Fenofibrate enhances urate reduction in men treated with allopurinol for hyperuricaemia and gout.

OBJECTIVE: To assess the short-term urate-lowering effect of fenofibrate in men on long-term allopurinol therapy for hyperuricaemia and gout. METHODS: Ten male patients (38-74 yr) with a history of chronic tophaceous or recurrent acute gout with hyperuricaemia and on established allopurinol at 300-900 mg/day for > or =3 months were studied in an open-crossover study of fenofibrate therapy. Allopurinol at the established dose was continued throughout the study. Clinical and biochemical assessments (serum urate and creatinine, 24-h urinary excretion of urate and creatinine, liver function tests, creatine kinase and fasting serum lipids) were undertaken at: (i) baseline, (ii) after 3 weeks of once-daily therapy with micronized fenofibrate (Lipantil Micro) at 200 mg and (iii) 3 weeks after fenofibrate was withdrawn. RESULTS: Fenofibrate was associated with a 19% reduction in serum urate after 3 weeks of treatment (mean+/-S.E. 0.37+/-0.04 vs 0.30+/-0.02 mM/l; P=0.004). The effect was reversed after a 3-week fenofibrate withdrawal period (0.30+/-0.02 vs 0.38+/-0.03 mM/l). There was a rise in uric acid clearance with fenofibrate treatment of 36% (7.2+/-0.9 vs 11.4+/-1.6 ml/min, normal range 6-11; P=0.006) without a significant change in creatinine clearance. Both total cholesterol and serum triglycerides were also reduced. No patient developed acute gout whilst taking fenofibrate. CONCLUSIONS: Fenofibrate has a rapid and reversible urate-lowering effect in patients with hyperuricaemia and gout on established allopurinol prophylaxis. Fenofibrate may be a potential new treatment for hyperuricaemia and the prevention of gout, particularly in patients with coexisting hyperlipidaemia or those resistant to conventional therapy for hyperuricaemia.

Cardiovascular autonomic function in systemic lupus erythematosus.

AIM: To determine whether cardiovascular autonomic function is impaired in systemic lupus erythematosus (SLE). METHODS: A case-control study of 23 patients with SLE was performed. Autonomic symptoms were assessed using a standard questionnaire. Cardiovascular autonomic function was measured using 10 non-invasive investigations. There were significant differences between patients and controls in three out of 24 parameters measured during the different tests (P < 0.002). These were reduction in systolic blood pressure at 5 min on head-up tilt, and heart rate responses to isometric exercise and cutaneous cold. Eleven out of 23 patients had an abnormal heart rate, blood pressure or Valsalva response (value below the age corrected 5th centile) while testing compared with six of the controls. Plasma adrenaline and noradrenaline levels were significantly lower in patients vs controls in both the supine (P < 0.05) and tilt position (P < 0.01). Twenty-one of the 23 patients had one or more symptoms that may be attributable to abnormalities in autonomic function. There was no significant association between the number of symptoms and presence of autonomic dysfunction. Cardiovascular autonomic impairment may be demonstrated in some patients with SLE. Symptoms attributable to autonomic dysfunction are common in SLE and autonomic assessment may be required.

The challenges and rewards of integrating diverse neuroscience information.

The design of database models and schemas for storing, cross-referencing, and retrieving neuroscience information faces issues that are similar but more complex than most of the other biomedical disciplines, such as genomics and proteonomics. Specifically, the visualization and manipulation of very large and diverse image data, such as digital brain atlases and functional magnetic resonance images, play a unique role in neuroscience while much of the associated information is textually recorded. Nongraphical information can include the annotation of large brain structures ranging from anatomical regions to intracellular structures, the description of cellular functional properties, and their various interrelationships, such as fiber connections. It is necessary that the heterogeneous and distributed types of data be cross-referenced to each other so that this diverse information can be efficiently retrieved, shared, and exchanged among the different neuroscientific disciplines. Continued advances in computers and Internet technologies appear to indicate that increasingly large data sets will be maintained on local or regional file servers and that informational interoperability will be achieved using a networked information system infrastructure. The authors and others have proposed and implemented models of semantically organized information systems that utilize centrally stored and highly structured archival information to index, cross-reference, and retrieve diverse, Web-based data sets.

Counter-proliferative effects of nucleosomal antigens in cultures from lupus patients.

