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Biomedical subjects

N J McHugh

Publications and source records attributed to N J McHugh.

At least 19 recordsLinked to original sources
PubMed2006

Evidence for unique association signals in SLE at the CD28-CTLA4-ICOS locus in a family-based study.

CD28, CTLA4 (cytotoxic T lymphocyte-associated protein 4) and ICOS (inducible T cell co-stimulator) are good candidate genes for systemic lupus erythematosus (SLE) because of their role in regulating T cell activation. CTLA4 inhibits CD28-mediated T cell activation. CTLA4 is expressed on CD4+ and CD8+ activated T cells, and also B cells, but CD28 and ICOS are largely restricted to T cells. An interval encompassing the CD28-CTLA4-ICOS locus on chromosome 2q33 was linked to lupus in two genome-wide linkage scans. This large family-based association study in 532 UK SLE families represents the first high-density genetic screen of 80 SNPs at this locus. There are seven haplotype blocks across the locus. In CTLA4, the strongest signal comes from two variants, located 2.1 kb downstream from the 3'-UTR. These polymorphisms, rs231726 (SNP 43) and rs231726 (SNP 44), are in complete linkage disequilibrium (LD) (r(2)=1) and are associated with SLE P=0.0008 (GH) and P=0.01 (family-based association test). There is also a signal in the distal 3' flanking region of CTLA4/ICOS promoter (P=0.003). There was no confirmation of published associations for SLE in the promoter or coding region of CTLA4. These SLE risk alleles are more distal than those identified in Graves' disease and are in LD with Graves' disease protective alleles identified in both of these regions of CTLA4 (Ueda et al. 2003). These factors suggest an SLE-specific pattern of association. The functional consequences of the associated polymorphisms are likely to influence CTLA4 expression, although it is possible that genetically modulated ICOS expression is involved in SLE susceptibility.

3' Flanking Region↗
PubMed2005

MHC class II, tumour necrosis factor alpha, and lymphotoxin alpha gene haplotype associations with serological subsets of systemic lupus erythematosus.

OBJECTIVE: To conduct a case-control study to investigate whether there are independent tumour necrosis factor alpha (TNFalpha) or lymphotoxin alpha (LTalpha) haplotype associations with SLE or with any of the major serological subsets of SLE. METHODS: 157 patients with SLE were genotyped for HLA-DRB1, HLA-DQB1, TNFalpha, and LTalpha alleles by polymerase chain reaction and compared with 245 normal white controls. For TNFalpha, six single nucleotide polymorphisms (SNPs) at positions -1031, -863, -857, -308, -238, and +488 and for LTalpha three SNPs at positions +720, +365, and +249 were studied to assign six TNFalpha haplotypes (TNF1-6) and four LTalpha haplotypes (LTA1-4). All SLE patients had full serological profiles on serial samples. RESULTS: The most significant association with SLE overall was with HLA-DR3 (p<0.001; odds ratio (OR) = 2.5 (95% confidence interval, 1.6 to 3.8)) and the extended haplotype HLA-DQB1*0201;DRB1*0301;TNF2;LTA2 (p<0.001; OR = 2.3 (1.4 to 3.7)). Associations were strongest in the anti-La positive group (13%) of SLE patients (HLA-DR3, OR = 71 (9 to 539); HLA-DQB1*0201, OR = 35 (5 to 267); TNF2, OR = 10 (2.8 to 36), and LTA2, OR = 4.9 (1.1 to 21)). There was an increase in the HLA-DR2 associated extended haplotype (HLA-DQB1*0602;DRB1*1501;TNF1;LTA1) in patients with anti-Ro in the absence of anti-La (p<0.005; OR = 3.9 (1.5 to 10)). The HLA-DR7 extended haplotype (HLA-DQB1*0303;DRB1*0701/2;TNF5;LTA3) was decreased in SLE overall (p<0.02; OR = 0.2 (0.05 to 0.8)). CONCLUSIONS: The strongest association in this predominantly white population with SLE was between HLA-DR3 and anti-La, which seemed to account for any associations with TNFalpha alleles on an extended DR3 haplotype.

Autoantibodies↗
PubMed2005

Joint and soft tissue injections: a survey of general practitioners.

