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C Gordon

Publications and source records attributed to C Gordon.

At least 37 records · Page 2Linked to original sources
PubMed2004

Proteins interacting with the 26S proteasome.

The 26S proteasome is the multi-protein protease that recognizes and degrades ubiquitinylated substrates targeted for destruction by the ubiquitin pathway. In addition to the well-documented subunit organization of the 26S holoenzyme, it is clear that a number of other proteins transiently associate with the 26S complex. These transiently associated proteins confer a number of different roles such as substrate presentation, cleavage of the multi-ubiquitin chain from the protein substrate and turnover of misfolded proteins. Such activities are essential for the 26S proteasome to efficiently fulfill its intracellular function in protein degradation.

Animals↗
PubMed2004

Interleukin (IL)-10, IL-1ra and IL-12 profiles in active and quiescent systemic lupus erythematosus: could longitudinal studies reveal patient subgroups of differing pathology?

Several cytokines have been implicated individually in the pathogenesis of systemic lupus erythematosus (SLE) and some, including interleukin (IL)-10, IL-12 and IL-1ra are raised during flares of disease activity. Few studies have been directed at examining the interactions between these cytokines and how their combined profile relates to disease activity. We have examined serum levels of IL-10, IL-12 and IL-1ra in a cohort of SLE patients obtained from the Queen Elizabeth Hospital, Birmingham in cross-sectional and, in a smaller group, longitudinal analyses. In the cross-sectional study, there were significant correlations between levels of the three cytokines. There were also significant correlations between levels of each cytokine and measures of disease activity. IL-10 levels correlated with ESR, anti-dsDNA antibody titres and C3D, IL-12 levels with anti-dsDNA antibody titres and IL-1ra levels with ESR, anti-dsDNA antibody titres and C3D. IL-1ra levels also correlated with CRP. Circulating IL-10 and IL-1ra levels were higher in patients with SLE than in normal controls, although in this study group they did not reach significance. Circulating IL-12 levels were, however, significantly higher in SLE compared to controls. This was true both in patients with active disease and those sampled during a quiescent phase. These data add to the evidence that cytokines such as IL-10, IL-12 and IL-1ra are important in SLE pathogenesis. In a retrospective study of serial serum samples from seven patients, we found two patients whose cytokine profile was very different from the rest of the group. In most patients normalized IL-10, IL-12 and IL-1ra levels mirrored BILAG scores closely, but in these two patients, IL-10, IL-12 and IL-1ra levels did not fluctuate with disease activity. It is possible that there is a subgroup of SLE patients whose cytokine profile could be an important indicator of their pathology. In order to confirm this and determine the frequency of such patients this study needs to be repeated with a much larger subject group. The coexistence of patient groups with different patterns of cytokine activity might explain conflicting reports of associations of levels of particular cytokines with SLE. As the observed differences could reflect different aetiologies of SLE, this information could reveal valuable endophenotypes for genetic and functional studies of SLE and might, ultimately, inform therapeutic management.

Adult↗
PubMed2004

EULAR randomised controlled trial of pulse cyclophosphamide and methylprednisolone versus continuous cyclophosphamide and prednisolone followed by azathioprine and prednisolone in lupus nephritis.