Blood mononuclear cells from 20 lupus patients were cultured in the presence of nucleosomal antigens to determine whether they induce lymphocyte proliferation. The predominant effect seen, however, was one of inhibition of the background proliferation. Such inhibition was rare with cells from female or male controls. Nucleohistone (NH), crude histone and enriched preparations of histones H2A/H4, H2B and H3 showed this effect in approximately one-third of patients, but H1 and single-stranded (ss) DNA had no such activity. Double-stranded (ds) DNA may show this inhibitory action, but further tests are required. ssDNA was the only antigen that showed evidence (two patients) of disease-related stimulation of proliferation. Histones and NH induced proliferation in many subjects but the strongest responders were controls. Patients responded poorly to tuberculin PPD but gave an exceptionally strong proliferative response to pokeweed mitogen. It is suggested that the inhibition of background proliferation in patients is a consequence of the interaction of nucleosomal antigens with sensitised T cells. If T cell sensitisation to histones is an important factor in the development of lupus, the disease may be preventable in those at risk by inducing tolerance to the appropriate peptides.

Reiter's syndrome following intravesical BCG immunotherapy.

A 71 year old woman developed conjunctivitis, asymmetrical oligoarthritis, and cystitis (Reiter's syndrome) secondary to intravesical BCG treatment for transitional cell carcinoma of the bladder. She received oral prednisolone, izoniazid, and pyridoxine and made a full recovery. Increasing use of BCG as immunotherapy will lead to an increase in the incidence of BCG associated reactive arthritis. Prompt recognition and early diagnosis will facilitate treatment and recovery.

Terminology Query Language: a server interface for concept-oriented terminology systems.

Designers of medical computing applications increasingly require terminology support for their systems. Yet, terminology systems today lack standard methodologies for providing terminology support. This invariably means increased implementation time and expense for system developers who need to use terminologies in their applications. We introduce Terminology Query Language (TQL), a simple query language interface to server implementations of concept-oriented terminologies. TQL is a declarative, set-based query language built on a generic entity-relationship (E/R) schema. TQL defines a common query-based mechanism for accessing terminology information from one or more terminology servers over a network connection.

Hybrid system for telepathology.

We introduce a novel hybrid telepathology system providing simultaneous transmission of both real-time microscopy and static imagery at a reasonable cost. It is capable of capturing static, true color images at resolution of 1,520 x 1,144 pixels and providing live transmission of real-time video images of the glass slide in Common Intermediate Format (CIF), which can be viewed at 1,024 x 768 pixels or higher. Instant freeze function can be enabled with 4x CIF resolution (1,408 x 1,152 pixels). This system comprises the advantages of real-time transmission and high-resolution static imagery, while direct visual and audio communications are maintained at the same time. It uses standard 'off-the-shelf' components with a total cost of around $30,000 to $40,000. We also conclude that differences in telepathology modality and image quality have an impact on diagnostic accuracy and should be considered for discussion and standards development by professional organizations in the field of telepathology. An effort to ascertain the diagnostic limitations of various telepathology modalities is essential to the future use of this modality of pathology practice.

Inhibition of hyperacute transplant rejection by soluble proteins with the functional domains of CD46 and FcgammaRII.

BACKGROUND: Recombinant soluble forms of complement regulatory molecules, including the human complement regulatory protein CD46 (rsCD46), have been shown to inhibit hyperacute transplant rejection (HAR) and protect against complement-mediated inflammatory tissue damage. Similarly, recombinant soluble forms of the immunoglobulin receptor FcgammaRII (rsFcgammaRII) can attenuate antibody-mediated inflammatory responses. We have produced and tested the function of novel recombinant chimeric proteins that incorporate the functional domains of both CD46 (membrane cofactor protein, MCP) and the low affinity human IgG receptor FcgammaRII (CD32). METHODS: Two recombinant soluble chimeric proteins (CD46:FcR and FcR:CD46) were designed and produced using a human cell expression system. Their ability to protect cells against complement-mediated lysis (through the CD46 domain) and bind human IgG (through the Fc receptor domain) was assessed in vitro. They were also tested in vivo in the rat reverse passive Arthus reaction and a murine model of hyperacute cardiac transplant rejection. RESULTS: In vitro, the functional domains of the chimeric proteins each retained their activity. In vivo, the serum half-life of the recombinant chimeric proteins in mice was more than either rsCD46 or rsFcgammaRII. In the rat reverse passive Arthus reaction, intradermal injection of each recombinant protein substantially reduced inflammatory skin edema (>50%) and polymorphonuclear neutrophil infiltration (>90%). In the hyperacute rejection model, i.v. treatment with FcR:CD46 prevented complement-mediated rejection, macroscopic bruising, edema, and thrombosis more effectively than rsCD46. CONCLUSIONS: CD46/FcgammaRII bifunctional proteins have an improved ability to control complement-mediated hyperacute graft rejection and have therapeutic potential in other conditions involving antibody-mediated inflammation.

