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ID PMID Title PublicationDate abstract
22153879 Genetic polymorphisms and surface expression of CTLA-4 and PD-1 on T cells of silica-expos 2012 Nov Exposure to silica dust has been examined as a possible risk factor for autoimmune diseases, including scleroderma, rheumatoid arthritis and systemic lupus erythematosus. Since CTLA-4 [CD152] and PD-1 [CD279] are important for the maintenance of peripheral tolerance by regulating T cell responsiveness, we evaluated the expression of these molecules on the surface of CD4 and CD8 T cells, as well as single nucleotide polymorphisms (SNP) in CTLA-4 and PDCD1 genes, of 70 silica-exposed workers and 30 non-exposed, age-, ethnically- and sex-matched controls. Expression of CTLA-4 was significantly (P<0.05) reduced in CD4 T cells of exposed individuals [median=0.1% and interquartile range, IQR 0.0-0.1% (exposed), median=0.20%, IQR 0.0-0.4% (control)]. Also the expression of PD-1 was significantly (P<0.0001) reduced in both CD4 [median=0.9%, IQR 0.4-2.3% (exposed), median=5.7%, IQR 1.4-13.3% (control)] and CD8 T cells [median=0.9%, IQR 0.3-1.9% (exposed), median=5.0%, IQR 3.4-8.9% (control)]. The study of polymorphisms demonstrated a lower frequency of the A allele in the analysis of the PD1.3 SNP in the exposed group, which might be associated with the lower expression of PD-1 on the surface of CD4 T cells. Our findings provide evidence for the association of silica exposure and the maintenance of self-tolerance, i.e., the susceptibility to autoimmune disorders.
22133624 Clinically relevant outcomes based on analysis of pooled data from 2 trials of duloxetine 2012 Feb OBJECTIVE: To determine response with duloxetine versus placebo in patients with osteoarthritis (OA) of the knee using the Outcome Measures in Rheumatoid Arthritis Clinical Trials-Osteoarthritis Research Society International (OMERACT-OARSI) responder index and other clinically relevant outcomes including minimal clinically important improvement (MCII) and patient acceptable symptom state (PASS) for pain and function. METHODS: Data were pooled from two 13-week, randomized, double-blind, placebo-controlled trials comparing duloxetine 60 to 120 mg/day with placebo in patients with symptomatic OA of the knee. Treatment response was determined according to the OMERACT-OARSI responder index, ≥ 30% pain reduction, ≥ 50% pain reduction, and MCII and PASS for pain and function. (ClinicalTrials.gov identifiers NCT00433290 and NCT00408421) RESULTS: Duloxetine-treated patients were 33% more likely to experience an OMERACT-OARSI response than placebo-treated patients [p < 0.001, number needed to treat (NNT) = 6]. A significantly greater percentage of duloxetine-treated patients, compared with placebo-treated patients, reported ≥ 30% improvement in pain from baseline to endpoint (p < 0.001, NNT = 5) and ≥ 50% improvement in pain relative to baseline (p < 0.001, NNT = 7). The duloxetine-treated patients were also more likely to fulfill MCII criteria for pain (p < 0.001, NNT = 6) and function (p < 0.001, NNT = 7), and to achieve PASS for pain (p < 0.001, NNT = 6) and function (p = 0.009, NNT = 9). More duloxetine-treated patients compared with placebo-treated patients experienced ≥ 1 treatment-emergent adverse event (p = 0.003, number needed to harm = 8). CONCLUSION: Significantly more patients receiving duloxetine than placebo achieved an OMERACT-OARSI response, improvements in pain and function exceeding the level accepted as MCII, and reached PASS. Results support the clinical relevance of outcomes of prior duloxetine studies in symptomatic OA of the knee.
