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ID PMID Title PublicationDate abstract
23202984 Structural analysis of the inhibition of APRIL by TACI and BCMA through molecular dynamics 2013 Feb APRIL (a proliferation-inducing ligand) is a member of the tumour necrosis factor (TNF) superfamily that binds the receptors (TNFRs) TACI and BCMA. Since it was discovered, a great amount of evidence has been reported about the involvement of APRIL in autoimmune diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS) and multiple sclerosis (MS). In addition, an important role of APRIL has been described in different types of tumour cell lines and in a variety of primary tumour tissues where, in contrast with the normal ones, high mRNA levels have been detected. Accordingly, the design of compounds mimicking the inhibition of APRIL by its receptors appears to be a promising way to treat autoimmune and cancer diseases. As a first step to achieve these goals and in order to better understand the key interactions involved in these systems, we report a structural analysis of the inhibition of human and murine APRIL by its human receptors TACI and BCMA obtained by molecular dynamics simulations. Although most of the key interactions can be obtained from the existing experimental information, new described interactions between human APRIL and its receptors can contribute to a better design of APRIL inhibitors.
23026290 Gleditsioside B, a triterpene saponin isolated from the anomalous fruits of Gleditsia sine 2013 Jan Angiogenesis has become an attractive target for the treatment of certain diseases such as cancer and rheumatoid arthritis. Our previous studies demonstrated that the saponin fraction from Gleditsia sinensis fruits had anti-angiogenic potential, and Gleditsiosides B (GB) was probably the main active constituent. In the present study, we assessed the effect of GB on endothelial cell migration, a crucial event in angiogenesis, and explored the underlying mechanisms. The migration of endothelial cells was assessed by transwell. The expressions of MMP-2/-9 and TIMP-1/-2 were analyzed by Western blotting, and the activities of MMP-2/-9 were detected by gelatin zymography assay. Moreover, migration-related proteins and signaling pathways, including FAK, MAPKs and PI3K/AKT, were analyzed by Western blotting. It was shown that GB, at a concentration of 10 μM without significant cytotoxicity, could effectively abrogate the migration of human umbilical vein endothelial cells (HUVECs) induced by bFGF. GB also inhibited the expression and activity of MMP-2, elevated the expression of TIMP-1, and restrained the phosphorylations of FAK, ERK, PI3K and AKT in a concentration-dependent manner. The findings suggest that GB was able to abrogate the migration of endothelial cells through down-regulating the activation of MMP-2 and FAK via preventing ERK and PI3K/AKT signaling pathways.
22956446 Confounding in the association of proton pump inhibitor use with risk of community-acquire 2013 Feb BACKGROUND: Use of proton pump inhibitors (PPIs) is associated with community-acquired pneumonia (CAP), an association which may be confounded by unobserved patient and prescriber characteristics. OBJECTIVE: We assessed for confounding in the association between PPI use and CAP by using a 'falsification approach,' which estimated whether PPI use is also implausibly associated with other common medical conditions for which no known pathophysiologic link exists. DESIGN: Retrospective claims-based cohort study. SETTING: Six private U.S. health plans. SUBJECTS: Individuals who filled at least one prescription for a PPI (N = 26,436) and those who never did (N = 28,054) over 11 years. INTERVENTIONS: Multivariate linear regression of the association between a filled prescription for a PPI and a diagnosis of CAP in each 3-month quarter. In falsification analyses, we tested for implausible associations between PPI use in each quarter and rates of osteoarthritis, chest pain, urinary tract infection (UTI), deep venous thrombosis (DVT), skin infection, and rheumatoid arthritis. Independent variables included an indicator for whether a prescription for a PPI was filled in a given quarter, and quarterly indicators for various co-morbidities, age, income, geographic location, and marital status. KEY RESULTS: Compared to nonusers, those ever using a PPI had higher adjusted rates of CAP in quarters in which no prescription was filled (68 vs. 61 cases per 10,000 persons, p < 0.001). Similar associations were noted for all conditions (e.g. chest pain, 336 vs. 282 cases, p < 0.001; UTI, 151 vs. 139 cases, p < 0.001). Among those ever using a PPI, quarters in which a prescription was filled were associated with higher adjusted rates of CAP (111 vs. 68 cases per 10,000, p < 0.001) and all other conditions (e.g. chest pain, 597 vs. 336 cases, p < 0.001; UTI, 186 vs. 151 cases, p < 0.001), compared to quarters in which no prescription was filled. CONCLUSION: PPI use is associated with CAP, but also implausibly associated with common medical conditions. Observed associations between PPI use and CAP may be confounded.
