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ID PMID Title PublicationDate abstract
20673622 Pro-inflammatory role of Anti-Ro/SSA autoantibodies through the activation of Furin-TACE-a 2010 Sep Prolonged inflammation can be detrimental because it may cause host toxicity and tissue damage. Indeed, excessive production of inflammatory cytokines is often associated with many autoimmune diseases. In this study we demonstrate that the anti-Ro/SSA autoantibodies (Abs) stimulate the production of pro-inflammatory cytokines IL-6 and IL-8 by human healthy salivary gland epithelial cells (healthy SGEC). The secretion of these cytokines is due to amphiregulin (AREG) that is overexpressed in healthy SGEC treated with anti-Ro/SSA Abs and in Sjögren's syndrome. We have discovered that the up-regulation of AREG occurs through TNF-alpha produced following anti-Ro/SSA Abs treatment. The gene silencing technique was used to study the AREG-TNF-alpha-IL-6/IL-8 secretion pathway, demonstrating that: (i) TNF-alpha gene silencing provokes a significant decrease of proinflammatory cytokines production and AREG expression in anti-Ro/SSA Abs-treated healthy SGEC; (ii) AREG gene silencing has a potent inhibitory effect on TNF-alpha-induced IL-6 and IL-8 secretion in healthy SGEC treated with anti-Ro/SSA Abs. These findings indicate that TACE-mediated AREG shedding plays a critical role in TNF-alpha-induced IL-6 and IL-8 secretion by the human healthy salivary gland epithelial cells, suggesting that this may be one of the possible intracellular mechanisms involved in the salivary glands inflammatory response in Sjögren's syndrome.
20336275 [Avascular necrosis of the bone after organ transplantation]. 2010 May Avascular bone necrosis under immunosuppressive therapy is a well known sequel following solid organ transplantation. Most cases affect hip, knees or shoulders in more than one location and occur in connection with the use of high-dose steroids. In this 50 year old female immunosuppressive therapy consisted of sirolimus and mycophenolate mofetil after a renal transplantation 2 years ago. Steroids had been completely withdrawn after avascular necrosis of the femoral head. Physical examination revealed a reddened and painful left ankle. C-reactive protein was elevated while autoimmune antibodies, rheumatoid factor and screening for reactive arthritis remained negative. Joint fluid examination ruled out infection or gout. Plain radiographs were normal. Under the presumptive diagnosis of erysipelas antibiotic therapy was started, however, without success. Magnetic resonance imaging finally revealed bilateral tibial and tarsal bone necrosis as the underlying cause. In conclusion, avascular bone necrosis should remain an important differential diagnosis in patients with bone or joint pain and a history of organ transplantation, regardless of the present use of steroid therapy.
19664141 Cells with regulatory function of the innate and adaptive immune system in primary Sjögre 2009 Sep The aim of the present study was to describe subsets of cells with regulatory properties in primary Sjögren's syndrome (pSS), and to correlate these cell populations with clinical symptoms. Among the 32 investigated patients, 23 had extraglandular manifestations (EGMs), while nine had only glandular symptoms. Twenty healthy individuals served as controls. The percentages of natural killer (NK), natural killer T cells (NK T), interleukin (IL)-10 producing T regulatory type 1 (Tr1) cells and CD4(+)CD25(+) regulatory T cells (T(reg)) cells were determined by flow cytometry and serum cytokine levels of IL-4, IL-6, IL-10, tumour necrosis factor (TNF)-alpha and interferon (IFN)-gamma were evaluated by enzyme-linked immunosorbent assay (ELISA). Functional tests were carried out to assess the suppressor properties of T(reg) cells in patients and controls. Peripheral NK, NK T and Tr1 cell percentages were elevated in pSS, while CD4(+)CD25(+) T(reg) cells showed reduced frequencies in patients compared to controls. In pSS, elevated percentages of NK T, Tr1 and CD4(+)CD25(+) T(reg) cells were observed in patients with EGMs, when compared to patients with sicca symptoms only. CD4(+)CD25(+) T(reg) cell percentages showed a negative correlation with sialometry values. The in vitro functional assay demonstrated lower suppression activity of CD4(+)CD25(+) T(reg) cells in patients compared to controls. Serum IL-6 and TNF-alpha levels were elevated, while IL-10 was decreased in patients compared to controls. Negative correlation was found between IL-10 levels and the percentages of Tr1 cells. Changes in the investigated subsets of regulatory cells in pSS may contribute to the development and progression of the disease.