OBJECTIVE: To compare the efficacy and side effects of intermittent pulse cyclophosphamide plus methylprednisolone with continuous oral cyclophosphamide plus prednisolone, followed by azathioprine, in patients with proliferative glomerulonephritis caused by systemic lupus erythematosus (SLE). METHODS: A multicentre randomised controlled trial was conducted between June 1992 and May 1996 involving eight European centres. All patients satisfied the American College of Rheumatology criteria for SLE and had biopsy proven proliferative lupus nephritis. All received corticosteroids in addition to cytotoxic drugs, as defined in the protocol, for two years. The trial was terminated after four years as recruitment was disappointing. RESULTS: 32 SLE patients with lupus nephritis were recruited: 16 were randomised to intermittent pulse cyclophosphamide and 16 to continuous cyclophosphamide plus azathioprine. Mean duration of follow up was 3.7 years in the continuous group (range 0 to 5.6) and 3.3 years in the pulse group (range 0.25 to 6). Three patients were excluded from the pulse therapy group as they were later found to have pure mesangial glomerulonephritis. Two patients in the continuous therapy group developed end stage renal failure requiring dialysis, but none in the intermittent pulse therapy (p = 0.488; NS). There were similar numbers of side effects and withdrawals from treatment in both groups. There were three deaths: two in the intermittent pulse therapy group and one in the continuous therapy group. CONCLUSIONS: There was no statistically significant difference in efficacy and side effects between the two regimens. Infectious complications occurred commonly, so careful monitoring is required during treatment.

Administration, Oral↗
PubMed2003

Definition and treatment of lupus flares measured by the BILAG index.

OBJECTIVES: The BILAG index is a clinical measure of lupus disease activity. It is valid, reliable and sensitive to change. Scoring in the BILAG index is based upon the physician's intention to treat. A flare of active lupus is defined as a new A or B score in at least one system. The main aim of this study was to determine whether patients with a lupus flare are treated as expected from the principles upon which the scoring system was devised. Secondly we wanted to establish whether patients with a new B score preceded by a C should be considered to have flared, as with patients scoring B following a D or E score. METHODS: Over a 12-month period, 250 patients regularly attending lupus clinics in Birmingham and London were assessed using the BILAG index at each visit. RESULTS: A new A or B score was observed in 154 (61.6%) patients. An A flare was observed in 26 (10.4%) patients. A B flare (in which the B score was preceded by a D or E score) was observed in 65 (26.0%) patients. There were 63 (25.2%) patients in whom there was a B score in a system in which a C score was previously recorded. Steroids were started or increased in 20 (77%) patients with an A flare. Almost all (92%) patients with a new A score had some increase in therapy. For the patients with new B scores, 53 (41%) had some increase in therapy, but multiple reasons were found for no change in therapy in 75 (59%) of these patients. There was no difference in the treatment of new B scores arising after a previous C score compared with previous D or E scores. Non-Caucasians were more likely to have a lupus flare than Caucasians. CONCLUSIONS: These results are consistent with the principles upon which the BILAG index was devised and suggest that a moderate disease flare can be defined as a new B score following a C, D or E score according to the BILAG index.

Adolescent↗
PubMed2003

Ultrasound guidance allows accurate needle placement and aspiration from small joints in patients with early inflammatory arthritis.

OBJECTIVES: To compare the accuracy of palpation-guided and high frequency ultrasound-guided needle placement in small joints and to develop a technique to obtain synovial fluid from these joints for diagnosis and research. METHODS: The accuracy of needle placement during palpation-guided proximal interphalangeal (PIP) or metacarpophalangeal (MCP) joint injection was assessed. This was compared with the accuracy of ultrasound-guided needle placement. A joint lavage technique was developed to obtain synovial fluid from these joints. RESULTS: Needle positioning was intra-articular in 59% of palpation-guided injections (6/12 PIP and 4/5 MCP joints). No fluid could be aspirated prior to injection. With ultrasound guidance, initial needle placement was intra-articular in 96% of cases (24/26 PIP and 27/27 MCP joints). Synovial fluid cells were lavaged from 63% of joints (19/25 PIP and 14/27 MCP joints). In only one case was a large effusion seen and this was aspirated directly. CONCLUSIONS: The use of high frequency ultrasound to guide needle placement within a small joint allows for significantly greater accuracy than a palpation-guided approach. When followed by lavage, synovial fluid cells and diluted synovial fluid can be obtained from the majority of small joints. This has important clinical and research implications.

Arthritis↗
PubMed2003

Cardiovascular risk in systemic lupus erythematosus--evidence of increased oxidative stress and dyslipidaemia.