22941566 Association between the CD226 rs763361 polymorphism and susceptibility to autoimmune disea 2012 Dec OBJECTIVE: The aim of this study was to explore whether the CD226 rs763361 polymorphism confers susceptibility to autoimmune diseases. METHODS: A meta-analysis was conducted on the associations between the CD226 rs763361 polymorphism and autoimmune diseases using: 1) allele contrast, and 2) the recessive, 3) dominant and 4) additive models. RESULTS: Ten articles that included 17 comparative studies on a total of 8900 patients and 10,295 controls were included in the meta-analysis. These studies were performed on seven European, five Asian and five South American sample populations. Meta-analysis of all study subjects revealed an association between the CD226 rs763361 T allele and the susceptibility to autoimmune diseases (odds ratio; OR 1.162, 95% confidence interval; CI 1.097-1.230, p < 1.0 × 10(-8)). Stratification by ethnicity indicated an association between the CD226 rs763361 T allele and autoimmune disease in Europeans and South Americans (OR 1.134, 95% CI 1.079-1.191, p = 6.7 × 10(-7); OR 1.308, 95% CI 1.160-1.475, p = 1.1 × 10(-5)) and between the CD226 rs763361 TT genotype and autoimmune disease in Asians (OR 1.366, 95% CI 1.130-1.650, p = 0.001). Disease-specific meta-analysis showed an association between systemic lupus erythematosus (SLE) and the CD226 rs763361 T allele (OR 1.150, 95% CI 1.040-1.271, p = 0.006), but no association between rheumatoid arthritis and the CD226 rs763361 polymorphism (OR for the T allele 1.207, 95% CI 0.913-1.596, p = 0.187). On the other hand, associations were found between the CD226 rs763361 T allele and systemic sclerosis (SSc) and type 1 diabetes (T1D) (OR 1.126, 95% CI 1.020-1.244, p = 0.019; OR 1.353, 95% CI 1.102-1.660, p = 0.004). CONCLUSIONS: This meta-analysis demonstrates the CD226 rs763361 polymorphism confers susceptibility to autoimmune disease in Europeans, South Americans and Asians, and in particular, shows that the CD226 rs763361 polymorphism is associated with SLE, SSc and T1D. These results support the existence of an association between the CD226 gene and a subgroup of autoimmune diseases.
22879895 N-terminal domain of nuclear IL-1α shows structural similarity to the C-terminal domain o 2012 Interleukin-1α (IL-1α) is a proinflammatory cytokine and a key player in host immune responses in higher eukaryotes. IL-1α has pleiotropic effects on a wide range of cell types, and it has been extensively studied for its ability to contribute to various autoimmune and inflammation-linked disorders, including rheumatoid arthritis, Alzheimer's disease, systemic sclerosis and cardiovascular disorders. Interestingly, a significant proportion of IL-1α is translocated to the cell nucleus, in which it interacts with histone acetyltransferase complexes. Despite the importance of IL-1α, little is known regarding its binding targets and functions in the nucleus. We took advantage of the histone acetyltransferase (HAT) complexes being evolutionarily conserved from yeast to humans and the yeast SAGA complex serving as an epitome of the eukaryotic HAT complexes. Using gene knock-out technique and co-immunoprecipitation of the IL-1α precursor with TAP-tagged subunits of the yeast HAT complexes, we mapped the IL-1α-binding site to the HAT/Core module of the SAGA complex. We also predicted the 3-D structure of the IL-1α N-terminal domain, and by employing structure similarity searches, we found a similar structure in the C-terminal regulatory region of the catalytic subunit of the AMP-activated/Snf1 protein kinases, which interact with HAT complexes both in mammals and yeast, respectively. This finding is further supported with the ability of the IL-1α precursor to partially rescue growth defects of snf1Δ yeast strains on media containing 3-Amino-1,2,4-triazole (3-AT), a competitive inhibitor of His3. Finally, the careful evaluation of our data together with other published data in the field allows us to hypothesize a new function for the ADA complex in SAGA complex assembly.
