Natural endocrine profiles of the group-living skunk anemonefish Amphiprion akallopisos in relation to their size-based dominance hierarchy.

Group-living animals commonly display differences in behaviour, physiology and endocrine profiles between conspecifics within the group, which are tightly linked to reproduction. Teleosts exhibit a variety of social systems, where social status, as well as sex, has been linked to different androgen and oestrogen profiles. Levels of gonadal androgen and oestrogen were investigated as a function of sex and position in a social hierarchy in free-living individuals of the skunk anemonefish Amphiprion akallopisos, a protandrous pomacentrid fish with a size-based dominance hierarchical social system. Plasma levels of 11-ketotestosterone (11-KT), testosterone (T) and 17ß-oestradiol (E2 ), as well as conversion ratios from T, were measured by ELISA from 111 individuals along a linear hierarchy from 38 social groups in the wild. Blood plasma levels of 11-KT and E2 showed sex differences, being higher in males and females respectively as expected based on their role as the major androgen and oestrogen in fish reproduction. However, no sex differences were found for T, which may represent its role in territorial defence or simply as a precursor for the synthesis of 11-KT and E2 . In terms of the hierarchical social system within males, 11-KT levels decline as the hierarchy is descended, which may represent their decreasing reproductive opportunity, as well as the decreasing levels of aggression towards males lower in the hierarchy. In summary, the size-based dominance hierarchy is associated with distinct steroid levels of 11-KT and E2 between individual free-living A. akallopisos that closely resemble those of species in which breeding individuals suppress reproduction of conspecifics lower in the hierarchy.

Incidence of anti-neutrophil cytoplasmic antibody-associated vasculitis before and after the February 2011 Christchurch Earthquake.

BACKGROUND: It has been suggested that environmental pollution from an earthquake might be associated with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). AIM: To determine the incidence of AAV during the 3-year period before (period 1), and the 3 years following (period 2), the earthquake that occurred on 22 February 2011 in Christchurch, New Zealand. METHODS: All ANCA tests performed in the Canterbury region for 3 years before the earthquake (period 1, 2007-2010), and for 3 years after the earthquake (period 2, 2011-2014) were examined. AAV was defined according to The European Medicines Agency classification algorithm. Medical records were reviewed and cases were included if they were newly diagnosed within the study period. Incidence was calculated using population data from the 2013 New Zealand census. RESULTS: A total of 52 new cases of AAV was identified. The incidence in period 1 was 1.87/100 000/annum (95% C.I. 1.23-2.72), and for period 2 was 1.73/100 000/annum (95% C.I. 1.12-2.55). There was no statistically significant difference in incidence between the two study periods. There was no difference when analysing by myeloperoxidase (MPO) or proteinase-3 status, or restricting the analyses to those residing in an urban environment. The mean age at diagnosis for MPO AAV was significantly younger in period 2 than period 1 (61 years vs 71 years, P = 0.05). There were no other clinically important differences between the two groups. CONCLUSION: This study does not support the hypothesis that an environmental agent, caused by dust pollution related to earthquake damage, has a causative role in the pathogenesis of AAV.

Wegener's granulomatosis: treatment and survival characteristics in a high-prevalence southern hemisphere region.

Our aim was to describe the treatment and survival characteristics of Wegener's granulomatosis (WG) in Canterbury, New Zealand. The medical records of 48 patients diagnosed between 1 July 1997 and 31 December 2008 and fulfilling validated classification criteria for WG were reviewed to characterise survivorship in the province of Canterbury, New Zealand. The age at diagnosis was 61 years (range 20 to 83 years) with an equal number of males and females. Using Kaplan-Meier product-limit analysis, the probability of survival at 1 and 10 years was 91% and 62% respectively. Of the 12 deaths in the cohort, four occurred within 12 months of diagnosis: two from pulmonary haemorrhage and two from renal failure. Beyond 12 months, two patients died of renal failure, two of myocardial infarction and one from cardiac arrhythmia, one from cerebrovascular disease and two from colorectal carcinoma. The median time to relapse was 6.75 years, and the probability of relapse within 10 years was 67%. Survivorship, treatment response rate and the rate of relapse from WG in a cohort of patients from this high-prevalence southern hemisphere region were similar to that reported for northern hemisphere cohorts with a similar prevalence.