OBJECTIVES: To determine the type of joint and soft tissue injections carried out by general practitioners (GPs) in the Bath area and factors affecting activity. METHODS: A questionnaire was sent to 360 GPs requesting information on injections carried out during the previous 12 months, referral pathways for injection, barriers to injecting and training. RESULTS: We received 251 replies. The commonest injections were for tennis elbow, glenohumeral joint, knee, supraspinatus tendonitis and carpal tunnel. The majority of GPs (66.4%) carry out most injections themselves, 26.3% refer to a colleague and 7.3% refer to secondary care. Over half (51%) of all the injections are carried out by 15.6% of the GPs. Factors associated with higher levels of injection activity were: male gender, partnership, more than 10 years' experience, a special interest in rheumatology or orthopaedics and working in a rural or mixed practice. The most important barriers to carrying out injections were lack of practical training, lack of confidence and inability to maintain skills. Most GPs have been trained on models. CONCLUSIONS: Most GPs carry out some joint and soft tissue injections, but limit themselves to knees, shoulders and elbows. A small highly active group receive referrals from colleagues. Gender and specialist training strongly influence activity. Many, especially female and part-time, GPs find it hard to maintain their skills and confidence. Training targeted at this group, based in practices and using models and other tools, is likely to increase the number of patients receiving timely injections in general practice.

Antirheumatic Agents↗
PubMed2003

Progression of peripheral joint disease in psoriatic arthritis: a 5-yr prospective study.

OBJECTIVE: To assess the evolution of disease subgroups and the frequency of progression of peripheral joint disease in a prospectively studied cohort of patients with psoriatic arthritis (PsA). METHODS: The cohort was identified as the first consecutive 100 patients attending a psoriatic arthritis clinic and who had been the subject of a previously published cross-sectional retrospective study. Nine of the 100 patients had died, three declined follow-up and one could not be traced. The remaining 87 patients (49 females, 38 males) completed the study proforma at a median follow-up interval of 65 months (range 39-90). An analysis of initial plasma viscosity compared with rates of progression of joint score was performed. RESULTS: Eighteen patients changed subgroup; 11 had an increase in the number of joints involved, six a decrease, and one changed from an oligoarticular pattern to predominant spondylitis. Within the polyarticular group 37/51 patients had an increase in the number of joints involved. For the whole population, there were significant increases in the number of joints involved (median 6 vs 11, P < 0.001 Wilcoxon signed rank) and Health Assessment Questionnaire scores (median 0.375 vs 0.5, P < 0.001). The median rate of joint progression was 0.42 peripheral joints per year (range 0-7.2). However, the rate of peripheral joint involvement was highest in the first year of arthritis (median 4.0 joints/yr) as measured in 13 patients who had onset within 12 months of baseline assessment. There were no significant differences in skin and nail scores although nine more patients had developed nail disease. There was a significant correlation between the initial viscosity and rate of progression of joint damage (Spearman correlation, P < 0.011). CONCLUSIONS: Peripheral joint disease is progressive in the majority of patients with PsA and reinforces the need for effective monitoring and treatment.

Adolescent↗
PubMed2003

Non organ based laboratory markers in systemic sclerosis.

Candidate markers for endothelial cell, lymphocyte and fibroblast function in systemic sclerosis have been reviewed. Autoantibody measurement and general inflammatory markers were considered the minimum requirements, with other markers needing further evaluation.

Autoantibodies↗
PubMed2001

European multicentre study to define disease activity criteria for systemic sclerosis. I. Clinical and epidemiological features of 290 patients from 19 centres.

OBJECTIVE: To investigate the existence of differences among European referral centres for systemic sclerosis (SSc) in the pattern of attendance and referral and in the clinical and therapeutical approaches. METHODS: In 1995 the European Scleroderma Study Group initiated a multicentre prospective one year study whose aim was to define the disease activity criteria in SSc. During the study period each participating European centre was asked to enroll consecutive patients satisfying American College of Rheumatology criteria for SSc and to fill out for each of them a standardised clinical chart. Patients from various centres were compared and differences in epidemiological, clinical, and therapeutical aspects were analysed. RESULTS: Nineteen different medical research centres consecutively recruited 290 patients. The patients could be divided into two subgroups: 173 with the limited (lSSc) and 117 with the diffuse (dSSc) form of the disease. The clinical and serological findings for the series of 290 patients seemed to be similar to data previously reported. However, when the data were analysed to elicit any differences between the participating centres, a high degree of variability emerged, in both epidemiological and clinical features and in the diagnostic and therapeutic approaches to the disease. CONCLUSIONS: The clinical approach to SSc, not only in different countries but also in different centres within the same country, is not yet standardised. To overcome this problem, it will be necessary for the scientific community to draw up a standardised procedure for the management of patients with SSc. This would provide a common research tool for different centres engaged in research on this complex disease.

Adolescent↗
PubMed2001

European multicentre study to define disease activity criteria for systemic sclerosis. II. Identification of disease activity variables and development of preliminary activity indexes.

