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ID PMID Title PublicationDate abstract
19874244 Anti-complementary effect of polysaccharide B3-PS1 in Herba Scutellariae Barbatae (Scutell 2009 The polysaccharide B3-PS1 was extracted and purified from Herba Scutellariae Barbatae (Scutellaria barbata D. Don), through bioactivity-guided fractionation. Average molecular weight of B3-PS1 was about 1,700,000 Da with a composition of Gal, Glc, Man and Ara in the ratio of 4.3:1.6:1.1:1.0, and trace of Rha, Fuc and Xyl. Preliminary data showed that 1) B3-PS1 inhibited complement activation of the classic pathway with CH(50) value of 0.12 +/- 0.02 mg/ml and of the alternative pathways with AP(50) value of 0.36 +/- 0.05 mg/ml; 2) B3-PS1 interacts with C1q, C1r, C1s, C2, C3, C4, C5 and C9 through a hemolytic assay. These results strongly suggested that B3-PS1 could be a potential candidate in treating those complement-associated diseases such as rheumatoid arthritis, Alzheimer's disease, and Adult Respiratory Distress Syndrome (ARDS).
19839821 IgA nephropathy associated with thin basement membrane with or without inflammatory diseas 2009 BACKGROUND: Thin basement membrane nephropathy (TBMN) patients with additional inflammatory diseases and IgA nephropathy (IgAN) have not been reported before. It was unclear that if the prognosis of these patients is better or worse than patients with IgAN and TBMN, or IgAN patients with normal glomerular basement membrane (GBM). METHODS: We first reported five TBMN patients with additional inflammatory diseases and IgAN: three were with rheumatoid arthritis, and two had Crohn's disease. Clinical and laboratory features were analyzed between this group (group 3), IgAN patients with normal GBM (group 1), and patients with TBMN and IgAN (group 2). RESULTS: Significant differences were observed in serum levels of IgG, IgA, and IgM between groups 1 and 3, p < 0.001, and between groups 2 and 3, p < 0.001. Glomerular filtration rate (GFR) in group 3 was significantly lower than that of groups 1 and 2, p < 0.01, respectively. CONCLUSION: The prognosis of these patients is worse than patients with IgAN and TBMN or IgAN patients with normal GBM. Serum immunoglobulin levels and GFR in these patients were different from patients with IgAN and TBMN, or IgAN patients with normal GBM.
19828090 IL-32: a newly-discovered proinflammatory cytokine. 2009 Jul IL-32, a newly-discovered proinflammatory cytokine that activates the p38MAPK and NF-kappaB pathways, is an important player in innate and adaptive immune response. IL-32, a cytokine produced mainly by T, natural killer, and epithelial cells induces significant amounts of TNFalpha and MIP-2 and increases the production of both cytokines in a dose-dependent manner. IL-32 has been implicated in inflammatory disorders, mycobacterium tuberculosis infections, inflammatory bowel disease, and influenza A virus infection, as well as in some autoimmune diseases, such as rheumatoid arthritis, ulcerative colitis and Crohn?s disease and in human stomach cancer, human lung cancer and breast cancer tissues. Moreover, it has been reported that IL-32 has pro-inflammatory effects on myeloid cells and causes the differentiation of osteoclast precursors into multinucleated cells expressing specific osteoclast markers. We recently found that human IL-32 has the capacity to provoke histamine release in human-derived cord blood mast cells (HDCBMC), but not in LAD 2 cells nor in rat peritoneal mast cells (RPMC), showing that IL-32 may be specie specific and act more in mature human mast cells (HDCBMC) than in transformed mast cells (LAD 2 cells). Certainly, IL-32 is another potent proinflammatory cytokine, however, the specific role of this newly-discovered protein in the network of cytokine biology remains to be determined.