22515979 Immunosuppressive properties of mesenchymal stem cells: advances and applications. 2012 Jun Mesenchymal stem cells (MSCs) have been isolated from a variety of tissues, such as bone marrow, skeletal muscle, dental pulp, bone, umbilical cord and adipose tissue. MSCs are used in regenerative medicine mainly based on their capacity to differentiate into specific cell types and also as bioreactors of soluble factors that will promote tissue regeneration from the damaged tissue cellular progenitors. In addition to these regenerative properties, MSCs hold an immunoregulatory capacity, and elicit immunosuppressive effects in a number of situations. Not only are they immunoprivileged cells, due to the low expression of class II Major Histocompatibilty Complex (MHC-II) and costimulatory molecules in their cell surface, but they also interfere with different pathways of the immune response by means of direct cell-to-cell interactions and soluble factor secretion. In vitro, MSCs inhibit cell proliferation of T cells, B-cells, natural killer cells (NK) and dendritic cells (DC), producing what is known as division arrest anergy. Moreover, MSCs can stop a variety of immune cell functions: cytokine secretion and cytotoxicity of T and NK cells; B cell maturation and antibody secretion; DC maturation and activation; as well as antigen presentation. It is thought that MSCs need to be activated to exert their immunomodulation skills. In this scenario, an inflammatory environment seems to be necessary to promote their effect and some inflammation-related molecules such as tumor necrosis factor-α and interferon-γ might be implicated. It has been observed that MSCs recruit T-regulatory lymphocytes (Tregs) to both lymphoid organs and graft. There is great controversy concerning the mechanisms and molecules involved in the immunosuppressive effect of MSCs. Prostaglandin E2, transforming growth factor-β, interleukins- 6 and 10, human leukocyte antigen-G5, matrix metalloproteinases, indoleamine-2,3-dioxygenase and nitric oxide are all candidates under investigation. In vivo studies have shown many discrepancies regarding the immunomodulatory properties of MSCs. These studies have been designed to test the efficacy of MSC therapy in two different immune settings: the prevention or treatment of allograft rejection episodes, and the ability to suppress abnormal immune response in autoimmune and inflammatory diseases. Preclinical studies have been conducted in rodents, rabbits and baboon monkeys among others for bone marrow, skin, heart, and corneal transplantation, graft versus host disease, hepatic and renal failure, lung injury, multiple sclerosis, rheumatoid arthritis, diabetes and lupus diseases. Preliminary results from some of these studies have led to human clinical trials that are currently being carried out. These include treatment of autoimmune diseases such as Crohn's disease, ulcerative colitis, multiple sclerosis and type 1 diabetes mellitus; prevention of allograft rejection and enhancement of the survival of bone marrow and kidney grafts; and treatment of resistant graft versus host disease. We will try to shed light on all these studies, and analyze why the results are so contradictory.
22482408 [Effect of monocytes activated with lipopolysaccharide on human Th17 cell differentiation] 2012 Apr AIM: To investigate whether monocytes activated with lipopolysaccharide(LPS) have an effect on Th17 cell differentiation in humans, CD4(+) T cell and CD14(+) monocytes activated with LPS were treated in the absence or presence of anti-CD3 mAb with various concentrations at different time points. METHODS: Purification of CD4(+) T cell and CD14(+) monocytes were performed by magnetic cell sorting and cultured together. Cultures were stimulated with LPS alone or anti-CD3 mAb alone or LPS plus anti-CD3 mAb for 3 days. In the anti-CD3 mAb stimulation cells were added different concentrations of LPS. Cells were activated under LPS/anti-CD3 costimulation for 3, 6, or 10 days. The percentage of IL-17(+) T cells and INF-γ(+) T was determined by flow cytometry. RESULTS: LPS or anti-CD3 mAb alone induced only very low levels of IL-17(+) T cells, (1.30 ± 0.19)%, (1.10 ± 0.21)%, respectively. The percentage was substantially higher in the LPS and anti-CD3 mAb costimulationa as much as(2.01 ± 0.46)%. In the presence of 0.1 μg/mL, 1 μg/mL, 10 μg/mL LPS, the proportion of Th17 reached to (1.92 ± 0.21)%, (1.30 ± 0.37)%, (1.01 ± 0.25)%. Low-concentration LPS (0.1 μg/mL) stimulation favored Th17 differentiation. The highest proportion of IL-17(+) T cells was found at day 3(2.13 ± 0.32)%, with levels declining at day 6 and day 10, while, Th1 at day 6(17.45 ± 3.04)%, declining at day 10. CONCLUSION: Low-concentration LPS stimulation plus anti-CD3 mAb in short term support optimal Th17 generation. Nevertheless, this model closely mimics the environment of rheumatoid arthritis in vivo and proposes an effective model for the generation of human Th17 cells.
22426112 LYP inhibits T-cell activation when dissociated from CSK. 2012 Mar 18 Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T-cell antigen receptor (TCR) and are thought to act in a cooperative manner when forming a complex. Here we studied the spatiotemporal dynamics of the LYP-CSK complex in T cells. We demonstrate that dissociation of this complex is necessary for recruitment of LYP to the plasma membrane, where it downmodulates TCR signaling. Development of a potent and selective chemical probe of LYP confirmed that LYP inhibits T-cell activation when removed from CSK. Our findings may explain the reduced TCR-mediated signaling associated with a single-nucleotide polymorphism that confers increased risk for certain autoimmune diseases, including type 1 diabetes and rheumatoid arthritis, and results in expression of a mutant LYP that is unable to bind CSK. Our compound also represents a starting point for the development of a LYP-based treatment of autoimmunity.