21821055 Dimethyl sulphoxide and dimethyl sulphone are potent inhibitors of IL-6 and IL-8 expressio 2011 Sep 26 AIMS: Reactive oxygen species (ROS) are highly diffusable and reactive molecules which modulate gene transcription, particularly of pro-inflammatory cytokines which play a crucial role in the nascency and progression of chronic inflammatory diseases such as rheumatoid arthritis (RA) and osteoarthritis (OA). Since thiols could be potent inhibitors of the production of cytokines, the effects of dimethyl sulphoxide (DMSO) and dimethyl sulphone (DMS) on constitutive and IL-1β-induced IL-6 and IL-8 expression in the human chondrocyte cell line C-28/I2 were evaluated. MAIN METHODS: C-28/I2 cells were incubated for 12h with different concentrations of DMSO or DMS. The secretion of IL-6 and IL-8 was quantified by enzyme-linked immunosorbent assays (ELISAs). The impact of DMSO and DMS on the regulation of p38 and ERK1/2 mitogen-activated protein kinases (MAPKs) was confirmed by Western blot experiments. Furthermore, C-28/I2 cells were stimulated with IL-1β in the absence or presence of DMSO and DMS and IL-6 and IL-8 expression was quantified by ELISAs and quantitative real-time polymerase chain reaction (qRT-PCR). KEY FINDINGS: C-28/I2 cells constitutively expressed large quantities of IL-6 and IL-8. Long-term exposure of cells to DMSO (1%) or DMS (100mM) led to a dramatic downregulation of IL-6 and IL-8 expression which was accompanied by the deactivation of ERK1/2. Both substances also blocked IL-1β-induced IL-6 and IL-8 expression. SIGNIFICANCE: In this study, we demonstrate that both DMSO and DMS represent strong anti-inflammatory properties by blocking constitutive as well as IL-1β-induced IL-6 and IL-8 expression in the human chondrocyte cell line C-28/I2.
21651860 [Effects of oral type II collagen on serum antibody and the cytokine cxpression in Peyer's 2011 Jun AIM: To explore the effects of oral type II collagen (CII) on the morphology, cytokine expressions of Peyer's patches(PP)and the levels of serum specific IgG, IgA, IgM. METHODS: CII was orally administrated to Kunming mice in continuous 10 days at different dosage. The CII or adjuvant immunization was given at 11 d and 21 d. The blood and Peyer's patches were collected at 11 d, 21 d and 31 d. The PP hyperplasy was observed by light microscope after HE staining. The fluorescent real time RT-PCR was used to detect the mRNA expressions of IL-17, TNF-α, IFN-γ and TGF-β1 in PP lymph node. The serum specific IgG, IgA, IgM contents were detected by ELISA. RESULTS: After oral administration of CII for 10 d, the PP lymph node hyperplasia was active and the cap-shape structure could be seen clearly in high dose group, the serum IgA could be detected, the gene expressions of IL-17, TNF-α and IFN-γ were inhibited. After the CII initial immunity, the IgA, IgM, IL-17 levels were descended and TGF-β1 level was increased in the experiment groups as compared with control group(P < 0.05 or P < 0.01). After the CII booster, IgA was notably increased in high dose group(P < 0.05), in experiment groups IgM was still suppressed (P < 0.05 or P < 0.01) and TGF-β1 levels were higher than control group(P < 0.05). In adjuvant immunization groups the cytokine expressions were similar to CII immunization groups, the differences of serum specific IgG, IgA, IgM could not be observed as compared with control group. CONCLUSION: The oral administration of CII can increase the serum specific IgA and suppress the gene expressions of IL-17, TNF-α, IFN-γ in the Peyer's patches. It can still have inhibitory action on the serum specific IgA, IgM and IL-17 gene expressions after CII immunization. The results indicate that the changes of the serum specific antibodies and cytokine gene expressions play an important role on treating rheumatoid arthritis by oral CII to induce immune tolerance.