18571695 Interferon-gamma is increased in patients with primary Sjogren's syndrome and Raynaud's ph 2009 Dec OBJECTIVES: To determine the prevalence of Raynaud's phenomenon (RP) in patients with primary Sjogren's syndrome (pSS) and to identify clinical and immunological characteristics associated with this manifestation. Since increased interferon-gamma (INF-gamma) has been associated with RP, we also compared the INF-gamma production in pSS patients with or without RP. METHODS: RP was diagnosed if pSS patients presented with characteristic sequence of skin color changes of the digits. In uncertain cases noninvasive vascular tests were performed by ultrasound examination. The secretion of INF-gamma by peripheral blood mononuclear cells was assessed by enzyme-linked immunospot analysis. Further, we examined the expression of different lymphocyte activation markers (CD25, CD45RO, CD69) on CD4+ T-cells by flow cytometric analysis. RESULTS: Thirty-six of 108 patients with pSS had RP. In these patients we found a significantly increased number of INF-gamma-secreting peripheral blood mononuclear cells compared with patients without RP or to healthy controls. Further, in patients with RP a significantly increased percentage of CD25-positive T-helper cells was detectable. In addition we found an association of leukopenia, thyroiditis, and lower C3 levels with RP in pSS patients. CONCLUSIONS: These results suggest a pathogenic role of INF-gamma in pSS patients with RP. Whether the RP is immune-mediated or whether INF-gamma directly causes vasospasm still remains to be elucidated.
19208598 Is there an urban-rural divide? Population surveys of rheumatic musculoskeletal disorders 2009 Mar OBJECTIVE: To estimate urban prevalence of rheumatic musculoskeletal (MSK) disorders and compare to an earlier rural regional study. METHODS: We screened 8145 adults from a preselected urban locality in Pune, India, for MSK pain in a cross-sectional house-to-house survey (Stage I) over 20 weeks. The World Health Organization-International League of Associations for Rheumatology (WHO-ILAR) Community Oriented Program for Control of Rheumatic Diseases (COPCORD) Bhigwan model was used. Thirty trained community volunteers completed Phases I and II questionnaires, concurrent with rheumatology evaluation (Phase III). Clinical diagnosis was based on standard diagnosis/classification criteria. Point prevalence rates from our survey and the earlier Bhigwan village (Pune district) survey were standardized (adjusted age-sex to India population census 2001) and are reported for osteoarthritis (OA), rheumatoid arthritis (RA), seronegative spondyloarthritis (SSA), and inflammatory arthritis (IA). RESULTS: One thousand one hundred fifty-two urban cases (65% women) were identified (14.1%, 95% confidence interval 13.4, 14.9). The self-reported pain sites (Phase II) were hip (0.4), knees (6.3), ankle (1.9), feet (0.7), shoulders (2), hands (1.3), wrist (1.2), neck (1.9), upper back (1.7), low back (5.5), thigh (1.5), calf (1.4), and sole (0.8); corresponding rural sites being hip (1.1), knees (13.7), ankle (7), feet (1.6), shoulders (7.9), hands (6.3), wrist (6.9), neck (6.8), upper back (8.4), low back (12.6), thigh (4.8), calf (7.1) and sole (2.2). OA disorders, soft tissue rheumatism (STR) and ill-defined aches and pains were predominant in both surveys; < 10% reported IA. The major disorders among urban cases were OA (4), STR (1.2), RA (0.2, ACR criteria 1988), undifferentiated IA (0.3), SSA (0.3), and gout (0.06); corresponding rates in Bhigwan were OA (6.3), STR (3.8), RA (0.5), undifferentiated IA (0.8), SSA (0.3), and gout (0.1). Infections were conspicuously absent. CONCLUSION: While similar in spectrum, standardized prevalence rates of self-reported pain sites and rheumatic MSK disorders were significantly lower in the urban (current Pune COPCORD surveys) versus rural (Bhigwan) community, and in both communities aches and pains that are poorly understood by modern science were predominant.
