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Biomedical subjects

A Gough

Publications and source records attributed to A Gough.

At least 37 records · Page 2Linked to original sources
PubMed1999

Larsen scoring of digitized X-ray images.

OBJECTIVE: To determine how Larsen scores from digitized X-rays compare to those from film originals. METHODS: A hundred sets of radiographs of patients recruited with early rheumatoid arthritis (RA) were assessed using the Larsen scoring system. Digitized copies of these sets were then viewed on a computer screen and scored according to Larsen in a random order. The quality of the digitized image was also recorded. For each set of X-rays, the signed difference between the score from film and the score from the digitized images was calculated. RESULTS: A total of 95% of the digitized X-ray sets were scored successfully; 5% were not scored due to the images being unreadable. The mean difference between the two sets of scores was -1.2 (95% CI [-2.06, -0.37]). There was no trend in the difference with respect to the mean of the two scores (P>0.1). CONCLUSION: The Larsen scoring of digitized X-ray images has been validated.

Analog-Digital Conversion↗
PubMed1998

Characterization and quantitation of NF-kappaB nuclear translocation induced by interleukin-1 and tumor necrosis factor-alpha. Development and use of a high capacity fluorescence cytometric system.

A new quantitative cytometric technique, termed the ArrayScanTM, is described and used to measure NF-kappaB nuclear translocation induced by interleukin (IL)-1 and tumor necrosis factor-alpha (TNFalpha). The amount of p65 staining is measured in both the nuclei defined by Hoechst 33342 labeling and in the surrounding cytoplasmic area within a preselected number of cells/well in 96-well plates. Using this technique in synchronously activated human chondrocytes or HeLa cells, NF-kappaB was found to move to the nucleus with a half-time of 7-8 min for HeLa and 12-13 min for chondrocytes, a rate in each case about 4-5 min slower than that of Ikappa Balpha degradation. IL-1 receptor antagonist and anti-TypeI IL-1 receptor antiserum on the one hand and anti-TNFalpha and monoclonal anti-TNF receptor 1 antibodies on the other hand could be shown to respectively inhibit IL-1 and TNFalpha stimulation in both cell types. In contrast, a polyclonal anti-TNF receptor 1 antiserum exhibited both a 50% agonism and a 50% antagonism to a TNFalpha stimulation in a dose-dependent fashion, indicating that subtle functional responses to complex agonist and antagonist stimuli could be measured. The effects of different proteasome inhibitors to prevent Ikappa Balpha degradation and subsequent NF-kappaB translocation could also be discriminated; Leu-Leu-Leu aldehyde was only a partial inhibitor with an IC50 of 2 microM, while clastolactacystin beta-lactone was a complete inhibitor with an IC50 of 10 microM. The nonselective kinase inhibitor K252a completely inhibited both IL-1 and TNFalpha stimulation in both cell types with an IC50 of 0.4 microM. This concentration, determined after a 20-min stimulation, was shown to be comparable with that obtained for inhibition of IL-6 production induced by a 100-fold lower IL-1 and TNFalpha concentration measured after 17 h of stimulation. These results suggest that the ArrayScanTM technology provides a rapid, sensitive, quantitative technique for measuring early events in the signal transduction of NF-kappaB.

Biological Transport↗
PubMed1998

Effect of vitamin D receptor gene alleles on bone loss in early rheumatoid arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) is a polygenic disease characterized by localized joint destruction and generalized osteoporosis resulting in increased fracture risk. The pathogenetic mechanisms that determine the severity of generalized bone loss in RA are poorly understood. Polymorphisms in the vitamin D receptor (VDR) gene have been described as a significant determinant of bone turnover and mass. In this prospective study we describe VDR gene allele effects on bone loss in patients with early RA. METHODS: We recruited 232 patients with early RA. Bone mineral density measurements were repeated in 167 patients. Serial clinical and laboratory measures were recorded during the period of followup. DNA extraction, polymerase chain reaction amplification, and restriction fragment length polymorphism analysis of VDR alleles were performed using standard techniques. Presence of the Taq restriction site for both alleles was denoted "tt", and absence "TT". RESULTS: In women with RA the tt genotype group lost bone more rapidly than subjects with TT genotype at both the lumbar spine (-0.1 vs -4.9% p.a, respectively; p < 0.05) and femoral neck (-3.9 vs -9.6%, respectively; p < 0.01). The effect was independent of other disease characteristics. CONCLUSION: The presence of the VDR gene "t" allele in female patients with RA was associated with accelerated bone loss.