Identification of intervals on chromosomes 1, 3, and 13 linked to the development of lupus in BXSB mice.

OBJECTIVE: To identify intervals containing systemic lupus erythematosus (SLE) susceptibility alleles in the BXSB strain of mice. METHODS: We analyzed 286 (B10 x [B10 x BXSB]F1) backcross mice for a range of phenotypic traits associated with the development of SLE in BXSB mice. The mice were genotyped using 93 microsatellite markers, and the linkage of these markers to disease was studied by extreme-phenotype and quantitative trait locus analysis. RESULTS: The disease phenotype in these backcross mice was less severe than that in BXSB mice. However, antinuclear antibody production was increased compared with the parental strain. We identified 4 areas of genetic linkage to disease on chromosome 1 (Bxs1-4), 1 on chromosome 3 (Bxs5), and another interval on chromosome 13 which were associated with various aspects of the phenotype. Bxs4 and Bxs5 are located in regions not previously linked to disease in other models of SLE. CONCLUSION: SLE in the BXSB mouse model has a complex genetic basis and involves at least 5 distinct intervals located on chromosomes 1 and 3. There is evidence that different intervals affect particular aspects of the SLE phenotype.

Characterization of platelet glycoproteins and platelet/endothelial cell antibodies in patients with thrombotic thrombocytopenic purpura.

Platelets and sera from 12 patients with thrombotic thrombocytopenic purpura (TTP) and 12 healthy normal control subjects were examined. As determined by quantitative flow cytometry, prior to plasma exchange therapy platelet surface glycoprotein (GP) Ib levels were similar in TTP patients and normal controls (mean 20 188 and 20 226 molecules/platelet, respectively). Platelets from patients with TTP did, however, have significantly reduced levels of GPIIb/IIIa prior to plasmapheresis (mean 36 348 v 52 505 molecules/platelet in controls; P = 0.0004) and of GPIV (mean 13 321 v 26 212 molecules/platelet in controls; P = 0.0002). An increase in activated platelets, as determined by CD62 expression, was observed in 82% of patients. Increased platelet-associated immunoglobulins and/or complement was also seen in approximately 60% of the patients. In general, with return of platelet counts to normal levels following seven plasmaphereses, the above abnormalities were reversed, although often not to normal levels. Western blot analysis indicated the presence of antibodies reactive to platelet GPIV (88 kD) in 70% of pretreatment sera from patients with TTP; a similar band was observed in 80% of patient sera against microvascular endothelial cells. Immunofluorescence microscopic examination indicated the presence of antibody in pretreatment sera from patients with TTP to microvascular (73%) and large vessel (36%) endothelial cells. As measured by an indirect flow cytometric assay, pretreatment sera from 55% of patients with TTP were reactive with large vessel endothelial cells and 100% reacted with microvascular endothelial cells; reactivity was significantly greater against the microvascular endothelial cells (P = 0.0048) and was reduced following plasma exchange therapy. These results indicate abnormalities in platelet glycoprotein expression in TTP and suggest that anti-platelet and anti-endothelial cell antibodies play a role in the thrombocytopenia and vasculitis characteristic of this disorder.

Anti-DNA antibodies in the urine of lupus nephritis patients.

BACKGROUND: It has previously been reported that patients with systemic lupus erythematosus (SLE) and glomerulonephritis do not have anti- (deoxyribonucleic acid) DNA antibodies in their urine. This finding was attributed to specific entrapment of anti-DNA antibodies by the immune complexes in the glomerular capillary walls. METHODS: This phenomenon has been re-investigated as part of a study of the use of desoxyribonuclease 1 (DNase 1) to treat lupus nephritis (LN). For this purpose an ELISA was developed for the detection of anti-DNA antibodies in urine. It was found that such an assay was very susceptible to the presence of DNase in urine which destroys the antigen coating the plates and gives rise to false negative results. For this reason, it is essential that all tests for anti-DNA antibodies in the urine are carried out in the presence of EDTA to inhibit the endogenous DNase 1 activity. RESULTS: Using this assay to test the urine from 24 patients with LN and non-selective proteinurea, it was found that they all contained anti-DNA antibodies. The amount of anti-DNA antibodies detected in the urine was compared with that expected by calculations from the anti-DNA antibody titre in the serum and total immunoglobulin levels in serum and in urine. It showed that in 20 patients there was neither specific entrapment nor specific excretion of anti-DNA in urine, only the expected amount of leakage. In only three patients was any appreciable entrapment demonstrated and in only one, any excess excretion. CONCLUSIONS: It is suggested that the failure to detect anti-DNA antibodies in the urine in the previous work was due to failure to inhibit the endogenous urinary DNase. It remains to be determined whether the retention of anti-DNA antibodies or excessive secretion is correlated with clinical phases of LN.