Lack of association between elevated mean red cell volume and haematological toxicity in patients receiving long-term methotrexate for rheumatoid arthritis.

AIMS: It has been suggested that elevated mean red cell volume (MCV) may be a predictor of haematological toxicity in rheumatoid arthritis (RA) patients receiving methotrexate (MTX). We wished to identify whether there was an association between MCV, red cell folate and haematological toxicity in patients on MTX monotherapy for the long-term management of RA. METHODS: Evidence of haematological toxicity was sought by note review of patients recruited in a cross-sectional study of MTX monotherapy in RA. Retrospective data included MCVs from before MTX initiation and after 3 and 6 months of treatment. Data were collected prospectively every 6 months for up to 2 years after enrolment. Any record of cytopenia or the development of haematological malignancy was recorded from commencement of MTX until the present day. Red cell folate concentrations were tested on enrolment to the study. RESULTS: A total of 165 patients was included, 74.5% female, median disease duration 7 years (range 3 months-57 years). The median duration of MTX treatment was 74.9 months (range 10-241 months) giving 1030.2 patient-years of MTX exposure. Twenty-four patients (14.5%) had a MCV > 98 fL on study entry. Evidence of haematological abnormality was found in six patients (3.6%); chronic lymphocytic leukaemia (1), persistent lymphocytosis (1), persistent monocytosis (1) and neutropenia (3). There was no association between red cell folate or MCV and haematological toxicity. CONCLUSION: Neutropenia and pancytopenia are rare side-effects of MTX therapy in this cohort. Elevated MCV or low mean red cell folate does not appear to be associated with haematological malignancy or toxicity in this cohort of patients on long-term MTX therapy.

Evidence for association of an interleukin 23 receptor variant independent of the R381Q variant with rheumatoid arthritis.

OBJECTIVE: The rare allele of a non-synonymous interleukin 23 receptor (IL23R) single nucleotide polymorphism (SNP) rs11209026 (p.Arg381Gln) confers strong protection against Crohn disease (CD) and psoriasis. Other IL23R variants also exhibit association with CD, genetically independent of rs11209026. In rheumatoid arthritis (RA), IL23 is an important determinant of the production of IL17A, a cytokine of consequence in inflammation and bone destruction. While there is no previous support for strong association of IL23R with RA, the possibility of a weaker role for IL23R variants in the aetiology of RA cannot be eliminated. METHODS: A New Zealand RA cohort was tested for association with six IL23R SNPs and the resulting data combined with a reanalysis of the Wellcome Trust Case Control Consortium data and a previously published Spanish data set. The combined data set totals over 3000 Caucasian cases and 3800 controls, which has sufficient power to detect a risk of as low as odds ratio (OR) = 1.2. RESULTS: Our data emphasise the lack of association of rs11209026 with RA (OR 1.01, 95% confidence interval (CI) 0.88 to 1.16, p = 0.86). However there was some evidence for association of rs1343151 with RA (OR 1.14, 95% CI 1.06 to 1.22, p = <0.001). CONCLUSIONS: While requiring further replication, these data further support a role for the IL17A/IL23 pathway in RA. Understanding how different variants of IL23R associate, at varying levels of strength, with contrasting groups of immune-mediated diseases (CD, psoriasis, ankylosing spondylitis, RA) will enhance knowledge on the aetiology of these diseases.

Evidence for an influence of chemokine ligand 3-like 1 (CCL3L1) gene copy number on susceptibility to rheumatoid arthritis.