Alleles↗
PubMed1998

Osteoclastic activation is the principal mechanism leading to secondary osteoporosis in rheumatoid arthritis.

OBJECTIVE: To use clinical measures and biochemical markers of bone turnover to investigate mechanisms of generalized bone loss in early rheumatoid arthritis (RA). METHODS: We studied 232 patients with RA of less than 2 years' duration and 72 healthy controls using serial dual x-ray absorptiometry scanning of lumbar spine and hips. Patients attended the clinic for clinical and laboratory assessment with storage of serum, urine, and plasma at each visit. Change in bone mineral density (BMD) was calculated for patients and controls and compared with baseline and mean serial values of bone markers over the same intervals. Serum was assayed for procollagen I carboxyterminal propeptide (PICP) and skeletal alkaline phosphatase (sALP); urine for pyridinoline and deoxypyridinoline corrected for creatinine; and plasma for interleukin 1 (IL-1) and IL-6. RESULTS: Patients lost bone significantly faster than controls at all sites (p < 0.01 for all). At first visit patients had significantly lower PICP levels than controls (p < 0.05) and sALP correlated with initial BMD in both patients (p < 0.01, r > 0.35, all sites) and controls (p < 0.0001, r > 0.50, all sites). We rescanned 167 patients at one year and 121 patients at 2 years. Mean urinary pyridinoline and deoxypyridinoline levels correlated strongly with BMD change at all sites, were increased in patients with active disease (p < 0.005), and correlated closely with mean C-reactive protein (CRP) (p < 0.005, r > 0.41 for both). CONCLUSION: This study suggests that osteoclastic activation, rather than suppression of bone formation, is the dominant process leading to bone loss in early RA. Although urinary pyridinoline and deoxypyridinoline were excellent markers of BMD change, CRP was found to be best overall. This provides a rational approach for selecting and treating patients with RA to reduce their established longterm risk of osteoporotic fracture.

Absorptiometry, Photon↗
PubMed1997

Randomised placebo-controlled trial of granulocyte-colony stimulating factor in diabetic foot infection.

BACKGROUND: Diabetic foot infections cause substantial morbidity and mortality. Neutrophil superoxide generation, a crucial part of neutrophil bactericidal activity, is impaired in diabetes. Granulocyte-colony stimulating factor (G-CSF) increases the release of neutrophils from the bone marrow and improves neutrophil function. We assessed G-CSF as adjuvant therapy for the treatment of severe foot infections in diabetic patients. METHODS: 40 diabetic patients with foot infections were enrolled in a double-blind placebo-controlled study. On admission, patients were randomly assigned G-CSF (filgrastim) therapy (n = 20) or placebo (n = 20) for 7 days. Both groups received similar antibiotic and insulin treatment. Neutrophils from the peripheral blood of these participants and from healthy controls were stimulated with opsonised zymosan, and superoxide production was measured by a spectrophotometric assay (reduction of ferricytochrome C). FINDINGS: G-CSF therapy was associated with earlier eradication of pathogens from the infected ulcer (median 4 [range 2-10] vs 8 [2-79] days in the placebo group; p = 0.02), quicker resolution of cellulitis (7 [5-20] vs 12 [5-93] days; p = 0.03), shorter hospital stay (10 [7-31] vs 17.5 [9-100] days; p = 0.02), and a shorter duration of intravenous antibiotic treatment (8.5 [5-30] vs 14.5 [8-63] days; p = 0.02). No G-CSF-treated patient needed surgery, whereas two placebo recipients underwent to amputation and two had extensive debridement under anaesthesia. After 7 days' treatment, neutrophil superoxide production was significantly higher in the G-CSF group than in the placebo group (16.1 [4.2-24.2] vs 7.3 [2.1-11.5] nmol per 10(6) neutrophils in 30 min; p < 0.0001). G-CSF therapy was generally well tolerated. INTERPRETATION: G-CSF treatment was associated with improved clinical outcome of foot infection in diabetic patients. This improvement may be related to an increase in neutrophil superoxide production.

Aged↗
PubMed1997

Measurement of markers of osteoclast and osteoblast activity in patients with acute and chronic diabetic Charcot neuroarthropathy.

