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ID PMID Title PublicationDate abstract
20657085 Evaluation of telomerase expression in chronic periodontitis. 2010 Apr BACKGROUND: Human telomerase is a multi subunit ribonucleoprotein enzyme concerned with telomeric lengthening and homeostasis in man. This enzyme has been found to be elevated in inflammatory conditions like rheumatoid arthritis and silica injury lung. Since chronic periodontitis is also an inflammatory condition where immune cells and cytokines mediate tissue destruction, we set out to evaluate telomerase in gingival tissue samples from healthy subjects and chronic periodontitis patients by reverse transcriptase polymerase chain reaction. MATERIALS AND METHODS: Gingival biopsies were obtained from eight healthy subjects and eight chronic periodontitis patients. Reverse transcriptase polymerase chain reaction (RTPCR) was carried out to evaluate telomerase gene expression in the samples. RESULTS: None of the healthy gingival tissue samples expressed the telomerase gene while all the chronic periodontitis samples expressed it. The severe chronic periodontitis samples expressed the gene more intensely than the moderate chronic periodontitis samples. CONCLUSION: Various mechanisms have been explained to account for telomerase elevation in chronic periodontitis .This study helps us understand the role of telomerase in the pathogenesis of periodontal disease. It could be concluded that telomerase could be used as a marker to assess the severity of inflammation in chronic periodontitis.
20403049 AA-type amyloidosis in association with non-Hodgkin's lymphoma following CMV viremia: Auto 2010 Mar Amyloidosis in non-Hodgkin's lymphoma (NHL) is known to be of the AL type, and AA-type amyloidosis in NHL is extremely rare. Herein is reported an autopsy case of follicular lymphoma that transformed to diffuse large B-cell lymphoma (DLBCL) in a relapse associated with systemic AA amyloidosis. CMV infection in an immunocompromised state with chemotherapy against DLBCL may have been involved in amyloid accumulation. The serum amyloid A (SAA)1 gene polymorphism, SAA1.2/1.3, might have also been another factor in this case, considering the risk of AA amyloidosis in Japanese patients with rheumatoid arthritis.
20227876 Identification of SD-0006, a potent diaryl pyrazole inhibitor of p38 MAP kinase. 2010 Apr 15 Starting from an initial HTS screening lead, a novel series of C(5)-substituted diaryl pyrazoles were developed that showed potent inhibition of p38alpha kinase. Key to this outcome was the switch from a pyridyl to pyrimidine at the C(4)-position leading to analogs that were potent in human whole blood based cell assay as well as in a number of animal efficacy models for rheumatoid arthritis. Ultimately, we identified a clinical candidate from this substrate; SD-0006.
20100008 Spiroindenes and spiroindanes as antagonists of CC chemokine receptor 2: WO 2009023754. 2010 Feb BACKGROUND: CC chemokine receptor 2 (CCR2) is a GPCR involved in the migration and activation of inflammatory monocytes. A number of studies have highlighted a role for CCR2 in preclinical animal models of atherosclerosis, restenosis, multiple sclerosis, rheumatoid arthritis and insulin resistance. Accordingly, pharmaceutical scientists have been investigating the antagonism of CCR2 as a potential therapy. OBJECTIVE: This patent evaluation examines the report of a new chemical subseries of CCR2 antagonists. METHODS: The compounds of the title invention are compared to the related earlier work in the area of CCR2 antagonism. CONCLUSIONS: The compounds disclosed in PCT application WO 2009023754 extend previous work in a dipiperidine series of CCR2 antagonists through the introduction of both a 1,2-disubstituted ethanol spacer and a 1'H-spiro[indene-1,4'-piperin]-1'-yl group. These compounds may represent a means of treating diseases driven by CCR2-bearing leukocytes.
