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CONTEXT: Adiponectin is an abundant adipokine, which has antiinflammatory, anti-atherosclerotic and vasoprotective actions, and potential antiresorptive effects on bone metabolism. It seems to be directly involved in the improvement and control of energy homeostasis, protecting bone health and predicting osteoporotic fracture risk. OBJECTIVE: To examine the relationship between adiponectin level and bone mineral density (BMD) in post-menopausal women with metabolic syndrome (MetS) and low BMD, and to estimate the prognostic significance of adiponectin in osteoporosis. DESIGN: Clinical-laboratory cross-sectional study including 120 middle-aged and elder women (average 69.18±7.56 years). SUBJECTS AND METHODS: The anthropometric parameters were measured for all examinees. Lumbar spine and hip BMD, as well as body fat percentage, were measured using a Hologic DEXA scanner. In all subjects serum adiponectin concentration was measured by ELISA method. RESULTS: The level of adiponectin was significantly positively correlated with BMD-total, BMD of the lumbar spine and BMD of the femoral neck (r=0.618, r=0.521, r=0.567; p<0.01). Levels of adiponectin and BMD are significantly lower in post-menopausal women with MetS and osteoporosis compared to patients with osteopenia (856.87±453.43 vs. 1287.32±405.21 pg/mL, p<0.01; BMD, p<0.05), and the highest values in healthy examinees. A cut-off value of adiponectin level for osteoporosis/osteopenia was 1076.22/1392.74 pg/mL. CONCLUSIONS: Post-menopausal women with MetS have significantly lower adiponectin level and low BMD compared to healthy examinees. Adiponectin may be an early, significant and independent predictor of developing osteoporosis in women with MetS, especially in post-menopausal period.

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OBJECTIVES: We longitudinally studied outcomes of patients with juvenile idiopathic arthritis (JIA) using the Childhood Health Assessment Questionnaire (CHAQ) for physical disability and the Juvenile Arthritis Damage Index for articular (JADI-A) and extra-articular damage (JADI-E), and we correlated them with various disease activity variables. METHODS: Eighty-seven patients with JIA were included in the prospective follow-up study with median age 14 years (4.6-18.0), disease duration 5.2 years (2.0-18.9) and follow-up of 4.0 years (2.0-5.2). Besides JADI-A and JADI-E, and the assessment of active joints count, joints with limited mobility, ESR, CHAQ and radiographic damage of joints was also done. A correlation analysis of CHAQ and JADI with various disease activity variables was performed. RESULTS: The patient's distribution of JIA subtypes were polyarticular (32), systemic onset (13), oligoarticular (31), and enthesitis related arthritis (11). After a follow-up period, 46% patients had active disease compared to 83% patients at baseline (p<0.01). The CHAQ disability index improved over baseline, while radiological damage (p<0.001) and JADI-A and JADI-E scores worsened (p<0.001). CHAQ and JADI significantly correlated with the majority of disease activity variables. CHAQ DI was significantly higher in the patients with coxitis (p<0.01) and wrist arthritis (p<0.001). The most pronounced deterioration in articular damage (JADI-A) was observed in patients with sJIA (3.69 at baseline vs. 5.69 at study endpoint). CONCLUSIONS: The improvement of functional disability (CHAQ DI) was observed over the course of the disease, whereas radiological joint damage, JADI-A and JADI-E scores worsened. Children with systemic JIA, wrist arthritis, coxitis and prolonged active disease are at higher risk of progression of severe disability.

