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ID PMID Title PublicationDate abstract
20016776 How safe are the biologicals in treating asthma and rhinitis? 2009 Oct 22 A number of biological agents are available or being investigated for the treatment of asthma and rhinitis. The safety profiles of these biologic agents, which may modify allergic and immunological diseases, are still being elucidated. Subcutaneous allergen immunotherapy, the oldest biologic agent in current use, has the highest of frequency of the most serious and life-threatening reaction, anaphylaxis. It is also one of the only disease modifying interventions for allergic rhinitis and asthma. Efforts to seek safer and more effective allergen immunotherapy treatment have led to investigations of alternate routes of delivery and modified immunotherapy formulations. Sublingual immunotherapy appears to be associated with a lower, but not zero, risk of anaphylaxis. No fatalities have been reported to date with sublingual immunotherapy. Immunotherapy with modified formulations containing Th1 adjuvants, DNA sequences containing a CpG motif (CpG) and 3-deacylated monophospholipid A, appears to provide the benefits of subcutaneous immunotherapy with a single course of 4 to 6 preseasonal injections. There were no serious treatment-related adverse events or anaphylaxis in the clinical trials of these two immunotherapy adjuvants. Omalizumab, a monoclonal antibody against IgE, has been associated with a small risk of anaphylaxis, affecting 0.09% to 0.2% of patients. It may also be associated with a higher risk of geohelminth infection in patients at high risk for parasitic infections but it does not appear to affect the response to treatment or severity of the infection. Clinical trials with other biologic agents that have targeted IL-4/IL-13, or IL-5, have not demonstrated any definite serious treatment-related adverse events. However, these clinical trials were generally done in small populations of asthma patients, which may be too small for uncommon side effects to be identified. There is conflicting information about the safety TNF-alpha blocking agents, which have been primarily used in the treatment of rheumatoid arthritis, with serious infections, cardiovascular disease and malignancies being the most frequent serious adverse events. An unfavorable risk-benefit profile led to early discontinuation of a TNF-blocking agent in a double-blind placebo controlled of severe asthmatics. In summary, the risk of anaphylaxis and other treatment-related serious events with of all of the biological agents in this review were relatively small. However, most of the clinical trials were done in relatively small patient populations and were of relatively short duration. Long term studies in large patient populations may help clarify the risk-benefit profile of these biologic agents in the treatment of asthma.
19796536 Human anti-alpha-enolase antibody in sera from patients with Behçet's disease and rheumat 2009 Mar OBJECTIVE: alpha-Enolase is a target antigen of IgM-type anti-endothelial cell antibody in patients with Behçet's disease (BD). The objective of this study was to assess the reactivity of serum anti-alpha-enolase antibodies in BD and in other rheumatologic diseases, and to evaluate the clinical significance of serum anti-alpha-enolase antibodies in BD. METHODS: Enzyme-linked immunosorbent assay (ELISA) and immunoblotting were used to examine serum samples from patients with BD (n=100), systemic lupus erythematosus (SLE) (n=50), systemic sclerosis (n=21), rheumatoid arthritis (RA) (n=20), Takayasu's arteritis (n=20), dermatomyositis (n=17), mixed connective tissue disease (MCTD) (n=11), and samples from healthy volunteer donors (n=23). The medical records of patients with BD were reviewed to investigate their clinical characteristics. RESULTS: Specific positive signals against recombinant human alpha-enolase were detected by IgM ELISA of serum samples from 56 of the 100 BD patients (56.0%), 24 of the 50 SLE patients (48.0%), 15 of the 21 systemic sclerosis patients (71.4%), 13 of the 20 RA patients (65.0%), 10 of the 20 Takayasu's arteritis patients (50.0%), 9 of the 17 dermatomyositis patients (52.9%), and 5 of the 11 MCTD patients (45.5%). The number of BD patients with vascular lesions was significantly higher in the anti-alpha-enolase antibody positive group than in the negative group (p=0.027). CONCLUSION: We demonstrated the reactivities of serum anti-alpha-enolase antibodies in BD and other rheumatologic diseases with moderate specificity and also found that serum anti-alpha-enolase antibodies in BD can be associated with vascular system involvement.
