Degenerative inter-vertebral disc disease osteochondrosis intervertebralis in Europe: prevalence, geographic variation and radiological correlates in men and women aged 50 and over.

Objectives: To assess the prevalences across Europe of radiological indices of degenerative inter-vertebral disc disease (DDD); and to quantify their associations with, age, sex, physical anthropometry, areal BMD (aBMD) and change in aBMD with time. Methods: In the population-based European Prospective Osteoporosis Study, 27 age-stratified samples of men and women from across the continent aged 50+ years had standardized lateral radiographs of the lumbar and thoracic spine to evaluate the severity of DDD, using the Kellgren-Lawrence (KL) scale. Measurements of anterior, mid-body and posterior vertebral heights on all assessed vertebrae from T4 to L4 were used to generate indices of end-plate curvature. Results: Images from 10 132 participants (56% female, mean age 63.9 years) passed quality checks. Overall, 47% of men and women had DDD grade 3 or more in the lumbar spine and 36% in both thoracic and lumbar spine. Risk ratios for DDD grades 3 and 4, adjusted for age and anthropometric determinants, varied across a three-fold range between centres, yet prevalences were highly correlated in men and women. DDD was associated with flattened, non-ovoid inter-vertebral disc spaces. KL grade 4 and loss of inter-vertebral disc space were associated with higher spine aBMD. Conclusion: KL grades 3 and 4 are often used clinically to categorize radiological DDD. Highly variable European prevalences of radiologically defined DDD grades 3+ along with the large effects of age may have growing and geographically unequal health and economic impacts as the population ages. These data encourage further studies of potential genetic and environmental causes.

Changes in proinflammatory cytokine activity after menopause.

There is now a large body of evidence suggesting that the decline in ovarian function with menopause is associated with spontaneous increases in proinflammatory cytokines. The cytokines that have obtained the most attention are IL-1, IL-6, and TNF-alpha. The exact mechanisms by which estrogen interferes with cytokine activity are still incompletely known but may potentially include interactions of the ER with other transcription factors, modulation of nitric oxide activity, antioxidative effects, plasma membrane actions, and changes in immune cell function. Experimental and clinical studies strongly support a link between the increased state of proinflammatory cytokine activity and postmenopausal bone loss. Preliminary evidence suggests that these changes also might be relevant to vascular homeostasis and the development of atherosclerosis. Better knowledge of the mechanisms and the time course of these interactions may open new avenues for the prevention and treatment of some of the most prevalent and important disorders in postmenopausal women.

Microvascular dysfunction in rheumatoid arthritis assessed by laser Doppler anemometry: relationship to soluble adhesion molecules and extraarticular manifestations.

In search of a noninvasive diagnostic test for rheumatoid vasculitis (RV), this study addressed the questions whether changes in capillary blood cell velocity (CBV) detected by laser Doppler anemometry in patients with rheumatoid arthritis (RA) were correlated with the levels of soluble adhesion molecules and whether cutaneous flow abnormalities may reflect extraarticular manifestations in RA. In 31 RA patients and 20 patients with osteoarthritis (OA), CBV was measured in the skin above the left ring finger at rest and after 3-min arterial occlusion. Serum levels of soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), and soluble P-selectin (sP-selectin) were assessed by enzyme linked immunosorbent assay. Peak CBV was reduced in RA patients compared to OA patients (0.42 +/- 0.07 mm/s vs. 0.70 +/- 0.13 mm/s; P = 0.013). Both CBV during rest and reactive hyperemia were not correlated with the levels of soluble adhesion molecules. There were no significant differences in resting or peak CBV between RA patients with or without extraarticular manifestations. The lack of an inverse correlation between the levels of soluble adhesion molecules and CBV during rest and reactive hyperemia contradicts the assumption that inflammatory vascular damage indicated by increased levels of soluble adhesion molecules was the main reason for the impairment of microcirculation. The present results do not suggest that cutaneous flow abnormalities may reflect extraarticular manifestations in RA.

The role of limited joint mobility in diabetic patients with an at-risk foot.

