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Biomedical subjects

K Welsh

Publications and source records attributed to K Welsh.

At least 55 records · Page 3Linked to original sources
PubMed1998

Influence of port site on central venous pressure measurements from triple-lumen catheters in critically ill adults.

BACKGROUND: Measurements of central venous pressure are generally obtained through one of the three ports of centrally placed triple-lumen catheters. However, no scientifically based literature is available that guides clinical practice and indicates which of the lumens is most appropriate for obtaining these measurements. OBJECTIVE: To determine if a difference exists between measurements of central venous pressure obtained via the proximal, medial, and distal ports of a triple-lumen catheter. METHODS: Measurements of central venous pressure in 48 adult ICU patients were obtained via each of the three ports of a triple-lumen catheter. Catheters were placed in either the right or left subclavian vein or the right or left internal jugular vein. The flush system was single-transducer, trifurcated pressure tubing system. Data were evaluated for variation among the three ports of the catheter for readings taken at a single point. RESULTS: A repeated-measures analysis of variance showed significant differences across port sites. Post hoc univariate F tests showed significant differences between the proximal and distal ports and between the medial and distal ports. In some patients, the difference between central venous pressure obtained from the distal port and pressure obtained from the proximal or the medial port may be clinically significant. CONCLUSION: Because measurements of central venous pressure may not always be comparable for all three ports of a triple-lumen catheter, care should be taken to distinguish when changes in pressure readings are a result of a change in port site rather than in the patient's condition.

Adult↗
PubMed1997

Genetic markers may predict disease behavior in patients with ulcerative colitis.

BACKGROUND & AIMS: Recent studies have suggested that HLA DRB1*0103 and allele 2 of the interleukin 1 receptor antagonist (IL-1RA) gene predict severe and extensive ulcerative colitis, respectively. The aim of this study was to test these hypotheses in patients undergoing surgery for their colitis. METHODS: HLA DRB1 and DQB1 genotyping was performed in 99 patients and 472 controls. Genotyping for polymorphisms of genes encoding tumor necrosis factor alpha and IL-1RA was performed in 107 patients and 89 controls. Measurement of antineutrophil cytoplasmic antibody (ANCA) was performed in 72 patients and 58 healthy subjects by fixed neutrophil enzyme-linked immunosorbent assay and indirect immunofluorescence. RESULTS: The DRB1*0103 allele was increased in patients (14.1% vs. 3.2% in controls; P < 1 x 10[-5]). This association was greatest in patients with extensive disease (15.8%; P < 0.0001) or extraintestinal manifestations (22.8%; P < 0.0001): mouth ulcers (25.8%; P < 0.0001), arthritis (27.2%; P < 0.0001), and uveitis (35.7%; P < 0.0001). The DRB1*04 alleles were reduced in patients (P = 0.005). Differences were noted between extensive and distal disease in the frequency of allele 2 of IL-1RA (10.9% in distal vs. 28.6% in extensive; P = 0.01) and allele 2 homozygosity. ANCA was detected in 76.4% of patients. Carriage of IL-1RA allele 2 and tumor necrosis factor 2 allele was increased in ANCA-positive patients. CONCLUSIONS: Genetic markers may predict disease behavior in ulcerative colitis.

Adolescent↗
PubMed1997

HLA-CW*0602 is a susceptibility factor in type I psoriasis, and evidence Ala-73 is increased in male type I psoriatics.

We investigated the HLA-C locus of 87 unrelated patients with chronic plaque psoriasis by genotyping with sequence-specific amplification primers. The HLA-Cw*0602 allele was significantly increased in male and female type I psoriatics but not significantly increased in either male or female type II psoriatics. The overall frequency of Ala-73 (present in Cw*04, Cw*0602, Cw*07, Cw*12, Cw*1503, and Cw*17) in psoriatics was 88.5% but the incidence of Ala-73 in our Caucasian controls was also high at 84.3%. Ala-73 was present in 97.2% of type I and 85.7% of type II male psoriatics (chi2 = 8.43, p = 0.001; chi2 = 0.01, p = nonsignificant, respectively), in contrast to 81.5% of type I and 80% of type II female psoriatics (nonsignificant). HLA-Cw*0602 appeared more discriminating in determining disease susceptibility in our population than Ala-73, in line with earlier serologic studies implicating HLA-Cw6. Thus, although the frequency of HLA-Cw*0602 decreased from 54.0% in type I to 29.2% in type II psoriatics, the overall frequency of Ala-73, present in 90.4% of type I and 83.3% of type II psoriatics, did not. (i) Thus this study confirms the strong association between psoriasis and HLA-Cw*0602 by using sequence-specific amplification primers. (ii) Results show that Ala-73 on HLA-C molecules is increased in frequency in psoriasis, but results observed show an association more subtle than previously thought, with HLA-Cw*0602 playing the major role. (iii) This report documents the differential association of HLA genes in male and female psoriatic patients. An interaction between gender and immunogenetics may influence susceptibility to psoriasis.