19900424 Intervention of alpha-lipoic acid ameliorates methotrexate-induced oxidative stress and ge 2010 Jan 5 Methotrexate (MTX) is an anti-metabolite, widely used in the cancer chemotherapy and rheumatoid arthritis. However, its long-term clinical use is restricted on account of its severe intestinal toxicity. The present study was aimed to investigate the intestinal toxicity of MTX and the possible protective effect of alpha-lipoic acid (LA) on Sprague-Dawley rats. MTX-induced intestinal toxicity was evaluated at the dose of 2.5mg/kg for short-term (5 days treatment) and 1mg/kg for long-term (5 days in a week for four consecutive weeks treatment) study. The possible protective effect of LA was evaluated in both short- as well as long-term study in a dose-dependent manner. MTX treatment induced diarrhoea and mortality in rats, indicating its severe toxicity in the target organ of investigation, i.e., intestine. Further, the intestinal toxicity of MTX was assessed by evaluating different parameters of oxidative stress, DNA damage, cytotoxicity as well as histological changes. Immunostaining for p53 revealed higher genotoxic assault in the intestinal cells due to MTX treatment. Pretreatment of rats with LA led to significant decrease in the oxidative stress, DNA damage, cellular damage, inflammatory changes and apoptosis as determined by malondialdehyde level, glutathione level, comet assay parameters, histological evaluation, immunostaining and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay. In the present investigation, we report that LA pretreatment ameliorates MTX-induced intestinal toxicity in rat as evident from the protection against oxidative stress, decrease in DNA damage and protection of cellular morphology as well as improvement in the stool consistency and animal survival rate.
19884267 A novel composite endpoint to evaluate the gastrointestinal (GI) effects of nonsteroidal a 2010 Jan OBJECTIVE: Nonsteroidal antiinflammatory drugs (NSAID) not only cause damage to the upper gastrointestinal (GI) tract but also affect the lower GI tract. To date, there is no endpoint that evaluates serious GI events in the entire GI tract. The objective of this report is to introduce a novel composite endpoint that measures damage to the entire GI tract - clinically significant upper and lower GI events (CSULGIE) - in patients with NSAID-induced GI damage. METHODS: We reviewed the data from largescale, multicenter, randomized, clinical trials on lower GI toxicity associated with NSAID use. The rationale for using CSULGIE as a primary endpoint in 2 ongoing trials - the Celecoxib vs Omeprazole and Diclofenac for At-risk Osteoarthritis (OA) and Rheumatoid Arthritis (RA) Patients (CONDOR) trial and the Gastrointestinal Randomized Events and Safety Open-Label NSAID Study (GI-REASONS) - is also discussed. RESULTS: Previous randomized trials focused primarily on damage to the upper GI tract and often neglected the lower GI tract. The CSULGIE endpoint extends the traditional "perforation, obstruction, and bleeding" assessment of upper GI complications by including events in the lower GI tract (small/large bowel) such as perforation, bleeding, and clinically significant anemia. CONCLUSION: By providing clinicians with a new, descriptive language for adverse events through the entire GI tract, the CSULGIE endpoint has the potential to become a standard tool for evaluating the GI effects of a range of therapies.
19857478 Thioflavin T fluorescence in human serum: correlations with vascular health and cardiovasc 2010 Feb OBJECTIVES: Amyloid fibrils and amyloid-like structures are implicated in atherosclerosis via macrophage activation and inflammation. A common property of amyloid-like structures is their ability to induce thioflavin T (ThT) fluorescence. We measured ThT fluorescence in serum and related these levels to traditional cardiovascular risk factors and non-invasive measures of vascular dysfunction (elasticity). In addition, chemically modified serum components that contribute to serum ThT fluorescence were explored and identified. DESIGN, METHODS, AND RESULTS: Sera from 105 people, including 35 healthy subjects, and 70 high cardiovascular risk patients (36 with rheumatoid arthritis and 34 with systemic lupus erythrematosus) showed an 8.75-fold variation in induced ThT fluorescence. Although mean (+/-SD) ThT fluorescence did not differ significantly between groups (controls 0.97+/-0.26, RA 1.12+/-0.45, and SLE 0.74+/-0.23), the combined data set showed significant inverse correlation (p=0.046) between ThT fluorescence tertiles and small artery elasticity. Correlation was also found between ThT fluorescence tertiles and LDL-cholesterol, total-cholesterol, and C-reactive protein. Floatation fractionation of apoB containing lipoproteins showed that ThT reactivity in this fraction correlated with both serum oxidised-LDL and LDL-cholesterol levels. However, approximately 94% of ThT reactivity in serum was associated with the non-apoB containing serum fraction, with the majority of ThT fluorescence associated with albumin. Incubation of purified albumin with glucose or with methylglyoxal induced ThT fluorescence, suggesting that glycated or chemical adducts of albumin contribute to the variation in ThT fluorescence of human serum. CONCLUSIONS: We propose that the detection of these adducts in serum using ThT fluorescence measurements may provide a marker for chemically modified protein structures that could assist the assessment of cardiovascular disease risk.
