The association between non-melanoma skin cancer and osteoporotic fractures--a population-based record linkage study.

UNLABELLED: We studied the association between osteoporotic fractures and prior non-melanoma skin cancer (NMSC, a biomarker for cumulative sun exposure). The risk of prior NMSC in our fracture cohort was significantly reduced (standardised incidence ratio 0.69, 95% CI 0.61, 0.78). Adequate lifetime sun exposure may be necessary to protect against osteoporotic fractures in later life. INTRODUCTION: The relationship between cumulative sun exposure and osteoporotic fractures is uncertain. We aimed to study the association between non-melanoma skin cancer (NMSC), a marker of cumulative sun exposure, and osteoporotic fractures in an older cohort. METHODS: A retrospective cohort study in southern Tasmania in people aged at least 50 years with incident radiographic fracture (n = 2,283) was carried out. By record linkage to the Tasmanian Cancer Registry the cohort was followed backwards through time until the occurrence of NMSC or end-of follow-up. Relative risk was estimated by the standardised incidence ratio (SIR) using sex-, age- and calendar year-specific cancer incidence rates in southern Tasmania as reference. RESULTS: The incidence of prior NMSC in the fracture cohort was 31% lower than for the general population (SIR 0.69, 95% CI 0.61, 0.78). This effect was significant for most fracture subtypes except pelvic and wrist fractures and observed for both NMSC subtypes, squamous cell carcinoma and basal cell carcinoma. CONCLUSIONS: Older people with osteoporotic fractures may have had lifestyles linked to lower cumulative sunlight exposure. Achieving a balance between adequate lifetime sun exposure and protection against its adverse effects (such as fractures and skin cancer) may require assessment of individual risks.

Falls risk is associated with pain and dysfunction but not radiographic osteoarthritis in older adults: Tasmanian Older Adult Cohort study.

OBJECTIVE: To describe the association between knee and hip radiographic osteoarthritis (ROA), a measure of knee pain, stiffness and functional ability and objectively measured physiological falls risk predictors. METHODS: Cross-sectional, population-based study of 850 randomly selected men and women aged 50-80 years (mean 62.5, SD 7.4). Falls risk (Z score) was determined objectively with the short form Physiological Profile Assessment (PPA). Two observers assessed knee and hip ROA using the Altman atlas. Pain, stiffness and functional ability were assessed using the Western Ontario McMasters Osteoarthritis index (WOMAC). RESULTS: Overall, the study population was at a mild risk of falling. In multivariable analysis, the WOMAC function and pain score were significantly associated with reaction time, balance, proprioception, knee extension strength, and edge contrast sensitivity. Stiffness was associated with knee extension strength and edge contrast sensitivity. Males had a dose response association between the global WOMAC score and falls risk (r=0.17, P<0.001). Those who reported a global WOMAC score of 50 and above had a higher risk of falling compared to those with a score below 50 (Z score: 0.53 vs 0.14, P<0.001). Hip joint space narrowing (JSN) was significantly associated with knee extension strength (r=-0.10, P=0.003), however, no other significant associations were observed between ROA and falls risk predictors. CONCLUSION: Self-reported functional ability and pain, and to a lesser extent, stiffness (but not knee and hip ROA), have a modest but independent association with physiological predictors of falls risk.

Association between age and knee structural change: a cross sectional MRI based study.

OBJECTIVE: To describe the associations between age, knee cartilage morphology, and bone size in adults. METHODS: A cross sectional convenience sample of 372 male and female subjects (mean age 45 years, range 26-61) was studied. Knee measures included a cartilage defect five site score (0-4 respectively) and prevalence (defect score of > or =2 at any site), cartilage volume and thickness, and bone surface area and/or volume. These were determined at the patellar, medial, and lateral tibial and femoral sites using T(1)weighted fat saturation MRI. Height, weight, and radiographic osteoarthritis (ROA) were measured by standard protocols. RESULTS: In multivariate analysis, age was significantly associated with knee cartilage defect scores (beta = +0.016 to +0.073/year, all p<0.01) and prevalence (OR = 1.05-1.10/year, all p<0.05) in all compartments. Additionally, age was negatively associated with knee cartilage thickness at all sites (beta = -0.013 to -0.035 mm/year, all p<0.05), and with patellar (beta = -11.5 microl/year, p<0.01) but not tibial cartilage volume. Lastly, age was significantly positively associated with medial and lateral tibial surface bone area (beta = +3.0 to +4.7 mm(2)/year, all p<0.05) and patellar bone volume (beta = +34.4 microl/year, p<0.05). Associations between age and tibiofemoral cartilage defect score, cartilage thickness, and bone size decreased in magnitude after adjustment for ROA, suggesting these changes are directly relevant to OA. CONCLUSION: The most consistent knee structural changes with increasing age are increase in cartilage defect severity and prevalence, cartilage thinning, and increase in bone size with inconsistent change in cartilage volume. Longitudinal studies are needed to determine which of these changes are primary and confirm their relevance to knee OA.