OBJECTIVES: Systemic lupus erythematosus (SLE) is associated with severe and premature cardiovascular disease, which is not explained by traditional risk factors alone. This study aimed to investigate markers of oxidative stress, lipid metabolism and inflammation as potential cardiovascular risk factors in women with SLE. METHODS: Venous blood samples were taken from 53 female Caucasian patients with SLE and from healthy age- and sex-matched controls. Samples were analysed for markers of oxidative stress, lipid metabolism [including low-density lipoprotein (LDL) subfraction profile] and C-reactive protein (CRP). RESULTS: Female SLE patients had an atherogenic lipid profile characterized by raised total cholesterol and triglycerides, and the presence of small, dense LDL subfractions compared with healthy controls. These changes were associated with increased oxidative damage and a moderately raised CRP. CONCLUSIONS: The results provide evidence for free radical and inflammatory activity in SLE and suggest potential targets to reduce the risk of cardiovascular disease in these patients.

Adult↗
PubMed2003

Influence of groundwater characteristics on the survival of enteric viruses.

AIMS: This study was undertaken to further understand the processes affecting the persistence of enteric viruses in groundwater. METHODS AND RESULTS: Varying temperature, oxygen and nutrient levels were tested in the presence and absence of groundwater micro-organisms to determine which of the factors tested had dominant influence on the decay of Escherichia coli, the bacteriophage MS2, poliovirus and coxsackievirus. The results indicated that the most influential factor affecting the decay of the viruses and E. coli was the presence of groundwater micro-organisms. The results also implied that temperature, the presence of oxygen and nutrient levels indirectly influence viruses and E. coli decay by influencing the activity of the groundwater micro-organisms. CONCLUSIONS: E. coli and the viruses displayed maximum decay under aerobic conditions, at 28 degrees C without the addition of nutrients in the presence of groundwater micro-organisms. SIGNIFICANCE AND IMPACT OF THE STUDY: The results suggest that if the mode of action of the groundwater micro-organisms could be determined then the decay of viral pathogens in recharged waters may be more easily predicted.

Antibiosis↗
PubMed2003

Association of damage with autoantibody profile, age, race, sex and disease duration in systemic lupus erythematosus.

OBJECTIVE: To determine if there is any association between autoantibody profile and damage in a cohort of patients with systemic lupus erythematosus (SLE). METHODS: A prospective cohort of SLE patients attending two SLE clinics in Birmingham was analysed. All patients fulfilled ARA criteria for SLE. Detailed clinical and serological information was recorded at each visit. Damage according to the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR DI) was recorded 6-monthly and the last score in the year 2000 or prior to death was used in the analysis. Univariate analysis was performed with the chi(2) test, Fisher's exact test or univariate analysis of variance. Multivariate analysis was done with binary logistic regression. RESULTS: A total of 348 patients (326 females) were studied, comprising 208 Caucasians, 65 Afro-Caribbeans, 59 Asians, four Orientals and 12 others. There were 32 (9.2%) deaths and 156 (44.8%) patients had damage recorded during follow-up. The presence of damage showed no significant association with race, sex or anti-cardiolipin, anti-Ro, anti-La, anti-Sm, anti-RNP and anti-dsDNA antibodies. Only age, disease duration and other antibodies to extractable nuclear antigens (ENA) were found to be associated with the presence of damage. When individual organ damage was analysed, the only significant associations were of anti-Ro with ocular damage and of other anti-ENA antibodies (anti-Scl-70 and/or anti-Jo-1) with premature gonadal failure. Other autoantibodies were not predictive of damage in individual organs. CONCLUSIONS: Although autoantibodies are useful in diagnosis and predicting disease activity in SLE, they do not appear to be useful in predicting damage in SLE.

Adolescent↗
PubMed2002

The intracellular localization of the proteasome.