21585344 Sinomenine protects against ischaemic brain injury: involvement of co-inhibition of acid-s 2011 Nov BACKGROUND AND PURPOSE: Sinomenine (SN), a bioactive alkaloid, has been utilized clinically to treat rheumatoid arthritis in China. Our preliminary experiments indicated that it could protect PC12 cells from oxygen-glucose deprivation-reperfusion (OGD-R), we thus investigated the possible effects of SN on cerebral ischaemia and the related mechanism. EXPERIMENTAL APPROACH: Middle cerebral artery occlusion in rats was used as an animal model of ischaemic stroke in vivo. The mechanisms of the effects of SN were investigated in vitro using whole-cell patch-clamp recording, calcium imaging in PC12 cells and rat cortical neurons subjected to OGD-R. KEY RESULTS: Pretreatment with SN (10 and 30 mg·kg(-1) , i.p.) significantly decreased brain infarction and the overactivation of calcium-mediated events in rats subjected to 2 h ischaemia followed by 24 h reperfusion. Extracellular application of SN inhibited the currents mediated by acid-sensing ion channel 1a and L-type voltage-gated calcium channels, in the rat cultured neurons, in a concentration-dependent manner. These inhibitory effects contribute to the neuroprotection of SN against OGD-R and extracellular acidosis-induced cytotoxicity. More importantly, administration of SN (30 mg·kg(-1) , i.p.) at 1 and 2 h after cerebral ischaemia also decreased brain infarction and improved functional recovery. CONCLUSION AND IMPLICATIONS: SN exerts potent protective effects against ischaemic brain injury when administered before ischaemia or even after the injury. The inhibitory effects of SN on acid-sensing ion channel 1a and L-type calcium channels are involved in this neuroprotection.
21365179 The prevalence of medical nomadism of the followed patients in rheumatology. 2012 Jun The nomads are defined as patients related to multiple practicians of the same speciality or different specialities for the same symptomatology during a certain period. The objectives of this investigation were to evaluate the prevalence of medical nomadism of the followed patients in rheumatology and compare their profile with those patients followed in neurology and gastroenterology. A multicentric transverse study (September 2009-March 2010) was conducted in three departments of CHU Ibn Sina Rabat-Salé, Morocco; rheumatology, gastroenterology and neurology. Only patients seen in external consultations were included. Patients' socio-economic and demographic background (familial status, instruction level, monthly revenue, social assistance) were recorded, as well as the clinical parameters related to the pathology (pathology, duration of the illness, diagnosis final time). A questionnaire containing variables on the patients' state concerning diagnosis, satisfaction degree of the patients and other variables evaluated the notion of taking medication and the practice of alternative medicine. Medical nomadism has been defined by the consultation for the same symptomatology of three different practicians, either of the same speciality or of different specialities during the study period of 6 months. There were 250 patients included in this study (150 patients in rheumatology, 50 in gastroenterology and 50 in neurology), the mean age was 46 ± 13 years and females dominated (65.6%). The average duration of the evolution was 7 ± 5 years, 35% of the patients were illiterate, 30% had a primary school education, 22% had a secondary school education and 13% had a university-level education. Sixty-two percent of the patients were jobless, 27% were workers, 9% were the functionary and 2% were the based liberal. Fifty-six percent had no social assistance. Rheumatoid arthritis and degenerative pathology were the most frequent diagnoses in rheumatology, being 20% and 40%, respectively. In gastroenterology, the most frequent pathologies were functional colopathy (25%) and proctology (20%), and migraine (42%) in neurology. The global prevalence of nomadism was 51%; 36% in rheumatology, 58% in neurology and 86% in gastroenterology. The associated factors of nomadism phenomena in rheumatology were: the satisfaction degree of the patient (P = 0.001), the wrong beliefs (P = 0.007), the practice of alternative medicine (P = 0.009), the pathology (P = 0.01) and the psychic profile (P = 0.001). Our study suggests that medical nomadism is frequent. It seems to be more frequent in the gastroenterology area, was linked with the degree of the patients' satisfaction, the alternative medicine practice and the type of the pathologies. Other studies of a high level would be necessary.