19787831 Use of agents stimulating erythropoiesis in digestive diseases. 2009 Oct 7 Anemia is the most common complication of inflammatory bowel disease (IBD). Control and inadequate treatment leads to a worse quality of life and increased morbidity and hospitalization. Blood loss, and to a lesser extent, malabsorption of iron are the main causes of iron deficiency in IBD. There is also a variable component of anemia related to chronic inflammation. The anemia of chronic renal failure has been treated for many years with recombinant human erythropoietin (rHuEPO), which significantly improves quality of life and survival. Subsequently, rHuEPO has been used progressively in other conditions that occur with anemia of chronic processes such as cancer, rheumatoid arthritis or IBD, and anemia associated with the treatment of hepatitis C virus. Erythropoietic agents complete the range of available therapeutic options for treatment of anemia associated with IBD, which begins by treating the basis of the inflammatory disease, along with intravenous iron therapy as first choice. In cases of resistance to treatment with iron, combined therapy with erythropoietic agents aims to achieve near-normal levels of hemoglobin/hematocrit (11-12 g/dL). New formulations of intravenous iron (iron carboxymaltose) and the new generation of erythropoietic agents (darbepoetin and continuous erythropoietin receptor activator) will allow better dosing with the same efficacy and safety.
19786771 Drug monitoring in inflammatory bowel disease: helpful or dispensable? 2009 Thiopurines, methotrexate and the calcineurin inhibitors cyclosporin A and tacrolimus are classical immunosuppressive treatment modalities for inflammatory bowel disease (IBD). Since a high inter-patient variability exists in drug efficacy and toxicity, their application requires the knowledge of appropriate indications as well as strategies for individualization of dosage and monitoring for adverse events. Results of pharmacogenetic studies that examine the relationship between single-gene polymorphisms and associated effects on the pharmacokinetics and pharmacodynamics may be helpful for the optimization of individualized therapy. Although 85-95% of patients worldwide present with the homozygote thiopurine S-methyltransferase (TPMT) wild-type genotype and a normal enzyme activity, cost-benefit analyses suggest assessment of TPMT enzyme activity prior to thiopurine therapy for IBD to prevent life-threatening toxicity. Monitoring of 6-mercaptopurine metabolites is a helpful, but not an indispensable tool in thiopurine non-responders to discriminate poor adherence and under-dosing from pharmacogenetic thiopurine resistance and thiopurine refractory disease. Response to and adverse events of methotrexate therapy are hard to predict. Pharmacogenetic indices of methotrexate metabolization have been evaluated in rheumatoid arthritis (RA) but not in IBD yet. In contrast to RA, concentration of methotrexate polyglutamates correlates positively with non-response and adverse effects in IBD. Calcineurin inhibitor metabolism is mainly controlled by cytochrome P-450 isoenzymes 3A4/3A5 and P-glycoprotein that underlie a variety of gene polymorphisms and are susceptible to drug interactions. Independent from pharmacokinetic alterations a MDR1 polymorphism may predict cyclosporin failure in severe ulcerative colitis. Frequent monitoring of whole blood levels is required since efficacy and toxicity are dose-dependent.
19779889 [Atacicept: a new B lymphocyte-targeted therapy for multiple sclerosis]. 2009 Dec Multiple sclerosis (MS) has traditionally been considered to be a T cell-mediated disease. However, there is an increasing body of evidence for the involvement of B cells and autoantibodies in the pathology of this disease, providing a rationale for treatment strategies directed against B cells. This paper summarizes the evidence for a key role of B cells in the immunopathology of MS and reviews data supporting the use of a novel B cell-targeted therapy, atacicept, for this condition. Atacicept is a human recombinant fusion protein that comprises the binding portion of a receptor for both BLyS (B Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), two cytokines that have been identified as important regulators of B cell maturation, function and survival. Atacicept has shown selective effects on cells of the B cell lineage, acting on mature B cells and blocking plasma cells and late stages of B cell development while sparing B cell progenitors and memory cells. The efficacy of atacicept in animal models of autoimmune disease and the biological activity of atacicept in patients with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) has been demonstrated. Ongoing clinical studies are investigating the safety, tolerability and efficacy of atacicept in patients with MS, SLE and RA.