19686606 Development and validation of the self-administered Fibromyalgia Assessment Status: a dise 2009 INTRODUCTION: The Fibromyalgia Impact Questionnaire (FIQ) is a composite disease-specific measure validated for fibromyalgia (FM), but it is rarely used in clinical practice. The objective was to develop and analyse the psychometric properties of a new composite disease-specific index (Fibromyalgia Assessment Status, FAS), a simple self-administered index that combines a patient's assessment of fatigue, sleep disturbances and pain evaluated on the basis of the 16 non-articular sites listed on the Self-Assessment Pain Scale (SAPS) in a single measure (range 0 to 10). METHODS: The FAS index was constructed using a traditional development strategy, and its psychometric properties were tested in 226 FM patients (209 women, 17 men); whose disease-related characteristics were assessed by means of an 11-numbered circular numerical rating scale (NRS) for pain, fatigue, sleep disturbances and general health (GH), the tender point score (TPS), the SAPS, the FIQ, and the SF-36. A group of 226 rheumatoid arthritis (RA) patients was used for comparative purposes. Of the 179 FM patients who entered the follow-up study, 152 completed the three-month period and were included in the responsiveness analyses. One hundred and fifty-four patients repeated the FAS questionnaire after an interval of one week, and its test/re-test reliability was calculated. Responsiveness was evaluated on the basis of effect size and the standardised response mean. RESULTS: The FAS index fulfilled the established criteria for validity, reliability and responsiveness. Factor analysis showed that SAPS and fatigue contributed most, and respectively explained 47.4% and 31.2% of the variance; sleep explained 21.3%. Testing for internal consistency showed that Cronbach's alpha was 0.781, thus indicating a high level of reliability. As expected, closer significant correlations were found when FAS was compared with total FIQ (rho = 0.347; P < 0.0001) and the FIQ subscales, particularly job ability, tiredness, fatigue and pain (all P < 0.0001), but the correlation between FAS and the mental component summary scale score (MCS) of the SF-36 (rho = -0.531; P < 0.0001) was particularly interesting. Test/re-test reliability was satisfactory. The FAS showed the greatest effect size. The magnitude of the responsiveness measures was statistically different between FAS (0.889) and the FIQ (0.781) (P = 0.038), and between the SF-36 MCS (0.434) and the SF-36 physical component summary scale score (PCS) (0.321) (P < 0.01). CONCLUSIONS: The self-administered FAS is a reliable, valid and responsive disease-specific composite measure for assessing treatment effect in patients with FM.
20190473 Distinct clinical courses in type 1 diabetes mellitus induced by peg-interferon-alpha trea 2010 We report two cases of type 1 diabetes mellitus (T1DM) which developed after interferon (IFN) therapy for chronic hepatitis C. The patients had experienced abrupt hyperglycemia with positive anti-glutamic acid decarboxylase antibodies, resulting in initiation of insulin therapy. In one case, insulin therapy could be discontinued because endogenous insulin secretion was preserved at the onset and pancreatic beta cell function was recovered thereafter. In the other case with Hashimoto's thyroiditis and Sjögren's syndrome, continuation of insulin therapy was necessary because blood glucose levels were unstably controlled. Lasting autoimmunity superior to immunosuppressive mechanism may be associated with distinct clinical courses in these cases.
18800250 Quantification and molecular characterization of regulatory T cells in connective tissue d 2009 Jan The aim of our study was to investigate and characterize regulatory T cells (Treg) in peripheral blood of patients with connective tissue diseases (Systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome, poly- and dermatomyositis) as compared with blood from healthy controls. Treg cells were quantified and phenotypically characterized by flow cytometry while the expression level of Foxp3 mRNA was evaluated by real time PCR. A reduced percentage of peripheral blood Treg cells was found in patients than in controls, irrespective of the type of connective tissue disease. Treg cells, especially those expressing one of the phenotypical markers, seemed to differ not only between patients and healthy controls but also among types of diseases. Additionally, the presence of autoantibodies as well as disease activity appeared to be correlated with particular Treg cell populations, especially those expressing one of the examined phenotypical markers. Correlations with therapy suggested that glucocorticoids plus antimalarial or other immunosuppressor drugs diminished the percentage of Treg cells, especially of those with memory phenotype. These findings indicated dysregulations at the level of Treg cells and suggested an involvement of these cells in the pathology of connective tissue diseases. Moreover, our data are in agreement with the suggestion that Treg cells could be therapeutic targets for some autoimmune diseases.