Investigation of chromosome 2q in osteoarthritis of the hand: no significant linkage in a Tasmanian population.

BACKGROUND: Previous studies have suggested a strong genetic component to osteoarthritis (OA), especially that of the hand, and three linkage studies have suggested the existence of susceptibility loci in disparate regions of chromosome 2q. OBJECTIVE: To examine for linkage to 2q in a Tasmanian population of women and men with familial hand OA. METHODS: Hand OA (distal interphalangeal, carpometacarpal, and Heberden's nodes) was assessed by a combination of hand photographs and radiographs. A non-parametric linkage (NPL) analysis was performed on chromosome 2q of 69 members in 22 families with severe distal interphalangeal joint OA using Genehunter. A quantitative trait linkage analysis of a larger group of 456 members in 68 families was also performed using SOLAR. RESULTS: The maximum non-parametric linkage score was 1.05 (p=0.15) at marker IL1R1, close to the centromere. All components of hand OA scores had significant heritability in this dataset (28%-35%, all p<0.001). Despite this, the quantitative trait analysis (after adjustment for age and, where appropriate, sex) yielded maximum LOD scores of 0.90 for Heberden's nodes (both sexes combined), and 1.19 for carpometacarpal OA score (women only). CONCLUSIONS: These results do not provide confirmation of linkage on chromosome 2q in the larger white population with hand OA. They suggest that there are regional variations in the genetic cause of hand OA and that other loci not on 2q may be important in this disease.

Baseline measurements of indicators for sublethal effects of metals in lake whitefish (Coregonus clupeaformis).

Histological and metallothionein (MT) analyses of liver and kidney and measurements of serum electrolytes and hematocrit from lake whitefish (Coregonus clupeaformis), 3.5 years of age, were conducted over a 90-day period that included maximal gonadal maturation in females. Condition factors were higher in females at day 1 and when all data were combined over the 90-day sampling period. Significant differences between females and males of 1.8-fold in hepatic MT concentrations were observed at day 20 when ovaries appeared to be in the most advanced state of maturation, although this parameter was not quantified. Hematocrits were slightly but significantly lower at day 90. No sex differences were observed in the quantitative assessments of epithelium cell height, lumen diameter (LD), tubule diameter (TD), and ratio of LD:TD in the second segment of the proximal tubule (P2); and of hepatocyte area, hepatocyte nuclear diameters, and nucleus area:cytoplasmic area (N:C) ratio. Positive correlations were observed between N:C ratios and fish weight, fork length, and liver weight. No significant correlations between these histological morphometrics and MT concentrations were observed in liver or kidney. The results of this study provide baseline information for investigations designed to determine sublethal effects of metals in lake whitefish.

Dietary accumulation and biochemical responses of juvenile rainbow trout (Oncorhynchus mykiss) to 3,3',4,4',5-pentachlorobiphenyl (PCB 126).

