMed1996

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↗