20032823 [Bone marrow edema: definition, diagnostic value and prognostic value]. 2009 Dec Bone marrow edema is easily identified on MRI. The terminology suggests that the water content of bone marrow is increased when it is T1W hypointense and T2W hyperintense. It is a misnomer since, histologically, the abnormality does not correspond to marrow edema. The histological findings vary based on the underlying etiology and the presence of fibrosis or inflammatory infiltrate is frequent and often predominant. In France, this terminology is used routinely to describe such lesions. The term osteitis is preferred to describe these marrow signal changes in the setting of rheumatic joint diseases. The detection of bone marrow edema is important because of its diagnostic and prognostic value. It occurs in isolation and is reversible in patients with bone contusion and complex regional pain syndrome. It indicates underlying structural damage and may modify management in patients with rheumatoid arthritis or spondylarthropathies. MR scores for disease activity rely mainly on the presence of marrow edema. Finally, diffusion weighted MR allows quantification of marrow edema and could be more sensitive than conventional MRI to detect inflammation. The purpose of this article is to review the imaging features of marrow edema, review the underlying etiologies and its diagnostic and prognostic value.
20018003 Detecting susceptibility genes for rheumatoid arthritis based on a novel sliding-window ap 2009 Dec 15 With the recent rapid improvements in high-throughout genotyping techniques, researchers are facing a very challenging task of large-scale genetic association analysis, especially at the whole-genome level, without an optimal solution. In this study, we propose a new approach for genetic association analysis based on a variable-sized sliding-window framework. This approach employs principal component analysis to find the optimal window size. Using the bisection algorithm in window size searching, the proposed method tackles the exhaustive computation problem. It is more efficient and effective than currently available approaches. We conduct the genome-wide association study in Genetic Analysis Workshop 16 (GAW16) Problem 1 data using the proposed method. Our method successfully identified several susceptibility genes that have been reported by other researchers and additional candidate genes for follow-up studies.
19619949 Tipping the balance: anti-tumour necrosis factor alpha therapy may damage cerebral nerve r 2009 Dec Anti-tumour necrosis factor alpha therapy has transformed the treatment of certain inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease and ankylosing spondylitis, but onset of demyelinating events associated with multiple sclerosis as an adverse event was continuously reported, and such adverse events were only viewed as occasional. Multiple sclerosis is an autoimmune demyelinating disorder affecting central nervous system, with varied clinical manifestations of cognitive, visual and motor network disorder. Recently, there is increasing evidence from functional magnetic resonance that cortical reorganization, a property that allows the central nervous system to adapt itself to various brain insults, which was viewed as to limit the clinical expression of tissue damage in patients with multiple sclerosis. In light of the mentioned above, we hypothesis that cerebral tissue damage may existed in a broader aspects of patients treated with anti-tumour necrosis factor therapy, but its clinical manifestations from brain lesions were compensated by cortical reorganization. In other words, cerebral nerve reservation may be damaged by the therapy. If confirmed, the hypothesis may lead to a safety concern of the therapy, and an insight of the pathophysiology of both multiple sclerosis and certain inflammatory diseases.
19485804 Infliximab for the treatment of ulcerative colitis. 2009 Jun Infliximab (IFX), an anti-TNF biologic agent, has been demonstrated to offer benefits for the treatment of autoimmune disorders, such as rheumatoid arthritis and Crohn's disease. Several trials have also investigated the efficacy of IFX for the treatment of ulcerative colitis (UC). IFX was found to be well tolerated. In most trials, IFX treatment was more effective than placebo for patients with moderate, moderate-to-severe or severe UC. However, its place in the treatment algorithms for UC remains to be defined and, to this end, clinical trials comparing IFX treatment to conventional therapies are needed.
19364087 Refractory Takayasu arteritis successfully treated with infliximab. 2009 Jan Takayasu arteritis (TA) is a chronic inflammatory disease of large arteries which progressively develop stenosis, occlusion or aneurismal degeneration. Proinflammatory cytokines and, among these, tumor necrosis factor-alpha (TNF-alpha) are increased and play a pathogenetic role in the development of disease. Conventional therapy often fails to determine clinical remission and, in these cases, pathogenetic strategies with anti-TNF-alpha drugs have been proposed. Infliximab is a human-murine chimeric monoclonal antibody that specifically binds to and neutralizes soluble TNF-alpha. It is an effective treatment for rheumatoid arthritis, spondyloarthritis, Crohn's disease and ulcerative colitis and it has been recently proposed for the treatment of TA in patients refractory to conventional therapy. Here we report the case of a patient affected by Takayasu arteritis unresponsive to conventional therapy who was then treated with infliximab and obtained a clinical remission of the disease.