Juvenile rainbow trout (Oncorhynchus mykiss) (initial weights 2-5 g) were exposed to three dietary concentrations (0, 12.4 and 126 ng g(-1), wet weight) of a 14C-labelled 3,3',4,4',5-pentachlorobiphenyl (PCB 126) for 30 days followed by 160 days of clean food. We assessed bioaccumulation, histology (liver and thyroid) and biochemical responses (liver ethoxyresorufin-O-deethylase (EROD), liver vitamins (retinoids and tocopherol) and muscle thyroid hormone levels) along with growth and survival. The half-life of PCB 126 in the rainbow trout ranged from 82 to 180 days while biomagnification factors (BMF) ranged from 2.5 to 4.1 providing further evidence that PCB 126 is among the most bioaccumulative PCB congeners. Toluene extractable 14C declined with time in the trout suggesting the possibility of some biotransformation and/or covalent bonding with biological macromolecules. The threshold for liver EROD induction by PCB 126 was approximately 0.1 ng g(-1) (wet weight). EROD activities in the low- and high treatments were 9 and 44 times greater than control, respectively, and remained elevated throughout the experiment. EROD activity was correlated with whole body concentrations of PCB 126 although there was evidence of EROD activity suppression in the highly exposed fish. Liver didehydroretinoids and tocopherol concentrations were depressed by the high PCB 126 dose after 30 days exposure. Initially, muscle concentrations of thyroxine (T4) and triiodo-L-thyronine (T3) declined as the fish grew during the experiment, and exposure to PCB 126 accelerated the growth related decline. More information is needed to assess the functional significance of the reduced muscular stores of thyroid hormones. Despite the changes in liver EROD, liver vitamins and muscle thyroid hormones, liver and thyroid histology in trout examined after 30 days exposure and growth parameters were unaffected by PCB 126. This indicates that the functional competences of the physiological factors associated with growth were maintained under the experimental conditions.

Symptomatic fracture incidence in those under 50 years of age in southern Tasmania.

OBJECTIVE: To document symptomatic fracture incidence in those aged under 50 years of age. METHODS: Fractures were ascertained from X-ray reports containing the word 'fracture' from all radiology providers for the geographically defined population of southern Tasmania (n = 165 175) for the period 1 July 1997 to 30 June 1999. RESULTS: In the 2-year study frame there were 2943 fractures in 164 730 person years in males and 1348 fractures in 165 620 person years in females. This represents a fracture incidence of 1787 per 100 000 person years in males and 819 per 100 000 person years in females. Peak fracture incidence was 10-14 years in females and 15-19 years in males although different fracture types had varying peak incidence suggesting different fracture-specific causes. The most common fractures were those of the hand (24%), forearm (17%), wrist (10%) and foot (9%). All fractures (including vertebral) were more common in males with relative risks ranging from 1.34 to 4.50. The estimated probability of at least one fracture between birth and 50 years of age was 59% for males and 34% for females. CONCLUSION: There are threefold as many fractures in this age group compared to those due to osteoporosis in the elderly in any given year. More research priority needs to be given to understanding the causes of these fractures so that preventive strategies can be formulated.

Symptomatic fracture incidence in southern Tasmania: does living in the country reduce your fracture risk?

There are limited data describing urban-rural differences in fracture incidence and the overall effect remains controversial. The aim of this study was to compare symptomatic fracture incidence occurring in geographically defined rural (n = 34619) and urban (n = 194974) populations of Southern Tasmania from July 1, 1997 to June 30, 1999. Fractures were ascertained by reviewing reports from all the radiology providers within the area. In the 2-year study time frame there were 3644 fractures in males and 2657 fractures in females. Fracture incidence was significantly higher in urban compared with rural populations in both sexes (male: RR 1.60, 95% CI 1.47-1.75; female: RR 1.77, 95% CI 1.58-1.98). This higher urban fracture incidence was present across all age groups and all fracture types with the exception of knee and pelvis fractures in males (although not all were statistically significant). In addition, urban men >50 years old had a higher fracture incidence than rural women >50 years old (RR 1.25, 95% CI 1.05-1.50), suggesting that in later life the factors responsible for the urban-rural difference are able to offset completely the effect of gender. While some of the reduced fracture incidence in the rural population may be explained by urban drift and underreporting of minor fractures such as foot fractures, the overall pattern of higher fracture risk was very consistent, suggesting a real difference in whole-of-life symptomatic fracture incidence. Further research at an individual level is required to determine what factors account for these large urban-rural differences, as they imply a substantial potential for fracture prevention.

A cross-sectional study of the association between Heberden's nodes, radiographic osteoarthritis of the hands, grip strength, disability and pain.