22355402 Defective expression and function of the leukocyte associated Ig-like receptor 1 in B lymp 2012 Systemic lupus erythematosus (SLE) is characterized by the production of a wide array of autoantibodies and dysregulation of B cell function. The leukocyte associated Immunoglobulin (Ig)-like receptor (LAIR)1 is a transmembrane molecule belonging to Ig superfamily which binds to different types of collagen. Herein, we have determined the expression and function of LAIR1 on B lymphocyte from SLE patients. LAIR1 expression in peripheral blood B lymphocytes from 54 SLE, 24 mixed connective tissue disease (MCTD), 20 systemic sclerosis (SSc) patients, 14 rheumatoid arthritis (RA) and 40 sex and age matched healthy donors (HD) have been analyzed by immunofluorescence. The effect of LAIR1 ligation by specific monoclonal antibodies, collagen or collagen producing mesenchymal stromal cells from reactive lymph nodes or bone marrow on Ig production by pokeweed mitogen and B cell receptor (BCR)-mediated NF-kB activation was assessed by ELISA and TransAM assay. The percentage of CD20(+) B lymphocytes lacking or showing reduced expression of LAIR1 was markedly increased in SLE and MCTD but not in SSc or RA patients compared to HD. The downregulation of LAIR1 expression was not dependent on corticosteroid therapy. Interestingly, LAIR1 engagement by collagen or collagen-producing mesenchymal stromal cells in SLE patients with low LAIR1 expression on B cells delivered a lower inhibiting signal on Ig production. In addition, NF-kB p65 subunit activation upon BCR and LAIR1 co-engagement was less inhibited in SLE patients than in HD. Our findings indicate defective LAIR1 expression and function in SLE B lymphocytes, possible contributing to an altered control of B lymphocytes behavior.
22083716 Fusion of HSA influences TNF-α neutralizing activity of shTNFRs. 2012 Mar Soluble human tumor necrosis factor receptors (shTNFRI and shTNFRII) are antagonists of tumor necrosis factor-α (TNF-α) and are under clinical investigation as therapy for autoimmune diseases and transplant rejection. However, shTNFRI and shTNFRII are limited for clinical usage because of their short half-lives in vivo. Recombinant TNF-α receptors (infliximab and etanercept) are used in treatment of rheumatoid arthritis and Crohn's disease but are also being tested for a number of other autoimmune diseases. Human serum albumin (HSA) has been used to construct long-acting fusion proteins. Here, we report the effect of fusion of HSA with shTNFRI and with shTNFRII on shTNFR's neutralizing activity against TNF-α. HSA fusion proteins were separately expressed in Pichia pastoris. Purified recombinant shTNFRI-HSA, HSA-shTNFRI and HSA-shTNFRII could block the cytolytic activity of TNF-α in L929 cells, and the fusion at N-terminus of shTNFRI could result in larger degree of activity decline than that at the C-terminus. Activity of three fusion proteins was much weaker than etanercept, which demonstrated that fusion of HSA significantly influenced TNF-α neutralizing activity of shTNFRs. Compared with Fc fragment, HSA fusion technology may therefore not be an ideal strategy in development of long-acting shTNFRs protein drugs.
22063737 Anti-inflammatory potential of an ethyl acetate fraction isolated from Justicia gendarussa 2012 Justicia gendarussa Burm.f. (J. gendarussa) is a plant used as traditional medicine in different parts of India and China to treat inflammatory disorders like rheumatoid arthritis. But its mechanism of anti-inflammatory action is still unclear. Hence in this context, the objective of our study is to reveal the mechanism of anti-inflammatory activity of J. gendarussa which would form an additional proof to the traditional knowledge of this plant. The anti-inflammatory function and mechanism(s) of action was studied in an ethyl acetate fraction isolated from methanolic extract of J. gendarussa roots (EJG). Anti-inflammatory studies were conducted on rats using partitioned fractions isolated from methanolic extract of J. gendarussa roots. In carrageenan-induced rat paw edema, ethyl acetate fraction brought about 80% and 93% edema inhibition at 3rd and 5th hour at a dose of 50 mg/kg, when compared to other extracts and Voveran. We investigated whether EJG inhibits the release of cycloxygenase (COX), 5-lipoxygenase (5-LOX), interleukin-6 (IL-6) and nuclear factor kappa B (NF-κB) in LPS stimulated human peripheral blood mononuclear cells (hPBMCs). Results shows that EJG dose dependently inhibited LPS-activated COX, 5-LOX, IL-6, and NF-κB in hPBMCs. EJG also reduced LPS induced levels of iNOS and COX-2 mRNA expression in hPBMCs. This study provides an insight into the probable mechanism(s) underlying the anti-inflammatory activity of EJG and therefore, we report the first confirmation of the anti-inflammatory potential of this traditionally employed herbal medicine in vitro.