19439663 The IL-1-like cytokine IL-33 is inactivated after maturation by caspase-1. 2009 Jun 2 IL-33 is a chromatin-associated cytokine of the IL-1 family that has recently been linked to many diseases, including asthma, rheumatoid arthritis, atherosclerosis, and cardiovascular diseases. IL-33 signals through the IL-1 receptor-related protein ST2 and drives production of pro-inflammatory and T helper type 2-associated cytokines in mast cells, T helper type 2 lymphocytes, basophils, eosinophils, invariant natural killer T cells, and natural killer cells. It is currently believed that IL-33, like IL-1beta and IL-18, requires processing by caspase-1 to a mature form (IL-33(112-270)) for biological activity. Contrary to the current belief, we report here that full-length IL-33(1-270) is active and that processing by caspase-1 results in IL-33 inactivation, rather than activation. We show that full-length IL-33(1-270) binds and activates ST2, similarly to IL-33(112-270), and that cleavage by caspase-1 does not occur at the site initially proposed (Ser(111)), but rather after residue Asp(178) between the fourth and fifth predicted beta-strands of the IL-1-like domain. Surprisingly, the caspase-1 cleavage site (DGVD(178)G) is similar to the consensus site of cleavage by caspase-3, and IL-33 is also a substrate for this apoptotic caspase. Interestingly, we found that full-length IL-33, which is constitutively expressed to high levels by endothelial cells in most normal human tissues, can be released in the extracellular space after endothelial cell damage or mechanical injury. We speculate that IL-33 may function, similarly to the prototypical alarmins HMGB1 and IL-1alpha, as an endogenous danger signal to alert cells of the innate immune system of tissue damage during trauma or infection.
19439388 Transglutaminase-catalyzed covalent multimerization of Camelidae anti-human TNF single dom 2009 Jun 15 Tumor necrosis factor (TNF) plays an important role in chronic inflammatory disorders, such as Rheumatoid Arthritis and Crohn's disease. Recently, monoclonal Camelidae variable heavy-chain domain-only antibodies (V(H)H) were developed to antagonize the action of human TNF (hTNF). Here, we show that hTNF-V(H)H does not interfere with hTNF trimerization, but competes with hTNF for hTNF-receptor binding. Moreover, we describe posttranslational dimerization and multimerization of hTNF-V(H)H molecules in vitro catalyzed by microbial transglutaminases (MTG). The ribonuclease S-tag-peptide was shown to act as a peptidyl substrate in covalent protein cross-linking reactions catalyzed by MTG from Streptomyces mobaraensis. The S-tag sequence was C-terminally fused to the hTNF-V(H)H and the fusion protein was expressed and purified from Escherichia coli culture supernatants. hTNF-V(H)H-S-tag fusion proteins were efficiently dimerized and multimerized by MTG whereas hTNF-V(H)H was not susceptible to protein cross-linking. Cell cytotoxicity assays, using hTNF as apoptosis inducing cytokine, revealed that dimerized and multimerized hTNF-V(H)H proteins were much more active than the monomeric hTNF-V(H)H. We hypothesize that improved inhibition by dimeric and multimeric single chain hTNF-V(H)H proteins is caused by avidity effects.