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OBJECTIVE: To validate ultrasonographic criteria for examination of the major salivary glands in the diagnosis of primary Sjögren's syndrome (SS). METHOD: A total of 209 consecutive patients with rheumatic diseases were selected according to the American-European Consensus Group (AECG) classification criteria for SS. One hundred and fifteen patients had primary SS, 44 had secondary SS, and 50 had sicca symptoms, and 36 subjects served as asymptomatic controls. This cohort was analysed for size, echogenicity, parenchymal inhomogeneity, focal changes, and posterior borders of the major salivary glands by ultrasonography (US). A novel US score for parenchymal inhomogeneity (0-12) was assigned and its diagnostic accuracy evaluated. RESULTS: Ultrasonographic abnormalities of salivary glands were detected in 107/115 (93.0%) patients with primary SS, in 12/44 (27.3%) with secondary SS, in 25/50 (50.0%) with sicca symptoms, and in 4/36 (11.1%) asymptomatic controls. Area under the receiver operating characteristic curve (AUC-ROC) for US inhomogeneity score was highly significant [0.96 +/- 0.01; 95% confidence interval (CI) 0.94-0.99, p < 0.000] for primary SS, with a sensitivity to specificity ratio of 91/83 for parotid and 93/90 for submandibular glands. Setting the cut-off US inhomogeneity score at 6 resulted in the best ratio of specificity (90.0%) to sensitivity (95.1%), with a positive predictive value of 72% and a negative predictive value of 96%. A US inhomogeneity score >or= 6 was closely correlated with positive biopsy (p < 0.000) and scintigraphy findings (p < 0.000). CONCLUSIONS: We demonstrate the high diagnostic value of a novel US score for parenchymal inhomogeneity (0-12) that could serve as a useful single US criterion in the evaluation of salivary gland involvement in primary SS.

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CD4(+) (Th) and CD8(+) (Tc) T and NK lymphocytes can be divided into type 1 and 2 subsets according to their cytokine secretion profile. Studies on the role of lymphocyte subsets in human diseases have been hampered by the lack of stable surface markers to define them. Recently, we reported that ST2L and IL-18R are stably expressed on murine Th2 and Th1 cells, respectively. In this study, we generated Abs to human homologues of ST2L and IL-18R and tested them against Th1/Th2, Tc1/Tc2, and NK1/NK2 lines and PBMCs from healthy individuals. We show for the first time that ST2L and IL-18R are stable selective cell surface markers for human Th2/Tc2/NK2 and Th1/Tc1/NK1 lymphocytes, respectively. We then investigated PBMCs from HIV-infected patients and HIV-negative individuals, to test whether Abs to these two surface markers could be used directly to monitor lymphocyte subset distribution in human diseases. We found a clear Th1 to Th2 shift in the HIV-infected individuals, thus settling a long-standing controversy and include, for the first time, Tc and NK cells as well. Therefore, these cell surface molecules could serve as important determinants of the immune status of human diseases in general, and thereby could be useful for therapeutic monitoring and intervention.

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Accessory cell content and some of their functional characteristics were determined in regional lymph nodes which drain burn injury (DLN) in rats. Increase in percentages of non-specific esterase-positive cells and NBT+ macrophages and in numbers of dendritic cells were noted in cytospin preparations of draining lymph node cells (DLC) 24 and 72 h following thermal injury. An accumulation of B cells was also noted in the DLN paracortex region at these time points. Enrichment of ED1+ (rat macrophage marker) cells was noted in the adherent DLC population. Increased activity of interleukin-1 (IL-1) in conditioned medium from adherent DLC population and the increased stimulatory capacity of whole DLC or dendritic cell enriched-DLC fraction were noted in functional assays. Enrichment in accessory cells and an increase in their functional activity could contribute to the endogenous activity of regional lymph nodes which drain burned areas.

