Serum S100A12 levels in children with childhood-onset systemic lupus erythematosus, systemic juvenile arthritis, and systemic undefined recurrent fevers.

BACKGROUND: We compared serum levels of S100A12, a proinflammatory protein predominantly secreted by neutrophils, in children with newly diagnosed childhood-onset systemic lupus erythematosus (cSLE), systemic juvenile arthritis (sJIA), and systemic undefined recurrent fevers (SURFS) to examine its role as a diagnostic and discriminative marker of inflammation and to indirectly point out the importance of neutrophils and innate immunity in the pathogenesis of these diseases. MATERIALS AND METHODS: In a cross-sectional study, the serum levels of S100A12 protein of 68 children (19 with cSLE, 18 with sJIA, 7 with SURFS, and 24 controls) were determined by enzyme-linked immunosorbent assay and compared between groups and with clinical and laboratory findings. RESULTS: The median serum S100A12 levels were 469 ng/mL in the cSLE group, 6103 ng/mL in the sJIA group, 480 ng/mL in the SURFS group, and 44 ng/mL in the control group. Children with cSLE, sJIA, and SURFS had significantly higher serum S100A12 levels compared to the control group (p < 0.0001). sJIA patients had the highest levels of S100A12 in comparison to other patients (p < 0.0001), while there was no significant difference between children with cSLE and SURFS. CONCLUSION: Elevated serum SA100A12 levels in children with cSLE, sJIA, and SURFS may indicate intense neutrophil activation, which may play an important role in innate immunity in chronic inflammation in these diseases. Serum S100A12 levels could be used as a diagnostic marker of inflammation and be suitable for distinguishing sJIA and other disorders.

Loci associated with N-glycosylation of human immunoglobulin G show pleiotropy with autoimmune diseases and haematological cancers.

Glycosylation of immunoglobulin G (IgG) influences IgG effector function by modulating binding to Fc receptors. To identify genetic loci associated with IgG glycosylation, we quantitated N-linked IgG glycans using two approaches. After isolating IgG from human plasma, we performed 77 quantitative measurements of N-glycosylation using ultra-performance liquid chromatography (UPLC) in 2,247 individuals from four European discovery populations. In parallel, we measured IgG N-glycans using MALDI-TOF mass spectrometry (MS) in a replication cohort of 1,848 Europeans. Meta-analysis of genome-wide association study (GWAS) results identified 9 genome-wide significant loci (P<2.27 × 10(-9)) in the discovery analysis and two of the same loci (B4GALT1 and MGAT3) in the replication cohort. Four loci contained genes encoding glycosyltransferases (ST6GAL1, B4GALT1, FUT8, and MGAT3), while the remaining 5 contained genes that have not been previously implicated in protein glycosylation (IKZF1, IL6ST-ANKRD55, ABCF2-SMARCD3, SUV420H1, and SMARCB1-DERL3). However, most of them have been strongly associated with autoimmune and inflammatory conditions (e.g., systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis, Crohn's disease, diabetes type 1, multiple sclerosis, Graves' disease, celiac disease, nodular sclerosis) and/or haematological cancers (acute lymphoblastic leukaemia, Hodgkin lymphoma, and multiple myeloma). Follow-up functional experiments in haplodeficient Ikzf1 knock-out mice showed the same general pattern of changes in IgG glycosylation as identified in the meta-analysis. As IKZF1 was associated with multiple IgG N-glycan traits, we explored biomarker potential of affected N-glycans in 101 cases with SLE and 183 matched controls and demonstrated substantial discriminative power in a ROC-curve analysis (area under the curve = 0.842). Our study shows that it is possible to identify new loci that control glycosylation of a single plasma protein using GWAS. The results may also provide an explanation for the reported pleiotropy and antagonistic effects of loci involved in autoimmune diseases and haematological cancer.

Childhood-onset systemic lupus erythematosus in Croatia: demographic, clinical and laboratory features, and factors influencing time to diagnosis.