19723088 Apoptosis of human primary osteoclasts treated with molecules targeting nuclear factor-kap 2009 Aug Osteoclasts (OCs) are involved in several pathologies associated with bone loss, including rheumatoid arthritis, osteoporosis, bone metastasis of myeloma, osteosarcoma, and breast cancer. In this review we determined the effects of natural compounds, including extracts from medicinal plants, on differentiation and survival of human primary OCs obtained from peripheral blood. We found that OCs from umbilical cord blood and peripheral blood behave differently in response to molecules inducing apoptosis in this experimental system. Apoptosis induced by decoy oligonucleotides was reproducibly obtained in OCs from peripheral blood but not in OCs derived from cord blood. With respect to effects of medicinal plants, we found that crude extracts of Emblica officinalis are able to induce specifically programmed cell death of mature OCs without altering the process of osteoclastogenesis. E. officinalis specifically increased the expression levels of Fas, a critical member of the apoptotic pathway. Gel shift experiments BioPharmaNet demonstrate that E. officinalis extracts specifically compete with the binding of a transcription factor involved in osteoclastogenesis NF-kappaB to its specific target DNA sequences. This might explain the observed effects of E. officinalis on the expression levels of IL-6, an NF-kappaB-specific target gene. We suggest the application of natural products as an alternative tool for therapy applied to bone diseases.
19689378 Small molecule inhibitors of phosphoinositide 3-kinase (PI3K) delta and gamma. 2009 In recent years, pharmaceutical companies have increasingly focused on phosphoinositide 3-kinases delta (PI3Kdelta) and gamma (PI3Kgamma) as therapeutic targets for the treatment of inflammatory and autoimmune diseases. All class 1 PI3-kinases (alpha/beta/gamma/delta) generate phospholipid second messengers that help govern cellular processes such as migration, proliferation, and apoptosis. PI3K delta/ gamma lipid kinases are mainly restricted to the hematopoetic system whereas PI3K alpha/beta are ubiquitously expressed, thus raising potential toxicity concerns for chronic indications such as asthma and rheumatoid arthritis. Therefore, the challenge in developing a small molecule inhibitor of PI3K is to define and attain the appropriate isoform selectivity profile. Significant advances in the design of such compounds have been achieved by utilizing x-ray crystal structures of various inhibitors bound to PI3Kgamma in conjunction with pharmacophore modeling and high-throughput screening. Herein, we review the history and challenges involved with the discovery of small molecule isoform-specific PI3K inhibitors. Recent progress in the design of selective PI3Kdelta, PI3Kgamma, and PI3Kdelta/gamma dual inhibitors will be presented.
19663791 Immunomodulator activity of 3-hydroxy-3-methilglutaryl-CoA inhibitors. 2009 Oct Statins, inhibitors of 3-hydroxy-3-methylglutaryl-CoA are best known for their lipid-lowering effects but they also possess immunomodulatory properties that are, at least in part, independent of changes in serum cholesterol. Some recent clinical trials (eg. PROVE-IT) have shown that statins exert beneficial cardiovascular effects independently of the resultant level of LDL cholesterol. These "pleiotropic" effects seem to be due to inhibition of prenylation of several proteins such as the small GTP-binding proteins Ras and Rho, and to the disruption, or depletion, of cholesterol rich membrane micro-domains (membrane rafts). Through these pathways statins are able to modulate immune responses by modulating cytokine levels and by affecting the function of cells involved in both innate and adaptive responses. Over the past decade, a large number of studies reported a prominent role of inflammation and immune response in atherosclerosis, thus, the ability of statins to modulate immune-inflammatory processes could explain their cardiovascular beneficial effects beyond lipid-lowering effects. Moreover, various studies demonstrated beneficial effects of statins in inflammatory and auto-immune diseases, such as rheumatoid arthritis, multiple sclerosis and others. The purpose of this review is to summarize clinical and experimental evidence of immunomodulatory properties of these drugs, highlighting their clinical and, thus, therapeutic implications.