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OBJECTIVE: Vitamin D analogues such as 1 alpha (OH) D3 (alphacalcidiol) have a possible physiological paracrine effect on cell proliferation and differentiation. Experimentally established possibilities to prevent autoimmune diseases suggest that alphacalcidiol may have therapeutic value as an immunomodulatory agent in patients with rheumatoid arthritis. METHODS: We organized a 3-month open-label trial on 19 patients being treated with standard DMARD therapy for acute RA. They were divided into 2 subgroups, those with highly active RA and those with moderately active RA. Their regular drug regimen was maintained during the trial and oral alphacalcidiol 2 micrograms/day was added. Therapy results were evaluated by ESR, CRP, morning stiffness, the Richie index, and the Lee index. Immunomodulatory effects were investigated by measuring lymphocyte proliferation and apoptosis both in the patients and in vitro in 10 nM alphacalcidiol-supplemented culture medium. RESULTS: After 3 months, high dose oral alphacalcidiol therapy showed a positive effect on disease activity in 89% of the patients (45% or 9 pts. with complete remission and 44% or 8 pts. with a satisfactory effect). Only two patients (11%) showed no improvement, but no new symptoms occurred. No side effects were observed. CONCLUSION: These results suggest that alphacalcidiol is a powerful immunomodulatory agent with fairly low hypercalcemic activity. Clinical improvement was strongly correlated with the immunomodulating potential of this agent. We noticed dual effects on lymphocyte proliferation and apoptosis according to the prior cell activation state. Alphacalcidiol could therefore possibly be used as an adjunct therapy with DMARDs in patients with rheumatoid arthritis.

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Four different monoclonal antibodies (mAbs) reactive with rat CD11b (ED7, ED8, OX-42 and 1B6c) have been characterized for their ability to induce homotypic aggregation of granulocytes or to modify granulocyte adhesiveness triggered by phorbol myristate acetate (PMA) or N-formyl-methionyl-leucyl-phenylalanine (fMLP). Cross-blocking experiments showed that these mAbs recognize at least three different epitopes on CD11b. OX-42 mAb recognizes an inhibitory epitope since the mAb inhibited homotypic aggregation of granulocytes and their adherence to plastic in the presence of PMA or fMLP. ED7 and ED8 induced homotypic aggregation of granulocytes which was blocked by OX-42 and anti-CD18 mAb (WT3) suggesting that CR3 itself is involved in the adhesion process. The aggregation was dependent on active cell metabolism, intact cytoskeleton, divalent cations and activation of tyrosine kinases sensitive to genistein. Staurosporine, okadaic acid and orthovanadate potentiated the aggregation. ED7 and ED8 potentiated homotypic aggregation and adhesion of granulocytes to plastic caused by fMLP, but inhibited granulocyte adhesion to plastic induced by PMA. 1B6c recognizes an epitope that transmits a proaggregatory signal upon binding of the mAb but only if the granulocytes are in contact with plastic or are activated by fMLP. In contrast, 1B6c inhibited granulocyte adhesion to plastic triggered by PMA or fMLP. These data suggest the existence of functionally different epitopes on rat CD11b and indicate that some anti-CD11b mAbs are able to functionally activate CR3.

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The acute inflammatory response associated with thermal injury was examined in rats. The appearance of mediators of inflammation in the systemic circulation, including cytokines interleukin-1 (IL-1), tumor necrosis factor (TNF) and interleukin-6 (IL-6) and acute phase proteins were assessed during initial 72 h following thermal injury. Increased levels of activity were noted for all three cytokines, but with a different time-course. While serum IL-1 activity was elevated throughout the 3-day period of observation, the levels of serum TNF activity were enhanced after 12 h and on days 1 and 3 following scalding injury. The values of IL-6 were already increased one hour after thermal injury and increased progressively up to day 1 following scalding. Alpha2-macroglobulin and haptoglobin levels were increased 12 h after thermal injury, rising further on days 1 and 3. Positive correlation was found between the time-course of increased serum IL-6 activity and alpha2-macroglobulin, as well as between TNF and haptoglobin in the serum.