24150614 The Effect of Omega-3 Fatty Acid Supplementation on the Inflammatory Response to eccentric 2011 Omega-3 fatty acids (omega-3) have anti-inflammatory properties. However, it is not known if omega-3 supplementation attenuates exercise-induced inflammation. We tested the hypothesis that omega-3 supplementation reduces inflammation that is induced by eccentric arm curl exercise. Healthy adult men and women (n=11; 35 ± 10 y) performed eccentric biceps curls on two occasions, once after 14d of dietary omega-3 restriction (control trial) and again after 7d of 3,000 mg/d omega-3 supplementation (omega-3 trial). Before and 48 h after eccentric exercise, signs of inflammation was assessed by measuring soreness ratings, swelling (arm circumference and arm volume), and temperature (infrared skin sensor). Arm soreness increased (p < 0.0001) in response to eccentric exercise; the magnitude of increase in soreness was 15% less in the omega-3 trial (p = 0.004). Arm circumference increased after eccentric exercise in the control trial (p = 0.01) but not in the omega-3 trial (p = 0.15). However, there was no difference between trials (p = 0.45). Arm volume and skin temperature did not change in response to eccentric exercise in either trial. These findings suggest that omega-3 supplementation decreases soreness, as a marker of inflammation, after eccentric exercise. Based on these findings, omega-3 supplementation could provide benefits by minimizing post-exercise soreness and thereby facilitate exercise training in individuals ranging from athletes undergoing heavy conditioning to sedentary subjects or patients who are starting exercise programs or medical treatments such as physical therapy or cardiac rehabilitation. Key pointsDietary supplementation with omega-3 fatty acids has been shown to reduce inflammation in numerous inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, and Chrohn's disease.Although strenuous exercise is known to cause acute increases in inflammation, it is not clear if omega-3 fatty acid supplementation attenuates this adverse response to exercise.Our research demonstrates that 3000 mg·d-1 omega-3 fatty acid supplementation minimizes the severe, delayed-onset muscle soreness that results from strenuous eccentric strength exercise.This information, along with a plethora of information showing that omega-3 fatty acid supplementation has other health benefits, demonstrates that a readily available over the counter nutritional supplement (i.e. omega-3 fatty acids) reduces delayed-onset soreness caused by strenuous strength exercise.This information has obvious relevance to athletic populations but also to other groups such as physical therapy patients and newly admitted cardiac rehabilitation patients, as muscle soreness, if left unchecked, can slow the progress in adapting to a new exercise program.Furthermore, as inflammation is known to be involved in the pathogenesis if numerous diseases, including heart disease, cancer, and diabetes, it is likely prudent for individuals to use inflammation-attenuating interventions, such as omega-3 supplementation, to keep inflammatory responses to physical activity at a minimum.
21459880 External hydrocephalus and subdural bleeding in infancy associated with transplacental ant 2012 Apr BACKGROUND: The isolated finding of an unexplained chronic subdural haematoma in an infant may suggest non-accidental head injury (NAHI). The authors report a previously undescribed cause of multifocal chronic subdural haematoma in infancy which could result in a misdiagnosis of previous NAHI. METHODS: Two infants, aged 3 and 4 months of age, presented with progressively increasing head circumference measurements from birth. There was no history of encephalopathy. Retinal haemorrhages were not present. CT and MRI demonstrated bilateral subdural fluid collections over the frontal regions that were consistent with either chronic subdural haematomas or haemorrhagic subdural effusions. In view of the possibility of NAHI, child protection investigations were initiated. FINDINGS: In neither case did the child protection investigations raise concerns. Comprehensive investigations for known haematological and metabolic disorders associated with subdural haematomas or effusions in infants were all normal. In both cases the infant's mother had a history of Sjögren's syndrome and both infants had positive anti-Ro antibody at presentation. CONCLUSIONS: Transplacental acquisition of anti-Ro antibodies has been associated with external hydrocephalus. External hydrocephalus has been recognised as a predisposing factor for subdural haemorrhage. These are the first reported cases linking the presence of anti-Ro antibodies and external hydrocephalus with subdural fluid collections in infancy.
22001522 In Sjögren's syndrome, B lymphocytes induce epithelial cells of salivary glands into apop 2012 Feb Sjögren's syndrome (SS) is a chronic autoimmune epithelitis associated with diffuse lymphocytic infiltration that varies in composition and differs according to lesion severity. T lymphocytes have been viewed as competent in their own right in the destruction of epithelial cells, whereas B lymphocytes that predominate in severe lesions have never been implicated in direct tissue damage. Using co-culture experiments with human salivary gland (HSG) cell line cells and tonsilar B lymphocytes, we observed that direct HSG cell-B lymphocyte contacts were able to induce apoptosis in epithelial cells. This B lymphocyte-mediated cell death could not be ascribed to Fas-Fas ligand interactions but required translocation of protein kinase C delta (PKC δ) into the nucleus of epithelial cells. Ultimately, activation of PKCδ resulted in histone H2B phosphorylation on serine 14 and poly (ADP-ribose) polymerase cleavage. Our results suggest that B lymphocytes infiltrating the SGs of patients with SS could evoke epithelial cell apoptosis.