OBJECTIVE: To describe the associations between hand osteoarthritis (OA), pain and disability in males and females and to further validate the Australian/Canadian OA hand index (AUSCAN LK3.0). DESIGN: Cross-sectional study of 522 subjects from 101 Tasmanian families (males N=174, females N=348). Hand OA was assessed by two observers using the Altman atlas for joint space narrowing and osteophytes at distal interphalangeal and first carpometacarpal joints as well as a score for Heberden's nodes based on hand photography. Hand pain and function were assessed by the AUSCAN LK3.0 and grip strength by dynamometry in both hands on two occasions. RESULTS: The prevalence of hand OA was high in this sample at 44-71% (depending on site). Pain and dysfunction increased with age while grip strength decreased (all P< 0.001). All three measures were markedly worse in women, even after taking the severity of arthritis into account. Hand OA explained 5.7-10% of the variation in function, grip strength and pain scores, even after adjustment for age and sex. Further adjustment suggested that the osteoarthritic associations with function and grip strength were largely mediated by pain. Severity of disease was more strongly associated with these scores than presence or absence. Lastly, the AUSCAN LK3.0 showed a comparable association to grip strength with structural damage providing further evidence of index validity. CONCLUSIONS: Hand OA at these two sites makes substantial contributions to hand function, strength and pain. The associations with function and strength measures appear mediated by pain. Gender differences in all three measures persist after adjustment for variation in age and OA severity indicating that factors apart from radiographic disease are responsible.

Examination of the behavior and liver and thyroid histology of juvenile rainbow trout (Oncorhynchus mykiss) exposed to high dietary concentrations of C(10)-, C(11)-, C(12)- and C(14)-polychlorinated n-alkanes.

Juvenile rainbow trout (Oncorhynchus mykiss) were exposed to high dietary concentrations of six polychlorinated n-alkane (PCAs) (C(10)H(15.5)C(6.5), C(10)H(15.3)Cl(6.7),C(11)H(18.4)Cl(5.6),C(12)H(19.5)Cl(6.5),C(14)H(24.9)Cl(5.1) and C(14)H(23.3)Cl(6.7)) for 21 to assess their effects on behavior and liver and thyroid histology and for 85 days to assess histology for a longer term exposure. This is the first histological work using PCAs of known carbon chain length and chlorine content and the first effort to examine the histopathology of fish exposed to PCAs. PCAs, also known as chlorinated paraffins, are complex industrial products for which there is a lack of toxicological data on individual congeners. With the exception of trout exposed to C(14)H(24.9)Cl(5.1), which had much lower exposure concentrations, many of the trout exposed to the PCAs (whole fish concentrations 0.22-5.5 microg g(-1)) showed a diminished or no startle response, loss of equilibrium, and developed a dark coloration. These responses are indicative of a narcotic toxicological mode-of-action. Histopathological lesions were observed in the livers of trout from each exposure group. However, the most severe histopathologies were observed in the livers of fish exposed to C(10)H(15.3)Cl(6.7) and C(11)H(18.4)Cl(5.6) (whole fish concentrations 0.92 and 5.5 microg g(-1), respectively), in which extensive fibrous lesions were present that were not observed in any other exposure group. Other alterations observed in all treatment groups included hepatocyte necrosis, sites of inflammation, and glycogen/lipid depletion. The relative sizes of hepatocytes of PCA exposed trout were smaller than control trout, although only a few of the observed differences were statistically significant. No lesions were present in the thyroid, although trout exposed to C(10)H(15.5)Cl(6.5) (whole fish concentration 0.84 microg g(-1)) had slightly more active thyroids, as indicated by an increased mean thyroid epithelium cell height relative to controls. It would appear that PCA toxicity is inversely related to carbon chain length, as has been observed in similar studies using mammals. The concentrations in the fish from this experiment were at levels that have been reported in invertebrates and fish from contaminated sites in the Great Lakes. However, the exposure concentrations were likely much greater in these experiments compared with the environment and require further study.

A population-based study of fracture incidence in southern Tasmania: lifetime fracture risk and evidence for geographic variations within the same country.