OBJECTIVES: Childhood-onset systemic lupus erythematosus (cSLE) presents with diverse clinical features and often with non-classical symptoms that may delay diagnosis and increase risk of morbidity and mortality. This paper aims to analyse incidence, and clinical and laboratory features of cSLE in Croatia between 1991 and 2010, and to identify factors influencing time to diagnosis. RESULTS: Medical records at three university-based tertiary care centres were analysed retrospectively for 81 children with cSLE (68 girls). Mean age at onset was 13.4±2.8 yr (interquartile range 3), and annual incidence varied from 1-15 per million at risk. The most frequent clinical and laboratory features were musculoskeletal symptoms (80%) and increased erythrocyte sedimentation rate (96%). The most frequent immunological laboratory findings were the presence of antibodies against histones (86%), double-stranded DNA (73%), and Sm protein (64%), as well as low levels of C3 complement (69%). Haematuria was present in 58% of children, proteinuria in 56%, and biopsy-confirmed lupus nephritis in 43%. Median time from symptom onset to diagnosis was 2 months (range 0-96). Time to diagnosis was inversely associated with ECLAM score (p<0.001), but it showed no association with age, gender, clinical features or distance from the nearest paediatric centre. CONCLUSIONS: This is the first large-scale, in-depth study of clinical and laboratory features of cSLE in Croatia. Among all demographic, laboratory and clinical features examined, ECLAM score alone was inversely associated with time to diagnosis. This highlights the need to improve detection of children with fewer symptoms early in the course of the disease, therefore serious consequences for prognosis could be avoided.

Pulmonary Arteriovenous Malformation Unmasked by Pregnancy: A Review of Pulmonary Arteriovenous Malformations and Cardiovascular and Respiratory Changes in Pregnancy.

Pulmonary arteriovenous malformations are abnormal, direct communications between the branches of the pulmonary artery and pulmonary veins, but without pulmonary capillaries between them. During pregnancy, PAVMs can enlarge and become symptomatic, causing even serious complications like haematothorax. To recognize the PAVM that becomes symptomatic in pregnancy, one must be able to distinguish the patient's symptoms caused by developing complications of PAVM, as in the case we present, from physiological changes accompanying a healthy pregnancy, including their degree in relation to the stage of pregnancy. The modified early obstetric warning score charts are a very helpful tool in the assessment of (ab)normal signs and symptoms in pregnant women, especially for physicians who rarely manage pregnant women.

Which clinical variables have the most significant correlation with quality of life evaluated by SF-36 survey in Croatian cohort of patient with ankylosing spondylitis and psoriatic arthritis?

The aim of our study was to assess clinical variables with the best correlation to quality of life (QOL) assessed by medical outcome survey Short-Form 36 (SF-36) in patients with spondyloarthritides, including ankylosing spondylitis (AS) and psoriatic arthritis (PsA). We analyzed the cohort of 54 patients (22 patients with PsA and 32 patients with AS), who filled the Croatian version of SF-36. For each type of arthritis, patients were clinically evaluated using the extensive list of clinical variables categorized into subjective and objective group. For AS patients, subjective and objective variables (spinal mobility measurements, clinical assessment of spinal pain, patient assessments of disease activity and pain) correlated mainly with the physical functioning concept of SF-36. Patients assessments of fatigue correlated with the energy/fatigue subscale, whereas patient assessment of enthesial pain correlated with the pain subscale. Correlations between clinical variables and SF-36 concepts of PsA patients showed more diverse distribution than for AS. Objective variables (spinal mobility measurements, a 76-joint score, clinical assessment of spinal pain) correlated with concepts concerning physical health and pain. Several subjective patient assessments correlated with energy/fatigue, emotional well-being, pain and general health subscales. Both patient and physician assessment of PsA activity correlated with the role limitations due to emotional problems. Bath ankylosing spondylitis functional index (BASFI) had the strongest correlation with the physical functioning concept of SF-36 in both diseases. Our findings provide important information to help selecting the variables with strongest impact on QOL, for better planning the management strategies and achieving better rehabilitation results.

Combination of the T7 Unilateral Erector Spinae Plane Block and T10 Bilateral Retrolaminar Blocks in a Patient with Multiple Rib Fractures on the Right and T10-12 Vertebral Compression Fractures: A Case Report.