22666682 Dyshidrotic eczema: relevance to the immune response in situ. 2009 Aug CONTEXT: Pompholyx (called dyshidrosis by some) is one of the most common conditions and its immune response is presently poorly understood. CASE REPORT: We describe a 58 year old African American female with a clinical history of rheumatoid arthritis and type II diabetes who presented a chronic five-year, itchy vesicular/blistering rash involving her hands and feet. A lesional skin biopsy was taken for hematoxylin and eosin (H & E) analysis. In addition, a multicolor direct immunofluorescence (MDIF) and immunohistochemistry (IHC) studies were performed. The major findings to be reported were: the H & E examination revealed spongiotic dermatitis and pompholix. IHC and MDIF studies demonstrated focally deposits of positive CD45, CD3, CD8, anti myeloperoxidase (MPO), and anti-human IgE, C3C, C3D and anti-human-fibrinogen within the epidermal spongiotic process, as well as around the blood vessels surrounding the inflammatory process especially at the sweat glands and respective ductus. The patient began mycophenolate mofetil therapy, with successful clearing of the palms and soles. CONCLUSION: The significance of our findings indicates a complex immunological process including complement, MPO and T-cell immune response. In addition, possibly a secondary allergic process for the presence of IgE immune response and possibly aggravation by application of other medicines. Further immunological studies on pompholyx are needed. (Abreu-Velez AM, Pinto FJ, Howard MS. North Am J Med Sci 2009; 1: 117-120).
19589124 Preparation, characterization and dissolution studies of fast release diclofenac sodium ta 2010 Mar Diclofenac sodium is a non-steroidal anti-inflammatory drug widely used in the treatment of ankylosing spondylitis, rheumatoid arthritis and osteoarthritis. In this context, a rapid onset of action is required. Thus, the aim of this study was to formulate diclofenac sodium-PVP K-30 fast release tablets from solid dispersions. The physical state and drug:carrier interactions were analyzed by X-ray diffraction and scanning electron microscopy and stability upon storage was also studied. Dissolution rate of diclofenac sodium from solid dispersions was markedly enhanced by increasing the polymer concentration.
19554508 Expression and distribution of GABAergic system in rat knee joint synovial membrane. 2009 Aug The GABAergic system, found in the adult mammalian brain and composed of gamma-aminobutyric acid (GABA), GABA synthesizing enzyme glutamate decarboxylase (GAD) and GABA receptors, is also located in many peripheral nonneuronal tissues. Studies suggest that synovial membranes possess GABA, and that GABA participates in the control of the inflammatory response in rheumatoid arthritis (RA). However, no studies on the GABAergic system in synovial membranes have been done so far. Therefore, expression and distribution of the GABAergic system in the synovial membrane of the normal rat knee joint were investigated by reverse transcription-polymerase chain reaction (RT-PCR) analyses and immunohistochemistry. Results of RT-PCR analysis showed that mRNA encoding the GAD65 and GABAB receptor subunits necessary for the assembly of functional receptors, R1 and R2, are expressed in the synovial membrane. GAD and GABAB receptor subunits were localized in macrophage-like A cells of the synovial membrane. Macrophage-like A cells of the synovial membrane have a GABA production system and GABAB receptors, and GABA seems to play functional roles in the synovial membrane.
19534859 [Results of the surgical treatment of atlantoaxial instability]. 2009 Mar BACKGROUND: Instability of the cervical spine is defined as an increase in flexibility farther than the physiological limits of one vertebra over another in some of its axes, conditioning symptoms for the patient. Traumatic, degenerative, metabolic and neoplastic causes have all been identified. METHODS: A retrospective, longitudinal, observational and descriptive study was carried out on patients surgically intervened specifically for atlantoaxial instability from January 1993 to May 2002, with a minimum 5-year follow-up. RESULTS: Eleven patients were evaluated. Ages ranged from 25 to 75 years (average age 56 years) with a female predominance. Etiology was iatrogenic in six cases, and there were four cases of rheumatoid arthritis and one case due to trauma. In all cases, fixation was accomplished with occipitocervical arthrodesis with posterior arch resection. Predominant preoperative neurologic deficit according to Ranawat was grade II and postoperatively was grade I. CONCLUSIONS: The average age of patients in our series was discreetly lower in regard to what has been reported in the literature. Female predominance was in accordance with previous publications. Eight of 11 patients showed improvement as in other series. A higher impact was observed in patients between 30 and 64 years of age. The occupational activity with the highest frequency was homemaker, and the neurologic deficit according to Ranawat showed improvement in 72% of the patients.