19838329 RNA recognition motif (RRM) of La/SSB: the bridge for interparticle spreading of autoimmun 2010 Jan Systemic lupus erythematosus (SLE) is characterized by the production of grouped sets of autoantibodies targeting mainly the U1 ribonucleoprotein (RNP) and/or Ro/La RNP particles. Intraparticle diversification of the autoimmune response is believed to occur via epitope spreading. So far, it is not known how the autoimmune response "jumps" from one particle to another. To the extent that the majority of nuclear autoantigens in SLE are RNA binding proteins and major epitopes were previously mapped within their RRM (RNA recognition motifs), conserved sequences within RRM could be involved in the intermolecular and inter-particle diversification process of the autoimmune response. We investigated the potential of RRM of the La/SSB autoantigen to induce antibodies that cross-recognize components of the U1-RNP particle and therefore its capacity to produce interparticle epitope spreading. We immunized New Zealand white rabbits with a peptide corresponding to the epitope 145-164 of La/SSB (belonging to the RRM of La/SSB), attached in four copies on a scaffold carrier. Sera were drawn from 20 sera of patients with SLE and anti-U1-RNP antibodies and 26 sera of primary Sjögren syndrome patients with anti-La/SSB antibodies. All sera were evaluated for reactivity against the major epitope of La/SSB (pep349-364), the RNP antigen and the RRM-related epitope of La/SSB (pep145-164). Specific antibodies against pep145-164 were purified with immunoaffinity columns from selected sera. After the immunization of the animals with pep145-164, a specific IgG antibody response was detected, directed against the La/SSB autoantigen (wks 3-7), the immunizing peptide (wks 3-27), and the RNP autoantigen (wks 7-20). This response gradually decreased to low levels between postimmunization wks 27-42. Purified antibodies against pep145-164 recognized La/SSB and a 70-kD autoantigen in Western blot and exhibited significant reactivity in anti-U1-RNP ELISA. Depletion of anti-pep145-164 antibodies eliminated anti-U1-RNP reactivity from immunized rabbit sera but not from human sera. In addition, pep145-164 was recognized to a greater extent by autoimmune sera with anti-RNP reactivity compared with anti-La/SSB-positive sera, in contrast to pep349-364 of La/SSB, which was recognized almost exclusively by sera with anti-La/SSB reactivity. These data suggest that the RRM region of La/SSB can trigger interparticle B-cell diversification to U1-RNP-70 autoantigen via molecular mimicry. Identification of key sequences that trigger and perpetuate the autoimmune process is particularly important for understanding pathogenetic mechanisms in autoimmunity.
19697095 A case of Mikulicz's disease with Th2-biased cytokine profile: possible feature discrimina 2009 This article concerns a male patient with Mikulicz's disease (MD) accompanied with marked elevation of serum immunoglobulin (Ig)G4 and IgE levels. His peripheral blood mononuclear cells (PBMC) showed markedly enhanced in vitro production of interleukin (IL)-4, IL-5, IL-13, but not interferon gamma (IFN-gamma) compared with patients with Sjögren's syndrome (SS) and healthy donors, suggesting distinct Th2 bias in this MD patient. Besides the prominent infiltration of IgG4-producing plasma cells, the enhanced expression of both CD40 and CD40 ligand (CD40L) were observed in the swollen salivary gland of the MD patient, suggesting enhanced signaling pathways for the induction of IgG4 and IgE switching. Possible differences between MD and SS in light of their underlying pathogenesis are discussed.