29320048 2009 May The Norwegian Knowledge Centre for the Health Sciences has been commissioned by the Norwegian Department of Health to produce a systematic review of the scientific evidence concerning effects of the use of personnel with special expertise in functional training and activation compared to standard care at achieving social participation and activity amongst users of municipal home care. Summary of the results: Social participation: Group activities apparently reduce social isolation and loneliness amongst elderly living at home or with assisted living. Occupational therapy (at home) probably has a small but positive effect on social participation and activity of stroke patients. Physical function: Inter-disciplinary measures (at home) probably have a small but positive effect on the general physical function amongst elderly. Occupational therapy (at home) probably has a small, positive effect on physical function amongst stroke victims and patients with rheumatoid arthritis. Quality of life: Long-term interventions (case management program) probably improve the quality of life for fragile elderly living in their own homes compared to those living in care homes. The quality of available research is too low to determine whether physiotherapy and multidisciplinary treatment for stroke victims and personal assistants for older or younger users have effect on social participation and activity. We performed a systematic search for systematic reviews in international research databases. We selected studies that met our inclusion criteria, scored their quality and summarized the results. We have only identified systematic reviews within rehabilitation and elderly care and have not found reviews in this context assessing mental health or drug addictions. Most included reviews have focused on measures taken in care, and not on the qualifications of the personnel. Only two of the reviews specifically referred to personnel. We identified studies on two occupations with specialized expertise in functional training and activation: occupational therapists and functional therapists. We therefore have little knowledge about other professions. In addition there are personal assistants - that have no formal competence in training function and activation. Several of the reviews included interdisciplinary measures and group therapies. We have limited information about what personnel were used in these studies. These reviews can only partially answer our question. There is little available research on the effects of using personnel with special expertise in municipal home care. We have not found systematic reviews that evaluated these measures for the areas of mental health or alcohol and drug addictions. Concerning the elderly, group activities seem to reduce isolation and loneliness. For stroke patients, occupational therapy probably has a small positive effect on social participation and activity, but present research does not address the applicability of these results to other patients.
19270431 Predominant promotion by tacrolimus of chondrogenic differentiation to proliferating chond 2009 Mar Tacrolimus (FK506) has been used as a therapeutic drug beneficial for the treatment of rheumatoid arthritis in humans. In this study, we investigated the effects of FK506 on cellular differentiation in cultured chondrogenic cells. Culture with FK506 led to a significant and concentration-dependent increase in Alcian blue staining for matrix proteoglycan at 0.1 to 1,000 ng/ml, but not in alkaline phosphatase (ALP) activity, in ATDC5 cells, a mouse pre-chondrogenic cell line, cultured for 7 to 28 days, while the non-steroidal anti-inflammatory drug indomethacin significantly decreased Alcian blue staining in a concentration-dependent manner, without altering ALP activity. FK506 significantly increased the expression of mRNA for both type II and type X collagen, but not for osteopontin, in ATDC5 cells. Similar promotion was seen in chondrogenic differentiation in both mouse metatarsals and chondrocytes cultured with FK506. However, FK506 failed to significantly affect transcriptional activity of the reporter construct for either sry-type HMG box 9 (Sox9) or runt-related transcription factor-2 (Runx2), which are both transcription factors responsible for chondrocytic maturation as a master regulator. These results suggest that FK506 may predominantly promote cellular differentiation into proliferating chondrocytes through a mechanism not relevant to the transactivation by either Sox9 or Runx2 in chondrogenic cells.
19196809 Plasma levels of matrix metalloproteinase-9 are independently associated with psychosocial 2009 Apr OBJECTIVE: To test the association between psychosocial factors and circulating levels of matrix metalloproteinase-9 (MMP-9) in a normal population sample. Psychosocial factors have been associated with inflammatory markers and are of prognostic significance for coronary artery disease (CAD). The degrading enzyme MMP-9 is upregulated in inflammatory processes and hypothesized to play a role in the rupture of atherosclerotic plaques. METHODS: A total of 402 participants (50% women), aged 45 to 69 years, were drawn randomly from a normal population. Psychosocial instruments covered depression (Center for Epidemiological Studies Depression Questionnaire, CES-D), vital exhaustion, hostile affect, cynicism, mastery, self-esteem, sense of coherence (SOC), emotional support, and social integration. Plasma MMP-9 was measured by an enzyme-linked immunosorbent assay method. Linear regression models were adjusted for age, sex, known CAD, rheumatoid arthritis, cancer, cardiovascular risk factors including C-reactive protein and ongoing medication. RESULTS: After full adjustment, there were independent associations of elevated MMP-9 levels with CES-D (+2.9 ng/ml per SD, p = .02), hostile affect (+3.0 ng/ml per SD, p = .02), cynicism (+3.5 ng/ml per SD, p = .006), and SOC (-2.5 ng/ml per SD, p = .046). A principal component analysis extracted three components. The first was mainly extracted from CES-D, vital exhaustion, self-esteem, mastery, and SOC; the second was mainly extracted from hostile affect and cynicism. Both were independently associated with MMP-9 (p = .02, p = .04) when run in the same model. CONCLUSIONS: MMP-9 levels were associated with psychosocial factors in a middle-aged normal population sample, independently of traditional risk factors. The findings may constitute a possible link between psychosocial factors and cardiovascular risk.