23489126 Antagonists of TNF action: clinical experience and new developments. 2009 Mar BACKGROUND: TNF is a central mediator of inflammation and key target for intervention in inflammatory diseases such as rheumatoid arthritis, psoriasis and Crohn's disease. The four at present approved protein therapeutics directly target TNF and inhibit binding to its two TNF receptors. Treatment with TNF antagonists results in significant clinical responses and is generally well tolerated. OBJECTIVE: Ten years of clinical experience with 1 million patients treated also revealed the limits of the available antagonists and potential therapy-associated risks, foremost being tuberculosis reactivation, but also neurologic and hematologic events, and even malignancies. These findings ask for improvement of established therapies. METHOD: We here review published literature on strategies interfering with TNF action and provide an overview of the now approved antagonists of TNF action as well as new reagents under development. CONCLUSION: Clinical experience with approved TNF antagonists shows that there is a demand for minimizing risks associated with persistent blocking of TNF action. With new TNF pathway-targeting reagents and new concepts based on receptor-selective intervention under development, it is foreseeable that efficacy and safety will be further improved and that TNF-targeting strategies will be exploited in further inflammatory and other diseases, including metabolic diseases and cancer.
20018050 Application of sex-specific single-nucleotide polymorphism filters in genome-wide associat 2009 Dec 15 We explored five sex-specific quality control filters in North American Rheumatoid Arthritis Consortium's Illumina 550 k datasets. Three X chromosome and three autosomal single-nucleotide polymorphisms flagged by sex quality control filters were missed by filters of call rate at 95% and Hardy-Weinberg equilibrium at 10-6. We applied a subset of these sex-specific quality control filters to eight chromosomes in the Framingham Heart Study samples genotyped by Affymetrix 500 k SNP arrays, and identified another two single-nucleotide polymorphisms that failed to be picked up by the above global filters.
19569279 [Enteritis and cystitis - a cause of abdominal pain in lupus]. 2009 Apr We present a case of a 28-year-old black female patient with a previous diagnosis of overlapping syndrome of lupus and rheumatoid arthritis, treated with corticosteroids and methotrexate, who was admitted to our department due to abdominal pain with vomits and diarrhea for 15 days. On complementary evaluation elevated C-reactive protein and erythrocyte sedimentation rate, lactate dehydrogenase and amylase levels were detected, C3 was reduced, blood, faeces, peritoneal fluid and urine cultures were negative; abdominal computerized tomography disclosed jejunal thickening with parietal edema, bilateral ureterohydronephrosis and bladder parietal thickening; on endoscopy with biopsy there was chronic pangastritis and duodenitis; cystoscopy with biopsy showed chronic cystitis. Those aspects suggested lupus enteritis and cystitis which appear rarely associated and have poor prognosis. This patient was treated with high dose corticosteroids followed by azathioprine and prednisolone, with clinical and imaging improvement.
19441905 Recent developments in CCR2 antagonists. 2009 Mar Monocyte chemoattractant protein-1 (MCP-1) is a major chemoattractant for monocytes and memory T cells by means of their binding to its specific cell-surface receptor, CC-chemokine receptor-2 (CCR2). CCR2 belongs to the G-protein-coupled seven-transmembrane receptor superfamily. The evidence in favor of CCR2 and MCP-1 having dominant roles in monocyte chemotaxis and chronic inflammation was provided by CCR2 and MCP-1 knockout mice. It has been recognized that CCR2 antagonists are potential therapeutic agents in preventing, treating, or ameliorating a CCR2-mediated inflammatory syndrome or disease such as psoriasis, uveitis, rheumatoid arthritis, multiple sclerosis, asthma, obesity, and chronic obstructive pulmonary disease. This review summarizes recent developments in small-molecule CCR2 antagonists disclosed by patent applications published between 2005 and 2008 and related publications.
