Survival in scleroderma: results from the population-based South Australian Register.

AIM: To ascertain the mortality risk and investigate clinical and serological factors influencing survival of patients listed on the South Australian Scleroderma Register (SASR). METHODS: The SASR is a population-based register, which was commenced in 1993 and has actively sought to recruit all scleroderma patients diagnosed in SA over a 15-year period. Clinical and serological details have been accessed from questionnaires or from clinical and laboratory files. Standardized mortality ratio (SMR) was calculated and survival analyses performed on all living and deceased patients listed on this SASR (n = 786). RESULTS: Patients with scleroderma had increased mortality compared with the general SA population (SMR 1.46 (95% confidence interval (CI) 1.28-1.69)). Factors that adversely altered survival included older age at onset, male gender, diffuse skin involvement, presence of scleroderma renal crisis, pulmonary fibrosis, pulmonary arterial hypertension, cancer and anti-topoisomerase (Scl-70) and anti-U1 RNP antibodies, while a trend was observed with increased nailfold capillary dropout. Mean age of death for patients with limited scleroderma was 74.1 years (95% CI 72.5-75.7), diffuse scleroderma 62.9 years (95% CI 59.4-66.4) and overlap disease 57.8 years (95% CI 48.7-66.9). Survival improved over the 15-year study period. CONCLUSIONS: Scleroderma substantially reduces life expectancy. Survival is influenced by age at onset, gender, diffuse involvement of skin fibrosis, visceral involvement, development of cancer, extent of microvascular capillary damage and by the presence of scleroderma-associated antibodies, Scl-70 and RNP. Scleroderma renal crisis continues to carry high mortality. Survival improved over the 15-year study period.

Engaging medical students in occupational and environmental medicine--a new approach.

BACKGROUND: For a number of reasons, engaging the interest of medical students in the discipline of occupational and environmental medicine (OEM) can be challenging. AIMS: To renew a curriculum in OEM within a graduate medical programme with an emphasis on student involvement to maximize their interest in the topic. METHODS: A second year student cohort of a 4 year graduate medical programme was surveyed as to their preferences for the content of a short course of OEM embedded in their medical course. The course was extensively rewritten as a result of the student survey, with a number of topics deleted from the old course and new topics added. In order to validate the content of the new course, local occupational physicians (OPs) were also surveyed as to their opinion of an appropriate curriculum in OEM for medical students. The new course was taught to the subsequent cohort of second year medical students. The students' ratings of the course pre- and post-revision were compared. RESULTS: The student satisfaction rates of the course significantly improved as a result of the changes. The content of the student-led curriculum was strikingly similar to the course proposed by the local OP with a few key exceptions. CONCLUSIONS: Student involvement in curriculum design in OEM is entirely feasible. It can result in a curriculum similar to that designed by expert opinion but has the advantage of strongly engaging student interest.

Effect of intra-articular infliximab on synovial membrane pathology in a patient with a seronegative spondyloarthropathy.

OBJECTIVE: To demonstrate the efficacy of intra-articular infliximab in a patient with a persistent monarthritis who had previously had two arthroscopic synovectomies with limited success, and to determine the effect of intra-articular infliximab on synovial membrane pathology METHOD: Arthroscopic synovial biopsy specimens were collected before and after treatment with intra-articular infliximab. The synovial tissue was stained for a range of inflammatory cell subsets, cell adhesion molecules and cytokines using immunohistochemical techniques and quantified using digital image analysis and a semiquantitative scoring method. RESULTS: Clinical improvement in the knee synovitis was seen after the first two intra-articular infliximab treatments, with a sustained clinical remission lasting for more than 12 months after the third treatment. Significant changes in cellular infiltration and expression of cytokines and cell adhesion molecules occurred as a result of treatment with intra-articular infliximab, with a reduction in some but not all cells in the inflammatory infiltrate, as well as a reduction in the expression of cell adhesion molecules (intercellular adhesion molecule-1 and vascular adhesion molecule-1) and production of cytokines (interleukin 1beta and tumour necrosis factor alpha). CONCLUSION: Intra-articular infliximab administration is a viable treatment for a persistent monarthritis resistant to other treatment options and can successfully modulate the inflammatory milieu within the synovial membrane.

The effect of rheumatoid arthritis on personal income in Australia.