21148743 Reduction of CXC chemokine receptor 3 in an in vitro model of continuous exposure to asbes 2011 Sep Because patients with silicosis who are chronically exposed to silica particles develop not only pulmonary fibrosis, but also complications involving autoimmune diseases such as rheumatoid arthritis and systemic sclerosis, exposure to asbestos may affect the human immune system. This immunologic effect may impair antitumor immune function because cancer complications such as lung cancer and malignant mesothelioma are found in patients exposed to asbestos. To elucidate the antitumor immune status caused by CD4(+) T cells exposed to asbestos, an in vitro T-cell model of long-term and low-level exposure to chrysotile asbestos was established from a human adult T-cell leukemia virus-1-immortalized human polyclonal T cell line, MT-2, and the resulting six sublines showed resistance to asbestos-induced apoptosis after more than 8 months of continuous exposure. The results of DNA microarray analysis showed that the expression of 139 genes was altered by long-term and low-level exposure to asbestos, and the profile was almost similar among the six sublines when compared with the original MT-2 cells that had never been exposed to asbestos. Pathway and network analysis indicated a down-regulation of IFN-γ signaling and expression of CXC chemokine receptor 3 (CXCR3) in the sublines, whereas ELISA and flow cytometry analysis demonstrated a reduction in Th1-related IFN-γ production and cell-surface CXCR3 expression. These findings suggest that chronic exposure to asbestos may reduce antitumor immune status in CD4(+) T cells, and that an in vitro T-cell model may be useful in identifying molecules related to the impairment of antitumor immune function.
20641497 [(18)F]-5-(2-fluoroethyl)2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxyl 2004 Adenosine is an important signaling molecule that is involved in several pathophysiological conditions such as asthma, inflammation, and neurodegeneration. It is known to mediate its effects through four G-protein–coupled receptors, A(1), A(2) (with sub types A(2A) and A(2B)), and A(3) (the receptors are also designated as A1AR, A2AR, and A3AR, respectively) in the mammalian system. These receptors have been identified in several human tissues and, because they play a role in different pathologies, are targeted for the clinical development of a variety of drugs (2, 3). Much information is available regarding the function and tissue distribution of the A(1) and A(2A) receptors; however, because of a lack of proper agonists and antagonists to study the A(2B) and A(3) receptors, the exact role of the latter two receptors in mammalian physiology is not clear (4). In addition to its possible involvement in the development of rheumatoid arthritis and brain, lung, and cardiac ischemia, the A(3) receptor was shown to be overexpressed and had a proliferative effect in certain cancer tissues and cell lines (5-7). Although this receptor is known to be involved in a number of diseases, little is known about its expression and distribution in the different regions and tissue of the body (4). In an attempt to study the ligand binding properties of the A(3) receptor, investigators developed antagonistic pyridine analogs that showed high affinity and specificity for the receptor (8, 9). Among these pyridine compounds, a fluoroethyl ester derivative, 5-(2-fluoroethyl)2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate (FE@SUPPY), was determined to have a high affinity and selectivity for the A(3) receptor (9). Recently, Wadsak et al. developed a suitable precursor for the synthesis of FE@SUPPY and labeled the A(3) ligand with radioactive fluorine ((18)F) to obtain [(18)F]FE@SUPPY (4). The labeled compound was subsequently studied for its biodistribution in rats and its specificity was determined by autoradiography. The metabolic properties of [(18)F]FE@SUPPY were compared to those of its analogue, [(18)F]FE@SUPPY:2 (5-ethyl-2,4-diethyl-3-((2-[(18)F]fluoroethylsulfanylcarbonyl)-6-phenylpyridine-5-carboxylate), in rodents by Haeusler et. al. (1). To compare the structures of [(18)F]FE@SUPPY and [(18)F]FE@SUPPY:2 see (1).