OBJECTIVE: To develop criteria for disease activity in systemic sclerosis (SSc) that are valid, reliable, and easy to use. METHODS: Investigators from 19 European centres completed a standardised clinical chart for a consecutive number of patients with SSc. Three protocol management members blindly evaluated each chart and assigned a disease activity score on a semiquantitative scale of 0-10. Two of them, in addition, gave a blinded, qualitative evaluation of disease activity ("inactive to moderately active" or "active to very active" disease). Both these evaluations were found to be reliable. A final disease activity score and qualitative evaluation of disease activity were arrived at by consensus for each patient; the former represented the gold standard for subsequent analyses. The correlations between individual items in the chart and this gold standard were then analysed. RESULTS: A total of 290 patients with SSc (117 with diffuse SSc (dSSc) and 173 with limited SSc (lSSc)) were enrolled in the study. The items (including Delta-factors-that is, worsening according to the patient report) that were found to correlate with the gold standard on multiple regression were used to construct three separate 10-point indices of disease activity: (a) Delta-cardiopulmonary (4.0), Delta-skin (3.0), Delta-vascular (2.0), and Delta-articular/muscular (1.0) for patients with dSSc; (b) Delta-skin (2.5), erythrocyte sedimentation rate (ESR) >30 mm/1st h (2.5), Delta-cardiopulmonary (1.5), Delta-vascular (1.0), arthritis (1.0), hypocomplementaemia (1.0), and scleredema (0.5) for lSSc; (c) Delta-cardiopulmonary (2.0), Delta-skin (2.0), ESR >30 mm/1st h (1.5), total skin score >20 (1.0), hypocomplementaemia (1.0), scleredema (0.5), digital necrosis (0.5), Delta-vascular (0.5), arthritis (0.5), TLCO <80% (0.5) for all patients with SSc. The three indexes were validated by the jackknife technique. Finally, receiver operating characteristic curves were constructed in order to define the value of the index with the best discriminant capacity for "active to very active" patients. CONCLUSIONS: Three feasible, reliable, and valid preliminary indices to define disease activity in SSc were constructed.

Adolescent↗
PubMed2000

Human ERp29: isolation, primary structural characterisation and two-dimensional gel mapping.

Recently we characterised a novel 29 kDa endoplasmic reticulum protein that is widely expressed in rat tissues, and named it ERp29. Several ERp29-like gene products have been reported in human tissues but uncertainty surrounds their relationships with each other and rat ERp29. To clarify these issues, ERp29 was isolated from human liver and characterised by primary structural analysis and two-dimensional gel mapping. Comparisons with rat ERp29 revealed striking homologies both in sequence and physical properties. Characterisation of the isoelectric heterogeneity and anomalous mass on two-dimensional gels enabled two reported homologues (UL35 and ERp31) to be identified as ERp29. Resolution of a sequence discrepancy led to unequivocal correlation of human ERp29 with the cognate cDNA previously named ERp31 and ERp28. Consequent links established to human genome and proteome projects showed that ERp29 is encoded by a gene on chromosome 12 that is expressed universally in human tissues. Together, these findings unified various ERp29 homologues as products of a single gene orthologous to rat ERp29 and established ERp29 as the only known member of a new protein class. Investigations of ERp29 function in human health and disease should benefit from the integrated links between genome, proteome and murine model organisms established here.

Amino Acid Sequence↗
PubMed2000

MHC class II associations with autoantibody and T cell immune responses to the scleroderma autoantigen topoisomerase I.

Topoisomerase I (topo I) is a major autoantigen recognized by autoantibodies in about 30% of sera from patients with systemic sclerosis (SSc). Certain HLA-DRB1 and HLA-DQB1 alleles have been reported to be associated with autoantibody and T-cell responses to topo I suggesting a T-cell dependent process. We have examined the MHC class II allele associations with anti-topo I antibodies in 16 patients with SSc compared to 250 healthy controls. Furthermore, we have studied the T cell responses to a recombinant full-length topo I molecule purified from a baculovirus expression system in eight patients with SSc and eight controls (five healthy and three with autoimmune disease). HLA-DR5 was significantly increased in patients with anti-topo I antibodies (P< 0.02). Proliferative peripheral blood mononuclear cell (PBMC) responses to soluble topo I were present in nine of 16 individuals (four of eight with SSc and five of eight controls), including the three SSc patients with anti-topo I antibodies. Homozygosity for HLA DQB1:30:Y alleles was present in five of nine responders (P< 0.03) compared to none of the non-responders. Our findings support the notion that the MHC class II background influences the ability to generate an autoimmune response to intracellular autoantigens to which the immune system may not have been tolerized. Additional factors associated with the generation of autoantibodies appear to be more intimately associated with the development of SSc.