OBJECTIVE: To assess the role of limited joint mobility (LJM) in causing abnormal high plantar pressures in the forefoot of diabetic patients with an at-risk foot. RESEARCH DESIGN AND METHODS: A total of 70 type 1 or type 2 diabetic patients and 30 control subjects participated in this cross-sectional study. Thirty-five diabetic patients with an at-risk foot, defined as a foot with neuropathy but without ulceration or previous ulceration, and 35 diabetic control subjects without neuropathy were selected for the subgroups. Joint mobility was assessed in the foot at the ankle and metatarsophalangeal I (first MTP) joints. Using the FastScan plantar pressure analyzer, the pressure-time integrals (PTIs) as dynamic variables were measured in each foot. The clinical assessment included standard measures of peripheral neuropathy. RESULTS: The mobility at the ankle and first MTP joint were significantly reduced in the foot-at-risk group compared with the diabetic control group and the control subjects (P < 0.0001). The PTIs were significantly higher in the foot-at-risk group compared with the two other groups (P < 0.0001). There was a strong inverse correlation between the mobility of the ankle or first MTP joint and the PTI of the diabetic patients (r = -0.67, P < 0.0001, and r = -0.71, P < 0.0001, respectively). The vibration perception threshold was positively correlated with the PTI of the diabetic patients (r = 0.44, P = 0.0001). CONCLUSIONS: Diabetic patients with an at-risk foot have reduced joint mobility and elevated PTIs on the plantar forefoot, placing them at risk for subsequent ulceration. Therefore, LJM may be a possible factor in causing high plantar pressures and may contribute to foot ulceration in the susceptible neuropathic at-risk foot.

Low Fcgamma receptor III and high granulocyte colony-stimulating factor serum levels correlate with the risk of infection in neutropenia due to Felty's syndrome or systemic lupus erythematosus.

PURPOSE: To determine whether serum levels of soluble Fcgamma receptor III and granulocyte colony-stimulating factor (G-CSF) are associated with the risk of infection in patients with neutropenia due to Felty's syndrome or systemic lupus erythematosus. SUBJECTS AND METHODS: Serum levels of G-CSF and soluble Fcgamma receptor III were measured by enzyme-linked immunosorbent assays in 13 patients with neutropenia due to Felty's syndrome, 10 patients with neutropenia due to systemic lupus erythematosus, and 41 controls with normal leukocyte counts (25 with systemic lupus erythematosus, 16 with rheumatoid arthritis). We calculated the area under the receiver operating characteristic (ROC) curves for the absolute neutrophil count, soluble Fcgamma receptor III levels, and G-CSF levels. RESULTS: Nine of the neutropenic patients (7 with Felty's syndrome, 2 with lupus) had one or more infections within 3 months before and after blood samples were obtained. Absolute neutrophil counts were similar in neutropenic patients who did or did not have infections. However, the median level of soluble Fcgamma receptor III (63 vs. 126 arbitrary units, P = 0.005) was significantly lower among patients who developed infections, whereas the median level of G-CSF (90.9 vs. 53.3 pg/mL, P = 0.04) was significantly higher compared with patients without infections. The area under the ROC curve was 0.58 (P = 0.49) for the absolute neutrophil count, 0.84 (P = 0.007) for soluble Fcgamma receptor III levels, and 0.73 (P = 0.03) for G-CSF levels. CONCLUSION: In patients with chronic neutropenia due to rheumatic diseases, low soluble Fcgamma receptor III levels and elevated G-CSF levels are better indicators of the risk of infection than is the neutrophil count.

Determinants and estimation of healing times in diabetic foot ulcers.

AIMS: To assess the wound size reduction and time course for healing and to establish equations to predict the time course of wound healing in neuropathic, neuroischemic, and ischemic diabetic foot ulcers. METHODS: This prospective study evaluates wound healing over at least a 10-week period in 31 Type 1 or Type 2 diabetic patients with plantar foot ulcers. Thirteen consecutive diabetic patients with neuropathic foot ulceration, 10 consecutive diabetic patients with neuroischemic ulceration, and 8 diabetic patients with peripheral occlusive vascular disease were selected for the study. All patients received identical ulcer wound care including use of proper footwear, non-weight-bearing limb support, use of appropriate antibiotics, debridement, tight control of serum glucose levels, and careful monitoring of the ulcer. Ulcer healing was assessed by planimetric measurement of the wound area every second week until wound healing. The time course of wound healing was calculated by the daily wound radius reduction. RESULTS: The wound area (mean+/-S.E.) in the patients with neuropathic foot ulceration was 61.2+/-17.1 at the beginning and 3.2+/-1.5 mm(2) after 70 days (P=.005). The wound radius decreased by 0.045 mm (95% confidence interval [CI] 0.039-0.055) per day, with most of the wound healing being achieved between the first and seventh week of ulcer care. The average healing time was 77.7 (95% CI 62-93) days. In the neuroischemic group, the initial average wound area was 26.6+/-7.0 mm(2), and 6.25+/-1.7 mm(2) after 10 weeks (P=.007). The wound radius reduction was 0.019 mm/day (95% CI 0.017-0.023) with an average healing time of 123.4 (95% CI 101-145) days. The diabetic patients with peripheral occlusive vascular disease had an average wound size of 32.6+/-13.1 at the beginning and 23.9+/-10.7 mm(2) after 70 days of ulcer care (P=.06). The daily wound radius reduction was 0.0065 mm (95% CI 0.0039-0.0091). Average ulcer duration was 133 (95% CI 116-149) days, but three of eight patients achieved no wound healing. CONCLUSIONS: Providing standard care, the time course of wound healing in diabetic foot ulcers is predominantly determined by etiologic factors, and less by wound size. Taking wound etiology and wound radius into account, the expected healing time can reliably be estimated in neuropathic and neuroischemic ulcers.

