Predictors of shoulder pain and shoulder disability after one year in diabetic outpatients.

OBJECTIVE: To investigate factors associated with changes in shoulder pain and disability in diabetic outpatients over 1 yr. METHODS: Cross-sectional study with 12-month follow-up in diabetic outpatients (n = 179) using the shoulder pain and disability index (SPADI) and SF-36 version 2. RESULTS: Patients with diabetes and shoulder pain or disability are more likely to be older and female. After 12 months of follow-up, one-quarter of participants without pre-existing symptoms at baseline developed clinically significant pain (28%) or disability (25%). Of the patients with pre-existing shoulder pain or disability, half reported clinically significant worsening (10 percentage points) in shoulder pain (58%) or disability (45%) over 12 months. Few patients demonstrated clinically significant improvement in pain (11%) or disability scores (19%). The remaining one-third of the patients reported no change in symptoms (30% pain; 35% disability). Increasing intensity of pain scores between baseline and 12 months was associated with older age, higher HbA(1c) and less pain at baseline. Increasing disability score between baseline and 12 months was associated with having had eye laser surgery, greater pain at baseline and less disability at baseline. CONCLUSION: Shoulder pain and disability are common, and persistent in adults with diabetes. Having higher HbA(1c) levels or having had treatment for retinopathy was associated with worsening shoulder pain and disability, confirming that glycaemic control and diabetic complications are associated with worsening shoulder pain or disability over 12 months of observation.

Musculoskeletal morbidity: the growing burden of shoulder pain and disability and poor quality of life in diabetic outpatients.

OBJECTIVE: To investigate shoulder pain and disability and quality of life (QoL) over 12 months in patients with diabetes and in a non-diabetic control group. METHODS: Cross-sectional study with 12-month follow-up in diabetic (n=189) and medical (n=99) outpatients employing the Shoulder Pain and Disability Index (SPADI) and SF-36 version 2. The results were analysed using restricted maximum likelihood (REML). RESULTS: The prevalence of current shoulder symptoms was 35% in diabetics and 17% in controls. Shoulder pain and disability as calculated by the SPADI were independently associated with diabetes (vs controls) and current shoulder symptoms, and worsened over 12 months. Disability scores worsened with age in diabetics, and pain scores were higher in diabetics than controls among patients reporting current shoulder symptoms. Poor physical QoL worsened over time in patients with diabetes and was worse in patients with current shoulder symptoms, whether they had diabetes or not. Mental QoL was worse only in patients with current shoulder symptoms. CONCLUSION: Shoulder symptoms are common, affecting 1 in every 3 diabetic patients and 1 in every 6 control patients. In this study shoulder pain, disability and physical QoL were poorer among diabetics and patients reporting current shoulder symptoms, and worsened over time. Mental QoL was worse in patients reporting current shoulder symptoms and was independent of diabetes. Therefore, shoulder symptoms are common, are associated with poor physical and mental QoL in addition to shoulder pain and disability, and are worse in patients with diabetes, even in a population with relatively moderate shoulder pain and disability.

Quantitative imaging of contaminant distributions in heterogeneous porous media laboratory experiments.

Intermediate-scale laboratory experiments on heterogeneous porous media have been increasingly used for the study of saturated and unsaturated ground water systems. While the ability to reproduce field-scale heterogeneity in these experiments has advanced, the use of visualization or image analysis methods to characterize the spatial distribution of solute concentrations has largely remained at the homogeneous media level. To advance these imaging techniques we developed a generic image analysis package that, for the first time, automatically segments regions in photographic images that require unique concentration calibration curves due to varying porous media properties or lighting nonuniformities. As a robust test, our image analysis package was applied to an intermediate-scale flow tank experiment characterized by a correlated random permeability field with unprecedented resolution. Twenty-five distinct classes of porous media were developed and binned to the synthetic permeability field, creating an experimental field of 3456 rectangular cells and thereby ensuring the emplaced field closely matched the statistics of the original continuous distribution. Concentration distributions were determined for an experimental tracer run and the corresponding dispersion parameters were calculated. The closeness of the experimental, image-processed longitudinal dispersivity (4.6 x 10(-2) m) to that obtained from the field statistics (9.1 x 10(-2) m) verifies our image analysis technique.

Failure of tachykinins including substance P and its fragments to influence proteoglycan and protein synthesis in bovine chondrocytes in vitro.

Adult bovine articular chondrocytes were exposed to substance P, neurokinins A and B or substance P fragments, SP1-4, SP1-6 and SP7-11 in vitro. Proteoglycan synthesis was assessed by measuring proteoglycans which were released into the culture medium or incorporated into the cell layer. The intact tachykinins or substance P fragments had no direct effect on proteoglycan synthesis. Nor was total protein production affected. Gel chromatography, under dissociative conditions, revealed that sulphated proteoglycans detected in the medium or cell layer following treatment of chondrocytes with substance P, contained proteoglycans of similar molecular weight to those produced by cells exposed only to diluent controls. Therefore, we conclude that the acceleration of arthritis by substance P does not appear to be mediated through an effect on chondrocyte synthetic function.