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The aim of this study was to find relevant signs and readily available parameters for the recognition of blast injuries and estimation of their severity. The injury severity, estimated by the Injury Severity Score (ISS), Red Cross Wound Classification (RCWC), and experimentally defined Pathology Scoring System for Blast Injuries (PSS/IS) according to Yelverton and modified for use in humans, was compared with a great number of subjective sensations, clinical signs, parameters of hemodynamic, metabolic, neuroendocrine and immune conditions. On the basis of these data, the confidence of the above-mentioned methods was analyzed in the evaluation of blast injuries. This study included 1303 casualties, wounded by explosive devices and with suspected blast injuries, treated at the Military Medical Academy in Belgrade (MMA) from 1991 to 1994. The patients were examined on admission at the MMA (<18 hours) and during hospitalization (1, 2, 5, and 7 days after wounding). The casualties with confirmed blast injury (n = 665, 51%) had an ISS ranging from 0 to 34 (mean 13) had wounds ranging from G1ST (soft tissue wounds caused by low energy transfer) to G3VF (massive wounds with fractures and injury of vital structures) according to the RCWC, with PSS/IS scores from 2 to 105 (mean 60). Statistically significant correlation was found between ISS and PSS/IS as well as RCWC and PSS/IS. Cytokines (IL-1, TNF|ga) and amino acids responded to a blast injury in similar manner as to gunshot wounds with a greater ISS or more severe RCWC injury type. The subjective sensations in blasted patients (deafness, thoracic pain, vertigo) and mediators, confirmed in previous experimental investigations as important factors in the pathogenesis of blast injuries (TxA2, sulfidopeptide leukotrienes) were relationed only to the PSS/IS.

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Disseminated Bacillus Calmette-Guérin infection occurs in few well-defined immunodeficiencies, such as severe combined immunodeficiency, chronic granulomatous disease and paediatric acquired immunodeficiency syndrome. This severe complication of immunization against tuberculosis has been lethal in the majority of children who had primary immunodeficiency. Our patient, a 9-y-old girl with hyperimmunoglobulin E syndrome developed disseminated Bacillus Calmette-Guérin infection in infancy. Patients with hyperimmunoglobulin E syndrome (HIES) are susceptible to serious staphylococcal and fungal infections. Disseminated Bacillus Calmette-Guérin infection has not previously been reported in this rare immunodeficiency.

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Antiphospholipid syndrome (APLS), is defined as the presence of antiphospholipid antibodies (APLA) associated with clinical phenomena of arterial or venous thrombosis, recurrent spontaneous abortions and thrombocytopenia. APLA represent the family of antibodies of different specificity. They are mostly directed to various anionic phospholipids (cardiolipin, phosphatidylcholine, phosphatidylserine, phosphatidyl acid and phosphatidyl ethanolamine). The part of APLA is directed towards epitope at the structurally changed beta-2-GPI, the so-called anti beta-2-GPI antibodies and the hypothesis was established that the subgroup of APLA was directed towards complex of beta-2-GPI with the phospholipids and oxidized lipoproteins of high and very low density. This could explain the clinically observed association of mutual onset of thrombosis and atherosclerosis. The most frequent target tissues for APLA are endothelial cells, thrombocytes, monocytes, natural anticoagulant system and placenta. APLA can be detected in a serum with one of the following assays: testing of lupus anticoagulant presence, determination of anticardiolipin antibodies (ACLA) concentration by ELISA and by testing the false positivity of VDRL test (standard test for syphilis). The pathological base for so-called vasculopathy in APLS are arterial and venous thrombosis. Clinical manifestations of APLS are mainly the result of blood vessels' occlusion but the thrombotic mass deposition on the surface of the heart valves may also occur. Clinically APLS can be divided into primary and secondary one, and manifestations of the secondary APLS are mainly expressed in the patients with SLE. Some clinical and serological variants of primary APLS were also described. The tendency for thrombotic process as a crucial characteristic of the syndrome and the lack of inflammation, imposes the choice of antithrombotic and anticoagulant therapy.