21655952 Functional polymorphism of cyclooxygenase-2 gene (G-765C) in chronic obstructive pulmonary 2012 Mar Cyclooxygenase two (COX-2) is an important enzyme metabolizing arachidonic acid. In contrast to constitutive cyclooxygenase one (COX-1), COX-2 is induced by proinflammatory factors. Polymorphism -765 G/C in COX-2-encoding gene promoter is associated with development of Alzheimer's disease, depression, carcinoma of the pancreas in smokers, breast cancer and rheumatoid arthritis. It is interesting whether the -765 G/C polymorphism in COX-2-encoding gene promoter can be associated with COPD, a disease which is inflammatory in character. It is highly probable as the breast and pancreas cancers, whose associations with the analyzed polymorphism have been studied, are smoking-dependent tumors. Additionally, tobacco smoke has been demonstrated to induce COX-2 in the lungs. The study group consisted of 122 COPD patients (48 females, 74 males). The control group consisted of 149 healthy nonsmoking subjects (83 females, 66 males). Polymerase chain reaction/restriction fragment length polymorphism was used for genotyping. A statistically significant difference in genotype distribution was observed as a result of the comparison between healthy subjects and patients with COPD. The distribution of alleles in both groups conformed with Hardy-Weinberg equilibrium. In the group of COPD patients, GG allele was found in 79 subjects, GC in 36, and CC in 7 subjects (F = 0.094, P = 0.296927); in the control group, 73 subjects had GG allele, 68--GC and 8--CC (F = 0.12728, P = 0.120265). The allele frequency revealed differences between those groups, attaining the level of statistical significance (χ(2) = 29.043, df = 2, P = 0.0000. The carriers of -765 G allele are at 1.53-fold higher risk of developing COPD. The presence of GG genotype does not increase significantly the risk of the disease. It is also noteworthy that the carriers of CC or GC genotypes are at significantly lower risk of developing COPD than the group of subjects with GG genotype.
21656983 Poly(ethylene glycol)-coated gold nanocages. 2004 Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (700–1,000 nm) detection avoids the background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have a wider dynamic range and minimal background as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low infrared background, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence imaging is becoming a noninvasive alternative to radionuclide imaging in small animals (4, 5). Photoacoustic imaging (PAI) is an emerging hybrid biomedical imaging modality based on the photoacoustic effect. In PAI, non-ionizing optical pulses are delivered into biological tissues. Some of the delivered energy is absorbed and converted into heat, leading to transient thermoelastic expansion and thus ultrasonic emission. The generated ultrasonic waves are then detected by ultrasonic transducers to form images. It is known that optical absorption is closely associated with physiological properties, such as hemoglobin concentration and oxygen saturation. As a result, the magnitude of the ultrasonic emission (i.e., the photoacoustic signal), which is proportional to the local energy deposition, reveals physiologically specific optical absorption contrast and tissue structures. However, exogenous NIR contrast agents are necessary to overcome the intrinsic low tissue- and hemoglobin-absorption and scattering of tissue. On the other hand, these small molecules exhibit fast clearance, small optical absorption cross section, and non-targeted specificity. Therefore, there is a need for contrast agents with long blood circulation and targeted specificity. Gold (Au) nanoparticles have been studied as molecular imaging agents because of their bright NIR fluorescence emission around 700–900 nm and low toxicity (6, 7). They can be tuned to emit in a range of wavelengths by changing their sizes, shapes, and composition, thus providing broad excitation profiles and high absorption coefficients. They can be coated and capped with hydrophilic materials for additional conjugation with biomolecules, such as peptides, antibodies, nucleic acids, and small organic compounds for in vitro and in vivo studies. Au nanoparticles have been approved by the United States Food and Drug Administration for treatment of patients with rheumatoid arthritis. Au nanoparticles have been studied as contrast agents in X-ray/computed tomography, NIR optical coherence tomography, PAI, and photoacoustic tomography (PAT) (8). NIR Au nanocages (AuNCs) are biocompatible, have low toxicity, and are tunable to strong NIR absorption (9). They have an outer edge of ~50 nm and an inner edge of ~42 nm, with a wall thickness of ~4 nm. Yang et al. (10) performed PAT of the cerebral cortex of rats with poly(ethylene glycol)-coated AuNCs (PEG-AuNCs) as the optical contrast agent. The investigators observed an enhanced optical contrast in the vasculature in the cerebral cortex.