Multiple lupus susceptibility loci map to chromosome 1 in BXSB mice.

BXSB mice spontaneously develop a lupus-like syndrome that is accelerated by the Yaa gene (Y-linked autoimmune accelerator). We studied the phenotype of disease in (B10 x BXSB)F1 and (BXSB x (B10 x BXSB)F1) backcross mice and genotyped 224 backcross animals to allow a microsatellite-based genome-wide linkage analysis to be conducted. In the backcross population, three intervals on chromosome 1 showed significant linkage to disease, suggesting that multiple loci contribute to the production of autoimmune disease. D1Mit5 at 32.8 cM was linked to development of nephritis (chi(2) = 15.68, p = 7.5 x 10(-5)), as was D1Mit12 at 63.1 cM (chi(2) = 20.17, p = 7.1 x 10(-6)). D1Mit403 at 100 cM was linked to anti-dsDNA Ab production (chi(2) = 17.28, p = 3.2 x 10(-5)). Suggestive linkages to antinuclear Abs and nephritis were identified on chromosome 3, to splenomegaly on chromosome 4, and to anti-ssDNA Ab production on chromosome 10. Chromosome 4 and the telomeric region of chromosome 1 have previously been linked to disease in other mouse models of systemic lupus erythematosus; however, the centromeric regions of chromosome 1 and chromosomes 3 and 10 are unique to BXSB. This implies that, though some loci may be common to a number of mouse models of lupus, different clusters of disease genes confer disease susceptibility in different strains of mice.

Platelet cold agglutinins: a flow cytometric analysis.

Spontaneous EDTA-independent cold platelet agglutination is a rare phenomenon that produces pseudothrombocytopenia when blood samples are analyzed in automated cell counters. We report a case of platelet cold agglutinins and an analysis by flow cytometry. A 49 year old woman presented with abnormal vaginal bleed secondary to uterine fibroids. Platelet clumping was observed in blood samples taken in EDTA-, heparin- and citrate-containing tubes. In flow cytometric tests, patient serum agglutinated 16% of normal platelets at 22 degrees C, and 7% of platelets after incubation at 37 degrees C; in contrast, 3% and < 1% of platelets were agglutinated at 22 and 37 degrees C, respectively, after incubation with normal serum. Minimal agglutination (< 10%) was observed with patient serum at a titre of 1:5 or at temperatures > 30 degrees C. After incubation at 4 degrees C, IgM antibody and C3 were increased on the patient's platelets; no significant amount of IgM or C3 was detected on normal platelets. The specificity of the platelet cold agglutinin was determined by competitive inhibition by monoclonal anti-CD41(GPIIbIIIa). Before the addition of monoclonal antibody, patient's serum agglutinated 16% of normal platelets at 22 degrees C; after addition of anti-CD41 only 2% of the platelets were agglutinated. This blocking effect was not observed with anti-CD42. The patient's platelets functioned normally as determined by CD62 and CD63 expression in response to thrombin, normal platelet aggregation in response to collagen, ADP, and ristocetin, and a normal template bleeding time. In summary, platelet agglutination by a platelet cold agglutinin was quantitated by flow cytometry, the responsible antibody was characterized as a low titre IgM with minimal activity > 30 degrees C, and competitive binding studies supported the GPIIbIIIa complex as the binding site for the antibody. Since the antibody did not affect platelet function, we believe that these patients will not suffer complications from their platelet cold agglutinin, but it could pose a problem under circumstances such as cardiac surgery with hypothermia.

Acute phase proteins, C-reactive protein and serum amyloid A protein, as prognostic markers in the elderly inpatient.