Alleles↗
PubMed1996

Two stage genome-wide search in inflammatory bowel disease provides evidence for susceptibility loci on chromosomes 3, 7 and 12.

Crohn's disease (CD) and ulcerative colitis (UC), the chronic inflammatory bowel diseases (CIBD), are common causes of gastro-intestinal disease in the Western world, with a combined prevalence of 100-200/100,000 (ref. 1). Epidemiological studies, particularly concordance rates in twin pairs and siblings, strongly implicate genetic susceptibility in the pathogenesis of CIBD. In fact, the relative contribution of genetic factors to the pathogenesis of CD may be greater than in schizophrenia, asthma or hypertension, and at least equivalent to that in insulin-dependent diabetes. Systematic screening of the entire human genome now provides a strategy for the identification of susceptibility genes in complex polygenic disorders. We undertook a two-stage genome search for susceptibility genes in inflammatory bowel disease involving 186 affected sibling pairs from 160 nuclear families. We provide strong evidence for the presence of susceptibility loci for both CD and UC on chromosome 3, 7 and 12. We obtained the highest lod score (5.47; P = 2.66 x 10(-7) with the marker D12S83 and lod scores of 3.08 and 2.69 for D7S669 and D3S1573, respectively. Our data suggest that CD and UC are closely related, but distinct, polygenic disorders that share some, but not all, susceptibility genes.

Chromosome Mapping↗
PubMed1996

Cytokine gene polymorphisms in inflammatory bowel disease.

BACKGROUND: Concordance rates in siblings and twins provide strong evidence that genetic susceptibility is important in the pathogenesis of inflammatory bowel disease. The number and identity of susceptibility genes is largely uncertain. Cytokine genes are attractive candidate loci. AIMS: To study allelic frequencies of polymorphisms of the interleukin-1 receptor antagonist (IL-1RA) gene and the tumour necrosis factor alpha gene in patients with inflammatory bowel disease. SUBJECTS: One hundred and twenty nine North European caucasoid patients with ulcerative colitis, 120 patients with Crohn's disease, and 89 healthy controls. METHODS: Genotyping was performed by polymerase chain reaction. A variable number of tandem repeats (VNTR) in the IL-1RA gene and a single base pair polymorphism in the TNF alpha gene promoter region (TNF-308) were analysed. RESULTS: No significant differences in IL-1RA VNTR allelic frequencies were noted between Crohn's disease (allele 1: 72.6%, allele 2: 24.7%, allele 3: 2.6%), ulcerative colitis (72.6%, 24.3%, 3.1%, respectively), and controls (76.9%, 20.8% and 2.3%). Some 42.4% of patients with ulcerative colitis and 43.4% patients with Crohn's disease were carriers of allele 2, compared with 34.8% healthy subjects. The TNF2 allele was modestly reduced in Crohn's disease (13.2%), compared with healthy subjects (21.3%; p = 0.04), and ulcerative colitis (21.6%). CONCLUSIONS: The associations demonstrated are modest: these polymorphisms are unlikely to be important determinants of overall disease susceptibility.

Adult↗
PubMed1995

The association between lichen sclerosus and antigens of the HLA system.

Although frequently linked clinically with autoimmune disease, no immunogenetic basis for lichen sclerosus has ever been established. In this study, we examined in detail the HLA antigens of 84 patients with histologically proven disease, compared with 357 controls. Patients with lichen sclerosus did not have the expected HLA A1, B8, DR3, DQ2 autoimmune profile. Instead, DQ7 was present in 39 of 78 (50%) of patients compared with 89 (25%) controls (P < 0.001). In addition, 61 of 78 patients (78%) had either DQ7, DQ8 or DQ9 antigens, or a combination of these, compared with 142 (40%) controls (P < 0.01). Raised levels of DQ7 correspond to a glutamic acid residue at position 45 of the DQB1 locus. Proline amino acids at position 55 of this DQB1 locus could explain the raised levels of DQ7, 8 and 9, and exert a secondary effect. There is preliminary evidence that the immunogenetic profile of patients with this disease may affect disease expression with regard to site and extent of involvement.