22336637 Improved detection of advanced oxidation protein products in plasma. 2012 May 18 BACKGROUND: Oxidative stress has been associated with many diseases and can among others be assessed as increased levels of advanced oxidation protein products (AOPP). Current AOPP methods suffer from poor reproducibility and accuracy due to precipitation of lipids in plasma samples. We therefore aimed to develop a robust method in which plasma lipids are solubilized. METHODS: Plasma was diluted with citric acid, and AOPP measured as absorbance at 340 nm. The method was optimized and validated, and then used to analyze AOPP levels in plasma from healthy control subjects (HC), and in three patients groups; chronic kidney disease (CKD), primary Sjögren's Syndrome (pSS) and systemic lupus erythematosus (SLE). RESULTS: AOPP was detected with improved precision compared to established methods where lipids precipitate. Within- and between days variations were less than 1.4% and 2.2%, respectively. A control chart was established and the long-term reproducibility followed over six months. CONCLUSIONS: This improved method detects plasma AOPP with significantly better reproducibility and accuracy compared to previously reported methods. Solubilization of plasma lipids before spectrophotometric measure of AOPP levels is novel. It prevents both loss of lipoproteins due to precipitation and overestimation as a result of light scattering.
21875379 An experimental protocol for the fractionation and 2DE separation of HeLa and A-253 cell l 2011 Dec Sjögren's syndrome (SS) is an autoimmune disease affecting exocrine glands, especially the salivary and lacrimal glands. Although most of the SS patients' sera have autoantibodies that can target a variety of antigens, it is not clear what determines which proteins will become autoantigens. The muscarinic receptor M3, an integral plasma membrane protein, has been proposed as a possible autoantigen in SS, and is endogenous in HeLa cells. The aim of this study was to develop a method that is able to separate and identify antigens recognised by sera from SS patients using lysates of HeLa and A-253 cells in 2D Western Blot (2DWB). The HeLa and A-253 cell lysates were fractionated in soluble and membrane-bound proteins, and the membrane-bound proteins were enriched for integral proteins. The fractions were tested using WB, confirming the presence of the main cell compartments. The rehydration solution containing ASB-14 performed better than the others in all three steps (active rehydration, focus and transfer), and efficiently separated the muscarinic receptor M3. The M3 receptor was also detected in lysates from A-253 cells. The presence of this receptor in this cell line has not been proven earlier. This work develops a suitable protocol to perform a mapping of the autoantibodies present in the sera of single SS patients, using lysates from epithelial cell lines that represent the main cell compartments as an antigen source. It is our future aim to use this protocol to perform a mapping of the antibodies present in the sera of individual SS patients.
21873333 Antibodies recognising sulfated carbohydrates are prevalent in systemic sclerosis and asso 2011 Dec BACKGROUND: Glycosylation represents an important modification that regulates biological processes in tissues relevant for disease pathogenesis in systemic sclerosis (SSc), including the endothelium and extracellular matrix. Whether patients with SSc develop antibodies to carbohydrates is not known. OBJECTIVES: To determine the prevalence and clinical phenotype associated with serum IgG antibodies recognising distinct glycans in patients with SSc. METHODS: Pooled serum samples from patients with SSc and controls were screened for the presence of specific anticarbohydrate antibodies using a novel array containing over 300 glycans. Antibody titres to 4-sulfated N-acetyl-lactosamine (4S-LacNAc, (4OSO3)Galβ1-4GlcNAc) were determined in 181 individual serum samples from patients with SSc by ELISA and associated with disease phenotype. RESULTS: 4S-LacNAc was identified as a target in pooled SSc serum. Anti-4S-LAcNAc antibodies were detected in 27/181 patients with SSc (14.9%) compared with 1/40 healthy controls (2.5%). Sulfation at position C4 of galactose (4S-LacNAc) was found to be critical for immunogenicity. Anti-4S-LacNAc antibody-positive patients with SSc had a higher prevalence of pulmonary hypertension by echocardiography than anti-4S-LacNAc-negative patients (15/27 (55.7%) vs 49/154 (31.8%), p=0.02) with an OR of 2.6 (95% CI 1.1 to 6.3). Anti-4S-LacNAc-positive patients accounted for 23.4% of all patients with pulmonary hypertension. CONCLUSION: Serum from patients with SSc contains IgG antibodies targeting distinct sulfated carbohydrates. The presence of anti-4S-LacNAc antibodies is associated with a high prevalence of pulmonary hypertension. These results suggest that specific post-translational carbohydrate modifications may act as important immunogens in SSc and may contribute to disease pathogenesis.