Multiple vertebral compression and rib fractures in elderly patients with pre-existing chronic obstructive pulmonary disease is a common scenario associated with significant morbidity and mortality. Severe pain prevents normal ventilation and leads to atelectasis, consolidation, and pneumonia. Subsequently, these patients frequently develop respiratory failure and require intubation and critical care. Therefore, adequate analgesia is often a life-saving intervention. Anesthetic management of a 78-year-old kyphotic patient with T6, T7, and T9 rib fractures on the right and T10-12 vertebral compression fractures sustained in an accidental fall is presented. She had inadequate pain control and was unable to take a deep breath or cough. Her respiratory status was deteriorating, with tachypnea and worsening hypoxia, necessitating bi-level positive airway pressure (BiPAP) support. Since thoracic epidural analgesia was contraindicated owing to compressive vertebral fractures and to the pending respiratory failure, we opted for a unilateral erector spinae plane (ESP) block at the T7 level and bilateral retrolaminar (RL) blocks at the T10 level. Following the procedure, the pain was immediately relieved and the patient was able to take deep breaths. Shortly thereafter, her respiratory status improved, with the respiratory rate coming back close to the baseline. The patient was subsequently weaned from BiPAP support and discharged from the intensive care unit. While the combination of ESP and RL blocks is not routinely used in patients with multiple rib and vertebral compression fractures, our report indicates that it may be an excellent alternative for analgesia in situations where thoracic epidural and/or paravertebral blocks are contraindicated and when timely intervention could be potentially life-saving.

Fas receptor is required for estrogen deficiency-induced bone loss in mice.

Bone mass is determined by bone cell differentiation, activity, and death, which mainly occur through apoptosis. Apoptosis can be triggered by death receptor Fas (CD95), expressed on osteoblasts and osteoclasts and may be regulated by estrogen. We have previously shown that signaling through Fas inhibits osteoblast differentiation. In this study we analyzed Fas as a possible mediator of bone loss induced by estrogen withdrawal. At 4 weeks after ovariectomy (OVX), Fas gene expression was greater in osteoblasts and lower in osteoclasts in ovariectomized C57BL/6J (wild type (wt)) mice compared with sham-operated animals. OVX was unable to induce bone loss in mice with a gene knockout for Fas (Fas -/- mice). The number of osteoclasts increased in wt mice after OVX, whereas it remained unchanged in Fas -/- mice. OVX induced greater stimulation of osteoblastogenesis in Fas -/- than in wt mice, with higher expression of osteoblast-specific genes. Direct effects on bone cell differentiation and apoptosis in vivo were confirmed in vitro, in which addition of estradiol decreased Fas expression and partially abrogated the apoptotic and differentiation-inhibitory effect of Fas in osteoblast lineage cells, while having no effect on Fas-induced apoptosis in osteoclast lineage cells. In conclusion, the Fas receptor has an important role in the pathogenesis of postmenopausal osteoporosis by mediating apoptosis and inhibiting differentiation of osteoblast lineage cells. Modulation of Fas effects on bone cells may be used as a therapeutic target in the treatment of osteoresorptive disorders.

Biological agents targeting interleukin-18.

Interleukin (IL)-18 is an important regulator of both innate and acquired immune responses. It is upregulated in several human autoimmune and inflammatory diseases, and, therefore, might represent a novel therapeutic target. This review highlights the biology of IL-18, its central role in inflammation and immune response, as well as provides evidence for the involvement of IL-18 in selected chronic inflammatory diseases. After that, the authors discuss various therapeutic strategies of IL-18 blockade in clinical and preclinical models, particularly the inhibition of IL-18 secretion, IL-18 binding protein, anti-IL-18 monoclonal antibodies and soluble IL-18 receptor.

Interleukin-18 as a mediator of systemic juvenile idiopathic arthritis.

The objective of this report is to explore the balance between serum and synovial fluid levels of interleukin (IL)-18 in children with juvenile idiopathic arthritis (JIA). Blood samples were obtained from 81 children with JIA and 18 control children. Synovial fluid samples were collected from 16 children with oligoarticular JIA. Concentrations of IL-18 were determined using commercial kit. Patients with systemic JIA had higher serum levels of IL-18 than patients with other forms of JIA or control children, both during the active (median, range: 6,240, 1,600-78,750 pg/ml) and inactive (1,615, 513-3,270 pg/ml) phase of disease [analysis of variance (ANOVA), P<0.05). Levels of IL-18 in sera of children with oligoarticular JIA (255, 89-4,342 pg/ml) were similar to the respective synovial fluid levels (217, 89-1,245 pg/ml). Serum levels of IL-18 were proportional to the erythrocyte sedimentation rate and levels of C-reactive protein, but inversely proportional to the haemoglobin levels. IL-18 appears to be an important mediator of systemic JIA, while it seems of a lesser relevance in pathogenesis of other JIA forms. Therefore, inhibition of IL-18 might be a base for a successful biological therapy for systemic JIA.