Alleles↗
PubMed2000

Antineutrophil cytoplasmic antibodies and HLA class II alleles in minocycline-induced lupus-like syndrome.

We report 14 patients with minocycline-induced lupus-like syndrome (four men, 10 women; mean age 27.8 years) who developed a lupus-like illness after chronic use of minocycline for acne (1-10 years, median 3.8). Clinical features resolved completely on drug withdrawal (mean follow-up 11 months) and reappeared in two patients who were rechallenged. Sera from all 14 patients contained antineutrophil cytoplasmic antibodies (ANCA) giving a perinuclear pattern on indirect immunofluorescence on ethanol-fixed human neutrophils (p-ANCA), whereas 14 control asymptomatic individuals taking minocycline for acne were ANCA-negative. Eleven of the 14 patients had elevated antimyeloperoxidase antibodies and 10 had antielastase antibodies on enzyme-linked immunosorbent assay, which diminished on extended follow-up, as did other serological abnormalities. Major histocompatibility complex class II typing demonstrated that all of the 13 patients tested were either HLA-DR4 (nine of 13) or HLA-DR2 (four of 13) positive, and all had an HLA-DQB1 allele encoding for tyrosine at position 30 of the first domain. Our findings suggest a model whereby the presence of p-ANCA may be a marker for the development of lupus-like symptoms in genetically susceptible individuals taking minocycline for acne.

Adolescent↗
PubMed2000

Isolation of ERp29, a novel endoplasmic reticulum protein, from rat enamel cells. Evidence for a unique role in secretory-protein synthesis.

UNLABELLED: Recently we cloned and described ERp29, a novel 29-kDa endoplasmic reticulum (ER) protein that is widely expressed in rat tissues. Here we report our original isolation of ERp29 from dental enamel cells, and the comprehensive sequence analysis that correlated ERp29 with its cognate cDNA, both in enamel cells and liver. Fractionation of enamel cells using a new freeze-thaw procedure showed that ERp29 partitioned with known reticuloplasmins, and not with soluble proteins from mitochondria or cytosol. The absence of ERp29 in secreted enamel matrix indicated that the C-terminal tetrapeptide (KEEL motif) confers effective ER-retention in enamel cells. ERp29 behaved as a single species (approximately 40 kDa) during size-exclusion chromatography of liver reticuloplasm, suggesting that most ERp29 is not stably associated with other proteins. Immunoblot analysis showed that ERp29 was up-regulated during enamel secretion and expressed most highly in secretory tissues, indicative of a role in secretory-protein synthesis. Unlike other reticuloplasmins, ERp29 was down-regulated during enamel mineralization and thereby dissociated from a calcium-handling role. Tissue-specific variations in ERp29 molecular abundance were revealed by quantification of reticuloplasmin mole ratios. IN CONCLUSION: (a) ERp29 is a novel reticuloplasmin of general functional importance; (b) a unique role in protein processing is implicit from the distinctive expression patterns and molecular structure; (c) ERp29 is primarily involved in normal protein secretory events, not the ER stress response; (d) a major role is likely in tissues where ERp29 was equimolar with established molecular chaperones and foldases. This study implicates ERp29 as a new member of the ER protein-processing machinery, and identifies tissues where the physiological role of ERp29 is most likely to be clearly manifested.

Amino Acid Sequence↗
PubMed2000

Lipoproteins and their subfractions in psoriatic arthritis: identification of an atherogenic profile with active joint disease.

OBJECTIVES: (a) To characterise the lipid profile in psoriatic arthritis and investigate whether there are similarities to the dyslipoproteinaemia reported in rheumatoid arthritis and other inflammatory forms of joint disease; (b) to investigate whether there is an atherogenic lipid profile in psoriatic arthritis, which may have a bearing on mortality. METHODS: Fasting lipids, lipoproteins, and their subfractions were measured in 50 patients with psoriatic arthritis and their age and sex matched controls. RESULTS: High density lipoprotein cholesterol (HDL cholesterol) and its third subfraction, HDL(3) cholesterol, were significantly reduced and the most dense subfraction of low density lipoprotein (LDL), LDL(3), was significantly increased in the patients with psoriatic arthritis. Twenty patients with active synovitis had significantly lower total cholesterol, LDL cholesterol, and HDL(3) cholesterol than their controls. 25% of the patients with psoriatic arthritis had raised Lp(a) lipoprotein levels (>300 mg/l) compared with 19% of controls, but this was not statistically significant. CONCLUSION: Raised levels of LDL(3) and low levels of HDL cholesterol are associated with coronary artery disease. Such an atherogenic profile in a chronic inflammatory form of arthritis is reported, which may be associated with accelerated mortality.

Adult↗