19513727 [Recommendations for tuberculosis screening before initiation of TNF-alpha-inhibitor treat 2009 Jul Due to the increased risk of tuberculosis (TB) under treatment with TNF-alpha inhibitors for rheumatoid arthritis and other autoimmune diseases, precautionary measures are required before initiating TNF-alpha-inhibitor therapy. Patients should have active TB ruled out and screening for latent TB infection should be performed. The screening should include chest X-ray, complete medical history, and the administration of a highly specific interferon-gamma-release assay (IGRA). (In the future, the reimbursement of IGRA tests under an analogue procedure code is expected to be formalized by the application of a code specific to the TB-IGRA procedure.) As tuberculin skin test (TST) results can be expected to be either false-positive or false-negative in these patients, the TST, as commonly performed in the past, is recommended only in exceptional situations. For chemopreventive treatment of latent TB infection (LTBI), isoniazid is usually given for 9 months.
19438970 NF-kappaB regulation: the nuclear response. 2009 Apr Nuclear factor kappaB (NF-kappaB) is an inducible transcription factor that tightly regulates the expression of a large cohort of genes. As a key component of the cellular machinery NF-kappaB is involved in a wide range of biological processes including innate and adaptive immunity, inflammation, cellular stress responses, cell adhesion, apoptosis and proliferation. Appropriate regulation of NF-kappaB is critical for the proper function and survival of the cell. Aberrant NF-kappaB activity has now been implicated in the pathogenesis of several diseases ranging from inflammatory bowel disease to autoimmune conditions such as rheumatoid arthritis. Systems governing NF-kappaB activity are complex and there is an increased understanding of the importance of nuclear events in regulating NF-kappaB's activities as a transcription factor. A number of novel nuclear regulators of NF-kappaB such as IkappaB-zeta and PDZ and LIM domain 2 (PDLIM2) have now been identified, adding another layer to the mechanics of NF-kappaB regulation. Further insight into the functions of these molecules raises the prospect for better understanding and rational design of therapeutics for several important diseases.
19389524 Methotrexate and psoriasis: 2009 National Psoriasis Foundation Consensus Conference. 2009 May BACKGROUND: Methotrexate remains a valuable option for the treatment of psoriasis. This report will summarize studies regarding the use of methotrexate since the last guidelines were published in 1998. OBJECTIVE: A task force of the National Psoriasis Foundation Medical Board was convened to evaluate treatment options. Our aim was to achieve a consensus on new updated guidelines for the use of methotrexate in the treatment of psoriasis. METHODS: Reports in the literature were reviewed regarding methotrexate therapy. RESULTS: A consensus was achieved on use of methotrexate in psoriasis including specific recommendations on dosing and monitoring. The consensus received unanimous approval from members of the Medical Board of the National Psoriasis Foundation. LIMITATIONS: There are few evidence-based studies on the treatment of psoriasis with methotrexate. Many of the reviewed reports are for the treatment of rheumatoid arthritis. CONCLUSIONS: Methotrexate is a safe and effective drug for the treatment of psoriasis. Appropriate patient selection and monitoring will significantly decrease the risks of side effects. In patients without risk factors for hepatic fibrosis, liver biopsies may not be indicated or the frequency of liver biopsies may be markedly reduced.
19370349 Validation of the Turkish version of the foot and ankle outcome score. 2009 Dec The objective is to develop a Turkish version of the foot and ankle outcome score (FAOS) and to investigate its validity and reliability. The Turkish version of FAOS was developed after the translation and back-translation. The translated version was pretested on 20 patients with rheumatoid arthritis. Then, the Turkish FAOS was administered to 55 patients having foot and ankle problems. They were also evaluated by using the four subscales of the Turkish version of AIMS2, and the Turkish version of SF-36 questionnaire to test validity. Fifty patients filled out the FAOS for second time to determine test–retest reliability. Construct validity was investigated with use of Spearman’s rank correlation coefficient. Test–retest reliability was assessed with use of the intraclass correlation coefficient (ICC) and Cronbach’s alpha score. The psychometric properties of the Turkish FAOS were generally similar to the original FAOS. The random ICC for the five subscales ranged from 0.70 to 0.96. The Cronbach’s alpha coefficient ranged from 0.79 to 0.97. Construct validity of the FAOS was good. The Turkish FAOS correlated with the SF-36 and AIMS2 scales. The Turkish version of FAOS was valid and reliable instrument to assess the foot and ankle related problems. However, to assess its responsiveness further studies are needed.
