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Biomedical subjects

R Williamson

Publications and source records attributed to R Williamson.

At least 127 records · Page 7Linked to original sources
PubMed1996

Evidence that a locus for familial psoriasis maps to chromosome 4q.

Psoriasis is an inflammatory skin disease that affects 2% of the population. It is characterised by red, scaly skin patches which are usually found on the scalp, elbows and knees, and may be associated with severe arthropathy. The lesions are caused by abnormal keratinocyte proliferation, and infiltration of inflammatory cells into the dermis and epidermis. The usual age of onset of psoriasis is between 15 and 30 years, although it can present at any age. Psoriasis is recognised to have a large genetic component. Twin studies show the concordance in monozygotic twins to be between 65-70%, compared to between 15-20% in dizygotic twins. Family studies estimate the risk to first degree relatives at between 8-23%. However, there are also several environmental factors, including streptococcal infection and stress, that affect the onset and presentation of the disease. The mode of inheritance of psoriasis is unclear. We conducted a genome-wide scan to search for psoriasis susceptibility loci in a single large multiplex family. Parametric linkage analysis indicated that a susceptibility locus for familial psoriasis was located on chromosome 4q. Investigation of this locus in five further multiplex families using both parametric and non-parametric methods gave significant localisation to chromosome 4q. The maximum total pairwise lod score obtained was 3.03 with the microsatellite marker D4S1535 at theta = 0.08. Non-parametric multipoint analysis with GENEHUNTER- demonstrated significant excess allele sharing, with a P value of 0.0026, at the same locus.

Chromosome Mapping↗
PubMed1996

Liposomes and viruses for gene therapy of cystic fibrosis.

Cystic fibrosis (CF) is a common, life-threatening autosomal recessive disease caused by mutations in the CFTR gene. It affects the function of the lung, gut, and liver. Present strategies for CF aim to correct the defect by introducing a normal copy of the CFTR gene into affected epithelial cells. Two vector systems have been proposed for gene therapy trials, replication defective adenovirus and cationic liposome/DNA complexes. Adenoviral vectors have been used in Phase I trials and in most cases give transient molecular and/or electrophysiological restitution of the ion transport cellular defects of CF. However, a dose of 10(9) pfu/ml applied to the lung led, in one patient, to a transient inflammatory reaction. New adenoviral vectors are presently being developed to solve this problem. Our studies using liposome/DNA complexes to deliver CFTR cDNA to the nasal epithelium were carried out in the double blind trial and showed no treatment-related local or general adverse reactions and significant small but transient correction of the ion transport defect. The results for both current approaches demonstrate the need for substantial improvement of the efficiency and duration of transgene expression to reach therapeutically relevant levels.

Adenoviridae↗
PubMed1996

No evidence for linkage of chromosome 6p markers to schizophrenia in southern African Bantu-speaking families.

Previous studies have yielded evidence for a locus conferring susceptibility to schizophrenia and schizophrenia spectrum disorders on chromosome 6p24-22 in a sample of multiply affected Irish families. We tested for linkage between highly polymorphic chromosome 6p24-22 markers and narrowly defined schizophrenia in a sample of 19 Southern African Bantu-speaking families, a population known to have diverged in the last 2000 years. There is no evidence to support the linkage of markers in this region of chromosome 6 to schizophrenia in this population.

Black People↗
PubMed1996

Ranitidine bismuth citrate: a novel anti-ulcer agent with different physico-chemical characteristics and improved biological activity to a bismuth citrate-ranitidine admixture.

BACKGROUND: Ranitidine bismuth citrate (RBC) is a new chemical entity for the treatment of peptic ulcer disease. RESULTS: RBC is freely soluble in water (more than 600 mg/mL at pH 4.6), whereas an equimolar admixture of its component molecules, bismuth citrate and ranitidine, formed an almost totally insoluble suspension. Even at very low pH values (around 2.0), the solubility of bismuth in ranitidine bismuth citrate was at least two-fold better than in the admixture. Comparison of several physico-chemical characteristics indicated that RBC possessed significantly different melting point properties, X-ray powder diffraction patterns, infra-red spectra and 13C-NMR solid-state spectra to the admixture. Ranitidine bismuth citrate inhibited human pepsin isoenzymes 1, 2, 3 and 5 but the admixture was inactive. RBC showed approximately two-fold greater anti-Helicobacter pylori activity in vitro than the admixture (geometric mean minimum inhibitory concentrations of 12.5 and 25.7 mg/L, respectively) and was more rapidly bactericidal. In a mouse model of gastric H. pylori colonization, 200 mg/kg of bismuth, given as RBC, eradicated the organism from all mice while only 10% of infections were eradicated by equivalent levels of bismuth in admixture form. CONCLUSION: It is believed that the significantly greater solubility of RBC, especially at lower pH values, is highly relevant to its better antipepsin and anti-H. pylori action compared to the insoluble admixture of bismuth citrate and ranitidine.