Efficacy of interferon-alpha in the treatment of chronic hepatitis C in dialysis patients: two therapeutic protocols compared.

BACKGROUND: Data on the efficacy of particular therapeutic protocols of interferon-alpha (IFN-alpha) treatment for chronic hepatitis C in patients on hemodialysis (HD) vary. AIM: To compare the efficacy of two different therapeutic protocols for HD patients. PATIENTS AND METHODS: 15 hepatitis C virus (HCV)-positive patients on chronic HD at two dialysis centers: 8 patients treated with IFN-alpha 3 x 3 MU/week s.c. for 6 months (group A), and 7 patients treated with IFN-alpha 3 x 5 MU/week for 3 months, then 1 x 5 MU/week for another 3 months (group B). End of treatment response (ETR) and sustained virologic response (SVR) were evaluated by HCV-RNA determination. There was no statistically significant difference between the two patient groups according to age, sex, duration of HD and HCV infection. RESULTS: ETR was 87.5% (7/8) in group A and 28.5% (2/7) in group B, being statistically significant (p < 0.05). Although better SVR [50% (4/8) vs. 28.5% (2/7)] and lower drop-out rate [0% (0/8) vs. 28.5% (2/7)] were achieved in group A compared to group B, these differences did not reach statistical significance (p > 0.05). CONCLUSION: Therapy with IFN-alpha 3 x 3 MU/week s.c. for 6 months seems to be more appropriate for treatment of hepatitis C in HD patients, mostly due to better tolerability, i.e. lower drop-out rate. These differences could be attributed to different pharmacokinetic properties of the particular therapy protocol.

Neopterin kinetics after cardiac surgery with or without cardiopulmonary bypass.

Cardiac surgery (CS) with cardiopulmonary bypass (CPB) induces systemic inflammatory response by activating plasma proteins and blood cells. Activated monocytes/macrophages produce inflammatory marker neopterin (NP). The aim was to explore the NP kinetics in first 24 hours after CS according to the CPB use. Significant difference between groups was found for NP levels 12 and 24 hrs after CS, being higher in on-pump group. Strong association was found between NP levels 12 hrs after CS and the length of ICU stay for on-pump group (r=0.744, p<0.001). Strong association was found between preoperative NP levels and the length of ICU stay for those on-pump patients with elevated preoperative NP (r=0.855, p=0.001; linear regression equation y=0.50x-5.14, p<0.001). Preoperative NP levels higher than 10 nmol/L in on-pump group could predict prolonged ICU stay and outpoint patients at higher risk for developing postoperative complications and, therefore, help to determine the necessary therapeutic interventions.

Non-functional Fas ligand increases the formation of cartilage early in the endochondral bone induction by rhBMP-2.

It has previously been shown that mice with a defect in Fas ligand-mediated apoptosis have an enhancement of ectopic bone formation. We investigated the expression of bone-related markers--alkaline phosphatase, collagen, bone sialoprotein, osteocalcin, osteopontin, and bone morphogenetic proteins (BMP) -2, -4, and -7; and cytokines interleukin-1alpha (IL-1), IL-1beta, and tumor necrosis factor-alpha (TNF-alpha) in ectopic new bone induced by recombinant human (rh) BMP-2 in mice without functional Fas-ligand (gld mice). At day 6 after rhBMP-2 implantation, gld mice formed more cartilage and mesenchyme compared with their wild type littermates. At later stages, gld mice did not differ from the control mice in the volume of newly formed tissue, expressing higher level of BMP genes and lower levels of genes involved in osteoblast maturation--bone sialoprotein and osteopontin. Differences in the levels of expression of IL-1alpha and TNF-alpha were observed only at day 12 after rhBMP-2 implantation. These results suggest that gld mice have an increased recruitment of cells of mesenchymal origin and an abnormal pattern of differentiation and maturation of the newly formed mesenchymal tissues.

