The genetic associations of acute anterior uveitis and their overlap with the genetics of ankylosing spondylitis.

Acute anterior uveitis (AAU) involves inflammation of the iris and ciliary body of the eye. It occurs both in isolation and as a complication of ankylosing spondylitis (AS). It is strongly associated with HLA-B*27, but previous studies have suggested that further genetic factors may confer additional risk. We sought to investigate this using the Illumina Exomechip microarray, to compare 1504 cases with AS and AAU, 1805 with AS but no AAU and 21 133 healthy controls. We also used a heterogeneity test to test the differences in effect size between AS with AAU and AS without AAU. In the analysis comparing AS+AAU+ cases versus controls, HLA-B*27 and HLA-A*02:01 were significantly associated with the presence of AAU (P<10(-300) and P=6 × 10(-8), respectively). Secondary independent association with PSORS1C3 (P=4.7 × 10(-5)) and TAP2 (P=1.1 × 10(-5)) were observed in the major histocompatibility complex. There was a new suggestive association with a low-frequency variant at zinc-finger protein 154 in the AS without AAU versus control analysis (zinc-finger protein 154 (ZNF154), P=2.2 × 10(-6)). Heterogeneity testing showed that rs30187 in ERAP1 has a larger effect on AAU compared with that in AS alone. These findings also suggest that variants in ERAP1 have a differential impact on the risk of AAU when compared with AS, and hence the genetic risk for AAU differs from AS.

Advances in classification, basic mechanisms and clinical science in ankylosing spondylitis and axial spondyloarthritis.

The field of spondyloarthritis (SpA) has seen huge advances over the past 5 years. The classification of axial disease has been redefined by the axial SpA criteria that incorporate disease captured before radiographic damage is evident as well as established erosive sacroiliac joint disease. Our knowledge of genetics and basic immunological pathways has progressed significantly. In addition, revolutionary progress has been achieved with the availability of tumour necrosis factor inhibitors for treating patients with moderate to severe disease. In parallel, several of novel biomarkers have been identified that show significant promise for the future. Advances in magnetic resonance imaging have helped define positive disease. We have identified that T1 and short tau inversion recovery sequences are best for the diagnosis of axial SpA, and gadolinium contrast is not additive for diagnosis. Progress has been made in identifying potential agents and strategies that reduce radiographic progression. Several referral strategies aimed at appropriate identification of patients have been trialled and found to be effective. There is still substantial work ahead, but the advances of the last 5 years have made a huge and tangible difference at the clinical coalface, and we suggest that this trend will continue.

Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis.

The mechanism by which human leukocyte antigen B27 (HLA-B27) contributes to ankylosing spondylitis (AS) remains unclear. Genetic studies demonstrate that association with and interaction between polymorphisms of endoplasmic reticulum aminopeptidase 1 (ERAP1) and HLA-B27 influence the risk of AS. It has been hypothesised that ERAP1-mediated HLA-B27 misfolding increases endoplasmic reticulum (ER) stress, driving an interleukin (IL) 23-dependent, pro-inflammatory immune response. We tested the hypothesis that AS-risk ERAP1 variants increase ER-stress and concomitant pro-inflammatory cytokine production in HLA-B27(+) but not HLA-B27(-) AS patients or controls. Forty-nine AS cases and 22 healthy controls were grouped according to HLA-B27 status and AS-associated ERAP1 rs30187 genotypes: HLA-B27(+)ERAP1(risk), HLA-B27(+)ERAP1(protective), HLA-B27(-)ERAP1(risk) and HLA-B27(-)ERAP1(protective). Expression levels of ER-stress markers GRP78 (8 kDa glucose-regulated protein), CHOP (C/EBP-homologous protein) and inflammatory cytokines were determined in peripheral blood mononuclear cell and ileal biopsies. We found no differences in ER-stress gene expression between HLA-B27(+) and HLA-B27(-) cases or healthy controls, or between cases or controls stratified by carriage of ERAP1 risk or protective alleles in the presence or absence of HLA-B27. No differences were observed between expression of IL17A or TNF (tumour necrosis factor) in HLA-B27(+)ERAP1(risk), HLA-B27(+)ERAP1(protective) and HLA-B27(-)ERAP1(protective) cases. These data demonstrate that aberrant ERAP1 activity and HLA-B27 carriage does not alter ER-stress levels in AS, suggesting that ERAP1 and HLA-B27 may influence disease susceptibility through other mechanisms.