21844143 Multiple oral Candida infections in patients with Sjogren's syndrome -- prevalence and cli 2011 Nov OBJECTIVE: To determine the prevalence of oral candidiasis and multiple oral Candida infections in patients with primary Sjögren's syndrome (SS), and the clinical and drug susceptibility profile. METHODS: Thirty patients with primary SS were enrolled in our study. The diagnosis of oral candidiasis was based on the clinical manifestation, and confirmed by a concentrated rinse culture. Candida spp. assessment was accomplished using standard methods: Sabouraud dextrose agar with 50 mg/l chloramphenicol and CHROMagar were used for the rapid screening of clinical species, followed by the API 20C system for further species identification. In vitro antifungal drug susceptibility of Candida isolates was determined by the minimal inhibitory concentrations. RESULTS: In our study, 87% (26/30) of subjects had oral candidiasis, in which 42% (11/26) had multiple Candida spp. infection. Although C. albicans remains the predominant isolate, other rare species such as C. tropicalis, C. glabrata, C. parapsilosis, and C. krusei were present, alone or in combination. Chronic atrophic candidiasis is the most common clinical type of oral candidiasis in patients with SS. The susceptibilities of the 44 Candida isolates to 7 antifungal agents varied dramatically. The resistance to azoles was remarkable, and the phenomenon of cross-resistance between itraconazole and fluconazole was observed. CONCLUSION: Patients with primary SS carry a high risk of oral candidiasis and a high frequency of multiple Candida infections. The azole resistance patterns of Candida spp. support the necessity for drug susceptibility testing as a routine procedure for patients with oral Candida infections.
23134988 Apremilast for discoid lupus erythematosus: results of a phase 2, open-label, single-arm, 2012 Oct BACKGROUND: Discoid lupus erythematosus (DLE) is a chronic inflammatory disorder mediated by Th1 cells. Apremilast is a novel oral PDE4 enzyme inhibitor capable of blocking leukocyte production of IL-12, IL-23, TNF-a, INF- with subsequent suppression of Th1 and Th17-mediated immune responses, and proven clinical efficacy for psoriasis as well as rheumatoid and psoriatic arthritis. OBSERVATIONS: Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI) showed a significant (P<0.05) decrease after 85 days of treatment with apremilast 20 mg twice daily in 8 patients with active discoid lupus. The adverse events related to the drug were mild and transient. CONCLUSIONS: This is the first open label study to use apremilast as a treatment modality for discoid lupus. Our observations indicate that apremilast may constitute a safe and effective therapeutic option for DLE.
22523259 Clinical Sindbis alphavirus infection is associated with HLA-DRB1*01 allele and production 2012 Aug BACKGROUND: Sindbis virus (SINV) is a mosquito-borne alphavirus found in Eurasia, Africa, and Oceania. Clinical SINV infection, characterized by arthropathic disease that may persist for years, is primarily reported in Northern Europe where the disease has considerable public health importance in endemic areas. The aim of this study was to investigate the role of genetic factors in the susceptibility and outcome of SINV infection and to elucidate the association between SINV infection and autoimmunity. METHODS: The study included 49 patients with serologically confirmed symptomatic SINV infection who were followed for 3 years after acute infection. Human leukocyte antigen (HLA) genes known to be associated with rheumatic and infectious diseases and complement C4 genes were determined in 35 patients. Furthermore, a set of autoantibodies was measured at the acute phase and 3 years after infection in 44 patients. RESULTS: The frequency of DRB1*01 was significantly higher among patients with SINV infection than in the reference population (odds ratio, 3.3; 95% confidence interval, 1.7-6.5; P = .003). The DRB1*01 allele was particularly frequent in patients who at 3 years postinfection experienced joint manifestations. The frequency of rheumatoid factor at 3 years postinfection was 29.5% and had increased significantly (P = .02) during the 3-year period. In addition, antinuclear and antimitochondrial antibodies were present in serum 3 years postinfection with frequencies of 15.9% and 6.8%, respectively. CONCLUSIONS: Our data show that symptomatic SINV infection is associated with the HLA system and that autoantibody titers are elevated in patients 3 years postinfection. These findings indicate that SINV-induced arthritis shares features with autoimmune diseases.