Dental caries in postwar Bosnia and Herzegovina.

OBJECTIVES: To present the prevalence of dental caries in postwar Bosnia and Herzegovina (BH). METHODS: A survey focused on dmft and DMFT indices was carried out in four cantons of the Federation of BH in 1997. The dental health of 6- and 12-year-olds was assessed in random samples (n = 238 and 318, respectively). DMFT index in adult population was assessed in clients coming to dental offices in the same area (35-44-year-olds; n = 401). All the subjects were clinically investigated. RESULTS: During the 1991-95 war, all four cantons were affected by the migration of population. The population per dentist ratio considerably increased in three cantons. In 6-year-olds, the average dmft (+/-SD) was 4.9 +/- 4.0, and 86% of the children were affected with dental caries. The average DMFT of 12-year-olds was 6.2 +/- 3.9. On the average, 94% of the 12-year-olds were affected with dental caries. Mean DMFT of adult clients was 15.1 +/- 7.0. Almost every adult (98%) was affected with dental caries. CONCLUSIONS: The dental status in postwar BH is rather poor and the mean DMFT in all investigated age groups may be considered high. The detrimental effect of 1991-95 war on social conditions and the health care system should be considered in explaining such poor dental health. Despite the limitations, the presented data may be used to assess the treatment needs, assure the visibility for dental issues in BH, and help the west European countries to plan dental services for refugees from BH.

Cranial base kyphosis and the surface morphology of the anterior cranial fossa.

We investigated the relationship between the surface morphology of the anterior cranial fossa and cranial base kyphosis (sphenoid angle) in 52 cephalometric craniograms. Among them there were 25 female (mean age 54 +/- 15; range 31-82) and 27 male (mean age 43 +/- 18, range 19-85) skulls. The sphenoid angle and the altitudes of the highest elevation of the endofrontal eminence (cranial base over the orbital roof in the anterior cranial fossa) and the middle point of the sphenoid planum, measured according to the Frankfort horizontal, were analysed using classical cephalometric and morphometric analysis. Statistical analysis was performed by Pearson's product-moment correlation and simple linear regression. The sphenoid angle ranged from 97 degrees to 137 degrees (mean 118 +/- 9 degrees). The altitude ratio of the highest elevation of the endofrontal eminence and the middle point of the sphenoid planum ranged from 1.5 to 1.8 (mean 1.6 +/- 0.1). A significant correlation was found between this ratio and the sphenoid angle (r = -0.65; p < 0.001; coefficient of determination = 0.43). The elevation of the endofrontal eminence relative to the sphenoid planum was higher in skulls with increased cranial base kyphosis, whereas reduced sphenoid angle was associated with an increase in the elevations of the endofrontal eminence. Although the sphenoid angle has a significant effect on the morphology of the anterior cranial fossa, only 43% of the variance in altitude of the endofrontal eminence is likely to be explained by its relationship with the sphenoid angle.

The presence of high mobility group box-1 and soluble receptor for advanced glycation end-products in juvenile idiopathic arthritis and juvenile systemic lupus erythematosus.

BACKGROUND: The involvement of high mobility group box-1 (HMGB1) in various inflammatory and autoimmune diseases has been documented but clinical trials on the contribution of this pro-inflammatory alarmin in children with juvenile idiopathic arthritis (JIA) and systemic lupus erythematosus (SLE) are basically absent. To address the presence of HMGB1 and a soluble receptor for advanced glycation end products (sRAGE) in different subtypes of JIA and additionally in children with SLE, we enrolled a consecutive sample of children harvested peripheral blood as well as synovial fluids (SF) at diagnosis and correlated it with ordinary acute-phase reactants and clinical markers. METHODS: Serum and synovial fluids levels of HMGB1 and sRAGE in total of 144 children (97 with JIA, 19 with SLE and 27 healthy controls) were determined by ELISA. RESULTS: The children with JIA and those with SLE were characterised by significantly higher serum levels of HMGB1 and significantly lower sRAGE levels compared to the healthy controls. A positive correlation between serum HMGB1 and ESR, CRP, α2 globulin was found while serum sRAGE levels were inversely correlated with the same inflammatory markers in children with JIA. Additionally, high level of serum HMGB1 was related to hepatosplenomegaly or serositis in systemic onset JIA. CONCLUSION: The inverse relationship of the HMGB1 and its soluble receptor RAGE in the blood and SF indicates that inflammation triggered by alarmins may play a role in pathogenesis of JIA as well as SLE. HMGB1 may serve as an inflammatory marker and a potential target of biological therapy in these patients. Further studies need to show whether the determination of HMGB1 levels in patients with JIA can be a useful guideline for detecting disease activity.