Adolescent↗
PubMed1994

HLA-DQB1 associations with anti-topoisomerase-1 antibodies in patients with systemic sclerosis and their first degree relatives. United Kingdom Systemic Sclerosis Study Group.

The frequency and functional properties of anti-topoisomerase-1 antibodies (ATA) have been studied in 58 systemic sclerosis (SSc) probands, 218 first degree relatives and 22 spouses. The dependence of ATA on the presence of certain HLA-DRB1 and HLA-DQB1 alleles was examined. ATA were detected by immunodiffusion, by absorption or inhibition of topoisomerase-1 enzymic activity, by immunoblotting of a K562 cell extract and by immunoprecipitation of 35S radiolabelled cell lines. HLA class II typing for HLA-DRB1 and HLA-DQB1 was performed by oligonucleotide typing in 49 families. Six probands and two relatives had ATA. The relatives with ATA had SSc. All eight individuals with ATA directly inhibited topoisomerase-1 function. Four of the eight had limited skin disease and four had diffuse skin involvement. The seven who were genotyped had at least one HLA-DQB1 allele encoding for tyrosine at position 30 of the first domain. Therefore, ATA are not widely dispersed within families, but rather are only present in those with SSc, and certain genetic requirements appear necessary for their generation.

Alleles↗
PubMed1994

Comparative analysis of the genetic associations of HLA-DR3 and tumour necrosis factor alpha with human IDDM.

Insulin-dependent diabetes mellitus (IDDM) is associated with class II molecules of the MHC on chromosome 6, in particular HLA-DR and -DQ alleles, but a pathogenic role for TNF-alpha in the class III region of the MHC has also been implied. We therefore tested whether there was any independent association between a biallelic TNF polymorphism and IDDM. The TNF2 allele was present in 61 of 114 (54%) IDDM patients compared to 101 of 253 (40%) control subjects (odds ratio 1.73; p < 0.02). Stratification analysis in individuals matched for HLA-DR3 revealed, however, that this association was not independent of HLA-DR3 and is most likely to be a result of linkage disequilibrium between these alleles.

Adult↗
PubMed1994

Anti-centromere antibodies (ACA) in systemic sclerosis patients and their relatives: a serological and HLA study.

Autoantibody reactivity to centromere proteins CENP-A, CENP-B and CENP-C was examined in 58 patients with systemic sclerosis (SSc), 218 first degree relatives and 22 spouses. HLA class II typing for HLA-DRB1 and HLA-DQA1 was performed by restriction fragment length polymorphism (RFLP) analysis in 50 families, and HLA-DRB1, HLA-DQA1 and HLA-DQB1 typing was performed by olignucleotide typing in 44 families. Eleven probands and two relatives had ACA. The two relatives with ACA also had SSc. One relative was an identical twin sister of a proband with ACA and the other relative was a sister of a proband with ACA. All ACA-positive probands and relatives were female, and all recognized CENP-A, CENP-B and CENP-C. The presence of at least one HLA-DQB1 allele not coding for leucine at position 26 of the first domain appeared necessary, although not sufficient for the generation of ACA. Therefore within SSc families ACA is strongly associated with female gender and disease phenotype, and is at least in part genetically determined.

Alleles↗
PubMed1993

A molecular and serologic analysis of the major histocompatibility complex and complement component C4 in systemic sclerosis.