19680106 The relationship between back pain and future vertebral fracture in postmenopausal women. 2009 Aug 15 STUDY DESIGN: Cross sectional and prospective observational study in Japanese postmenopausal women. OBJECTIVE: The aim of the study was 2-fold. The first was to investigate what kind of comorbidities could be found in conjunction with back pain in Japanese postmenopausal women. The second was to investigate whether significant relationship between baseline back pain and future fracture exists or not. SUMMARY OF BACKGROUND DATA: Back pain has been reported to be associated with vertebral degeneration or vertebral fracture. However, there has been no available data that indicates the relationship between back pain and future fracture risks. METHODS: The subjects who visited their practitioner were examined for their prevalent back pain or pains in other site. Bone mineral density, body height, body weight, and serum parameter were measured at baseline, and comorbidities were investigated by interview. Fragility fractures were also assessed at baseline and then followed up with 1- to 2-year intervals. The correlation between back pain and baseline characteristics was investigated by logistic regression analysis. The hazard ratio of back pain to future vertebral fracture was estimated by multivariate Cox regression analysis. RESULTS: A total of 899 postmenopausal ambulatory women (62.5 +/- 10.3 years old) were enrolled and 81 subjects were dropped out from the study within 1 year. The remaining 818 postmenopausal women (62.1 +/- 10.3 years) were followed-up for 5.7 +/- 3.5 years. Compared to the group without pain, the group with back pain had significantly higher age, lower bone mineral densities at lumbar spine and hip, and higher number of prevalent vertebral fractures. The back pain was significantly associated with rheumatic arthritis (odds ratio [OR]: 2.01, P < 0.05), prevalent vertebral fracture (OR: 4.60, P < 0.001) and osteoporosis (OR: 2.14, P < 0.001). A total of 189 future fractures were observed, of which the most frequent was vertebral fractures (78.3%). The fact that baseline back pain was a significant risk factor for time-dependent vertebral fractures (hazard ratio: 1.62, 95% confidence interval: 1.16-2.27, P = 0.005) was demonstrated by the Cox hazards model after adjusting for traditional risk factors, such as age, bone mineral density, and prevalence of vertebral fractures. CONCLUSION: The data obtained in this study indicated that the back pain is significantly associated with osteoporosis and rheumatoid arthritis and that it can be useful predictor for future vertebral fracture risk in Japanese postmenopausal women in clinical settings.
19570209 Increased production of soluble CTLA-4 in patients with spondylarthropathies correlates wi 2009 INTRODUCTION: Spondylarthropathies (SpA) are characterized by abnormal immune responses including T cell activation. Cytotoxic T lymphocyte associated molecule-4 (CTLA-4) is involved in down-regulating immune responses. A soluble form of CTLA-4 (sCTLA-4), resulting from an alternative splicing, has been identified and was found increased in several autoimmune diseases. Here, we evaluated circulating levels of sCTLA-4 as a marker of immune dysregulation in SpA. Intracellular CTLA-4 and levels of CTLA-4 transcript expression in peripheral blood lymphocytes (PBL) were also studied. METHODS: Sera from 165 patients with SpA were evaluated for sCTLA-4 measurements. Results were compared with those from 71 patients with rheumatoid arthritis (RA) and 88 healthy subjects. In 32 patients with SpA, 22 patients with RA and 15 healthy controls, we analyzed the intracellular CTLA-4 expression in CD4+ T cells, CD8+ T cells, activated (HLA-DR+Foxp3-) CD4+ T cells, CD4+ regulatory (CD25+Foxp3+) T cells and in CD3 negative cells by flow cytometry. Expression of the full length (coding for membrane CTLA-4) and spliced form (coding for sCTLA-4) of CTLA-4 transcripts in PBL were analyzed by quantitative real-time polymerase chain reaction (QRT-PCR). RESULTS: High levels of sCTLA-4 were found in the SpA group compared to the RA group and healthy controls (P < 0.0001). Soluble CTLA-4 serum levels strongly correlated with clinical index of disease activity BASDAI (r = 0.42, P < 0.0001) and C-reactive protein (CRP) levels (r = 0.17, P = 0.037). In contrast to RA patients, SpA patients did not exhibit changes in intracellular CTLA-4 expression in the different PBL subsets tested. Finally, the SpA group showed a preferential expression of the spliced CTLA-4 mRNA (P = 0.0014) in PBL. CONCLUSIONS: SpA patients exhibit high levels of circulating sCTLA-4 that may result from an alternative splicing of CTLA-4 transcripts. This may influence immune activation and regulation in SpA.