The safety of flexible fibre-optic bronchoscopy and proceduralist-administered sedation: a tertiary referral centre experience.

BACKGROUND: Flexible fibre-optic bronchoscopy has become an essential investigation and is widely regarded as safe, but wider published prospective data regarding delayed complications are limited. There is continuing debate concerning the safety of proceduralist-administered sedation. We evaluated complication rates of bronchoscopy and proceduralist-administered sedation at our tertiary institution, and their clinical significance. METHODS: Prospective evaluation of all patients undergoing bronchoscopy over a 12-month period at a tertiary referral centre. Immediate minor and major complications were documented within 4 h of bronchoscopy, delayed complications at 48 h, case notes and bronchoscopy records were reviewed 1 month later. RESULTS: Five hundred and fifty-eight flexible fibre-optic bronchoscopies were performed, 216 with transbronchial biopsy or nodal aspiration, 19 had therapeutic airways intervention. The minor complication rate at 4 h was 4.12% (23), rising to 26% (145) at 48 h. All 2.2% (12) major complications occurred exclusively within 4 h of bronchoscopy. No complications could be attributed to proceduralist-administered sedation. DISCUSSION: Complication rates at 4 h were comparable with previously reported data. Delayed minor complications were greater than expected, and did not require additional medical input. There were no complications from proceduralist-administered sedation. Flexible fibre-optic bronchoscopy and proceduralist-administered sedation within our institution's guidelines are safe.

Systematic review of the prevalence of gout and hyperuricaemia in Australia.

AIMS: Gout is a growing health problem worldwide especially in affluent countries, such as Australia. Gout and hyperuricaemia are associated with the metabolic syndrome, diabetes mellitus, obesity and hypertension. More importantly, Australia has a growing prevalence of these important health problems. The aim of this study was to systematically review published information regarding the prevalence of gout and hyperuricaemia in Australia. METHODS: A systematic search was undertaken of the MEDLINE, EMBASE and Web of Science databases, as well as relevant websites for journal articles and reports relating to the prevalence of hyperuricaemia and gout in Australia. RESULTS: Twenty-five journal articles and five reports were included in the review. Data collected in a standardised way show gout increased in prevalence from 0.5% population prevalence to 1.7% population prevalence from 1968 to 1995/1996. There has been a significant rise in the prevalence of gout in the Australian Aboriginal population from 0% in 1965 to 9.7% in men and 2.9% in women in 2002. Consistent with the rise in gout prevalence, serum uric acid in blood donors has increased from 1959 to 1980 (17% in 30- to 40-year-old men). CONCLUSIONS: The rate of gout and hyperuricaemia in Australia is high in relation to comparable countries and is increasing. The prevalence of gout in elderly male Australians is second only to New Zealand, which has the highest reported rate in the world. Further research on Aboriginal and Torres Strait Islander gout and hyperuricaemia is required as a result of the lack of contemporary data.

Appropriateness of antineutrophil cytoplasmic antibody testing in a tertiary hospital.

AIMS: To determine whether indications for ordering antineutrophil cytoplasmic antibodies (ANCA) meet the 1999 guidelines proposed for ANCA testing; and to examine the test characteristics of the ANCA test. METHODS: The indications for all ANCA tests over a two-year period were assessed and compared to the 1999 guidelines for the appropriate testing of ANCA. RESULTS: 1127 tests were examined. Overall 33.4% had an indication meeting the 1999 guidelines. The commonest non-guideline indications were ocular or orbital inflammation, liver disease and inflammatory bowel disease. All tests with a positive ANCA had indications for testing in line with the 1999 guidelines. In all but one case an ANCA associated small vessel vasculitis (AASVV) was present. CONCLUSIONS: ANCA is ordered for a wide range of guideline and non-guideline indications. No cases of AASVV would have been missed if ordering were restricted to tests meeting the 1999 guidelines.