OBJECTIVE: To investigate the contributions of the major histocompatibility complex (MHC) and C4 alleles to systemic sclerosis (SSc), and to pulmonary fibrosis and autoantibody expression in SSc, by analysis at the DNA level. METHODS: One hundred fifteen patients with SSc were tested serologically for alleles of the class I MHC loci, and were tested for class II alleles (DRB, DQA, and DPB) by a combination of restriction fragment length polymorphism (RFLP) analysis and oligonucleotide probes with polymerase chain reaction amplification. C4 was studied by protein phenotyping and RFLP analysis in 80 patients. Correlations were made between disease status, pulmonary fibrosis, and expression of anticentromere antibodies (ACA) and anti-Scl-70. RESULTS: The C4A-null phenotype was found to provide the strongest disease association factor of the MHC region (P = 0.000064, relative risk [RR] = 2.8, etiologic fraction [EF] = 32.1). The primary MHC susceptibility allele was found to be DQA2 (Pcorr = 0.0009, RR = 2.5, EF = 35.6), which is in linkage disequilibrium with both DR3 and DR11. DR2 was protective, but only for female patients (P = 0.0021, RR = 0.42, protective fraction = 19.4). DR52a was the primary MHC allele associated with pulmonary fibrosis in SSc patients. Expression of ACA was associated with the presence of either DR1 or DR4 (P = 0.0015, RR = 6.7, EF = 78.0). Anti-Scl-70 expression correlated with an acidic residue of DP beta (DPB1:69:E) (P = 0.0063, RR = 4.6, EF = 53.1). CONCLUSION: Of all the potential markers of disease susceptibility analyzed, the C4A locus was the strongest. C4AQ0 and DQA2 are independent susceptibility factors for SSc. The development of pulmonary fibrosis in SSc patients can be predicted using combined MHC and autoantibody analysis. The MHC alleles associated with the expression of disease-specific autoantibodies are not markers for disease susceptibility.

Alleles↗
PubMed1992

Initiation of methyl-directed mismatch repair.

Escherichia coli MutH possesses an extremely weak d(GATC) endonuclease that responds to the state of methylation of the sequence (Welsh, K. M., Lu, A.-L., Clark, S., and Modrich, P. (1987) J. Biol. Chem. 262, 15624-15629). MutH endonuclease is activated in a reaction that requires MutS, MutL, ATP, and Mg2+ and depends upon the presence of a mismatch within the DNA. The degree of activation correlates with the efficiency with which a particular mismatch is subject to methyl-directed repair (G-T greater than G-G greater than A-C greater than C-C), and activated MutH responds to the state of DNA adenine methylation. Incision of an unmethylated strand occurs immediately 5' to a d(GATC) sequence, leaving 5' phosphate and 3' hydroxy termini (pN decreases pGpAp-TpC). Unmethylated d(GATC) sites are subject to double strand cleavage by activated MutH, an effect that may account for the killing of dam- mutants by 2-aminopurine. The mechanism of activation apparently requires ATP hydrolysis since adenosine-5'-O-(3-thiotriphosphate) not only fails to support the reaction but also inhibits activation promoted by ATP. The process has no obligate polarity as d(GATC) site incision by the activated nuclease can occur either 3' or 5' to the mismatch on an unmethylated strand. However, activation is sensitive to DNA topology. Circular heteroduplexes are better substrates than linear molecules, and activity of DNAs of the latter class depends on placement of the mismatch and d(GATC) site within the molecule. MutH activation is supported by a 6-kilobase linear heteroduplex in which the mismatch and d(GATC) site are centrally located and separated by 1 kilobase, but a related molecule, in which the two sites are located near opposite ends of the DNA, is essentially inactive as substrate. We conclude that MutH activation represents the initiation stage of methyl-directed repair and suggest that interaction of a mismatch and a d(GATC) site is provoked by MutS binding to a mispair, with subsequent ATP-dependent translocation of one or more Mut proteins along the helix leading to cleavage at a d(GATC) sequence on either side of the mismatch.

Adenosine Triphosphatases↗
PubMed1992

Immunoglobulin heavy chain gene associations in myasthenia gravis: new evidence for disease heterogeneity.

Susceptibility to myasthenia gravis (MG) is known to involve genes residing in the major histocompatibility complex class I and II regions (HLA-B8 and DR3). Immunoglobulin heavy chain constant region (IgCH) allotypes have also shown some associations with MG. We have used restriction fragment length polymorphism analysis with probes to the IgCH switch (S) regions mu and alpha 1 and the downstream marker D14S1 to investigate 189 Caucasoid patients with well-defined MG. A highly significant increase in the frequency of the 2.6 kilobase (kb) S mu homozygous genotype and the 2.6 kb S mu allele was found in patients with disease onset after the age of 40 years (late onset) compared with normal controls (P less than 0.00075 and P less than 0.025 respectively). No association was found at the S alpha 1 or D14S1 loci. In patients with an associated thymoma there was a moderate increase in the frequency of the 2.6 kb S mu and 7.4 kb S alpha 1 genotypes. These results independently support the previous separation of the late-onset subgroup. Finally, the stronger association at S mu rather than at the downstream S alpha 1, Gm and D14S1 loci suggest that the genes predisposing to MG are located within the variable region of the Ig heavy chain loci.

Adult↗