[Glutamic acid decarboxylase and tyrosine phosphatase-like IA-2 antibodies for diabetes classification in unselected diabetic patients]. / Antikörper gegen Glutamatdecarboxylase und Tyrosinphosphatase-ähnliches Protein IA-2 in der Klassifikation von unselektionierten Diabetespatienten.

BACKGROUND: The determination of glutamic acid decarboxylase and tyrosine phosphatase-like antibodies (GAD-AB and IA-2-AB) may be useful for the classification of diabetes, and in selected patient groups the measurement of these autoantibodies has been shown to be rather sensitive and specific. PATIENTS AND METHODS: In this study we examined the use of these antibody determination in a clinical setting of 157 diabetic outpatients recruited randomly from our diabetes clinic. The prevalence of the different antibodies was set in relation to the clinically classified diabetes type and to diabetes duration. RESULTS: Among the patients with a clinical diagnosis of type 1 diabetes, the GAD-AB were clearly positive in 44% and borderline positive in 10%, whereas the IA-2-AB were positive or borderline positive in 36% of these patients. The prevalence of positive autoantibodies declined with increasing duration of type 1 diabetes. Among the patients with clinically diagnosed type 2 diabetes, the GAD-AB were clearly positive in 25.2% and borderline positive in 13.1%, IA-2-AB were only found in 4.7%. Patients with a clinical diagnosis of type 2 diabetes but positive for GAD-AB could not clearly be identified as having latent autoimmune diabetes in adults (LADA), since some of them did not need insulin therapy up to 10 years after the diagnosis of diabetes. The prevalence of GAD-AB in type 2 diabetic/LADA patients did not depend on diabetes duration. CONCLUSION: We conclude that the determination especially of GAD-AB may be useful for the classification of diabetes in clinically unclear cases. The additional determination of IA-2-AB appears to provide only limited additional information.

Autoantibodies against granulocyte colony-stimulating factor in Felty's syndrome and neutropenic systemic lupus erythematosus.

OBJECTIVE: Cytokines and growth factors can be a target of autoantibodies in systemic inflammatory diseases. We examined whether patients with neutropenia and either Felty's syndrome (FS) or systemic lupus erythematosus (SLE) have autoantibodies against granulocyte colony-stimulating factor (G-CSF) and whether these autoantibodies are functionally relevant. METHODS: Fifteen patients with neutropenia due to FS were matched for age, sex, and disease activity with 16 normocytic rheumatoid arthritis (RA) control patients. Sixteen patients with SLE and neutropenia were matched with 16 normocytic SLE control patients. Antibodies against G-CSF were measured by enzyme-linked immunosorbent assay and Western blotting. Antibody specificity was verified by competitive inhibition using recombinant human G-CSF. The effect of anti-G-CSF antibodies on the functional activity of their target molecule was measured in a bioassay using G-CSF-sensitive murine 32D cells. RESULTS: IgG anti-G-CSF was found in 11 FS patients, 6 SLE patients with neutropenia, 6 SLE control patients, and none of the RA control patients. IgM anti-G-CSF was found in 6 neutropenic and 3 normocytic SLE patients. Anti-G-CSF antibodies were associated with an exaggerated serum level of G-CSF and a low neutrophil count. A neutralizing effect of anti-G-CSF antibodies on its target molecule was found in 3 of the 9 patients tested. Irrespective of the presence or absence of anti-G-CSF antibodies, neutropenic patients with FS and SLE had exaggerated serum levels of G-CSF. CONCLUSION: Anti-G-CSF autoantibodies are common in neutropenia due to FS and SLE. In individual patients, these autoantibodies have a neutralizing capacity. In patients without neutralizing antibodies, hyposensitivity of the myeloid cells to G-CSF appears to be central to the pathogenesis of the neutropenia in FS and SLE.