Idiopathic pulmonary fibrosis. Abnormalities in the bronchoalveolar lavage content of surfactant protein A.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung characterized by an inflammatory infiltrate, alveolar type II cell hypertrophy and hyperplasia, and ultimate parenchymal scarring. The phospholipid composition of the surface-active material recovered by bronchoalveolar lavage (BAL) is abnormal in this disease. In the present study we have extended the analysis of surfactant components in IPF to include the major surfactant-associated protein, surfactant protein A (SP-A). SP-A has been reported to be essential for the formation of tubular myelin, to facilitate the adsorption of phospholipid to the air/liquid interface, and to stimulate uptake and inhibit secretion of surfactant in vitro. The BAL of 25 normal volunteers and 42 patients with interstitial lung disease (ILD) was analyzed for surfactant protein A content by ELISA and for phospholipids. The changes in BAL components were correlated to histopathologic markers at open-lung biopsy, clinical status, and survival. The total phospholipid (PL) recovered at lavage was reduced in patients with IPF relative to normal volunteers (p less than 0.0005). In addition, the percentage of phosphatidyl-glycerol (% PG) was decreased in patients with IPF (p less than 0.0001), whereas the percentage of phosphatidylcholine that was saturated was not altered. The content of surfactant protein A in lavage was reduced, even when normalized for the total amount of surface-active material recovered (SP-A/PL) (p less than 0.007). The reduction in SP-A was not specific to IPF but also occurred in other interstitial lung diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

Tuberculosis surveillance in the South Australian aboriginal community.

Tuberculosis (TB) is still a significant problem in Aboriginal people. There are higher rates of active TB and evidence of continuing transmission among this group. We sought to define the specific epidemiological risks and best methods of surveillance for TB in Aboriginal people in South Australia. We compared the incidence of active TB in Aboriginal people in South Australia with that of the total number of cases in non-Aboriginal people from 1978 to 1988, and studied the prevalence of infection in four Aboriginal communities in South Australia. Incidence rates of active TB were four times higher in South Australian Aboriginal people than the total South Australian rates. Specific age analysis revealed higher active disease notification rates in Aboriginal people aged 45-54 years and 55-64 years. The notification rate for Aboriginal men was almost three times the rate for women. Standardized incidence ratios of active TB cases for Aboriginal communities were higher in rural and traditional communities than in urban Aboriginal people. Infection prevalence, measured by tuberculin skin testing, varied from 7.7% to 30.8% in the different communities but did not correlate with the standardized incidence ratios. We conclude that (i) South Australian Aboriginal people are suffering a higher rate of active TB disease than the total South Australian community, and (ii) that the disease and infection rates vary between communities and between age and sex groups. The discrepancy between disease notifications rates, as measured by standardized incidence ratios, and infection prevalence requires further investigation. To improve TB control in Aboriginal people, programmes need to be altered to be more appropriate for this group.

Idiopathic pulmonary fibrosis. Abnormalities in bronchoalveolar lavage fluid phospholipids.

Bronchoalveolar lavage has been used to sample cells and proteins in the distal lung. One of the major secretory products of the alveolar type II epithelial cells, pulmonary surfactant, can be recovered by lavage. Abnormalities in alveolar type II cells are found in biopsies of patients with idiopathic pulmonary fibrosis (IPF), and abnormalities of pulmonary surfactant phospholipids have been reported after diffuse lung injury in animals and in humans. Therefore, we questioned if abnormalities in lavage phospholipids might also occur in IPF, a chronic inflammatory disease of the alveolar epithelium and interstitium, and, if present, would these abnormalities reflect histopathologic changes or predict responsiveness to therapy. Fifteen untreated patients with IPF, diagnosed by open lung biopsy, were studied and were found to have less than half the amount of bronchoalveolar lavage phospholipid as that recovered from healthy volunteers (p less than 0.05). In addition, patients with IPF had a lower proportion of phosphatidylglycerol and a higher proportion of phosphatidylinositol in the recovered phospholipids than did healthy volunteers (p less than 0.05). The severity of these alterations in phospholipid composition correlated with more advanced fibrotic histopathologic changes. Patients with less depression of total phospholipids in lavage improved with corticosteroid therapy, whereas the patients with more severely decreased total phospholipid recovered in lavage did not.

Reduction of the human body burdens of hexachlorobenzene and polychlorinated biphenyls.