20925239 [The ERG contribution in early diagnosis of chloroquine and hydroxychloroquine maculopathy 2010 Apr Derivates of chloroquine (Plaquenil, Delagil), used for long-term treatment of rheumatic diseases, may cause clinically proven irreversible maculopathy, which may progress even after the discontinuation of their application. The optimal early diagnosis of ocular toxicity of chloroquine or hydroxychloroquine drug remains controversial up to now. The aim of this review paper was to evaluate how appropriate is the indication of the electroretinographic (ERG) examination due to the early diagnosis of cumulative drug-related maculopathy. Photopic, pattern, and multifocal ERG (Retiscan, according to the ISCEV methodology) were examined in 10 patients (20 eyes) treated by means of antimalarics, 9 due to the rheumatoid arthritis (RA) and 1 due to the systemic lupus erythremathodes (SLE). The average age of the patients was 60 +/- 15 years, the treatment period was 10 +/- 11 years; the median of the treatment period was 5 years. The control group consisted of 12 healthy, age matched patients (20 eyes) without any obvious ocular pathology. In all of them, the complete ophthalmologic examination was performed: the best corrected visual acuity (BCVA) for far using the Snellen charts, intraocular pressure (IOP) measured by means of the non contact tonometer NIDEK NT-2000, the Amsler grid test, examination of the anterior segment and the posterior segment with the slit lamp. The entry criteria in both groups were BCVA 5/7,5 (0.67) and better, the IOP in the normal range, negative Amsler grid test, anterior segment without significant decrease of the transparency, and physiological posterior segment or with subtle granular pigment dysgrupancies in the macula only. The significant difference between the group treated with chloroquine or hydrochloroquine and the control group at the 1% level of significance was found in following parameters: in the photopic ERG the value of the b wave latency [ms], in pattern ERG, the values of the waves N35 - P50 [microV] and P50 - N95 [microV] amplitudes, and at the 5 % level of significance in photopic ERG, the wave a amplitude value [microV] and in multifocal ERG, the value of the P1 [ms] a N1 [ms] parts latency in the pericentral ring. It follows from the results, that the ERG examination is suitable for the early diagnosis drug cumulative maculopathy caused by chloroquine derivates. Optimal is the individual comparison of the ERG values of the patient before and in certain time intervals after the beginning of the chloroquine derivates treatment.
20575580 "One-step" detection of matrix metalloproteinase activity using a fluorogenic peptide prob 2010 Jul 21 Matrix metalloproteinases (MMPs) have been shown to be abundant in pathological conditions such as cancer, osteoarthritis (OA), and rheumatoid arthritis (RA). The extent of MMPs detected in biological samples provides important clinical information for diagnosis, prognosis, and therapeutic monitoring of various diseases relating with MMPs. Herein, we developed a new high-throughput MMP diagnostic kit (MMP-D-KIT) based on a 96-well plate by immobilizing MMP-13 specific fluorogenic peptide probes (MMP peptide probe), which is a pair consisting of a near-infrared (NIR) fluorophore (Cy5.5) and a quencher (BHQ-3), onto the biocompatible glycol chitosan (GC) polymer anchored 96-well plate. When MMP enzymes were simply added and incubated in a MMP-D-KIT, the fluorescence of each well was recovered and the fluorescence intensity showed distinct difference within minutes through NIR fluorescence imaging system. The fluorescence was recovered not only by MMP-13 activity, but also by other MMPs activity. Furthermore, recovery of NIR fluorescent signals in MMP-D-KIT was proportional to concentrations of immobilized MMP peptide probe-GC conjugates and, importantly, MMP concentration. The MMP-D-KIT is most specific for target MMP, compared with other enzymes including caspase-3 and 20s proteasome. Additionally, the MMP-D-KIT was used to detect MMP activity in biological samples such as synovial fluid from 12 OA patients (grades 1-4 based on the Kellgren-Lawrence grading scale). It was found that the fluorescence intensity measured using MMP-D-KIT decidedly correlates with the progression of OA. The MMP-D-KIT could be applicable in detecting MMP activities in various biological samples and evaluating the effects of MMP inhibitors in a rapid and easy fashion.
20350659 Antigenic modulation and rituximab resistance. 2010 Apr Several types of B-cell lymphoma have been successfully treated with rituximab, and approval by the US Food and Drug Administration for use of rituximab in the treatment of rheumatoid arthritis has increased interest in targeting CD20 on B cells for other indications. Although large amounts of rituximab can be infused into humans with no apparent dose-limiting toxicity, recent evidence suggests that the body's effector mechanisms, including complement-mediated cytotoxicity and natural killer (NK) cell-mediated killing, can be saturated or exhausted at high burdens of rituximab-opsonized B cells. One of the consequences of this saturation phenomenon is that the opsonized B cells are instead processed by a different pathway mediated by FcgammaR on effector cells. In this alternative pathway, both rituximab and CD20 are removed ("shaved") from the B cells and are taken up by monocytes/macrophages. This process, formerly called antigenic modulation, appears to occur in several compartments in the body and may play a key role in the development of resistance to rituximab therapy.
