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Biomedical subjects

K Welsh

Publications and source records attributed to K Welsh.

At least 73 records · Page 4Linked to original sources
PubMed1992

Genetic analysis using DNA polymorphism of the linkage between chromosome 11q13 and atopy and bronchial hyperresponsiveness to methacholine.

Previous studies have suggested that there is a genetic predisposition for the development of asthma and atopy. A recent study has also demonstrated that there is a striking link between chromosome 11q and the IgE response underlying asthma and rhinitis. To assess the linkage between chromosome 11q (region D11S97) and atopy or bronchial hyperresponsiveness (BH), we have studied nine families of two and, in many instances, three generations with the index case having asthma and/or atopy. With variable number of tandem repeat analysis with the probe, p lambda-MS.51, we have been unable to confirm a significant link between region D11S97 of chromosome 11q and either atopy or BH to methacholine. We have demonstrated that atopy and BH produce similar log of odds scores with linkage analysis at each recombination fraction from 0.001 to 0.5 with both Hinf1 and Taq1 restriction digests and that the use of either a positive skin prick test or positive RAST as a definition of atopy does not significantly alter the log of odds score.

Adolescent↗
PubMed1992

The immunogenetic background of scleroderma--an overview.

Currently it may be stated that the MHC associations in scleroderma support the classification of disease subsets, but in no ethnic group is the overall association strong enough for clinical use. In different ethnic groups, the distribution of MHC alleles varies, as does the degree of linkage disequilibrium between alleles of the linked loci. This concept is even relevant to relatively close populations. Thus Whiteside noticed that, if those patients referred from more than 100 miles from the study centre were excluded, then the strength of the DR1 association increased. The environmental contribution to scleroderma is unknown, except in the case of toxin or solvent associated disease. Different causal environmental agents found in different global regions might result in separate MHC associations and hence explain the discrepancies noted above. There are indications that associations between specific subsets of SSc patients and genetic markers will assume greater importance both diagnostically and prognostically. The lung fibrosis group look prime candidates, for example. Genetic markers are also a useful means of relating chemically-induced SSc-like disorders to the classical disease. Vinyl chloride disease provides an example. There is much heterogeneity within the disease, in terms of extent of skin involvement, severity, and of organ involvement. It is clear that the different clinical subsets of scleroderma are characterized by different associated MHC alleles. There are also many cases of clinical overlap with related diseases, and certain of these diseases have a different HLA association, which could detract from the primary HLA type associated with SSc.(ABSTRACT TRUNCATED AT 250 WORDS)

Autoantibodies↗
PubMed1991

Detection of abnormal memory decline in mild cases of Alzheimer's disease using CERAD neuropsychological measures.

The present study was designed to determine which of the memory tasks included in the CERAD (Consortium to Establish a Registry for Alzheimer's Disease) neuropsychological battery best differentiate patients with early Alzheimer's disease from cognitively normal elderly control subjects and also best distinguish between the various levels of severity of the dementia process. A sample of CERAD patients with Alzheimer's disease was stratified by disease severity into those with mild, moderate, or severe dementia and matched with control subjects for sex, age, and education. Using multivariate procedures and cutting scores, the efficacy of each memory measure in distinguishing between these groups and control subjects was determined. The test for delayed recall was found to be the best overall discriminatory measure. The other tests of memory, ie, immediate recall, intrusion errors, and recognition memory, had poor overall discriminability. None of the CERAD memory measures were found to be particularly powerful in staging the severity of dementia. These findings suggest that tests for delayed recall may be particularly useful in the early detection of Alzheimer's disease and should be considered in screening batteries for dementia in community surveys.

Aged↗
PubMed1991

Treatment of rapidly progressive glomerulonephritis by extracorporeal immunoadsorption, prednisolone and cyclophosphamide.

Ten patients with rapidly progressive glomerulonephritis and acute renal failure were treated with extracorporeal immunoadsorption, prednisolone, and cyclophosphamide. Three patients had systemic lupus erythematosus, five had microscopic polyarteritis and two had Wegener's granulomatosis. All ten patients were dialysis-dependent prior to immunoadsorption. Nine of ten patients rapidly regained renal function and seven continue to have independent renal function between 9 and 30 months after immunoadsorption. Three patients at presentation were not dialysis dependent. Despite treatment with methylprednisolone, cyclophosphamide, and oral prednisolone, renal function continued to deteriorate and they required dialysis. Immunoadsorption was then started without alteration in baseline immunosuppression. Within a mean of 4.6 days, range 3-7 days, renal function improved and the patients no longer required dialysis. Antineutrophil cytoplasmic antibodies and double-stranded DNA antibodies were rapidly removed by immunoadsorption. Only one patient with systemic lupus erythematosus and two with microscopic polyarteritis had significant resynthesis of antibody at 1 month post-immunoadsorption. Renal biopsy before and after immunoadsorption and immunosuppressive therapy showed resolution of glomerular crescents and no evidence of active disease. Immunoadsorption coupled with prednisolone and cyclophosphamide may be of value in the treatment of rapidly progressive glomerulonephritis.