20380722 Platelet-derived growth factor and transforming growth factor beta synergistically potenti 2010 INTRODUCTION: The objective of this study was to model the effects of transforming growth factor beta (TGF-beta) and platelet-derived growth factor (PDGF), both present in rheumatoid arthritis (RA) synovia, on the behavior of fibroblast-like synoviocytes (FLS) in response to pro-inflammatory cytokine (interleukin (IL)1beta, tumor necrosis factor-alpha (TNFalpha)) challenge. METHODS: Gene and protein expression by fibroblast-like synoviocytes in vitro was studied by quantitative Polymerase Chain Reaction (qPCR), ELISA and multiplex bead cytokine assays. Intracellular signaling pathway activation was determined by Western blot for phospho-kinases and the use of specific inhibitors. RESULTS: In combination, TGF-beta and PDGF (2GF) synergistically augmented TNFalpha- or IL1beta-induced matrix metalloproteinase 3 (MMP3), IL6, IL8, and macrophage inflammatory protein 1 alpha (MIP1alpha) secretion by FLS. Other FLS-derived mediators remained unaffected. Individually, neither growth factor significantly potentiated TNFalpha or IL1beta-induced MMP3 secretion, and only slightly enhanced IL6. The effect of 2GF on TNFalpha-induced gene expression was transcriptionally mediated; blocked by imatinib mesylate; and occurred even if 2GF was added as much as four hours prior to TNFalpha. In addition, a 15-minute pulse of 2GF four hours prior to TNFalpha stimulation yielded a synergistic response. The extracellular-signal-regulated kinase (ERK) and phosphoinositide 3-kinase (PI3K) signaling pathways were induced for at least four hours by 2GF, as demonstrated by persistently upregulated levels of phospho-Akt and phospho-ERK. However, pharmacologic inhibitor studies demonstrated that the potentiating action of 2GF was dependent on PI3 kinase only, and not on ERK. CONCLUSIONS: The combination of PDGF and TGF-beta dramatically potentiates FLS response to cytokines in a receptor-mediated and PI3 kinase-dependent fashion. These data suggest that 2GF contribute to synovitis by directing synovial fibroblasts toward a more aggressive phenotype in response to TNFalpha. Therefore, inhibition of growth factor signaling may constitute a complementary therapeutic approach to cytokine-targeted treatments for RA.
19455118 Novel genetic risk markers for ulcerative colitis in the IL2/IL21 region are in epistasis 2009 Jul OBJECTIVES: Recently, a genome-wide association study showed that single-nucleotide polymorphisms (SNPs) in the chromosome 4q27 region containing IL2 and IL21 are associated with celiac disease. Given the increased prevalence of inflammatory bowel disease (IBD) among celiac disease patients, we investigated the possible involvement of these SNPs in IBD. METHODS: Five SNPs strongly associated with celiac disease within the KIAA1109/TENR/IL2/IL21 linkage disequilibrium block on chromosome 4q27 and one coding SNP within the IL21 gene were analyzed in a large German IBD cohort. The study population comprised a total of 2,948 Caucasian individuals, including 1,461 IBD patients (ulcerative colitis (UC): n=514, Crohn's disease (CD): n=947) and 1,487 healthy unrelated controls. RESULTS: Three of the five celiac disease risk markers had a protective effect on UC susceptibility, and this effect remained significant after correcting for multiple testing: rs6840978: P=0.0082, P(corr)=0.049, odds ratio (OR) 0.77, 95% confidence interval (CI) 0.63-0.93; rs6822844: P=0.0028, P(corr)=0.017, OR 0.73, 95% CI 0.59-0.90; rs13119723: P=0.0058, P(corr)=0.035, OR 0.75, 95% CI 0.61-0.92. A haplotype consisting of the six SNPs tested was markedly associated with UC susceptibility (P=0.0025, P(corr)=0.015, OR 0.72, 95% CI 0.58-0.89). Moreover, in UC, epistasis was observed between the IL23R SNP rs1004819 and three SNPs in the KIAA1109/TENR/IL2/IL21 block (rs13151961, rs13119723, and rs6822844). CONCLUSIONS: Similar to other autoimmune diseases such as celiac disease, rheumatoid arthritis, type 1 diabetes, Graves' disease, and psoriatic arthritis, genetic variation in the chromosome 4q27 region predisposes to UC, suggesting a common genetic background for these diseases.