OBJECTIVE: There is increasing evidence that gene copy-number variation influences phenotypic variation. Chemokine ligand 3-like 1 (CCL3L1) is encoded by a variable copy-number gene, and binds to several pro-inflammatory cytokine receptors, including chemokine receptor 5 (CCR5). Considering lymphocyte recruitment by beta-chemokines is a feature of autoimmunity, and that the CCR5Delta32 variant is associated with protection to rheumatoid arthritis (RA), we hypothesised that CCL3L1 copy-number influences susceptibility to RA and type 1 diabetes (T1D). METHODS: We measured CCL3L1 copy-number in 1136 RA cases from New Zealand (NZ) and the UK, 252 NZ T1D cases and a total of 1470 controls. All subjects were ancestrally Caucasian. RESULTS: A copy-number higher than 2 (the most common copy number) was a risk factor for RA in the NZ cohort (odds ratio (OR) 1.34, 95% CI 1.08-1.66, p = 0.009) but not the smaller UK RA cohort (OR 1.09, 95% CI 0.75-1.60, p = 0.643). There was evidence for association in the T1D cohort (OR 1.46, 95% CI 0.98-2.20, p = 0.064) and in the combined RA/T1D cohort (OR 1.30, 95% CI 1.00-1.54, p = 0.003). Genetic interaction between CCL3L1 dosage and CCR5 genotype was found; the increased genetic risk conferred by higher CCL3L1 copy-number was ablated by a dysfunctional CCR5 (CCR5Delta32). CONCLUSIONS: These data suggest that increased CCL3L1 expression may enhance inflammatory responses and increase the chance of autoimmune disease. Genetic interaction data were consistent with a biologically plausible model; CCR5Delta32 protects against RA and T1D by blocking signalling through the CCR5 pathway, mitigating the pro-inflammatory effects of excess CCL3L1.

Emerging therapies in the long-term management of hyperuricaemia and gout.

Gout is a common chronic arthritis that can lead to significant disability. Gout is one of the few rheumatological conditions that can be diagnosed with certainty, has a known cause and can be cured with appropriate therapy. Hypouricaemic agents reduce uric acid concentrations through inhibiting uric acid production (allopurinol) or enhancing uric acid excretion (probenecid, benzbromarone). Allopurinol is the most commonly used hypouricaemic agent but at recommended doses often fails to reduce adequately uric acid concentrations and prevent acute attacks of gout. The use of probenecid is limited by lack of efficacy in renal impairment. In the last few years, new agents in the management of hyperuricaemia and gout have become available. Febuxostat, a new xanthine oxidase inhibitor, is an effective hypouricaemic agent although further data are required for patients with renal impairment and other significant medical conditions. Rasburicase, a recombinant uricase (which catalyses the conversion of uric acid to the more readily excreted allantoin) is available for prevention of tumour lysis syndrome. However, its repeated use, as would be required in chronic gout, is limited by antigenicity. A less antigenic PEGylated uricase can rapidly reduce serum uric acid concentrations and promote resorption of tophi. However, further information with regard to the long-term risks and benefits of these agents is required. These agents may ultimately be used in the short term to rapidly deplete urate stores (induction therapy) followed by long-term therapy with an alternative hypouricaemic agent to prevent subsequent accumulation of uric acid (maintenance therapy).

Wegener's granulomatosis in New Zealand: evidence for a latitude-dependent incidence gradient.

BACKGROUND: The aim of the study was to determine whether there was evidence for a geographic gradient in the incidence of Wegener's granulomatosis (WG) and WG-like disease in New Zealand (NZ). METHODS: The National Minimum Dataset of the Ministry of Health, NZ was searched for individual patient discharges coded by the International Classification of Diseases 10th Revision, Australian Modification as either M301 (polyarteritis with lung involvement, including Churg Strauss and allergic granulomatous angiitis) or M313 (WG, necrotizing respiratory granulomatosis) for the period 1 January 1999 to 31 December 2003. Data were standardized using the 2001 NZ census. RESULTS: One hundred and ninety-five patients (95 men) were given a first-time discharge code of either M301 (40 patients) or M313 (155 patients). No gender bias was seen. The rate among Europeans was twice that of NZ Maoris or Asians. The rate of disease peaked in the age band 70-79 years and during winter months. A significant positive north-south geographic gradient was present for M313. No difference in the rate of readmission or time to relapse between geographic regions was found for M313. CONCLUSION: A north-south gradient in the rate of patient discharges given a diagnostic code of M313 (WG, necrotizing respiratory granulomatosis) was present in NZ. This finding supports the hypothesis that there is a latitude-dependent risk factor(s) for WG possibly common to both global hemispheres.

Soluble human leukocyte antigen: a diagnostic indicator of rheumatoid arthritis?