Excess osteoclast activity is believed to be responsible for the early bone changes associated with Charcot neuroarthropathy in diabetes mellitus. Markers of osteoclast and osteoblast activity were measured in four groups of patients: 16 with an acute Charcot foot, 16 with a chronic Charcot foot, 10 diabetic controls, and 10 non-diabetic controls. Serum carboxyterminal telopeptide of type 1 collagen (1CTP), a marker of osteoclastic bone resorption, was significantly raised in the dorsal venous arch of the acute Charcot foot, 6.1 +/- 1.5 microg l(-1) (mean +/- SD) compared with the chronic Charcot foot 4.1 +/- 1.4, diabetic controls 3.3 +/- 1.4, and non-diabetic controls 2.8 +/- 1.4, p < 0.0001. This local increase in 1CTP was also reflected systemically in a study subgroup of 6 patients with acute Charcot neuroarthropathy, in whom peripheral antecubital vein 1CTP was 9.2 +/- 2.6 compared with 9.0 +/- 3.1 in the foot. In 6 chronic Charcot neuroarthropathy patients, foot (3.8 +/- 1.3) and systemic (4.0 +/- 1.5) 1CTP values were similar. Serum procollagen carboxyterminal propeptide (P1CP), an indicator of osteoblastic bone formation, was not significantly different between the feet of patients with acute Charcot neuroarthropathy 112 +/- 1.5 microg l(-1), patients with chronic Charcot neuroarthropathy 109 +/- 1.5 microg l(-1), diabetic controls 93.5 +/- 2.3 microg l(-1), and non-diabetic controls 90.1 +/- 1.5 microg l(-1). These results suggest that the acute Charcot foot demonstrates excess osteoclastic activity without concomitant increase in osteoblastic function. This may be important in its pathogenesis.

Acute Disease↗
PubMed1997

Intercellular adhesion molecule-1 expression in dextran sodium sulfate-induced colitis in rats.

Orally administered dextran sodium sulfate (DSS) produces an acute colitis in rodents. The pathogenesis is unknown but may relate to DSS-mediated toxicity of colonic crypt epithelium and/or DSS-induced inflammation. The purpose of this study was to determine when colonic mucosal inflammation, as indicated by histopathology and intercellular adhesion molecule-1 (ICAM-1) expression, occurs relative to crypt epithelial damage. Groups of eight adult male Wistar rats were administered 5.0% DSS solution in the drinking water for 2-6 days. Clinical signs at 3 days consisted of loose stool, progressing to marked rectal hemorrhage by days 5 and 6 that correlated with marked intraluminal colonic hemorrhage at necropsy. Histological lesions of predominantly the distal colon consisted of multifocal areas of mucosal erosion, reduction in goblet cells, dilated crypts, crypt collapse, increased lamina propria neutrophils, and submucosal edema on days 2 and 3, progressing to locally extensive ulceration and marked mixed inflammatory infiltrates by days 4-6. Enhanced expression of ICAM-1, demonstrated by both immunohistochemical and northern blot analysis, was evident in colonic mucosa as early as day 2, with consistent increases through days 3-6. Results demonstrate that enhanced colonic mucosal endothelial cell ICAM-1 expression is an early event in the inflammatory cascade of DSS-induced colitis.

Acute Disease↗
PubMed1997

The acute phase and function in early rheumatoid arthritis. C-reactive protein levels correlate with functional outcome.

OBJECTIVE: To discover whether normalization of C-reactive protein (CRP) in patients with rheumatoid arthritis (RA) results in stabilization of their functional state, and whether a measure of disease activity can be used as a predictor of functional outcome. To examine the relationship between change of CRP and Health Assessment Questionnaire (HAQ) over a 24 mo period to define the sensitivity of HAQ to change. METHODS: A prospective study of 109 consecutive patients who fulfilled the American College of Rheumatology criteria for RA and had elevated CRP before steroid or 2nd line therapy. A full clinical assessment including HAQ was performed at presentation and at 3, 6, 12, and 24 mo. On the basis of the change in CRP at 6 mo, patients were divided into 3 groups: (1) CRP suppression to normal, (2) 50% reduction in CRP, and (3) less than 50% CRP change. RESULTS: The 3 groups were clinically and immunologically similar at onset. At 6 mo the median HAQ fell to 5 (lower to upper quartiles 7.5 to 19) in Group 1 (CRP normalized, n = 34), 6 (3.75 to 10) in Group 2 (CRP reduced by 50%, n = 30), and 12 (6 to 18) in Group 3 (less than 50% CRP change, n = 44), p < 0.005 for Groups 1 and 2 versus Group 3. At 12 and 24 mo HAQ remained significantly lower in Groups 1 and 2 compared with Group 3. In Group 1, patients either maintained a normal CRP (n = 28) or their CRP became elevated (n = 6). Only in those patients in whom a re-elevation of the CRP occurred was deterioration in HAQ subsequently seen. CONCLUSION: Suppression of elevated CRP in patients with active RA is associated with improvement in functional score, whereas persistent elevation of CRP is associated with functional deterioration. Once abnormal CRP is suppressed, no functional deterioration is likely to occur without re-elevation in CRP. Therefore, elevated CRP provides a convenient short term correlation with functional outcome and can be used as a guide for therapy. A HAQ score is a sensitive indicator of change in early disease.