Adipose-tissue concentrations of hexachlorobenzene (HCB), four other pesticides and 10 polychlorinated biphenyl congeners were significantly reduced by enhanced mobilization and excretion through the method developed by Hubbard. Electrical workers paired by age, sex and potential for polychlorinated biphenyl exposure were divided into treatment and control groups. Adipose-tissue concentrations were determined pre- and post-treatment, and 3 months post-treatment. Daily treatment was provided for 3 weeks, consisting of heat stress and niacin administration to enhance mobilization and polyunsaturated-oil administration to enhance excretion, with other components administered to provide protection from mobilized chemicals. Adjusted for re-exposure as represented in the control group, HCB body burdens were reduced by 30% at post-treatment and 28% 3 months post-treatment. Mean reduction of polychlorinated biphenyl congeners was 16% at post-treatment and 14% 3 months post-treatment. Analysis of variance indicates these reductions are statistically significant (f less than 0.001). Enhanced excretion appeared to keep pace with mobilization, as blood-serum levels in the treatment group did not increase during treatment. Post-treatment remission of symptoms associated with chemical exposure has been summarized according to reports from related studies.

Stimulation of DNA synthesis in cultured rat alveolar type II cells.

Restoration of the alveolar epithelium after injury is thought to be dependent on the proliferation of alveolar type II cells. To understand the factors that may be involved in promoting type II cell proliferation in vivo, we determined the effect of potential mitogens and culture substrata on DNA synthesis in rat alveolar type II cells in primary culture. Type II cells cultured in basal medium containing 10% fetal bovine serum (FBS) exhibited essentially no DNA synthesis. Factors that stimulated 3H-thymidine incorporation included cholera toxin, epidermal growth factor, and rat serum. The greatest degree of stimulation was achieved by plating type II cells on an extracellular matrix prepared from bovine corneal endothelial cells and then by culturing the pneumocytes in medium containing rat serum, cholera toxin, insulin, and epidermal growth factor. Under conditions of stimulation of 3H-thymidine incorporation there was an increased DNA content per culture dish but no increase in cell number. The ability of various culture conditions to promote DNA synthesis in type II cells was verified by autoradiography. Type II cells were identified by the presence of cytoplasmic inclusions, which were visualized by tannic acid staining before autoradiography. These results demonstrate the importance of soluble factors and culture substratum in stimulating DNA synthesis in rat alveolar type II cells in primary culture.

Isolation and culture of human alveolar type II epithelial cells. Characterization of their phospholipid secretion.

Alveolar type II epithelial cells have been isolated previously from rodents but not from humans. The aims of this study were to isolate and culture alveolar type II cells from human lungs, and to study their phospholipid secretion. Lung tissue was obtained from 13 patients after lobectomy or pneumonectomy. Type II cells were isolated by a modification of our method for isolating rat type II cells with porcine pancreatic elastase and discontinuous metrizamide density gradients. Cells were purified further by differential adherence and they were then cultured on an extracellular matrix prepared from bovine corneal endothelial cells. We obtained 1.3 to 4.8 X 10(6) cells per gram of tissue with cell viability on the day of isolation of 96 +/- 1% (mean +/- SE, n = 10). Type II cell purity, assessed by Papanicolaou stain on Day 1 in culture, was 84 +/- 4% (mean +/- SE) in 9 of the 13 experiments. In the remaining 4 experiments, the purity was less than 50%. Electron microscopy showed well-preserved ultrastructure. The cells, radiolabeled with 32Pi, secreted the phospholipids characteristic of pulmonary surfactant, primarily phosphatidylcholine (68%) and phosphatidylglycerol (12%). Phospholipid secretion was stimulated by tetradecanoyl phorbol acetate (4.5 times baseline) and by the beta adrenergic agonist terbutaline (2.0 times baseline), but not by the cholinergic agonist carbamylcholine chloride. In summary, human alveolar type II epithelial cells can be isolated from resected lung and maintained in culture, and they secrete the phospholipids characteristic of pulmonary surface active material.

Abdominal pain following intravenous benzyl penicillin administration.

The occurrence of abdominal pain (in three patients) and lower chest pain (in one patient) either during or immediately after the intravenous administration of high doses of benzyl penicillin is reported. All four patients were diagnosed as having bacterial endocarditis and had been receiving between 8 and 18 mega units of the drug per day for 2--3 weeks, when the symptoms were first noticed. A skin rash also appeared in each case, at this time. Both the rash and abdominal pain disappeared when an alternative antibiotic was substituted for the penicillin.