Symptomatic fractures are a significant problem in terms of both morbidity and financial cost. Marked variation in both total and site-specific fracture incidence has been documented internationally but there is limited within-country data. This prospective population-based study documented the incidence of all symptomatic fractures occurring from July 1, 1997 to June 30, 1999 in adults > or =50 years of age resident in Southern Tasmania (total population > or = 50 years: 64688). Fractures were ascertained by reviewing reports from all the radiology providers within the area. There were 701 fractures in men and 1309 fractures in women. The corresponding fracture incidence in men and women was 1248 and 1916 per 100000 person-years, respectively. Residual lifetime fracture risk in a person aged 50 years was 27% for men and 44% for women with fractures other than hip fractures constituting the majority of symptomatic fracture events. These fracture risk estimates remained remarkably constant with increasing age. In comparison to Geelong, there were significantly lower hip fracture rates (males: RR 0.59, 95% CI 0.45-0.76; females: RR 0.61, 95% CI 0.53-0.71) but significantly higher distal forearm fractures (males: RR 1.87, 95% CI 1.10-3.78; females: RR 1.31, 95% CI 1.11-1.55) and total fractures in men (RR 1.31, 95% CI 1.17-1.46) but not women (RR 1.05, 95% CI 0.98-1.13). In contrast, Southern Tasmania had lower age-standardized rates of all fractures compared with Dubbo (RR 0.28-0.79). In conclusion, this study provides compelling evidence that fracture incidence varies between different geographic sites within the same country, which has important implications for health planning. In addition, the combination of high residual fracture risk and short life expectancy in elderly subjects suggests fracture prevention will be most cost-effective in later life.

Epstein-Barr virus reactivation associated with diminished cell-mediated immunity in antarctic expeditioners.

Epstein-Barr virus (EBV) reactivation and cell-mediated immune (CMI) responses were followed in 16 Antarctic expeditioners during winter-over isolation at 2 Australian National Antarctic Research Expedition stations. Delayed-type hypersensitivity (DTH) skin testing was used as an indicator of the CMI response, that was evaluated 2 times before winter isolation and 3 times during isolation. At all 5 evaluation times, 8 or more of the 16 subjects had a diminished CMI response. Diminished DTH was observed on every test occasion in 4/16 subjects; only 2/16 subjects exhibited normal DTH responses for all 5 tests. A polymerase chain reaction (PCR) assay was used to detect EBV DNA in saliva specimens collected before, during, and after the winter isolation. EBV DNA was present in 17% (111/642) of the saliva specimens; all 16 subjects shed EBV in their saliva on at least 1 occasion. The probability of EBV shedding increased (P = 0.013) from 6% before or after winter isolation to 13% during the winter period. EBV appeared in saliva during the winter isolation more frequently (P < 0.0005) when DTH response was diminished than when DTH was normal. The findings indicate that the psychosocial, physical, and other stresses associated with working and living in physical isolation during the Antarctic winter result in diminished CMI and an accompanying increased reactivation and shedding of latent viruses.

Clinical and serological associations of anti-Ku antibody.

OBJECTIVE: To ascertain the clinical and serological associations of anti-Ku antibody. METHODS: Twenty-seven patients over a 7 year period (1987-1996) had anti-Ku antibody detected by counterimmunoelectrophoresis (CIEP). Nineteen patients were available for clinical review. Five patients were assessed by chart review. Serum was taken at review for repeat antibody analysis. Patients were assigned to diagnostic groups based on the American College of Rheumatology criteria. RESULTS: There were 22 women and 5 men. The duration of symptoms ranged from one year to 28 years. Nine patients fulfilled criteria for systemic lupus erythematosus (SLE), 4 scleroderma, 3 rheumatoid arthritis (RA), one discoid lupus, and 7 had an undifferentiated connective tissue disease. There was a low incidence of renal (2/24) and central nervous system involvement (1/24); 19/24 had Raynaud's phenomenon, 15/24 had inflammatory arthritis but only one had erosions on radiograph; 11/24 reported esophageal reflux symptoms. Three of 24 patients had myositis. All patients had anti-nuclear antibody using indirect immunofluorescence of > 640 titer with a speckled and nucleolar pattern. Anti-Ku antibody was detected on CIEP in 15/19 sera available for repeat testing. Three patients had anti-Ro antibody, 2 had anti-U1RNP antibody, one patient had anti-topoisomerase-1 and anti-Ro. CONCLUSION: Anti-Ku antibody is found in a wide variety of connective tissue syndromes. While several patients fulfilled diagnostic criteria for SLE, scleroderma, and RA, their clinical features were usually mild and did not form a distinctive clinical pattern. Common features associated with anti-Ku were Raynaud's phenomenon, arthralgia, skin thickening, and esophageal reflux. Few patients had associated autoantibody specificities found in SLE or scleroderma.