AIM: to study the clinical significance and potential utility of measuring serum amyloid A protein (SAA) compared with the classical acute phase protein, C-reactive protein (CRP). METHOD: a 3 month prospective study on 66 women, mean age 83 years (range 69-106) and 33 men, mean age 84 years (range 69-95), admitted to the geriatric medicine unit at Hammersmith Hospital. CRP and SAA were determined on admission and at intervals throughout hospital stay; outcome end-points were death during the study, detection of infection, duration of admission and early re-admission to hospital after discharge. RESULTS: CRP and SAA responses were highly correlated (r = 0.75, P = 0.0001). However, the SAA response was greater than that of CRP in most individuals, with a median ratio of initial SAA to CRP of 2.2 in patients with infective pathology and 1.6 in those with inflammatory pathology. Median (range) SAA on admission was 98 (0.1-940) mg/ml in patients with infection and was twice that observed in patients with other causes of inflammation, median value 50 (0.6-699) mg/l. There was no difference between median CRP on admission in patients with infection or inflammation, median value 53 (0.1-235) and 51.5 (5-246) mg/l respectively. Initial and peak levels of CRP, but not of SAA, were significantly greater in patients who subsequently died, whereas high levels of both proteins predicted length of admission and early re-admission. CONCLUSION: major elevations of the serum concentrations of CRP and SAA indicated serious disease and predicted poor outcome. Measurement of SAA as well as CRP enhanced the clinical utility of monitoring the acute phase response in 7% of patients with a diagnosis of infection.

Nutritional supplementation in elderly medical in-patients: a double-blind placebo-controlled trial.

The aim of this study was to assess the effect of vitamin and/or glucose energy supplementation in elderly medical patients on an intention-to-treat basis. One hundred and six elderly medical in-patients were entered into a double-bind placebo-controlled factorial trial of glucose energy and vitamin supplementation. Supplementation was given for 1 month. This trial was designed to detect a > 2 kg increase in weight and > 3 g/l increase in serum albumin between active and placebo supplementation in 100 patients with 90% power (p < 0.05). Other outcome measures included changes in Barthel activities of daily living, length of stay, and mental test score (MTS). No interaction between vitamin and glucose supplementation was demonstrated. Active energy supplementation with glucose alone was associated with a +0.6 kg change in weight and +0.7 g/l change in albumin [95% confidence interval (CI) -0.8, +2.0 and -1.3, +2.8, respectively]. The respective changes for active vitamin supplementation were -0.6 kg for weight and +0.5 g/l for albumin (95% CI -2.1, +0.8 and -1.5, +2.6, respectively). There were no significant differences in mental test score, Barthel score, or length of stay between the two groups. Compliance with the glucose energy supplementation was poor with only one-third of patients consuming more than 50% of the offered drink. We conclude that the giving of glucose alone and/or vitamin supplementation in elderly patient is of no benefit on an intention-to-treat basis.

Autoantibodies to the collagenous region of C1q occur in three strains of lupus-prone mice.

We have developed an ELISA to measure murine autoantibodies to the collagenous region (CLR) of C1q, using the whole human C1q molecule as the solid-phase ligand, in the presence of 1 M NaCl. The assay was validated by testing positive sera from 20 mice using purified mouse C1q, and from 10 mice using purified human C1q-CLR, as the solid-phase ligands. There were highly significant correlations between results obtained with human C1q (whole molecule) and: (i) mouse C1q (rsp = 0.73, P less than 0.001), and (ii) human Clq-CLR alone (rsp = 0.86, P = 0.001). Antibodies to Clq were measured in 53 MRL/lpr, 17 BXSB and 25 NZB/W lupus-prone mice. Median (range) anti-C1q (CLR) antibody levels in MRL/lpr, BXSB, and NZB/W autoimmune mice aged 3 months were 22 (16-66), 21 (17-39) and 19 (15-27) EU, respectively. The median anti-Clq antibody level in MRL/lpr mice aged 5 months was 76 (35-142) EU, significantly higher than that at 3 months (U = 558, P less than 0.0005). Median anti-C1q antibody level in NZB/W mice at 8 months was 37 (13-74) EU and in BXSB mice at 11 months was 62 (31-231) EU, significantly higher than corresponding values at 3 months (U = 326, and U = 4, P less than 0.001, respectively). This is the first demonstration of anti-C1q (CLR) antibodies in NZB/W and BXSB mice. The pathologic significance and the potential utility of these antibodies for monitoring disease in lupus-prone mice are under evaluation.