21093020 Cancer in patients with rheumatic diseases exposed to TNF antagonists. 2011 Aug OBJECTIVE: To describe the risk of cancer in patients exposed to tumor necrosis factor (TNF) antagonists. METHODS: The following 2 clinical cohorts were studied: (1) BIOBADASER 2.0: a registry of patients suffering from rheumatic diseases exposed to TNF antagonists (2531 rheumatoid arthritis (RA), 1488 spondyloarthropathies, and 675 other rheumatic conditions); and (2) EMECAR: a cohort of 789 RA patients not exposed to TNF antagonists. Cancer incidence rates (IR) per 1000 patient-years and incidence rate ratios (IRR) were calculated for BIOBADASER 2.0 and EMECAR patients. The IR over time in BIOBADASER 2.0 patients was analyzed by joinpoint regression. The IRR was estimated to compare cancer rates in exposed versus nonexposed RA patients. Standardized incidence and mortality ratios (SIR, SMR) were also estimated. Risk factors for cancer in patients exposed to TNF antagonists were investigated by generalized linear models. RESULTS: The SMR for cancer in BIODASER 2.0 was 0.67 (95% CI: 0.51-0.86), and the SIR was 0.1 (95% CI 0.03-0.23). The IR in RA patients exposed to TNF antagonists was 5.8 (95% CI: 4.4-7.6), and the adjusted IRR was 0.48 (95% CI: 0.09-2.45). The IR in patients with previous cancer was 26.4 (95% CI: 4.1-171.5). Age, chronic obstructive pulmonary disease, and steroids were associated with a higher risk of developing cancer. The IR decreased after the first 4 months of exposure, without statistical significance. CONCLUSION: Overall cancer and mortality rates in patients with rheumatic diseases exposed to TNF antagonists are no higher than in the background Spanish population. However special attention should be paid to elderly patients, those with previous cancers, and patients treated with steroids.
23285494 Indocyanine green derivative 02-Glu-c(RGDyK)(2). 2004 Optical fluorescence imaging is increasingly used to monitor biological functions of specific targets in small animals (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 (650–900 nm) detection avoids the natural background fluorescence interference of biomolecules, providing a high contrast between target and background tissues. NIR fluorophores have wider dynamic range and minimal background fluorescence as a result of reduced scattering compared with visible fluorescence detection. They also have high sensitivity, resulting from low background fluorescence, 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 a noninvasive complement to radionuclide imaging in small animals or with probes in close proximity to the target in humans (4). Among the various optical imaging agents, only indocyanine green (ICG), with NIR fluorescence absorption at 780 nm and emission at 820 nm, is approved by the United States Food and Drug Administration for clinical applications in angiography, blood flow evaluation, and liver function assessment (5-8). It is also under evaluation in several clinical trials for other applications, such as optical imaging and mapping of both the lymphatic vessels and lymph nodes in cancer patients for surgical dissection of tumor cells and endoscopic imaging of the pancreas and colon. Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (9). 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 (10-17). 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. The peptide sequence 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). The α(v)β(3) antagonists are being studied as anti-tumor and anti-angiogenic agents (12, 16, 18). Various radiolabeled (such as (18)F, (64)Cu, (68)Ga, and (99m)Tc) and NIR fluorescence-labeled (such as Cy5.5, Cy7, and Cypate) RGD peptides have been introduced for imaging of tumors and tumor angiogenesis (19). ICG derivative 02 (ICG-Der-02), a hydrophilic dye, contains one carboxyl functional group for covalent conjugation to the amino group of biomolecules. Cao et al. (20) conjugated ICG-Der-02 via the α-amino group of Glu residue of Glu-c(RGDyK)(2) (dimer) peptide to form ICG-Der-02-c(RGDyK)(2.) ICG-Der-02 was also conjugated to the Ɛ-amino group of the lysine residue of RGD (linear) and c(RGDyK) (monomer) to form ICG-Der-02-RGD and ICG-Der-02-c(RGDyK), respectively. The three ICD-Der-02-labeled conjugates were evaluated for in vivo NIR optical imaging in tumor-bearing mice.