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Clinical manifestation and immunoserological features of secondary antiphospholipid syndrome (SAPS) were analyzed in this paper in 107 patients with systemic connective tissue diseases. In the group of patients with confirmed systemic lupus erythematosus (SLE), antiphospholipid antibodies (aPL) were positive in 43/93 (46.23%), while in 50/93 (53.76%) they were negative. Among aPL positive patients, 33/43 (76.74%) had clinical manifestations of SAPS, while 10 patients (23.26%) were without any clinical manifestations. The most frequent manifestations of SAPS associated with SLE were: arteriovenous thrombosis in 20/43 (46.51%), thrombocitopenia in 15/43 (34.88%) and autoimmune hemolytic anemia in 7/43 (16.27%). In our patients, rare manifestations of SAPS associated with SLE were recurrent fetal loss (1 case), livedo reticularis (1 case), transversal myelitis (2 cases), neuropathy (2 cases) and aseptic endocarditis (Libman-Sacks) (5 cases). Among 7 patients, with Sjögren's syndrome, clinically manifested SAPS was observed in 2, while in other 5 only increased aPL levels were found, as well as in patients with systemic vasculitis-3, MCTD-2 and Sy. Sjögren with vasculitis-1. One RA patient had thrombosis of v. cava inferior. In majority of patients with clinically present SAPS the levels of both examined immunoglobulin isotypes (IgG + IgM) were decreased-21/40 or 52.5%, while isolated increase of IgG was found in 14 (35%) and isolated increase of IgM in 5 (19.22%) patients. In three out of five patients with Libman-Sacks only LA test was positive. This investigation have shown that arterial and venous thromboses are the most common manifestations of SAPS in SLE. Every blood vessel may be involved (from arteriolae to the aorta and from postcapilar venules to the v. cava).

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Patients with inflammatory bowel diseases are susceptible to thrombosis in the active phase of the disease. Tests and some factors of coagulability have shown the existence of hypercoagulability of the blood in the active phase of these diseases. In the last few years some authors have found increased levels of antiphospholipid antibodies in the blood of patients with severe forms of Crohn's disease and ulcerative colitis. In a prospective study anticardiolipin antibodies have been measured in the blood of 12 patients, eight with ulcerative colitis and four with Crohn's disease. Six patients with ulcerative colitis and two with Crohn's disease were in the active phase of the disease, and the others in the remission. None of the patients had any clinical signs of thrombosis. Anticardiolipin antibodies were slightly increased in only one patient with severe ulcerative colitis complicated with erythema nodosum and swelling of the ankles. In nine patients anticardiolipin antibodies were in the normal range, but in two they were not found. Results of our study do not allow any definite conclusion regarding the possible role of antiphospholipid antibodies in the development of thrombosis in inflammatory bowel diseases: the number of the patients is relatively low and in half of the cases the disease was moderately active. Further studies are therefore necessary.

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Examination of the risk factors for peritonitis appearance in patients on chronic peritoneal dialysis is on great importance for better understanding of its therapy and prevention. The aim of the study was to confirm the significance of some local defense parameters of peritoneal space and its role in peritonitis incidence. The methodology was: radial immunodifussion (IgG), nephelometry (C3), ingestion of the yeast particles (phagocytosis) and bioassays for cytokine determination. The level of termostable opsonines (IgG) was significantly lower in patients with high peritonitis incidence. Also, TNF, IL6 and IL1 activity was elevated or very high in 42.1%, 57.8% and 47.3% in the same group of patients but almost unmeasurable in patients with low peritonitis incidence. Phagocytosis by peritoneal macrophages was similar in all patients and the level of termolabile opsonines was critically low in the peritoneal fluid of all patients. The presented differences in local defense parameters may partly explain the susceptibility to infection in some patients being on chronic peritoneal dialysis.