23833800 Optimization and characterization of a pan protein arginine deiminase (PAD) inhibitor. 2010 The protein arginine deiminases (PADs) are a family of Ca(2+)-dependent enzymes that catalyze the conversion of peptidyl-arginine to peptidyl-citrulline in numerous protein substrates. Disruption of normal PAD activity plays a role in the pathogenesis of multiple inflammatory diseases such as rheumatoid arthritis (RA), chronic obstructive pulmonary disease, ulcerative colitis, multiple sclerosis, psoriasis, Alzheimer’s disease, and in various cancers. PAD inhibitors described in the literature have been useful chemical tools to study the role of PAD enzymes in inflammatory diseases and cancer biology. Most published PAD inhibitors are mechanism-based inactivators belonging to the halogen-amidine chemotype. For emerging targets such as the PADs, it can be difficult to distinguish compound-specific effects from those truly resulting from enzyme inhibition. We therefore initiated a fluorescence polarization activity-based protein profiling (fluopol-ABPP) high throughput screening (HTS) campaign to identify a second PAD inhibitor chemotype. The PAD4 HTS campaign identified the natural product streptonigrin (SID 11532976) as an irreversible PAD4-specific inhibitor. We describe herein the medicinal chemistry optimization of streptonigrin to the pan PAD probe ML325 (SID 118043677). ML325 inhibits PAD1, 2, 3, and 4 in vitro with IC50 values of 70 nM, 200 nM 170 nM, and 240 nM respectively. In a kinetic assay of inhibition more appropriate for irreversible inhibitors, ML325 has k(inact)/K(I) values of 3500, 7300, 1900, and 5300 M(−1)min(−1) for PAD1, 2, 3 and 4 respectively; indicating it has less than 4-fold selectivity among the four family members. Despite its promiscuity within the PAD family, ML325 exhibits high selectivity vs. more than 20 cysteine-reactive proteins as assayed by activity-based protein profiling. ML325 was also demonstrated to inhibit all four PAD isozymes irreversibly and to be non-cytotoxic to NIH-3T3 cells. The complete properties, characterization, and synthesis of ML325 are detailed in this report.
21511075 Psychiatric morbidity in HIV-positive subjects: a study from India. 2011 May OBJECTIVE: To study the psychiatric morbidity in HIV-positive subjects. DESIGN: Cross-sectional. METHODS: The purposive sample included HIV-positive subjects not receiving antiretroviral therapy (HIV) (n=100). Rheumatoid arthritis (severe) subjects not receiving steroids or disease-modifying antirheumatic drugs (RA) (n=40) were included as a comparison group. The 12-item General Health Questionnaire in Hindi (GHQ) was used to screen the psychiatric morbidity in both groups. In GHQ-positive cases, psychiatric diagnoses were made using the Structured Clinical Interview for DSM-IV (SCID). RESULTS: The HIV group reported sexual contact as the commonest source of infection (58%) and had a lower age at onset (32.53 vs. 36.60 years, P=.011), shorter duration of illness (12.95 vs. 83.37 months, P<.001), lower GHQ score (28.3 vs. 30.15, P=.043), similar Mini Mental State Examination (MMSE) score (28.01 vs. 27.37, P=.093) and lower psychiatric morbidity by both GHQ (score >2) (52% vs. 85%) and current SCID diagnoses (45% vs. 60%, P=.021), as compared to the RA group. The HIV group also had a lower prevalence of psychiatric disorders (45% vs. 60%), mood disorders [24% vs. 52% including major depressive disorder (19% vs. 45%)] and anxiety disorders (1% vs. 2.5%), but a higher prevalence of substance use disorders (17% vs. 2.5%), adjustment disorders (7% vs. 5%) and psychotic disorders (1% vs. 0), as compared to the RA group. CONCLUSION: The high prevalence of psychiatric disorders, especially the mood disorders, in our HIV-positive subjects was generally similar to that reported from the rest of the world.