Animals↗
PubMed1996

A comparison of intramuscular ketorolac with indomethacin suppositories in the treatment of pain after oral surgery.

The analgesic effects of 30 mg intramuscular ketorolac were compared with those of rectal indomethacin in 100 mg and 200 mg doses in 66 patients in a single-blinded trial. Pain scores and the incidence of nausea and vomiting were assessed at 30, 60 and 120 minutes postoperatively, at discharge (4 hours) and on the evening of surgery. Area under the curve of pain scores versus time for pain at 30, 60 and 120 minutes postoperatively was significantly lower in the ketorolac group compared to indomethacin 100 mg and 200 mg groups. There were no significant differences in the pain scores at discharge or at home on the evening of surgery. At 60 minutes postoperatively there was significantly more nausea and vomiting in the indomethacin 200 mg group; at all other time-points there was no significant difference between the groups with regard to nausea and vomiting. The power of the study to determine the significance of side-effects between the groups was low.

Adult↗
PubMed1996

The views of general practitioners on community carrier screening for cystic fibrosis.

BACKGROUND: Recent developments in molecular genetics have made it possible to identify carriers of the cystic fibrosis (CF) mutation, regardless of family history, before they have an affected child. Using these techniques, population or 'community' carrier screening can offer informed reproductive choice to individuals and couples who would not otherwise know of their risk of having a CF child. AIM: This study set out to assess the views of general practitioners (GPs) on community carrier screening for CF and to consider the factors that influence their willingness to offer it themselves. METHOD: A self-administered questionnaires was sent to all 616 GPs in four areas of North Thames (West) Region. RESULTS: Two-thirds of respondents indicated that identifying carrier couples to offer genetic counselling before conception was a very important benefit of community carrier screening. Two-thirds felt that general practice was the most appropriate place in which to offer it, and similar proportions that the most appropriate times to do so were when a close relative was diagnosed and when seeking family planning. About half wanted to offer community carrier screening themselves; this was related to experience with CF patients and CF carrier testing, and estimates of the numbers of CF carriers in the practice. CONCLUSIONS: There is considerable support among GPs for community carrier screening for CF in general practice, particularly in the context of family planning services. Knowledge and experience of CF increase GPs' willingness to offer it themselves.

Attitude of Health Personnel↗
PubMed1996

Prophylactic gene therapy for cancer.

Attempts at cancer gene therapy to date have focused on the treatment of existing neoplasms, using genetic techniques either to target toxic compounds at or enhance the host's response to a tumour. These cytotoxic and immunological approaches have to be tailored to a specific tumour, and often fail because new cellular mutations can overcome the treatment, as for traditional lines of therapy. There has been less attention given to the possibility of using gene therapy to prevent malignant transformation in certain specific contexts for high-risk tissues. Such approaches could add functional proto-oncogenes or tumour suppressor genes, or nullify pathogenic mutations in such genes using antisense or gene replacement techniques. These strategies will not apply to all tumours, but are more likely to be effective where tissue-specific stem cells can be targeted, and for tumours where mutations in one of several genes are involved in carcinogenesis, as for cancer of the colon. Safer vectors for gene delivery will also be required if therapy is to be considered for prevention rather than treatment.

Animals↗
PubMed1995

The time of appearance and disappearance of fetal DNA from the maternal circulation.