Early stage rheumatoid arthritis (RA) is often difficult to diagnose because initial symptoms are non-specific. To aid diagnosis, suitable serological diagnostic markers are sought. Elevated levels of soluble MHC class II (soluble human leukocyte antigen; sHLA-DR) in human serum have been associated with rheumatoid and 'rheumatoid-like' autoimmune diseases. As a result, sHLA-DR has been suggested as a specific marker of RA. However, reported levels of sHLA-DR in sera of healthy donors vary significantly and the mechanism of release of HLA-DR into serum is poorly understood. Investigations into the diagnostic potential of this molecule necessitate the development of a sensitive and specific sHLA-DR assay. We have investigated multiple ELISA setups to develop such an assay and false positive signal has been carefully removed using a combination of isotype-matched controls and immuno-depletion. sHLA-DR levels in sera of RA patients were not significantly different from those in healthy donors which suggests sHLA-DR has limited utility in the diagnosis of RA. In RA patients, we detected high levels of sHLA-DR in aspirated synovial fluid (SF), but this did not correlate with sHLA-DR levels in serum.

Unicentric Castleman's disease: a surprising neck mass.

BACKGROUND: We present the case of a 36-year-old female with a three-week history of a pulsatile, tender mass in the anterior triangle of the neck. METHODS: Radiology demonstrated that this was a vascular tumour deep to the sternocleidomastoid muscle. RESULTS: Pre-operative embolisation and complete surgical resection was performed. Histology revealed Castleman's disease. CONCLUSION: Unicentric hyaline vascular Castleman's disease is an unusual cause of neck mass. Surgical resection remains the best chance for cure in unicentric disease. Long term follow-up is necessary as the risk of subsequent malignancy exists.

Prolonged remission of longstanding systemic lupus erythematosus after autologous bone marrow transplant for non-Hodgkin's lymphoma.

We describe a patient with longstanding steroid-dependent systemic lupus erythematosus (SLE) in whom clinical and serological remission was achieved following high-dose therapy and autologous bone marrow rescue for high-grade non-Hodgkin's lymphoma. However, 3 years later, autoimmune disease re-presented in the form of immune thrombocytopenia (ITP), which had not previously been a feature of the SLE, necessitating reintroduction of steroid immunosuppression. Relapse of SLE is most likely, although de novo ITP post-BMT is also a possibility. The case suggests that severe long-standing autoimmune disease may be controlled by high-dose therapy and autologous stem cell reconstitution. However, further studies are required to determine the mechanism of re-emergence of autoimmunity and to evaluate optimal regimens and the potential value of such therapy in severe autoimmune diseases.

Dual CD45RA, CD45RO positive T-lymphocytes within rheumatoid arthritic joints.

This report documents the presence of an expanded population of dual CD45RA, CD45RO positive T cells (up to 91% of T cells) in the rheumatoid joint. Cells from peripheral blood (PB) and synovial fluid (SF) were analysed by dual immunofluorescence labelling. Synovium from a separate patient population was analysed by single and dual immunoenzyme staining of serial sections. Dual CD45RA, CD45RO positive T cells were found in PB (up to 74%), SF (up to 91%) and synovium. This was associated with a lack of early activation antigens (4F2, interleukin-2 receptor, transferrin receptor) but increased HLA-Class II antigens (HLA-DR, -DP, -DQ) in SF compared with PB. This intermediate activation phenotype may support the hypothesis that T cell activation or reactivation occurs within the rheumatoid joint.

Prostaglandin E2 content in herniated lumbar disc disease.

STUDY DESIGN: A prospective series of biochemical assays for prostaglandin E2 content in symptomatic herniated lumbar disc specimens. OBJECTIVES: To help clarify the pathogenesis of lumbar radiculopathy. SUMMARY OF BACKGROUND DATA: Three recent studies have shown elevated levels of prostaglandin E2 in intervertebral disc herniations. None of these studies correlated symptoms with prostaglandin E2 levels. METHODS: Twenty-four disrupted disc samples were purified by a standard solid phase extraction method and analyzed for prostaglandin E2 with an enzyme-linked immunosorbent assay. Clinical and anatomic correlations were sought with analysis of variance and t test. RESULTS: Sequestered discs tended to be associated with a higher prostaglandin E2 content than extruded discs, which in turn, tended to be associated with higher prostaglandin E2 content than protruded ones. A positive straight leg raising test appeared to be associated with a higher prostaglandin E2 content than a negative test. CONCLUSIONS: Prostaglandin E2 appears to mediate some of the inflammatory effects of lumbar disc herniation. An intact anulus may provide some protection against this stimulus.