23193614 (64)Cu-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-Arg-rich Cys knot scaffold 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. 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 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. α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents, and the agonists 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) and α(v)β(6). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Integrin α(v)β(6) plays an important role in the development of epithelial cells and is nearly undetectable on adult normal tissues. However, the levels of α(v)β(6) integrin can be upregulated during tissue remodeling and wound healing (11). On the other hand, α(v)β(6) integrin is strongly expressed on tumor cells of the oral cavity, pancreas, breast, ovary, colon, and stomach (12-14). α(v)β(6) integrin affects tumor growth, tumor invasiveness, and metastasis (13). α(v)β(6) binds to the RGD motif in fibronectin, tenascin, and the viral protein 1 (VP1) of foot-and-mouth disease virus (FMDV) (15). FMDV binds to cells through the RGD motif of the GH loop of the VP1. A consensus α(v)β(6)-binding motif DLXXL was identified by using phage display screening with minimal binding to α(v)β(3), α(IIb)β(3), and α(v)β(5) (16). Engineered cysteine knot peptides (knots) comprise a rigid molecular scaffold of ~4 kDa with three disulfide bonds and a centrally located β sheet. Kimura et al. (17) grafted a α(v)β(6)-binding peptide (RSLARTDLDHLRGR) into the loop 1 of an Arg-rich knot to produce the knot known as R(0)1, which was radiolabeled with (64)Cu via 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugation to form (64)Cu-DOTA-R(0)1 as a positron emission tomography (PET) probe for in vivo imaging of α(v)β(6) integrin in tumor-bearing nude mice.
23193623 (64)Cu-1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid-Ser-rich Cys knot scaffold 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. 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 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. α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents, and the agonists 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) and α(v)β(6). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Integrin α(v)β(6) plays an important role in the development of epithelial cells and is nearly undetectable on adult normal tissues. However, the levels of α(v)β(6) integrin can be upregulated during tissue remodeling and wound healing (11). On the other hand, α(v)β(6) integrin is strongly expressed on tumor cells of the oral cavity, pancreas, breast, ovary, colon, and stomach (12-14). α(v)β(6) integrin affects tumor growth, tumor invasiveness, and metastasis (13). α(v)β(6) binds to the RGD motif in fibronectin, tenascin, and the viral protein 1 (VP1) of foot-and-mouth disease virus (FMDV) (15). FMDV binds to cells through the RGD motif of the GH loop of the VP1. A consensus α(v)β(6)-binding motif DLXXL was identified by using phage display screening with minimal binding to α(v)β(3), α(IIb)β(3), and α(v)β(5) (16). Engineered cysteine knot peptides (knots) comprise a rigid molecular scaffold of ~4 kDa with three disulfide bonds and a centrally located β sheet. Kimura et al. (17) grafted a α(v)β(6)-binding peptide (RSLARTDLDHLRGR) into the loop 1 of a Ser-rich knot to produce the knot known as S(0)2, which was radiolabeled with (64)Cu via 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) conjugation to form (64)Cu-DOTA-S(0)2 as a positron emission tomography (PET) probe for in vivo imaging of α(v)β(6) integrin in tumor-bearing nude mice.
22660580 F-box protein FBXL19-mediated ubiquitination and degradation of the receptor for IL-33 lim 2012 Jun 3 The ST2L receptor for interleukin 33 (IL-33) mediates pulmonary inflammation and immune system-related disorders, such as asthma and rheumatoid arthritis. At present, very little is known about the molecular regulation of ST2L expression. Here we found that FBXL19, an 'orphan' member of the Skp1-Cullin-F-box family of E3 ubiquitin ligases, selectively bound to ST2L to mediate its polyubiquitination and elimination in the proteasome. Degradation of ST2L involved phosphorylation of ST2L at Ser442 catalyzed by the kinase GSK3β. Overexpression of FBXL19 abrogated the proapoptotic and inflammatory effects of IL-33 and lessened the severity of lung injury in mouse models of pneumonia. Our results suggest that modulation of the IL-33-ST2L axis by ubiquitin ligases might serve as a unique strategy for lessening pulmonary inflammation.