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OBJECTIVE: To study the effect of a burn injury on the course of cellular and cytokine changes in a wound and the relationship of these cytokines to the amounts of protein and collagen deposited at the site of the wound. DESIGN: A randomized control trial was done in which one group of rats were subjected to a severe burn injury. With the use of a sponge matrix model, the wound-healing parameters were evaluated. MATERIALS: A random sample of eight inbred albino Oxford rats per group were used in all experiments. INTERVENTIONS: Rats were subjected to a severe scald injury. Polyvinyl sponges were used as the wound-healing model. MAIN OUTCOME MEASURE: The obtained results implied that the wound-healing process is impaired after a severe burn injury. RESULTS: The wounds in these animals with burn injuries contained a lower number and an altered type of infiltrating cells with aberrant levels of cytokines, higher levels of interleukin-6, and lower levels of tumor necrosis factor and interleukin-1 in the fluids of the wounds. The parameters of healing (amounts of protein and collagen deposited at the site of the wound) were significantly lower in animals with burn injuries on days 7 and 14. CONCLUSION: The underlying mechanism of the impaired healing of a wound after burn injury could lie in the altered migration of inflammatory cells to the site of the wound and in the aberrant cytokine levels within the wound.

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Proliferative and phenotypic characteristics of cells in regional lymph nodes that drain burn injury were examined in rats on day 3 postburn, i.e. at the time of maximal spontaneous proliferation and of interleukin-2 and accessory cytokine (IL-1 and IL-6) production. The importance of IL-1 in spontaneous proliferation of draining lymph node cells was demonstrated by stimulation of IL-2-driven proliferation by recombinant IL-1 in vitro and by susceptibility of unstimulated proliferation to anti-IL-1 antibodies, while requirements for IL-6 in draining lymph node cell proliferation were less pronounced. Cell surface phenotyping revealed a slightly increased percentage of CD25+ cells in the blast cell population of freshly isolated draining lymph node cells after injury, which increased further during cultivation. Enrichment in CD8+ cells on day 3 following burn injury was demonstrated, while no changes in total cell population and CD4+ cells was noted. This was however preceded by pronounced percentual decrease of total T cells and CD4+ cells and by increases of B cells and MHC class II+ cells on day 1 postburn. Inhibition of draining lymph node cell proliferation by anti-MHC class II antibodies suggested that this proliferation was class II MHC dependent. The contribution of cell proliferation and/or cell influx to day 3 postburn draining lymph node cell activity is discussed.

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We have raised a monoclonal antibody (mAb), NG2B12, directed against rat CD18, capable of inducing lymphocyte homotypic adhesion and granulocyte adherence to plastic. NG2B12-induced aggregation is temperature sensitive and requires metabolic energy, an intact cytoskeleton and the presence of Mg2+, but is independent of protein synthesis. Ca2+ is not only dispensable but exerts a suppressive effect on the NG2B12-induced adhesion. The adhesion is readily observed in thymocytes and concanavalin A blasts of thymocytes and splenocytes but is very weak in resting spleen and lymph node cells. NG2B12 also enhances phorbol 12-myristate 13-acetate (PMA)-induced aggregation in an additive fashion. The NG2B12-induced homotypic adhesion is mediated by LFA-1. mAb against ICAM-1 completely inhibited the induced adhesion of activated cells but inhibited only partially and in a time-dependent manner the adhesion of resting thymocytes. The activation of protein phosphatases 1 and 2A (as assessed by the use of okadaic acid) is necessary for the NG2B12-induced adhesion of both resting and activated thymocytes. In contrast, H-7 (an inhibitor of protein kinase C and A), substantially suppressed the adhesion of resting thymocytes, whereas W-7 (an inhibitor of calmodulin-dependent protein kinase) inhibited the adhesion of activated thymocytes. NG2B12 induces both adherence to plastic and homotypic aggregation of granulocytes; the events being blocked by anti-CD18 (WT.3) and anti-CD11b/CD11c (OX-42) mAb, augmented by okadaic acid and not modified by H-7 and W-7. Additionally, we have demonstrated that NG2B12 and PMA employ distinct intracellular signaling pathways in inducing adhesion of both thymocytes and granulocytes.

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