In summary, localization of proteasomes does appear to be important in the regulation of proteolysis. In yeast, a discrete localization is observed at the nuclear periphery for cells undergoing mitotic growth. This localization is clearly important as degradation by the ubiquitin/proteasome pathway is impaired in mutants that mislocalize proteasomes. In mammalian cells, proteasomes are present throughout the cell. However, the proteasome does appear to be enriched at the MTOC upon aggresome formation. The inhibition of the ubiquitin/proteasome pathway in aggresome-containing cells could provide an explanation for the pathogenicity of a number of neurodegenerative diseases.

Animals↗
PubMed2002

Unilateral varicella zoster virus ophthalmicus and contralateral acute retinal necrosis.

We report two patients who developed varicella zoster virus (VZV) ophthalmicus complicated by ipsilateral keratouveitis, and within 4 weeks developed acute retinal necrosis (ARN) in the contralateral eye. The ipsilateral retina was spared in each case. One patient had systemic lupus erythematosus (SLE) and the other Hodgkin's disease. Both patients were in remission at the time of presentation.

Adult↗
PubMed2002

Immune responses to native beta(2)-glycoprotein I in patients with systemic lupus erythematosus and the antiphospholipid syndrome.

OBJECTIVE: To identify HLA class II associations with anti beta(2)-glycoprotein I (beta2GPI) antibodies in a cohort of Caucasian patients with systemic lupus erythematosus (SLE) and to determine whether these HLA genotypes act as restriction elements for lymphocyte proliferation to native human beta2GPI in vitro. METHODS: Anti-beta2GPI antibodies were detected in patient sera using enzyme-linked immunosorbent assays (ELISAs). HLA class II alleles (DRB1, DQB1) were determined by polymerase chain reaction-based DNA genotyping. In vitro peripheral blood mononuclear cell (PBMC) responses to native human beta2GPI were measured in a 7-day proliferation assay. RESULTS: We identified three groups of Caucasian SLE patients using these ELISAs. In group 1, 16 out of 18 SLE patients (89%) with anti-beta2GPI antibodies were positive for HLA-DRB1*0401/4/8, DR11 or DRB1*1302 (P=0.001 vs controls) compared with 23 out of 53 patients (43%) in group 2 with anti-cardiolipin antibodies only, 57 out of 151 patients (38%) in group 3 (SLE patients without anticardiolipin antibodies) and 109 out of 225 controls (48%). Fourteen patients with anti-beta2GPI antibodies had greater median stimulation indices to beta2GPI in vitro compared with the 15 controls studied (P=0.04). CONCLUSION: The HLA class II and PBMC proliferation data suggest that beta2GPI may be both a T- and B-cell autoantigen in SLE.

Adolescent↗
PubMed2002

Management of pregnancy in women with pulmonary hypertension secondary to SLE and anti-phospholipid syndrome.

Pulmonary hypertension is found in about 10% of patients with systemic lupus erythematosis (SLE). Pulmonary hypertension may be present at the time of diagnosis or may develop after the diagnosis of SLE or anti-phospholipid syndrome (APS). It often presents in the reproductive years and has a significant impact on pregnancy outcome, being a significant cause of indirect maternal deaths. In our observational case series of three patients there were two deaths (66%). In cases 1 and 2 the pulmonary hypertension developed during pregnancy and deteriorated rapidly with markedly abnormal mean pulmonary artery pressures of 80 and 70 mmHg respectively prior to death. Both patients died within 48 hours of delivery. In case 3 the pulmonary hypertension was milder and was diagnosed very early in pregnancy. The patient received multidisciplinary care from the first trimester and the management of the pregnancy, delivery and the early puerperium was planned. Careful epidural anaesthesia was used and the patient had invasive monitoring on the intensive therapy unit (ITU) for 72 hours. Women with pulmonary hypertension need to be aware of the high risk of maternal mortality associated with pregnancy but we believe that an improvement in outcome can be achieved by careful assessment and the use of a multidisciplinary approach from early in pregnancy.

Adult↗