21964043 [Prevalence of osteoporosis in male patients with risk factors]. 2011 Nov Male osteoporosis is often secondary to other conditions. However the causes of osteoporosis in men are dramatically variable according to the authors. The aim of this observational multicenter study was to assess the main risk factors and causes for male patients with low bone mineral density (LBM). METHODS: The study was performed in a cohort of rheumatologists who usually prescribe bone mineral density assessment according to HAS criteria (one or more criteria) for bone mineral density (BMD) measurement as defined by: (a): vertebral fracture; (b): non traumatic non vertebral fracture; (c): corticosteroid therapy; (d): hypogonadism or GnRH agonist therapy; (e): endocrine disorders; (f): osteogenesis imperfecta (OI). BMD was measured by dual photon absorptiometry (DXA) at lumbar spine, femoral or total neck sites. Osteoporosis was defined as a T-score value less or equal to 2.5 at one of those region of interest (ROI); LBM as a T-score value between -1 and -2.5. RESULTS: A total of 431 rheumatologists included 1198 male patients (66.6 ± 12.2 years). According to DXA results, 888 patients (74.1 %) had osteoporosis and 231 (19.3 %) had osteopenia. BMD was considered as normal for 79 patients (6.6 %). A total of 1146 patients (95.7 %) satisfied to the criteria of reimbursement of DXA measurement. Six hundred and eighty-six patients (57.3 %) had suffered from vertebral fractures and 349 patients (29.2 %) from non vertebral fractures. Corticosteroids had been prescribed in 28.7 % of patients and 6.6 % were treated with GnRH agonists for prostate cancer. Hypogonadism was diagnosed in 27 %. Five patients suffered from OI. Other risk factors were detected: alcoholism and smoking in 28.1 % and 42.9 % respectively; rheumatoid arthritis or spondylarthropathy in 12.5 % of patients; chronic pulmonary disorders in 16.1 %. By contrast endocrinopathies were rare (2.5 %). Several risk factors were more frequently encountered for patients with osteoporosis as compared with osteopenia, i.e., smoking, alcohol abuse, low calcium intake, vitamin D insufficiency and maternal history of hip fracture. CONCLUSION: A diagnosis of osteoporosis (BMD ≤ 2.5) was established by rheumatologists in 74.1 % of patients with clinical risk factors: LBM was found in 93.4 %. In 95.7 % the criteria for reimbursement of DXA measurement were satisfied. DXA is useful in male patients with classical risk factors of osteoporosis to confirm the diagnosis of the disease and start a treatment.
21683641 Anti-mutated citrullinated vimentin (anti-MCV) and anti-65 kDa heat shock protein (anti-hs 2012 Jan INTRODUCTION: Citrullination as well as anti-citrullinated protein/peptide antibodies (ACPA) have been implicated in the pathogenesis of rheumatoid arthritis (RA). While ACPAs are specific and sensitive markers for RA, there have been hardly any reports regarding ACPAs in ankylosing spondylitis (AS). The possible role of antibodies to Mycobacterial 65 kDa heat shock protein (hsp65) has not been characterized in AS. As new laboratory biomarkers of AS are needed, we investigated the prevalence of anti-mutated citrullinated vimentin (MCV) and anti-hsp65 antibodies in AS. METHODS: Altogether 43 AS and 44 healthy controls were included in the study. Anti-MCV and anti-hsp65 were determined in sera by commercial and in-house ELISA, respectively. Serum autoantibody levels were correlated with ESR, CRP, HLA-B27 status, smoking habits, pain intensity, BASDAI, BASFI and BASMI indices. RESULTS: Patients with AS had significantly higher serum anti-MCV levels (17.3 U/mL, range: 8.3-31.5 U/mL) in comparison to healthy subjects (8.9 U/mL, range: 5.4-13.3 U/mL) (p<0.01). Sixteen of the 43 AS patients (37%) and none of the 44 healthy controls (0%) were anti-MCV positive using the cut-off value recommended by the manufacturer (>20 U/mL). The mean anti-hsp65 concentration in AS sera was 124.8 AU/mL (range: 27.2-1000 AU/mL), while controls exerted significantly lower anti-hsp65 levels (mean: 51.8 AU/mL; range: 22.5-88.5 AU/mL) (p<0.001). Correlation analysis revealed that both anti-MCV positivity (r=0.613; p=0.012) and absolute serum anti-MCV levels (r=0.553; p=0.021) correlated with anti-hsp65 levels. Anti-MCV positivity also correlated with ESR (r=0.437; p=0.03). CONCLUSIONS: Anti-MCV and anti-hsp65 may be novel biomarkers in AS.