20227751 IL-32 is expressed by human primary keratinocytes and modulates keratinocyte apoptosis in 2010 Apr BACKGROUND: Keratinocyte (KC) apoptosis is an important mechanism of eczema and spongiosis in patients with atopic dermatitis (AD) and is mediated by IFN-gamma, which is secreted by T(H)1 cells. IL-32 is a proinflammatory cytokine that is involved in the inflammatory processes of rheumatoid arthritis, chronic obstructive pulmonary disease, and Crohn disease. Recently, it was shown that upregulation of IL-32 induces apoptosis. OBJECTIVE: The aim of the study was to investigate the expression and function of IL-32 in patients with AD. METHODS: The expression of IL-32 in KCs was analyzed by means of RT-PCR, ELISA, and flow cytometry. Transfections of small interfering RNA were performed in primary KCs, and apoptosis was analyzed by means of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling, annexin-V, and 7-amino actinomycin D stainings. Immunofluorescence stainings were used to detect IL-32 in skin biopsy specimens, and serum levels of IL-32 were analyzed by means of ELISA. RESULTS: We report that IL-32 is expressed in human primary KCs on stimulation with IFN-gamma, TNF-alpha, and T(H)1 cells in contrast to T(H)2, regulatory T (Treg), or T(H)17 cells, which showed no effect. Transfection of primary KCs and artificial skin equivalents with small interfering RNA to IL-32, which resulted in a clear decrease in IL-32 expression, significantly reduced KC apoptosis. Immunofluorescence staining demonstrated that IL-32 was expressed in AD lesional skin, whereas it was present in neither skin biopsy specimens from healthy donors nor in lesional skin from patients with psoriasis. Serum levels of IL-32 from patients with AD correlated with disease severity, but increased serum levels of IL-32 were also detected in asthmatic patients. CONCLUSION: The present study demonstrates KCs as a source of IL-32, which modulates KC apoptosis and contributes to the pathophysiology of AD.
20194224 Regulatory polymorphisms in EGR2 are associated with susceptibility to systemic lupus eryt 2010 Jun 1 Systemic lupus erythematosus (SLE) is an autoimmune disease induced by the combinations of environmental and genetic factors. Recently, mice in which the early growth response 2 (EGR2) gene, a zinc-finger transcription factor, is conditionally knocked out in CD2(+) T cells have been shown to develop a lupus-like autoimmune disease. Here, we evaluated if polymorphisms in the EGR2 gene influence SLE susceptibility in humans. We first analyzed the effect of SNPs in the EGR2 region on EGR2 expression, and a significant positive correlation with expression was identified in an SNP located at the 5' flanking region of EGR2 (rs10761670, R=0.23, P=0.00072). We then performed a case-control association study using three sets of SLE cohorts by genotyping 14 tag SNPs in the EGR2 gene region. A peak of association with SLE susceptibility was observed for rs10761670 [Pooled: OR = 1.23 (95% CI 1.10-1.37), P=0.00023). This SNP was also associated with susceptibility to rheumatoid arthritis (RA) [OR = 1.15 (95% CI 1.05-1.26), P = 0.0019), suggesting that EGR2 is a common risk factor for SLE and RA. Among the SNPs in complete linkage disequilibrium with rs10761670 (r(2) = 1.0), two SNPs (rs1412554 and rs1509957) affected the binding of transcription factors and transcriptional activity in vitro, suggesting that they may be candidates of causal regulatory variants in this region. Therefore, EGR2 is a genetic risk factor for SLE, in which increased gene expression may contribute to SLE pathogenesis.