Analysis of Variance↗
PubMed1996

Minocycline induced autoimmune hepatitis and systemic lupus erythematosus-like syndrome.

Monocycline is the most widely prescribed systemic antibiotic for acne largely because it needs to be given only once or twice a day and seems not to induce resistance. Up to April 1994 11 cases of minocycline induced systemic lupus erythematosus and 16 cases of hepatitis had been reported to the Committee on Safety of Medicines. An analysis of these cases together with seven other cases shows the severity of some of these reactions. Two patients died while taking the drug for acne and a further patient needed a liver transplant. Acne itself can induce arthritis and is often seen in association with autoimmine liver disease, but the clinical and biochemical resolution seen after withdrawal of the drug, despite deterioration of the acne, suggests a drug reaction. In five cases re-exposure led to recurrence. Because reactions may be severe early recognition is important to aid recovery and also to avoid invasive investigations and treatments such as corticosteroids and immunosuppresants. Safer alternatives should be considered for treating acne.

Acne Vulgaris↗
PubMed1996

Antibodies to type II collagen in early rheumatoid arthritis. Correlation with disease progression.

OBJECTIVE: To establish that frequencies and levels of IgG antibodies to type II collagen are higher in early rheumatoid arthritis (RA), and to correlate these results with disease activity. METHODS: Forty-four patients were characterized as having early RA. Patient sera obtained at initial presentation and at 12 months were tested by enzyme-linked immunosorbent assay for IgG antibodies to native and denatured type II collagen. RESULTS: IgG antibodies to native and denatured type II collagen were detected at initial presentation in 27% and 82% of patients, respectively, and after 12 months in 14% and 50%, respectively. The presence of antibodies to native collagen was associated with activity of RA and severity of symptoms, and loss of antibodies at 12 months was associated with initially erosive RA and the DRB1 disease susceptibility motif. CONCLUSION: Levels of serum IgG antibodies to collagen in RA decrease over time and, therefore, are not attributable simply to cartilage destruction. The presence of early positivity for these antibodies, together with the RA susceptibility motif, appears to be predictive of rapidly progressive RA.

Adult↗
PubMed1996

Quinolone arthropathy in immature rabbits treated with the fluoroquinolone, PD 117596.

To study the potential of the fluorquinolone, PD 117596 to cause arthropathy in experimental animals, immature rabbits were orally administered the drug for five days at 0, 100, 350, 500 and 750 mg/kg. Characterization of changes induced in major synovial joints was based on: macroscopic and histopathologic observations, transmission electron microscopic examinations and magnetic resonance imaging. Preferentially targeting the knee, PD 117596 produced vesicles and erosions in articular cartilage which resembled, morphologically, those described in other laboratory species. Lesion incidence was not clearly dose-related. In the perivesicular region, degenerate chondrocytes were intermixed with hypertrophic cartilage cells and chondrocyte clusters. Ultrastructurally, hypertrophic chondrocytes were the consequence of karyomegaly and RER proliferation. Matrix density was reduced due to collagen and proteoglycan loss. Joint structures were readily visualized by magnetic resonance imaging which identified thickened articular cartilage, surface irregularities consistent with ruptured vesicles and separation of opposing articular surfaces secondary to synovival effusions. The immature rabbit, although less sensitive than the juvenile dog to the arthropathic effects of quinolones, was nonetheless a good model to study this experimental osteoarticular disease.

Animals↗