A single copy Y-chromosome DNA sequence was amplified using the polymerase chain reaction (PCR) from the peripheral blood of 30 women who had achieved a pregnancy through an in vitro fertilization (IVF) programme. The time of conception was known precisely and was confirmed by serial ultrasound scans. Conceptions were dated as the number of weeks after fertilization plus 2, to give a time equivalent to the obstetric menstrual dating of the pregnancy (LMP). Y-chromosome-specific DNA was detected in all pregnancies with a male fetus (18/30). The earliest detection was at 4 weeks and 5 days, and the latest at 7 weeks and 1 day. Y-chromosome-specific sequences were no longer detected in any of the male pregnancies 8 weeks after delivery. No Y-chromosome sequences were detected in any of the pregnancies where only female babies were delivered. This demonstrates that fetal DNA appears in the maternal circulation early in the first trimester, that it can be identified in all pregnancies tested by 7 weeks, that it continues to be present throughout pregnancy, and that it has been cleared from the maternal circulation 2 months after parturition. Early non-invasive prenatal diagnosis for aneuploidies and inherited disorders will be possible in all pregnancies if fetal cells can be isolated free from maternal contamination (or identified accurately in the presence of maternal cells) without problems of contamination from previous pregnancies.

DNA↗
PubMed1995

Prenatal ultrasound diagnosis of amelia.

Amelia is a very rare form of limb reduction defect. The incidence of isolated amelia with or without other limb reductions is 0.4 per 100,000 births. We report a cluster of three cases diagnosed prenatally. One was isolated tri-amelia and two were isolated tetra-amelia.

Adult↗
PubMed1995

Friedreich's ataxia: a defect in signal transduction?

We have previously assigned the mutation causing Friedreich's ataxia (FRDA) to 9q13 by genetic linkage and fluorescent in situ hybridization analysis, and identified recombination events which position the gene centromeric to D9S5. We report here the extension of a yeast artificial chromosome contig to span the 860 kb interval immediately proximal to this marker, which includes the D9S886 and D9S887/888 loci reported to flank the FRDA locus, and the construction of a high resolution cosmid contig initiated from the D9S888 locus. Exon trapping and cDNA library screening strategies have resulted in the isolation of a candidate gene which traverses the centromeric boundary of the FRDA critical region. The gene spans a genomic interval greater than 220 kb with at least two of the coding exons located proximal to the D9S887/888 loci. Expression is complex, with multiple transcripts detected in a variety of tissues and evidence of alternative splicing and developmental control. The predicted amino acid sequence for the 2.7 kb transcript reported here shows a marked homology to the deduced amino acid sequence of the Saccharomyces cerevisiae MSS4 protein, proposed to function within the phosphoinositide cycle, suggesting a potential role for the human homologue in signal transduction. Whilst no evidence for mutation has been detected in this transcript, the sequence represents only one of the shorter alternatively spliced species identified by Northern analysis and direct sequencing. This gene remains a strong candidate for FRDA.

Alternative Splicing↗
PubMed1995

The introduction of two silent mutations into a CFTR cDNA construct allows improved detection of exogenous mRNA in gene transfer experiments.

Phase one clinical trials for gene therapy of cystic fibrosis are in progress using either liposomes or adenoviral vectors for CFTR gene transfer to epithelial cells in the airways. In addition to electrophysiological measurements, expression of vector CFTR is usually assessed by RT-PCR. We have developed a CFTR-expression vector, pCFAS, that simplifies the distinction of transgene-derived CFTR mRNA from endogenous mRNA. Two point mutations were introduced into CFTR cDNA which eliminated a SphI restriction site and created a new, unique AgeI restriction site. Neither mutation altered the predicted amino acid sequence of the protein. Restriction digestion of RT-PCR products from cells transfected with pCFAS allowed the differentiation of transgene and endogenous CFTR transcripts. To verify function of the mutated CFTR, the plasmid was transferred into freshly obtained nasal epithelial cells from CF patients ex vivo using cationic liposomes. Fluorescence microscopy using the halide-sensitive fluorophore SPQ demonstrated restoration of cAMP-mediated Cl- secretion. This plasmid will be useful for CFTR gene transfer studies in vitro and in vivo.

Base Sequence↗
PubMed1995

Genetic variation in the COL6A1 region is associated with congenital heart defects in trisomy 21 (Down's syndrome).