19411955 Visual outcome and corneal topography after eccentric "shaped" corneal grafts. 2009 May PURPOSE: To study the clinical and visual outcome and corneal topography in eyes that underwent full-thickness or lamellar eccentric-"shaped" (biconvex/crescentic) corneal grafts. SETTING: Tertiary care center in south India. METHODS: In this retrospective, interventional, noncomparative case series, eccentric-shaped corneal grafts were performed in 10 eyes (10 patients). Biconvex grafts were performed in 7 eyes, and crescentic grafts were done in 3 eyes. The indications for biconvex grafts were peripheral infected corneal ulcer (3 eyes), limbal dermoid (1 eye), squamous cell carcinoma at limbus (1 eye), rheumatoid arthritis-associated peripheral corneal melt (1 eye), and peripheral corneal perforation of unknown etiology (1 eye). Crescentic graft was performed for perforated Mooren ulcer in 3 eyes. RESULTS: All grafts were tectonically effective. Three grafts developed stromal haze with fine vascularization. Visual acuity was equal to or better than that before surgery in all eyes but one. This eye had deterioration in visual acuity because of progression of cataract. Corneal topography was performed in 5 eyes, which revealed corneal asymmetry but regular central corneal surface. CONCLUSION: Shaped corneal grafts for peripheral corneal diseases are tectonically viable and result in good visual outcomes.
19327244 Hematologic manifestations of connective autoimmune diseases. 2009 Jan Autoimmune connective tissue diseases (ACTDs) constitute a heterogeneous group of chronic immune-mediated inflammatory disorders, primarily affecting connective tissues and usually characterized by multisystem involvement with variable and frequently overlapping clinical manifestations. Abnormal immune regulation patterns and persistent inflammation are ACTD hallmarks. In such a context, autoimmunity/inflammation-associated cellular and molecular networks drive a complex of reactions that may involve hemopoietic tissue and peripheral blood cells. Hematologic abnormalities affecting one or more cellular lineages are frequent manifestations of ACTDs, and may represent an important prognostic factor, reflecting the rate of activation of autoimmune/inflammatory processes. Moreover, an increased frequency of hematologic malignancies, mainly lymphoproliferative disorders, has been observed in ACTDs, such as Sjögren's syndrome, systemic lupus erythematosus, rheumatoid arthritis, and polymyositis/dermatomyositis. A proliferative drive likely constitutes the link between chronic immune activation/dysregulation and malignant transformation, creating an increased risk for genetic aberrations that may lead to uncontrolled clonal proliferation. Revealing the nature of lymphomagenesis in relation to autoimmunity/inflammation will allow the identification of subjects at risk in order to select the appropriate diagnostic and therapeutic options. In this paper, the main hematologic manifestations of adulthood ACTDs are reviewed and discussed.
20981223 Tufting Enteropathy with EpCAM Mutations in Two Siblings. 2010 Sep Tufting enteropathy is a rare autosomal recessive disorder presenting with early-onset severe intractable diarrhea. The epithelial cell adhesion molecule gene (EpCAM) has recently been identified as the gene responsible for tufting enteropathy. Based on histology, a diagnosis of tufting enteropathy was made in two Korean siblings. They developed chronic diarrhea and failure to thrive. They had a broad nasal bridge and micrognathia. Duodenal and colonic biopsies showed villous atrophy, disorganization of surface enterocytes, and focal crowding resembling tufts. Protracted diarrhea continued and so cyclic parenteral nutrition was supplied. The sister had juvenile rheumatoid arthritis. Mutation analysis of EpCAM identified two compound heterozygous mutations in these siblings: 1) a donor splicing site mutation in intron 5 (c.491+1G>A) and 2) a novel nonsense mutation in exon 3 (c.316A>T, Lys106X). Analysis of EpCAM will be useful for genetic counseling and prenatal diagnosis of tufting enteropathy.
20974667 Covariate-adjusted response-adaptive designs for longitudinal treatment responses: PEMF tr 2012 Aug Response-adaptive designs have become popular for allocation of the entering patients among two or more competing treatments in a phase III clinical trial. Although there are a lot of designs for binary treatment responses, the number of designs involving covariates is very small. Sometimes the patients give repeated responses. The only available response-adaptive allocation design for repeated binary responses is the urn design by Biswas and Dewanji [Biswas A and Dewanji AA. Randomized longitudinal play-the-winner design for repeated binary data. ANZJS 2004; 46: 675-684; Biswas A and Dewanji A. Inference for a RPW-type clinical trial with repeated monitoring for the treatment of rheumatoid arthritis. Biometr J 2004; 46: 769-779.], although it does not take care of the covariates of the patients in the allocation design. In this article, a covariate-adjusted response-adaptive randomisation procedure is developed using the log-odds ratio within the Bayesian framework for longitudinal binary responses. The small sample performance of the proposed allocation procedure is assessed through a simulation study. The proposed procedure is illustrated using some real data set.