Long-term outcome of autoimmune disease following allogeneic bone marrow transplantation.

OBJECTIVE: To investigate the long-term outcome of autoimmune disease following allogeneic bone marrow transplantation (BMT), and its relationship to hemopoietic chimerism. METHODS: Three previously described patients with rheumatoid arthritis (RA) who underwent allogeneic BMT for therapy-related severe aplastic anemia and 1 new patient with psoriasis who received BMT for chronic myeloid leukemia (CML) were followed up. Molecular studies were performed to assess hemopoietic and immune reconstitution in 3 cases. RESULTS: In 2 of the RA patients, the RA remained in remission without treatment, with nonprogressive disease, 11 and 13 years after BMT. The third patient with RA had a relapse 2 years after BMT, although the previously aggressive disease subsequently ran an attenuated course with treatment-free remission for the last 11 years. Comparison with other cases of RA suggests that graft-versus-host disease may influence the long-term outcome, perhaps through ongoing inhibition of the immune system. In the patient with psoriasis, BMT was followed by remission, but the psoriatic rash recurred and arthropathy developed 12 months later. The psoriasis and arthropathy remained active 4.5 years post-BMT, although the CML remained in remission. Molecular studies in the 2 patients whose RA remained in continued remission and in the patient with psoriasis that relapsed confirmed complete donor hemopoietic reconstitution. CONCLUSION: Long-term followup of autoimmune disease after allogeneic transplantation confirmed cure of the autoimmune disease in some, but eventual relapse in others. The occurrence of relapse despite complete donor hemopoietic reconstitution is evidence for the development of de novo, as opposed to persistent, disease, and is possibly related to intrinsic susceptibility of the transplanted stem cells or to host factors. There may be a relationship between remission of autoimmune disease and graft-versus-host reaction. These findings have relevance for the evolving application of stem cell transplantation as a therapy for autoimmune diseases.

Outcome of rheumatoid arthritis and psoriasis following autologous stem cell transplantation for hematologic malignancy.

Based on successful results in animal models, it has been proposed that high-dose myeloablative therapy followed by autologous bone marrow or stem cell transplantation (ABMT/ASCT) may cure autoimmune disease. The coexistence of autoimmune disease and hematologic malignancy provides an opportunity to examine the response of autoimmune disease to ABMT or ASCT. We describe 4 patients with autoimmune disease (3 with psoriasis and 1 with rheumatoid arthritis) and hematologic malignancy. In each patient, the autoimmune disease remitted posttransplantation, but, in 4 patients with long-term followup, it recurred at 8-24 months. The earliest relapse occurred in a patient treated with interferon-alpha. Our experience suggests that a single autograft with unpurged stem cells is unlikely to cure autoimmune disease, but that other strategies building on this approach are worthy of investigation.

Monozygotic twins discordant for congenital complete heart block.

OBJECTIVE: Isolated congenital complete heart block (CCHB) occurs in 1/20,000 live births. More than 85% of mothers giving birth to affected infants are anti-Ro antibody positive, but only approximately 1% of babies with anti-Ro-positive mothers develop CCHB. We studied 2 sets of monozygotic twins discordant for CCHB. METHODS: Monozygosity was determined using placental examination and DNA microsatellite analysis. HLA typing was performed. Autoantibody studies were performed using counterimmunoelectrophoresis, immunoblotting, Ro 52 and Ro 60 enzyme-linked immunosorbent assay (ELISA), and indirect immunofluorescence (IIF) on Ro 60- and Ro 52-transfected HEp-2 cells. RESULTS: Both sets of twins were monozygotic. They had similar birth weights. Twin 2 in the second set required a pacemaker at age 2 months. Both mothers were positive for anti-Ro 52 and anti-Ro 60 antibody, and neither had anti-La antibody on immunoblot. One set of twins was studied at birth. Similar titers of anti-Ro 52 and anti-Ro 60 antibody were found by IIF and ELISA. CONCLUSION: There are no previous well-documented reports of monozygotic twins discordant for CCHB. These cases demonstrate that there is still discordance in the development of CCHB despite identical genetics and environmental exposure to anti-Ro antibody.