Genetic variation in the COL6A1-COL6A2 gene cluster on chromosome 21 was studied in 113 controls and 58 European families (including control and family subgroups of British/Irish origin) having a child with trisomy 21. There were statistically significant differences among subgroups of trisomic children with and without congenital heart defects (CHD) in distributions of definitive, 3-RFLP haplotype classes received from their nondisjoining and disjoining parents. Haplotypes received by trisomic children with CHD from their disjoining parents were not a random sample of controls' haplotypes. Analysis of parental single-RFLP genotypes and linkage disequilibrium patterns confirmed this parent subgroup differed from a random sample of controls. There were no significant differences in parent subgroup genotype distribution at any of nine control loci distributed along chromosome 21q. This sample showed an association between genetic variation in the COL6A1 gene region and congenital heart defects in trisomy 21.

Adolescent↗
PubMed1995

Expression of the APC gene after transfection into a colonic cancer cell line.

Mutations in the adenomatous polyposis coli (APC) gene cause the hereditary cancer syndrome familial adenomatous polyposis and are implicated in the early stages of sporadic colorectal carcinogenesis. APC is therefore a promising candidate for use in prophylactic gene therapy of intestinal tissues at high risk of becoming malignant. The aim of the study was to discover if functional full length APC gene can be introduced into somatic gut epithelial cells and to define the optimum conditions for such transfer. Copies of the normal APC gene were introduced into SW480 cells, a colonic epithelial cell line with an APC gene mutation, using plasmid DNA combined with liposomes. Reverse transcriptase polymerase chain reaction and restriction enzyme digestion allowed the endogenous gene to be distinguished from the transgene. It was shown that the normal APC gene is expressed at high levels for 72 hours after transfection and disappears within one week. This study shows that short-term expression of normal APC gene can be achieved after transfection with liposome-DNA complexes at sufficiently high levels to permit assessment of biological effects.

Base Sequence↗
PubMed1995

Evidence for exclusion of a mutation in NRAMP as the cause of familial disseminated atypical mycobacterial infection in a Maltese kindred.

In mice, susceptibility to intracellular infections in inbred strains is controlled by a single locus, Lsh/Ity/Bcg, and the gene responsible has been cloned and designated Nramp (Natural resistance associated macrophage protein). We have identified a group of related children who appear to have a single gene defect, inherited recessively, which results in increased susceptibility to myocabacterial infection. The immunological defect observed in the affected children resembles that in mice homozygous for the Lsh/Ity/Bcg susceptible allele. To test the hypothesis that a mutation in NRAMP is responsible for the immunodeficiency observed in the affected children, we have typed eight markers in the region of human 2q34-q37 where NRAMP, the human homologue of Nramp, maps. We have shown discordance with the defect in one family and the chromosomes in the three affected children have different haplotypes making it unlikely that inheritance of an ancestral mutation in the NRAMP gene is the cause of increased mycobacterial susceptibility in this group of children.

Animals↗
PubMed1995

Confirmation of genetic heterogeneity in familial psoriasis.

Psoriasis affects approximately 2% of the European population and is often familial. Linkage of a subset of psoriasis families to loci on chromosome 17q has recently been reported. We have studied members of a large multiply affected family from the north east of England and analysed genotypes for markers from 17q, including the polymorphic microsatellite markers AFM210xa5, AFM163yg1, AFM044xg3, AFMa353yg1, and AFM217yd19. Two point and multipoint analysis clearly show exclusion of linkage between the telomeric region of 17q and psoriasis in this family. This confirms the genetic heterogeneity of psoriasis and the existence of at least one other major psoriasis locus.

Chromosomes, Human, Pair 17↗
PubMed1995

Physical evidence for the position of the Friedreich's ataxia locus FRDA proximal to D9S5.

Orientation of the Friedreich's ataxia locus (FRDA) with respect to D9S15 and D9S5 has proved critical to the design of subsequent cloning strategies. The rarity of recombination events between FRDA and these markers, originally used to determine assignment to human chromosome region 9q13-->q21.1, has necessitated the instigation of physical mapping studies to determine order and, hence, the precise location of the disease gene. Simultaneous fluorescence in situ hybridisation using cosmid clones located in close proximity to the ends of a 1.2-Mb yeast artificial chromosome clone extending into the FRDA candidate region provides physical evidence for the order of the marker loci to be cen-D9S202-D9S5-D9S15-qter. The possibility that a pericentric inversion, occurring naturally in approximately 1% of the normal population, may affect the order of markers within this region has been eliminated. Considered in association with the interpretation of a recombination event detected in a single affected individual, these data indicate that the FRDA locus is located proximal to D9S5.

Adaptor Proteins, Signal Transducing↗