Health care in early infancy.

The pattern of illness and of health care during the first 16 weeks of life in a cohort of 1210 infants was examined. Children from families in the lower social strata had a significantly increased risk of respiratory illness and gastrointestinal disturbance and received less routine well baby care than children from more socially advantaged backgrounds. A number of policy changes which might improve the distribution of health care resources are examined.

Relationship between serum urate and plasma oxypurinol in the management of gout: determination of minimum plasma oxypurinol concentration to achieve a target serum urate level.

The treatment of gout requires a lowering of serum urate (SU) levels, and allopurinol is the drug that is most commonly used for this purpose. The objectives of this study were to define the relationships between allopurinol dose on the one hand and plasma oxypurinol, renal function, and SU levels on the other and to determine the minimum plasma oxypurinol concentration that would result in a target level of <6 mg/dl (0.36 mmol/l) of SU. For this purpose, 82 patients who had been receiving allopurinol for at least 1 month were recruited. Patients with SU <6 mg/dl were followed up quarterly for 12 months. In patients with SU ≥6 mg/dl, the dose of allopurinol was increased to bring the level of SU to <6 mg/dl. These patients were followed up once a month until the SU level remained at <6 mg/dl for 3 consecutive months; thereafter they were seen quarterly. SU, creatinine, and plasma oxypurinol were measured 6-9 hours after administration of the allopurinol dose. There were significant inverse correlations between creatinine clearance (CrCl) and plasma oxypurinol (P = 0.002), between allopurinol dose and SU (P < 0.0001) and between plasma oxypurinol and SU (P < 0.0001). Using receiver operating characteristic analysis, the target SU of <6 mg/dl was achieved in 75% of serum samples with plasma oxypurinol levels of >100 µmol/l (15.2 mg/l). Increasing the allopurinol dose resulted in increased plasma oxypurinol and reduced SU concentrations. Plasma oxypurinol concentrations >100 µmol/l were required to achieve SU <6 mg/dl.

The epidemiology of Wegener's granulomatosis and microscopic polyangiitis in a Southern Hemisphere region.

OBJECTIVE: To determine the prevalence of Wegener's granulomatosis (WG) and microscopic polyangiitis (MPA) in the province of Canterbury, New Zealand. METHOD: Three hospital clinical databases and the immunology laboratory database were searched and case notes reviewed for patients fulfilling either the 1990 American College of Rheumatology (ACR) criteria for WG or a modification of those criteria that allowed for antineutrophil cytoplasmic antibody (ANCA) positivity in the absence of granulomatous vasculitis. MPA was defined by the Chapel Hill consensus definition; however, in the absence of histological evidence of pauci-immune glomerulonephritis, ANCA positivity in association with evidence of active glomerular disease was included as a criterion. The point prevalence at 31 December 2003 and the 5-yr period prevalence for the interval 1 January 1999 to 31 December 2003 were calculated. RESULTS: Seventy-three patients with WG and 28 patients with MPA fulfilled the inclusion criteria. A 5-yr period prevalence of 152 WG cases/million [95% confidence interval (CI) 117-186] and 58 MPA cases/million (95% CI 37-80) was calculated using 2001 census data as denominator. Nineteen patients with WG died and 10 patients with MPA died during the study period, resulting in a point prevalence for survivors at 31 December 2003 of 112 cases/million (95% CI 82-142) and 37 cases/million (95% CI 20-55), respectively. Using unmodified ACR criteria the 5-yr period and point prevalence for WG were 131/million (95% CI 99-163) and 93.5/million (95% CI 66-121), respectively. Apart from respiratory tract involvement, which formed part of the case definition of WG, organ involvement was similar in both diseases. CONCLUSION: The prevalence of WG and MPA in Canterbury is the highest reported to date. Restricting the case definition of WG to the ACR classification criteria we found a prevalence equivalent to that described in northern Norway. The clinical severity and serological characteristics were similar to descriptions in other WG and MPA patient cohorts. Studies of disease prevalence in other Southern Hemisphere centres will determine if the observed north-south negative disease gradient in the Northern Hemisphere is reciprocated.