Targeting Fas in osteoresorptive disorders.

IMPORTANCE OF THE FIELD: Fas receptor is a mediator of the external apoptotic pathway in many cells and tissues. It is proposed that Fas receptor mediates osteoresorptive effects of estrogen deficiency and local/systemic inflammation. AREAS COVERED IN THIS REVIEW: This review covers the past two decades of research on the expression and function of the Fas-Fas ligand system on bone cells, involvement in the pathogenesis of osteoresorption and potential therapeutic modulation. WHAT THE READER WILL GAIN: We review the structure, biological function and intracellular signaling pathways of the Fas-Fas ligand system emphasizing the role of the non-apoptotic signaling pathways in bone cells, particularly osteoblast differentiation. We also present data on the in vitro expression and function of the Fas-Fas ligand system on osteoblast/osteoclast lineage cells, animal and human studies confirming its involvement in osteoresorptive disorders and potential therapeutic approaches to modulate its function. TAKE HOME MESSAGE: Tissue specific therapeutic approaches need to be established to modify the Fas-Fas ligand system in osteoresorptive disorders as systemic targeting has many side effects. The most promising approach would be to target Fas signaling molecules coupled with osteoblast/osteoclast differentiation pathways, but a precise definition of these targets is still needed.

Peripheral blood expression profiles of bone morphogenetic proteins, tumor necrosis factor-superfamily molecules, and transcription factor Runx2 could be used as markers of the form of arthritis, disease activity, and therapeutic responsiveness.

OBJECTIVE: To assess whether different forms of arthritis and disease activity could be distinguished by peripheral blood expression profiles of bone-regulatory factors including tumor necrosis factor (TNF)-superfamily [TNF-related apoptosis-inducing ligand (TRAIL), the Fas ligand (FasL), and the ligand for herpesvirus entry mediator (LIGHT)] and bone morphogenetic protein (BMP)-family members (BMP-2, BMP-4, BMP-6) as well as osteoblast differentiation gene Runx2. METHODS: Blood cells from healthy controls (n = 25) and patients at different disease stages with rheumatoid arthritis (RA; n = 49), osteoarthritis (OA; n = 17), or spondyloarthritis, including ankylosing spondylitis (AS; n = 27) or psoriatic arthritis (PsA; n = 23), were processed for quantitative polymerase chain reaction. Gene expression was assessed in comparison with control samples, correlated with clinical data of different forms of arthritis, and analyzed for discriminative efficacy between groups by receiver-operation characteristic (ROC) curves. Results were confirmed on diagnostic RA (n = 5) and AS (n = 8) samples. RESULTS: BMP-4, BMP-6, and Runx2 expressions were significantly decreased in patients with RA and OA versus controls. Patients with RA also had decreased FasL and LIGHT expression, while patients with AS had increased Runx2 expression. Negative correlation with disease activity was found for BMP-4, FasL, and Runx2 in RA and for Runx2 in PsA, while positive correlation was found for BMP-4 in PsA. Gene expression was higher in the therapy-resistant form of AS (for BMP-4, LIGHT, and Runx2) and in methotrexate-treated patients in RA (for BMP-2 and LIGHT). ROC curve analysis confirmed discrimination between groups, particularly decreased LIGHT and Runx2 for RA and increased Runx2 for AS. CONCLUSION: Our study identified BMP and Runx2 as possible biomarkers of bone metabolism in several forms of arthritis, while lower FasL and LIGHT were associated with RA. Correlation between gene expression and disease activity may be clinically useful in assessing therapeutic effectiveness and disease monitoring.