20089001 Laboratory findings in CD4(+) large granular lymphocytoses. 2010 Feb Large granular lymphocytic (LGL) leukemia is an uncommon disorder of mature T or natural killer (NK) cells. Most T-LGL proliferations are CD3(+)/CD8(+), although rare CD4(+) clonal T-LGL expansions have been reported. We report the clinicopathologic features of eight patients with aberrant CD4(+), cytotoxic T-cell lymphocytoses. Median follow-up was 29 months (range 8-100), during which all were alive without requirement for therapy. Four of eight patients had an additional malignancy; none had a history of rheumatoid arthritis, lymphadenopathy or hepatosplenomegaly. Morphologic expansions of granulated lymphocytes were evident in 6/8. All had immunophenotypically aberrant populations of CD4(+) T cells with uniform, moderate or bright CD56. Seven of eight expressed CD57, and four were CD8(partial dim +). Abnormal levels of expression of two or more T-cell antigens were seen in all cases. All tested cases were Tgamma PCR positive. Our results support that CD4(+) T-LGL lymphocytosis is a clonal disorder with clinicopathologic characteristics distinct from the more common CD8(+) variant.
20442747 Genome-wide gene and pathway analysis. 2010 Sep Current GWAS have primarily focused on testing association of single SNPs. To only test for association of single SNPs has limited utility and is insufficient to dissect the complex genetic structure of many common diseases. To meet conceptual and technical challenges raised by GWAS, we suggest gene and pathway-based GWAS as complementary to the current single SNP-based GWAS. This publication develops three statistics for testing association of genes and pathways with disease: linear combination test, quadratic test and decorrelation test, which take correlations among SNPs within a gene or genes within a pathway into account. The null distribution of the suggested statistics is examined and the statistics are applied to GWAS of rheumatoid arthritis in the Wellcome Trust Case-Control Consortium and the North American Rheumatoid Arthritis Consortium studies. The preliminary results show that the suggested gene and pathway-based GWAS offer several remarkable features. First, not only can they identify the genes that have large genetic effects, but also they can detect new genes in which each single SNP conferred a small amount of disease risk, and their joint actions can be implicated in the development of diseases. Second, gene and pathway-based analysis can allow the formation of the core of pathway definition of complex diseases and unravel the functional bases of an association finding. Third, replication of association findings at the gene or pathway level is much easier than replication at the individual SNP level.
19174558 Dihydroorotate dehydrogenase inhibitor A771726 (leflunomide) induces apoptosis and diminis 2009 Feb Multiple myeloma is still an incurable disease; therefore, new therapeutics are urgently needed. A771726 is the active metabolite of the immunosuppressive drug leflunomide, which is currently applied in the treatment of rheumatoid arthritis, BK virus nephropathy, and cytomegaly viremia. Here, we show that dihydroorotate dehydrogenase (DHODH) is commonly expressed in multiple myeloma cell lines and primary multiple myeloma cells. The DHODH inhibitor A771726 inhibits cell growth in common myeloma cell lines at clinically achievable concentrations in a time- and dose-dependent manner. Annexin V-FITC/propidium iodide staining revealed induction of apoptosis of multiple myeloma cell lines and primary multiple myeloma cells. The 5-bromo-2'-deoxyuridine cell proliferation assay showed that inhibition of cell growth was partly due to inhibition of multiple myeloma cell proliferation. A771726 induced G(1) cell cycle arrest via modulation of cyclin D2 and pRb expression. A771726 decreased phosphorylation of protein kinase B (Akt), p70S6K, and eukaryotic translation initiation factor 4E-binding protein-1 as shown by Western blotting experiments. Furthermore, we show that the stimulatory effect of conditioned medium of HS-5 bone marrow stromal cells on multiple myeloma cell growth is completely abrogated by A771726. In addition, synergism studies revealed synergistic and additive activity of A771726 together with the genotoxic agents melphalan, treosulfan, and doxorubicin as well as with dexamethasone and bortezomib. Taken together, we show that inhibition of DHODH by A771726/leflunomide is effective in multiple myeloma. Considering the favorable toxicity profile and the great clinical experience with leflunomide in rheumatoid arthritis, this drug represents a potential new candidate for targeted therapy in multiple myeloma.