21656989 Gold nanocages. 2004 Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets (1-3). However, the intrinsic fluorescence of biomolecules poses a problem when fluorophores that absorb visible light (350–700 nm) are used. Near-infrared (NIR) fluorescence (700–1,000 nm) detection avoids the background fluorescence interference of natural biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have a wider dynamic range and minimal background as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low infrared background, and high extinction coefficients, which provide high quantum yields. The NIR region is also compatible with solid-state optical components, such as diode lasers and silicon detectors. NIR fluorescence imaging is becoming a noninvasive alternative to radionuclide imaging in small animals (4, 5). Photoacoustic imaging (PAI) is an emerging hybrid biomedical imaging modality based on the photoacoustic effect. In PAI, non-ionizing optical pulses are delivered into biological tissues. Some of the delivered energy is absorbed and converted into heat, leading to transient thermoelastic expansion and thus ultrasonic emission. The generated ultrasonic waves are then detected by ultrasonic transducers to form images. It is known that optical absorption is closely associated with physiological properties, such as hemoglobin concentration and oxygen saturation. As a result, the magnitude of the ultrasonic emission (i.e., the photoacoustic signal), which is proportional to the local energy deposition, reveals physiologically specific optical absorption contrast and tissue structures. However, exogenous NIR contrast agents are necessary to overcome the intrinsic low tissue- and hemoglobin- absorption and scattering of tissue. On the other hand, these small molecules exhibit fast clearance, small optical absorption cross section, and non-targeted specificity. Therefore, there is a need for contrast agents with long blood circulation and targeted specificity. Gold (Au) nanoparticles have been studied as molecular imaging agents because of their bright NIR fluorescence emission around 700–900 nm and low toxicity (6, 7). They can be tuned to emit in a range of wavelengths by changing their sizes, shapes, and composition, thus providing broad excitation profiles and high absorption coefficients. They can be coated and capped with hydrophilic materials for additional conjugation with biomolecules, such as peptides, antibodies, nucleic acids, and small organic compounds for in vitro and in vivo studies. Au nanoparticles have been approved by the United States Food and Drug Administration for treatment of patients with rheumatoid arthritis. Au nanoparticles have been studied as contrast agents in X-ray/computed tomography, NIR optical coherence tomography, PAI, and photoacoustic tomography (PAT) (8). NIR Au nanocages are biocompatible, have low toxicity, and are tunable to strong NIR absorption (9). They have an outer edge of ~50 nm and an inner edge of ~42 nm, with a wall thickness of ~4 nm. Yang et al. (10) performed PAT of the cerebral cortex of rats with poly(ethylene glycol)-coated Au nanocages (PEG-AuNCs) as the optical contrast agent. The investigators observed an enhanced optical contrast in the vasculature in the cerebral cortex. Song et al. (11) demonstrated the use of Au nanocages as a PAI probe for detection of sentinel lymph node (SLN) of rats.
21595126 (68)Ga-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-cyclo(Arg-Gly-Asp-D-Phe-Ly 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Dijkgraaf et al. (13) reported the development of (111)In-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-Glu-cyclo(Arg-Gly-Asp-D-Phe-Lys) ((111)In-DOTA-E-c(RGDfK)) for single-photon emission computed tomography imaging α(v)β(3) receptors in nude mice bearing ovarian carcinoma tumors. In this chapter, Dijkgraaf et al. (14) also reported the evaluation of (68)Ga-DOTA-E-c(RGDfK) for positron emission tomography (PET) imaging α(v)β(3) receptors in tumor, which is the topic of this chapter.