Insulin-like growth factor binding protein-5 proteolytic activity in ovine articular chondrocyte culture.

We have previously demonstrated that ovine articular chondrocytes synthesise and release insulin-like growth factor binding protein-5 (IGFBP-5) which subsequently undergoes proteolysis in the tissue culture medium. The IGFBP-5 proteolytic activity has now been characterised and its substrate specificity analysed using recombinant IGFBP-5 and purified chondrocyte-derived IGFBPs. Iodinated human recombinant IGFBP-5 was incubated with chondrocyte culture or conditioned medium in the presence or absence of various inhibitors. Serine protease inhibitors aprotinin and heparin effectively inhibited the breakdown of IGFBP-5. Furthermore, insulin-like growth factor-I (IGF-I) but not its structural analogues with reduced affinity for IGFBP-5, was also able to partially protect IGFBP-5 from degradation indicating that the association of IGF with the binding protein was required for the inhibition of the proteolytic activity. The inflammatory cytokine interleukin-1 did not have any effect on IGFBP-5 proteolysis. The proteolytic activity appears to be IGFBP-5-specific since the incubation of chondrocyte-derived IGFBPs with chondrocyte conditioned medium resulted in the loss of IGFBP-5 while the levels of the other two IGFBPs (IGFBP-2 and a 24 kDa IGFBP) remained unchanged. In conclusion, we show that IGFBP-5 is specifically cleaved by a serine protease released by primary cultures of ovine articular chondrocytes and also demonstrate the ability of IGF-I to inhibit the proteolytic activity both in cell culture and in cell-free conditions.

Insulin-like growth factor binding proteins (IGF-BPs) in bovine articular and ovine growth-plate chondrocyte cultures: their regulation by IGFs and modulation of proteoglycan synthesis.

Cultured chondrocytes respond to insulin-like growth factors (IGFs) by increasing the production of proteoglycans and insulin-like growth factor binding proteins (IGF-BPs). To investigate the biological effects of IGFs and IGF-BPs, isolated bovine articular and ovine growth-plate chondrocytes were cultured at high density in the presence of IGF-1, and its truncated form, des (1-3) IGF-I. Both growth factors stimulated the production of IGF-BPs in articular and growth-plate chondrocyte monolayers. Western ligand blots showed that bovine articular chondrocytes released two forms of IGF-BPs into conditioned medium with molecular weights of 29 and 31 kDa. Ovine growth-plate chondrocytes released four different forms of IGF-BPs of approx. 22, 24; 29-30 and 34 kDa. IGF-I and des (1-3) IGF-I stimulated total proteoglycan synthesis by articular chondrocytes up to 1.5-fold. The truncated analogue was more potent at lower concentrations, particularly in stimulating incorporation of newly synthesized proteoglycans into the cell-layer. The maximal stimulation of proteoglycan synthesis in ovine growth-plate chondrocyte culture was 3-fold with des (1-3) IGF-I, while IGF-I enhanced proteoglycan production by only 2-fold over the concentrations used. Our results suggest that endogenous IGF-BPs in chondrocyte cultures act as a part of a feed-back mechanism which diminishes the bioactivity of IGF-I.

Regulation of insulin-like growth factor-binding protein-5 by insulin-like growth factor I and interleukin-1alpha in ovine articular chondrocytes.