BACKGROUND: The aim of this study was to estimate the effect of rheumatoid arthritis (RA) on the personal income of a cohort of individuals with RA in Australia. METHODS: A cross-sectional study of a sample of 497 working age people with RA in Adelaide, South Australia was carried out. RESULTS: The average personal income of an individual with RA in our cohort in 2003-2004 was $A22 400 compared with the Australian mean annual income of $A38 000. When standardized, the income of our cohort was 66% that of the average income of the Australian population. Overall one-third of the RA cohort relied principally on the social security system for their income and more than 75% of the cohort estimated they had lost greater than $A10 000 per annum in personal income as a result of their disease. Individuals with RA who were not working had annual incomes on average of more than $A20 000 less than those who continued to work. CONCLUSION: The personal income loss associated with RA in Australia is of enormous significance. It reduces a large population of individuals to relative financial poverty and potentially limits their access to a range of services including private health services.

Scleroderma in South Australia: further epidemiological observations supporting a stochastic explanation.

The aim of this study was to determine the incidence, prevalence, survival and selective demographic characteristics of scleroderma occurring in South Australia over the 10-year period 1993-2002. Analysis of the database of the South Australian Scleroderma Register: a population-based register established in 1993. Patients with scleroderma resident in South Australia (n = 353 at 2002) were ascertained from multiple sources and clinical and demographic data were obtained from mailed questionnaire and from review of computerized hospital databases, case notes or referring letters. Time-space cluster analysis was carried out according to the Knox method. Control data were obtained from the Australian Bureau of Statistics census. The mean prevalence was 21.4 per 10(5) (95% confidence interval 20.2-22.6) and the mean cumulative incidence of 1.5 per 10(5) (95% confidence interval 1.32-1.73) with no significant change in incidence over the study period (P = 0.13). Cumulative survival improved over the study period, with patients with diffuse disease having significantly reduced survival (as compared with limited disease, P < 0.001). The proportion with diffuse disease ( approximately 22%) remained steady. There was a small but significant predisposition in patients with a continental European birthplace (P < 0.001). A family history of scleroderma was noted in 1.6% with lambda1 (familial risk) of 14.3 (95% confidence interval 5.9-34.5). However, a family history of systemic autoimmunity (especially rheumatoid arthritis) was more common (6%). No socioeconomic stratification, temporal clustering nor spatio-temporal clustering was observed either at time of initial symptom or at 10 years before disease onset. Scleroderma occurs relatively infrequently in South Australia with no significant change in incidence observed over the 10-year study period. However, cumulative survival has improved. Identified risk factors include family history of scleroderma (risk approximately 14-fold), female sex (risk approximately 5-fold) and European birthplace (risk approximately 2.5-fold); however, the majority of the disease variance appears unexplained. A stochastic explanation based on genetic instability is favoured to explain this paradox.

The Felty syndrome: a case-matched study of clinical manifestations and outcome, serologic features, and immunogenetic associations.

Thirty-two patients with the Felty syndrome, defined by the presence of rheumatoid arthritis, splenomegaly, and neutropenia, have been studied in comparison with 32 patients with rheumatoid arthritis matched for age, sex, and disease duration, and 9 patients with rheumatoid arthritis and idiopathic neutropenia. Patients with the Felty syndrome had severe destructive arthritis, which progressed during follow-up despite little evidence of objective synovitis, and a higher frequency of extra-articular manifestations, including vasculitis. Bacterial infection tended to occur in patients with the lowest neutrophil count but continued to occur in some despite normalization of the WBC. Prognosis was poor and 8 deaths occurred, predominantly from sepsis. Serologic features were prominent. High titers of IgG rheumatoid factor and circulating immune complexes characterized patients with persistent neutropenia. A family history of rheumatoid arthritis was more common in patients with the Felty syndrome. The association with HLA DR4 was very strong; in addition there was an increased frequency of the DQw3 variant, 3b, suggesting that HLA Class II genes in linkage with DR4 may contribute to disease expression.

Effects of ex vivo manipulation on the expression of cell adhesion molecules on neutrophils.