19226045 Supracondylar femur fracture after knee manipulation: a report of 3 cases. 2009 Jan Supracondylar femur fracture is a rare but devastating complication of knee manipulation following total knee arthroplasty (TKA). Avoidance of this complication can be achieved by careful attention to the indications and contraindications, timing, and technique of closed manipulation. We performed a retrospective chart and radiographic review to identify all patients who underwent closed manipulation under anesthesia for a diagnosis of aseptic arthrofibrosis after TKA. This article presents 3 cases of supracondylar femur fracture following closed knee manipulation of stiff TKAs that occurred at our institution over a 4-year period (1999-2002). Patient age ranged from 44 to 73 years. All patients underwent cruciate retaining TKA. Time from TKA to manipulation ranged from 3 months to 3 years. Two patients sustained an extension type supracondylar fracture. Two of the 3 patients were treated with closed reduction and casting/bracing. At a minimum 8-month follow-up after fracture, range of motion was poor with average flexion to 77 degrees and average flexion contracture of 13 degrees . In our patients, risk factors for fracture included prolonged time from arthroplasty to manipulation, arthrofibrosis, radiographic osteopenia, and rheumatoid arthritis. To our knowledge, this represents the largest case series of iatrogenic supracondylar femur fractures reported in the literature. Two manipulation techniques are described in detail. The alternative manipulation technique is highlighted with no fractures or complications over the same period. We believe that the alternative manipulation technique is a safe and effective technique to manipulate stiff TKA's and has been used for over >10 years by the senior surgeon (J.V.B.).
19220326 Copy number variation in the human genome and its implication in autoimmunity. 2009 Apr The causes of autoimmune disease remain poorly defined. However, it is known that genetic factors contribute to disease susceptibility. Hitherto, studies have focused upon single nucleotide polymorphisms as both tools for mapping and as probable causal variants. Recent studies, using genome-wide analytical techniques, have revealed that, in the genome, segments of DNA ranging in size from kilobases to megabases can vary in copy number. These changes of DNA copy number represent an important element of genomic polymorphism in humans and in other species and may therefore make a substantial contribution to phenotypic variation and population differentiation. Furthermore, copy number variation (CNV) in genomic regions harbouring dosage-sensitive genes may cause or predispose to a variety of human genetic diseases. Several recent studies have reported an association between CNV and autoimmunity in humans such as systemic lupus, psoriasis, Crohn's disease, rheumatoid arthritis and type 1 diabetes. The use of novel analytical techniques facilitates the study of complex human genomic structures such as CNV, and allows new susceptibility loci for autoimmunity to be found that are not readily mappable by single nucleotide polymorphism-based association analyses alone.
19164922 Pro-apoptotic effect of aurothiomalate in prostate cancer cells. 2009 Jan 15 It has been recently demonstrated that small gold compounds could have a potential anti-tumoral activity. Here, we report that aurothiomalate (ATM), a gold compound already used in clinical therapy for the treatment of rheumatoid arthritis, has a pro-apoptotic effect in aggressive prostate cancer (PC3U) cells. In contrast, treatment of human primary epithelial prostate cells (PrEC) with ATM did not cause apoptosis. We demonstrated that ATM is able to disrupt the PKCiota-Par6 complex in PC3U cells and that this disruption leads to the activation of ERK in a dose-dependent manner. Interestingly, we also showed that ERK acts upstream of the activation of caspase 3, leading to apoptosis. ATM treatment also causes activation of p38 and JNK MAP kinases. Moreover we could link ATM treatment to activation of the mitochondrial or so called intrinsic pathway, as we observed release of cytochrome c from mitochondria to cytoplasm, suggesting that the mitochondrial pathway is involved in the pro-apoptotic effect mediated by ATM. Taken together our data suggest that ATM could be a new promising drug for the treatment of advanced prostate cancer.