Insulin-like growth factors (IGFs) contribute to the maintenance of the cartilage matrix by stimulating proteoglycan synthesis. In contrast, interleukin-1 (IL-1), an inflammatory cytokine, suppresses the synthesis of proteoglycans. In pathological conditions the chondrocytes' responsiveness to IGF-I is decreased, and elevated levels of IGF-binding proteins (IGFBPs) have been implicated as a possible cause. The aim of this study was to investigate the effects of IGF-I and IL-1 on IGFBP production by ovine articular chondrocytes (OAC) and the roles of these IGFBPs in the regulation of proteoglycan synthesis. As revealed by Western ligand and immunoblotting, OACs secreted IGFBP-2 and a 24-kDa IGFBP in culture medium under basal conditions. Exposure of the cells to IGF-I for 48 h resulted in the appearance of IGFBP-5 in the medium. Des(1-3)IGF-I, an IGF-I analog with reduced affinity for IGFBPs, also increased the level of IGFBP-5, but to a lesser extent than IGF-I, whereas LR3IGF-I, which has virtually no affinity for IGFBPs, had no effect on IGFBP-5. Furthermore, IGFBP-5 underwent a time-dependent limited proteolysis when incubated with OAC-conditioned medium, degrading into 22- and 16-kDa fragments. The degradation of IGFBP-5 was significantly inhibited by IGF-I, but not by des(1-3)IGF-I or LR3IGF-I. Basic fibroblast growth factor, transforming growth factor-beta, and platelet-derived growth factor had no effect on OAC IGFBPs. However, IL-1alpha increased the IGFBP-5 level in a dose-dependent manner, showing maximum activity at 200 U/ml. Furthermore, IL-1alpha, but not IGF-I, induced IGFBP-5 messenger RNA expression, as assessed by Northern blot analysis. Coincubation of IGF-I with IL-1alpha resulted in a substantially increased IGFBP-5 protein level, suggesting a synergism between the mechanisms of action of these two factors. Des(1-3)IGF-I and LR3IGF-I were 10 times more potent than IGF-I in stimulating proteoglycan synthesis, indicating inhibition of IGF-I activity by endogenous IGFBPs. IL-1alpha reduced the IGF-I bioactivity, but had no effect on the activities of the IGF-I analogs, thus implying that locally produced IGFBPs, particularly IGFBP-5, which was substantially increased when IGF-I and IL-1alpha were coincubated, mediated the reduction of the IGF-I activity. Our results demonstrate that IGF-I and IL-1alpha synergistically increase the level of IGFBP-5 in OAC by inhibiting the proteolysis and stimulating the expression of IGFBP-5, respectively. Furthermore, the attenuation of IGF-I-stimulated proteoglycan synthesis by IL-1alpha in OAC appears to be mediated by chondrocyte IGFBPs. We conclude that locally produced IGFBPs, in particular IGFBP-5, may play a critical role in the regulation of cartilage matrix degradation in inflammatory and degenerative arthritides.

Osseous sarcoidosis--a magnetic resonance imaging diagnosis.

Bone involvement in sarcoidosis is not uncommon but may be overlooked as a cause of symptoms. Magnetic resonance imaging (MRI) is emerging as a sensitive diagnostic tool for osseous sarcoid. We document a case in which MRI suggested the diagnosis in the absence of abnormality with more conventional imaging techniques.

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.

A metabolite of substance P, SP7-11 is involved in the pathogenesis of inflammatory joint disease.

The possibility that neuropeptides, in particular members of the tachykinin family are involved in inflammatory joint disease is widely disputed. Both clinical and experimental observations indicate that the tachykinin substance P (SP) may be involved in the pathogenesis of arthritis. We have studied the effects of tachykinins and the metabolites of SP on chondrocyte function. We have shown that the C-terminal pentapeptide sequence; H-Phe-Phe-Gly-Leu-Met-NH2 is biologically active in bovine chondrocyte cultures. The production of SP7-11 is limited by hydrolysis of the intact peptide by neutral endopeptidase (E.C. 3.4.24.11). The regulation of this enzyme would modulate the activity of substance P on articular cartilage chondrocytes.

A multi-disciplinary curriculum for 11- to 13-year-olds: immunization, plus!

A sixth grade curriculum entitled "Immunization, Plus!" Was developed to promote adolescent immunization. This targeted immunization curriculum utilized contemporary learning theory and innovative teaching approaches and styles to maximize acceptability among educators. Because instructional time in school was limited, a thematic curriculum was created to embed immunization and communicable disease content within mathematics, science/health, and language arts units. The curriculum, which reflected the theory of multiple intelligences among students, offered an array of different learning formats, including linguistic, logical-mathematical, spatial, and bodily-kinesthetic. The curriculum was made available free of charge to school districts in California, and its evaluation was planned to track distribution, utilization, and changes in students' knowledge, attitude, and behavior.

Leukoencephalopathy in a patient taking low dose oral methotrexate therapy for rheumatoid arthritis.

We describe the case of a man who developed a dementing illness with leukoencephalopathy while receiving low dose weekly oral methotrexate (MTX) therapy for rheumatoid arthritis. The white matter changes seen on magnetic resonance imaging and computerized tomogram scan were the same as those seen in cases of leukoencephalopathy that have been reported in patients receiving intravenous or intrathecal methotrexate. Extensive investigation excluded other known causes of white matter disease. Although no improvement either subjectively or objectively occurred in his mental status after cessation of treatment with MTX, he has remained stable. We believe that this may represent a case of oral MTX induced leukoencephalopathy, which has not previously been reported.

Cryofibrinogenaemia: a case report.

A case of chronic acral ulceration is described in a 54-year-old man with cryofibrinogenaemia. Initial management with prednisolone and azathioprine was unsuccessful in controlling the disease. Introduction of a programme of plasmapheresis in addition to treatment with cyclophosphamide and prednisolone has brought about marked improvement.

Musculoskeletal manifestations of diabetes mellitus.