21553931 Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and cli 2011 Jun Non-steroidal anti-inflammatory drug (NSAID) intake is associated with high prevalence of gastrointestinal or cardiovascular adverse effects. All efforts to develop NSAIDs that spare the gastrointestinal tract and the cardiovasculature are still far from achieving a breakthrough. In the last two decades, preparations of the gum resin of Boswellia serrata (a traditional ayurvedic medicine) and of other Boswellia species have experienced increasing popularity in Western countries. Animal studies and pilot clinical trials support the potential of B. serrata gum resin extract (BSE) for the treatment of a variety of inflammatory diseases like inflammatory bowel disease, rheumatoid arthritis, osteoarthritis and asthma. Moreover, in 2002 the European Medicines Agency classified BSE as an 'orphan drug' for the treatment of peritumoral brain oedema. Compared to NSAIDs, it is expected that the administration of BSE is associated with better tolerability, which needs to be confirmed in further clinical trials. Until recently, the pharmacological effects of BSE were mainly attributed to suppression of leukotriene formation via inhibition of 5-lipoxygenase (5-LO) by two boswellic acids, 11-keto-β-boswellic acid (KBA) and acetyl-11-keto-β-boswellic acid (AKBA). These two boswellic acids have also been chosen in the monograph of Indian frankincense in European Pharmacopoiea 6.0 as markers to ensure the quality of the air-dried gum resin exudate of B. serrata. Furthermore, several dietary supplements advertise the enriched content of KBA and AKBA. However, boswellic acids failed to inhibit leukotriene formation in human whole blood, and pharmacokinetic data revealed very low concentrations of AKBA and KBA in plasma, being far below the effective concentrations for bioactivity in vitro. Moreover, permeability studies suggest poor absorption of AKBA following oral administration. In view of these results, the previously assumed mode of action - that is, 5-LO inhibition - is questionable. On the other hand, 100-fold higher plasma concentrations have been determined for β-boswellic acid, which inhibits microsomal prostaglandin E synthase-1 and the serine protease cathepsin G. Thus, these two enzymes might be reasonable molecular targets related to the anti-inflammatory properties of BSE. In view of the results of clinical trials and the experimental data from in vitro studies of BSE, and the available pharmacokinetic and metabolic data on boswellic acids, this review presents different perspectives and gives a differentiated insight into the possible mechanisms of action of BSE in humans. It underlines BSE as a promising alternative to NSAIDs, which warrants investigation in further pharmacological studies and clinical trials.
21212376 Validity and responsiveness of presenteeism scales in chronic work-related upper-extremity 2011 Feb BACKGROUND: The Work Limitations Questionnaire-25 (WLQ-25) and the Work Instability Scale for Rheumatoid Arthritis (RA-WIS) have been used to measure at-work disability related to musculoskeletal disorders. However, a recent systematic review has shown that important psychometric properties still needed to be evaluated. OBJECTIVE: The purpose of this study was to establish the validity and responsiveness of the WLQ-25 and RA-WIS in people with chronic work-related upper-extremity disorders. DESIGN: Two-hundred six participants with chronic upper-extremity disorders who attended a specialty clinic operated by the Workplace Safety & Insurance Board of Ontario were evaluated at their initial visit and 6 months later. METHODS: Questionnaires completed at each evaluation were: the WLQ-25, the RA-WIS, the QuickDASH, the pain subscale of the Shoulder Pain and Disability Questionnaire, and the Chronic Pain Grade Questionnaire. At the 6-month evaluation, participants completed a global rating of change question. Known-group and construct convergent validity were assessed using analysis of variance and Pearson correlations, and standardized response means (SRMs) were used to assess responsiveness. Clinically important differences (CIDs) also were determined. RESULTS: The WLQ-25 and RA-WIS had low to moderate correlations with pain and disability scales (.28
21130161 Essential role of neutrophil mobilization in concanavalin A-induced hepatitis is based on 2011 Mar Neutrophil depleted mice are protected from concanavalin A-mediated hepatitis, showing that neutrophils are critical for cellular liver damage. Interleukin-6 has pro- and anti-inflammatory properties and mediates neutrophil recruitment in diseases such as rheumatoid arthritis. In classic signaling, interleukin-6 binds to the membrane-bound interleukin-6-receptor and initiates signaling via gp130. In interleukin-6 trans-signaling, the agonistic soluble interleukin-6-receptor can form a soluble interleukin-6/interleukin-6-receptor complex and stimulate cells which only express gp130 but no interleukin-6-receptor. Interleukin-6 trans-signaling was shown to be important for liver regeneration and development of liver adenomas. Here, we show that blocking classic interleukin-6 signaling but not interleukin-6 trans-signaling reduced concanavalin A-induced liver damage in mice, with reduced liver STAT3 phosphorylation and liver neutrophil accumulation. However, the level of neutrophil-attracting chemokine KC is only reduced by inhibition of interleukin-6 trans-signaling. Analysis of circulating neutrophils after concanavalin A challenge revealed that classic interleukin-6 signaling is required for the mobilization of blood neutrophils. Reduced neutrophil infiltration was accompanied by increased levels of hepatoprotective monocyte chemoattractant protein-1 and reduced level of hepatodestructive interleukin-4. Abrogated classic interleukin-6 signaling in concanavalin A-mediated hepatitis exhibited liver-protective effects indicating that interleukin-6 classic but not interleukin-6 trans-signaling is responsible for liver damage. Classic interleukin-6 signaling is required to mount an efficient neutrophilia during concanavalin A-induced immune response, which might have clinical implications in the regard that blocking global interleukin-6 signaling pathways is a treatment option in different chronic inflammatory diseases.