21095183 Stable formyl peptide receptor agonists that activate the neutrophil NADPH-oxidase identif 2011 Feb 1 The neutrophil formyl peptide receptors (FPR1 and FPR2) are G-protein coupled receptors that can induce pro-inflammatory as well as anti-inflammatory activities when activated. Accordingly, these receptors may become therapeutic targets for the development of novel drugs to be used for reducing the inflammation induced injuries in asthma, rheumatoid arthritis, Alzheimer's disease, cardiovascular diseases and traumatic shock. We screened a library of more then 50K small compounds for an ability of the compounds to induce a transient rise in intracellular Ca(2+) in cells transfected to express FPR2 (earlier called FPRL1 or the lipoxin A(4) receptor). Ten agonist hits were selected for further analysis representing different chemical series and five new together with five earlier described molecules were further profiled. Compounds 1-10 gave rise to a calcium response in the FPR2 transfectants with EC(50) values ranging from 4×10(-9)M to 2×10(-7)M. All 10 compounds activated human neutrophils to release superoxide, and based on the potency of their activity, the three most potent activators of the neutrophil NADPH-oxidase were further characterized. These three agonists were largely resistant to inactivation by neutrophil produced reactive oxygen species and shown to trigger the same functional repertoire in neutrophils as earlier described peptide agonists. Accordingly they induced chemotaxis, granule mobilization and secretion of superoxide. Interestingly, the oxidase activity was largely inhibited by cyclosporine H, an FPR1 selective antagonist, but not by PBP10, an FPR2 selective inhibitor, suggesting that FPR1 is the preferred receptor in neutrophils for all three agonists.
21040004 Pre-admission education in surgical rheumatology nursing: towards greater patient empowerm 2010 Nov AIMS AND OBJECTIVES: This study compared the pre-admission education received by two groups of rheumatoid arthritis (RA) patients scheduled for hip arthroplasty. The specific aim was to compare these patients' knowledge about care-related issues and sense of certainty about that knowledge, empowering learning experience, length of admission discussion, length of hospital stay and number of health problems. BACKGROUND: Previous studies have shown that surgical pre-admission education is beneficial, but there is no evidence on the relative effectiveness of different methods of education. DESIGN: We used a pre-post-test design with two groups of surgical RA patients (Group I pre-admission education via telephone and standard written educational material, n = 29; Group II standard written educational material, n = 30). METHODS: The data were collected with previously used instruments (OPKQ, MEQ), and demographic and clinical variables were asked. RESULTS: The mean score for knowledge about care-related issues and sense of certainty about that knowledge for Group I and for Group II showed no statistically significant differences at baseline and at admission. At discharge, however, a significant difference was seen between the scores--in favour of Group II. On the other hand, patients in Group I were found to be more empowered in all areas than patients in Group II. CONCLUSIONS: Written educational material seems to be a good choice for pre-admission patient education compared with telephone counselling, particularly when patients are knowledgeable about care-related issues before admission. However, education via telephone is experienced by patients as more empowering than written educational material. RELEVANCE TO CLINICAL PRACTICE: To increase patient's knowledge written educational material can be recommended for use, but to increase patient's empowerment telephone education is better.
20553955 Spleen tyrosine kinases: biology, therapeutic targets and drugs. 2010 Jul Spleen tyrosine kinase (Syk) is an intriguing protein tyrosine kinase involved in signal transduction in a variety of cell types, and its aberrant regulation is associated with different allergic disorders and antibody-mediated autoimmune diseases such as rheumatoid arthritis, asthma and allergic rhinitis. Syk also plays an important part in the uncontrolled growth of tumor cells, particularly B cells. For these reasons, Syk is considered one of the most interesting biological targets of the last decade, as proved by the great number of papers and patents published, and the possibility of treating these pathologies by means of Syk kinase inhibitors has led to a great interest from the pharmaceutical and biotech industry.
20508602 The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibili 2010 Jul Genome-wide association studies (GWAS) have revealed that different diseases share susceptibility variants. Twelve single-nucleotide polymorphisms (SNPs) previously associated with different immune-mediated diseases in GWAS were genotyped in a Caucasian Spanish population of 2864 multiple sclerosis (MS) patients and 2930 controls. Three SNPs were found to be associated with MS: rs1678542 in KIF5A (P=0.001, odds ratio (OR)=1.13, 95% confidence interval (CI)=1.05-1.23); rs3184504 in SH2B3 (P=0.00001, OR=1.19, 95% CI=1.10-1.27) and rs763361 in CD226 (P=0.00007, OR=1.16, 95%CI=1.08-1.25). These variants have previously been associated with rheumatoid arthritis and type 1 diabetes. The SH2B3 polymorphism has additionally been associated with systemic lupus erythematosus. Our results, in addition to validating some of these loci as risk factors for MS, are consistent with shared genetic mechanisms underlying different immune-mediated diseases. These data may help to shape the contribution of each pathway to different disorders.