Rheumatic complaints are common in patients with diabetes. Maintaining good glycaemic control by exercise, diet, and medication improves or prevents the development of rheumatic conditions.

The generation of reducing ends by exposure of hyaluronic acid to oxygen derived free radicals.

Enzymatic depolymerization of hyaluronic acid (HA) is accompanied by the release of reducing ends irrespective of the linkage cleaved. In this investigation we have examined HA exposed to oxygen-derived free radicals (oxy radicals) in order to determine whether reducing ends are released upon depolymerization. Reducing ends were detected by the assay of Park and Johnson, which is a non-specific but sensitive assay for reducing ends, but only to a minimal degree by the Reissig modification of the Morgan Elson reaction, which will detect N-acetylglucosamine at the reducing end. Exposure of a sample of HA, pre-exposed to streptomyces hyaluronidase, to an oxy radical flux did not result in a decrease in Morgan Elson reactivity thus indicating that post cleavage modification of the reducing end by further reaction with oxy radicals does not account for the lack of Morgan Elson reactivity. In addition reducing ends were also detected by reaction with radiolabelled cyanide to the degree predicted by molecular weight. These findings were interpreted as being consistent with the hypothesis that oxy radical induced depolymerization of HA occurs by preferential cleavage of the glucuronidic linkage thus leaving D-glucuronic acid at the reducing end.

Depolymerisation products of hyaluronic acid after exposure to oxygen-derived free radicals.

Preparative chromatographic fractions of human umbilical cord hyaluronic acid (HA) of a molecular weight of 10(6) were subjected to graded oxygen-derived free radical (oxy radical) fluxes produced by: (a) the autoxidation of ferrous ions; (b) the action of xanthine oxidase (XO) on hypoxanthine (HX); and (c) by peripheral blood polymorphonuclear leucocytes that had been stimulated by phorbol myristate acetate (PMA). Analysis by gel chromatography of the products obtained with each of the oxy radical generating systems showed polydispersity in size. The smallest molecules detected had a molecular weight of 10(4). This limiting size was not reduced further by exposure to a second oxy radical flux. The relative proportions of large, medium, and small degradation products were established for various levels of oxy radical flux. Consistently a relatively rapid transition from large to small material was seen on Sepharose 2B chromatography, suggesting an ordered element to the breakdown process. Although the decrease in molecular weight after oxy radical exposure was confirmed by analytical ultracentrifugation, this procedure showed that those samples of lowest viscosity did not have the lowest sedimentation values, possibly reflecting oxy radical-induced repolymerisation. If the size and possibly the conformational characteristics of HA are altered, oxy radical exposure might be expected to alter its biological properties.

The effects of hyaluronic acid on macrophage Fc receptor binding and phagocytosis are independent of the mode of depolymerization.

In order to determine whether exposure of hyaluronic acid to oxygen radicals caused an alteration in its properties, independent of the change in molecular weight induced, we examined its effect upon macrophage Fc receptor binding. High molecular weight hyaluronic acid (Healon-Pharmacia) caused a dose dependent inhibition of binding between the concentrations of 0.2-1 mg/ml. At a concentration of 0.3 mg/ml both oxygen radical depolymerized and enzymatically degraded hyaluronic acid caused an inhibition of Fc receptor binding at molecular weights of 1 x 10(6), 1.5 x 10(6) and 2 x 10(6). Oxygen radical degraded hyaluronic acid caused a stimulation of Fc receptor binding at molecular weights of 2 x 10(5) and 3.5 x 10(5), and enzyme degraded hyaluronic acid causes stimulation at a molecular weight of 2.5 x 10(6). Thus this "biological property" of hyaluronic acid is dependent upon molecular weight solely and not upon the mode of depolymerization.

Elevated nerve growth factor levels in the synovial fluid of patients with inflammatory joint disease.

A novel pH shock extraction procedure was used to measure nerve growth factor (NGF) levels in both normal and inflamed synovial fluids using a sensitive and specific two-site enzyme linked immunosorbant assay. To date no data is available on NGF levels in normal synovial fluids. Synovial fluids were taken from 5 normal volunteers, 12 patients with rheumatoid arthritis and 10 patients with other inflammatory arthropathies. The mean +/- SEM NGF concentration in normal synovial fluids was 95 +/- 33.2 pg/ml (range 39.1-143.1 pg/ml), whereas the mean NGF concentration in the synovial fluids taken from patients with rheumatoid arthritis was 532.5 +/- 123.8 pg/ml (range 152-1686 pg/ml). The mean NGF concentration in patients with other inflammatory arthropathies was also raised (430.6 +/- 90 pg/ml; range 89-1071 pg/ml). The NGF concentrations were significantly higher in the synovial fluids from both inflamed groups (ANOVA p < 0.05) compared to normals. Raised levels of NGF in synovial fluid may contribute directly to joint inflammation via activation of inflammatory cells.