In vitro studies of neutrophil adhesion generally utilise purified populations and are often performed at 37 degrees C. This study determines the effects of temperature changes and neutrophil separation procedures on the expression of cell adhesion molecules on neutrophils. We found that neutrophil separation procedures involving erythrocyte sedimentation and hypotonic lysis are associated with a significant increase in the expression of both a structural and functional epitope of the beta 2 integrin CD11b, an increase in the expression of sialyl Lewisx (CD15s) and the hyaluronate receptor (CD44) as well as a significant decrease in L-selectin (CD62L) expression. Separated neutrophils are also more resistant than unseparated neutrophils to PMA induced upregulation of a functional epitope of CD11b. Incubating neutrophils at 37 degrees C is associated with increases in the expression of structural and functional epitopes of CD11b. Neutrophil separation is also associated with increases in the expression of both structural and functional epitopes of CD11b which is greater when neutrophil separation is performed at room temperature compared with neutrophil separation at 0-4 degrees C. However, this difference is lost when the latter are incubated at 37 degrees C. Furthermore, neutrophil separation at both 0-4 degrees C and room temperature is associated with a significant increase in CD15s expression. This increase is less when separation is performed at room temperature. These findings suggest that neutrophil separation should be performed at room temperature unless the cells are going to be used at 0-4 degrees C. Researchers using purified neutrophil populations need to be aware of these significant structural and functional changes when extrapolating in vitro results to in vivo situations.

Central nervous system toxoplasmosis in homosexual men.

Many opportunistic infections have been associated with an acquired immunodeficiency state in which cellular immune status has been altered. Two homosexual patients are described who presented with fever, peripheral eosinophilia, and a travel history to Haiti and were found to have central nervous system toxoplasmosis. Despite definitive diagnosis and appropriate therapy, both died. Techniques for diagnosis of central nervous system toxoplasmosis are discussed, and the importance of brain biopsy in this clinical situation is stressed. Eosinophilia may serve as an early diagnostic marker for disseminated toxoplasmosis in homosexual patients.

Cytomegaloviral infection presenting as a solitary pulmonary nodule.

Cytomegaloviral infection presenting in an immunologically compromised host as a solitary pulmonary nodule has not previously been reported. A patient with a renal transplant and with no pulmonary symptoms was noted to have a single nodule on a chest roentgenogram. At autopsy, this proved to be secondary to cytomegaloviral infection. Differential diagnostic considerations in the immunosuppressed patient are discussed.

Factors regulating osteoclast formation in human tissues adjacent to peri-implant bone loss: expression of receptor activator NFkappaB, RANK ligand and osteoprotegerin.

Aseptic bone loss adjacent to orthopedic joint implants is a common cause of joint implant failure in humans. This study investigates the expression of key regulators of osteoclast formation, receptor activator NFkappaB (RANK), Receptor activator of NFkappaB ligand (RANKL) and osteoprotegerin (OPG), in the peri-implant tissues of patients with osteolysis compared with levels in synovial tissues from osteoarthritic and healthy subjects. Immunohistochemical studies demonstrated that significantly higher levels of RANKL protein (p<0.05) were found in the peri-implant tissues of patients with implant failure than in similar tissues from osteoarthritic and healthy subjects. In contrast, OPG protein levels were similar in all tissues. RANKL, expressed as mRNA and protein, was predominantly associated with cells containing wear particles. Dual labeling studies showed that the cells expressing RANKL protein were macrophages. In situ hybridization studies confirmed that mRNA encoding for these proteins is also expressed by cells in the peri-implant tissues. In addition, RANK mRNA was expressed in cells that contained wear particles. These findings show that abnormally high levels of RANKL are expressed in peri-implant tissues of patients with prosthetic loosening and that these abnormal levels of RANKL may significantly contribute to aseptic implant loosening.

Comparative evaluation of CD5 B cells in patients with rheumatoid arthritis and essential mixed cryoimmunoglobulinemia using FACS analyzer and FACSCAN flow cytometer.

In this study, using both a FACSCAN flow cytometer and the FACS analyzer, and two-color fluorescence, CD5 B cells have been enumerated in the peripheral blood (PB) of normal controls (NC) and patients with rheumatoid arthritis (RA) or essential mixed cryoimmunoglobulinemia (EMC). Using a FACSCAN flow cytometer, no significant difference was observed between the percentage of CD5 B cells in the NC (21.24% +/- 3.71) and RA (24.83% +/- 3.85), or EMC (21.03% +/- 6.38). Using the FACS analyzer, however, there was significant difference between the NC (9.14% +/- 3.82) and EMC (2.84% +/- 2.58) (p less than 0.05), but no significant difference between the NC and RA (7.17% +/- 2.55). Further analysis of 10,000 B cells selected by live gating showed that there were three populations of B cells, with the majority of B cells unstained, a small number of cells brightly stained for CD5 in the NC (3.78% +/- 1.09) or RA (2.80% +/- 0.96), and about 6.45% to 9.43% with intermediate staining in patients with RA and the NC, respectively. In addition, serum low molecular weight IgM (LMW IgM) from patients with RA was detected by an enhanced chemiluminescence detection system combined with a modified immunoblot technique. A significant linear correlation was observed between the percentage of CD5 B cells and the height of LMW IgM peak (r = 0.69, p less than 0.05).