Adult↗
PubMed1990

Stereochemical mechanism of action for thymidylate synthase based on the X-ray structure of the covalent inhibitory ternary complex with 5-fluoro-2'-deoxyuridylate and 5,10-methylenetetrahydrofolate.

The structure of the Escherichia coli thymidylate synthase (TS) covalent inhibitory ternary complex consisting of enzyme, 5-fluoro-2'-deoxyuridylate (FdUMP) and 5,10-methylene tetrahydrofolate (CH2-H4PteGlu) has been determined at 2.5 A resolution using difference Fourier methods. This complex is believed to be a stable structural analog of a true catalytic intermediate. Knowledge of its three-dimensional structure and that for the apo enzyme, also reported here, suggests for the first time how TS may activate dUMP and CH2-H4PteGlu leading to formation of the intermediate and offers additional support for the hypothesis that the substrate and cofactor are linked by a methylene bridge between C-5 of the substrate nucleotide and N-5 of the cofactor. By correlating these structural results with the known stereospecificity of the TS-catalyzed reaction it can be inferred that the catalytic intermediate, once formed, must undergo a conformational isomerization before eliminating across the bond linking C-5 of dUMP to C-11 of the cofactor. The elimination itself may be catalyzed by proton transfer to the cofactor's 5 nitrogen from invariant Asp169 buried deep in the TS active site. The juxtaposition of Asp169 and bound tetrahydrofolate in TS is remarkably reminiscent of binding geometry found in dihydrofolate reductase where a similarly conserved carboxyl group serves as a general acid for protonating the corresponding pyrazine ring nitrogen of dihydrofolate.

Binding Sites↗
PubMed1990

Genetic factors in scleroderma.

1. In no ethnic group is the overall association between SSc and the MHC, T-cell receptors, or drug metabolism phenotypes strong enough for direct clinical use. 2. Indications are that associations between specific subsets of SSc patients and genetic markers will assume greater importance both diagnostically and prognostically. The lung fibrosis group may be a prime candidate. 3. Genetic markers are useful means of relating chemically induced SSc-like disorders with the classical disease. Vinyl chloride disease is an example. 4. Evidence is emerging of strong associations between certain genetic markers and autoantibody production; a similar story has emerged in SLE. We believe that genetic testing will influence therapy in at least a subset of SSc patients, but that a dramatic breakthrough will not be made until we know how the genetics of the disease relate to the primary biochemical disease characteristic, that is the overproduction of collagen. In this respect, it has been suggested that the 5' flanking DNA of dermal collagen genes is particularly susceptible to the binding by Scl-70 (topoisomerase I). A problem is how to combine this and the other observations discussed above. Chromosomal instability can be linked to both the MHC and SSc-inducing chemicals, and the association of autoantibodies to topoisomerase I provides a tentative link between the MHC and collagen gene expression. Although the role and reason for anti-Scl 70 in SSc is unknown, humoral autoimmunity, at least in SLE, appears to be strongly dependent on specific HLA genes.

Chromosome Aberrations↗
PubMed1989

Effect of graft perfusion with two CD45 monoclonal antibodies on incidence of kidney allograft rejection.

In a blind trial, 77 patients were randomised to receive first cadaver kidney allografts that had been perfused either with a pair of CD45 monoclonal antibodies (mAbs), in an attempt to reduce the immunogenicity of passenger leucocytes, or with control human albumin solution. No complications of mAb perfusion were observed. Patient and allograft survival were similar in both groups. Rejection episodes were recorded in 7 (18%) of the patient with mAb perfused allografts compared with 24 (63%) of the controls.

Animals↗
PubMed1989

Removal of anti-HLA antibodies by extracorporeal immunoadsorption to enable renal transplantation.

10 highly and persistently sensitised patients awaiting renal transplantation underwent extracorporeal immunoadsorption to remove anti-HLA antibodies. 7 patients have since received transplants. Only 1 allograft has been lost because of rejection, and there have been no serious side-effects attributable to treatment. Extracorporeal immunoadsorption may therefore be of considerable value in the management of highly sensitised patients.

Adult↗
PubMed1988

HLA antigens in the Guillain-Barré syndrome.

HLA typing for class I and II antigens was performed on 89 caucasoid patients with Guillain-Barré syndrome and compared with controls. No significant association, between HLA type and susceptibility to disease, prognosis at 12 months or antecedent event was discovered. HLA antigen DR2 was more frequent among patients with the most profound muscle weakness.

Campylobacter Infections↗
PubMed1987

Callosal apraxia.

A 39-year-old right-handed woman suffered a ruptured pericallosal aneurysm. Serial MRI studies showed damage to the genu and most of the body of the corpus callosum but not the splenium. Both supplementary motor areas (SMA) appeared intact. We studied the patient's praxis performance at intervals over a 4-month period with a standardized battery. The study suggests that apraxia seen in patients with callosal lesions is probably due to the callosal damage, not to the usually associated SMA lesion. Our findings support Liepmann's idea that the left hemisphere is dominant for praxis in both hands. We propose, however, that the dominance effect is related to the type of test given and varies among individuals. As regards the latter, in some individuals the left hemisphere is strongly dominant for motor tasks, while in others it is less so. As regards the type of test, the most enduring left-hand apraxia is seen in verbal, not visuomotor tests.

Adolescent↗