20086033 Hepatic clearance of reactive glucuronide metabolites of diclofenac in the mouse is depend 2010 Apr Diclofenac is an important analgesic and anti-inflammatory drug that is widely used for the treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Diclofenac is extensively metabolized in the liver, and the main metabolites are hydroxylated and/or glucuronidated conjugates. We show here that loss of multidrug resistance protein 2 (MRP2/ABCC2) and breast cancer resistance protein (BCRP/ABCG2) in mice results in highly increased plasma levels of diclofenac acyl glucuronide, after both oral and intravenous administration. The absence of Mrp2 and Bcrp1, localized at the canalicular membrane of hepatocytes, leads to impaired biliary excretion of acyl glucuronides and consequently to elevated liver and plasma levels. Mrp2 also mediates the biliary excretion of two hydroxylated diclofenac metabolites, 4'-hydroxydiclofenac and 5-hydroxydiclofenac. We further show that the sinusoidal efflux of diclofenac acyl glucuronide, from liver to blood, is largely dependent on multidrug resistance protein 3 (MRP3/ABCC3). Diclofenac acyl glucuronides are chemically instable and reactive, and in patients, these metabolites are associated with rare but serious idiosyncratic liver toxicity. This might explain why Mrp2/Mrp3/Bcrp1(-/-) mice, which have markedly elevated levels of diclofenac acyl glucuronides in their liver, display acute, albeit very mild, hepatotoxicity. We believe that the handling of diclofenac acyl glucuronides by ATP binding cassette transporters may be representative for the handling of acyl glucuronide metabolites of many other clinically relevant drugs.
20080359 Salsalate may have broad utility in the prevention and treatment of vascular disorders and 2010 Sep In the high proportion of vascular disorders associated with excessive oxidative stress and production of pro-inflammatory cytokines, activation of NF-kappaB plays a key pathogenic role. Thus, there is considerable evidence that NF-kappaB is a mediator of atherogenesis, plaque destabilization, ischemia-reperfusion damage, cardiac remodeling, atrial fibrillation, and aneurysm formation and rupture; some studies suggest that it may also play a role in the microvascular complications of diabetes. I kappaB kinase-beta (IKK beta) is the upstream kinase that appears to be primarily responsible for NF-kappaB activation in these disorders; moreover, chronic IKK beta activation plays a prominent role in induction of insulin resistance in the metabolic syndrome. Salicylate inhibits IKK beta in concentrations that are achievable with dose schedules traditionally used in treating rheumatoid arthritis (3-4.5 g daily); indeed, this is likely to be the mechanism responsible for salicylate's utility in this disorder. Salicylate, unlike aspirin, is only a very weak, reversible inhibitor of cyclooxygenase in clinical doses, and thus is not associated with the potentially dangerous side effects seen with NSAIDs; fully reversible ototoxicity, the dose-limiting side effect in salicylate therapy, can be avoided in most patients by dosage adjustment. Hence, it is proposed that salicylate may have practical utility in the prevention or management of a wide range of vascular disorders as well as of metabolic syndrome and diabetes; its efficacy in these regards would likely be complemented by effective antioxidant measures, which would lessen the stimulus to NF-kappaB activation while providing benefits independent of NF-kappaB activity. Salsalate, consisting of two salicylate molecules united by an ester bond, is a venerable drug that may be the best tolerated delivery vehicle for salicylate. Appropriate rodent studies should pave the way for clinical trials with salsalate in patients at vascular risk.
27022522 WRIST ARTHRODESIS WITH MINIMAL FIXATION PRESERVING THE CARPOMETACARPAL JOINTS. 2010 Jan OBJECTIVE: Wrist arthrodesis is a surgical procedure that should always be considered in cases of pathological conditions in which anatomical and functional structures are altered. In general, the results are very satisfactory, particularly for pain relief, and in the majority of cases, there is considerable functional improvement. Various techniques have been described, with different methods of internal fixation, most of which include the carpometacarpal joints in the fusion. The objective of this study was to evaluate the results from wrist arthrodesis using a technique that is simpler, more biological, less expensive, and does not involve the carpometacarpal joints. METHODS: Fifteen patients with wrist arthrodesis were evaluated (six with sequelae from trauma, four with rheumatoid arthritis, three with Kienbock grade IV, one with Preiser and one with panarthrosis). The technique consisted of using an iliac bone plate and internal fixation with Kirschner wires, avoiding the carpometacarpal joints. RESULTS: The evaluation was based on consolidation time (93% in seven weeks); movements of the fingers and pronosupination; pinch and grasp strength; functional evaluation through the DASH, pain and patient satisfaction questionnaires. In general, the results were similar to those of other, more aggressive techniques, and the non-inclusion of the carpometacarpal joints did not affect the final result. CONCLUSION: Wrist arthrodesis with fixation using Kirschner wires and an iliac bone plate, preserving the carpometacarpal joints, gives good or excellent results that are not inferior to those of other techniques that have been described. However, it presents major advantages over other methods: it is less aggressive and cheaper, and does not have the inconvenience and complications associated with the use of plates and screws.