Response of soluble IL-2 receptor levels during gold therapy for rheumatoid arthritis.

Soluble IL-2 receptor (sIL2R) levels were measured at week 0 and week 24 in the sera of 27 patients with active rheumatoid arthritis who had taken part in a chrysotherapy study. At entry (wk 0) although sIL2R levels were significantly elevated in the rheumatoid patients there was no significant correlation with a clinical disease activity score, C reactive protein (CRP) or rheumatoid factor (RF). After 24 weeks of chrysotherapy there was no significant change in sIL2R levels although the clinical activity score, CRP and RF were significantly reduced. However, measurement of sIL2R in 7 patients who had obtained clinical remission following 38-73 months of gold treatment showed significantly lower levels of sIL2R than patients with continuing active disease.

Use of artificial sweeteners to promote alcohol consumption by rats.

Cirrhosis may be reliably produced in rats by exposing them intermittently to low levels of carbon tetrachloride vapour while feeding alcohol in the Lieber-DeCarli liquid diet. Providing the alcohol in drinking water that has been sweetened with sucrose is a cheaper and more convenient method but it does not yield reliable results. This study aimed to determine whether alcohol in drinking water sweetened with artificial sweeteners would give adequate alcohol intake to achieve the desired hepatic effects. Rats were fed alcohol (8% v/v) in drinking water sweetened with sucrose (5% w/v) (n = 12), or with one of the artificial sweeteners aspartame (0.025%), saccharin (0.025%) or cyclamate (0.05%) (n = 8 per agent). During the alcohol treatment the animals were exposed to carbon tetrachloride vapour, 40 ppm, six hours per night for five nights per week, over a period of 14 weeks. All groups achieved good alcohol intakes of 5-6 g/kg/day. Only one rat, in the aspartame group, became cirrhotic; all the others had varying degrees of fibrosis which did not differ significantly among the treatments. Although it was not effective in reliably achieving cirrhosis, sweetening the alcohol solution with artificial sweeteners led to reasonable alcohol intakes with resultant hepatic fibrosis, and without the high carbohydrate intake which occurs when sucrose is used.

A technique for obtaining repeated liver biopsies from rats.

Many morphological, pharmacological and toxicological studies of hepatotoxicity require frequent sampling of liver over time. In the past this has been achieved by including large numbers of animals in the study and killing subgroups at different times. In this paper we describe a technique for repeated liver biopsy that procures sufficient liver tissue for histopathological assessment and for additional studies, for example measurement of hepatic iron concentration or vitamin A measurement. The advantages and disadvantages of this technique are discussed.

South Australian Scleroderma Register: analysis of deceased patients.

The demographic, clinical, pathological and serological features of 123 decreased patients with systemic sclerosis have been analysed. These patients consisted of all identified patients dying with this disease in South Australia between 1983 and 1996 inclusive. There were 85 females and 38 males, with the ratio of limited:diffuse:overlap disease subset being 9:5:1. Disease characteristics revealed that patients with the limited disease tended to be female with high frequencies of the centromere autoantibody, while patients with the diffuse disease had equal gender representation with the frequent presence of nucleolar, speckled or homogeneous antinuclear antibody. Mean duration of disease and mean age of death for the limited:diffuse:overlap subsets differed significantly between groups (p < 0.05) and were 16.5, 9.3 and 10.9 years and 71.9, 57.8 and 52.8 years respectively. Cumulative survival curves for the subsets differed highly significantly, with patients with the limited diseases dying more commonly from right heart failure (documented terminally in 25% of the centromere positive limited subset), cardiovascular disease or cancer, while patients with the diffuse subset died from respiratory failure, renal failure or cardiovascular disease. In conclusion, this retrospective analysis has revealed that scleroderma is a relatively common but clinically heterogeneous disorder. There are important clinical and prognostic implications in defining limited versus diffuse versus overlap disease.