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ID PMID Title PublicationDate abstract
20099082 Lubricin: a novel potential biotherapeutic approaches for the treatment of osteoarthritis. 2011 Jun Osteoarthritis (OA) is a multi-factor disorder of sinovial joints, which characterized by escalated degeneration and loss of articular cartilage. Treatment of OA is a critical unmet need in medicine for regeneration of damaged articular cartilage in elderly. On the other hand, lubricin, a glycoprotein specifically synthesized by chondrocytes located at the surface of articular cartilage, has been shown to provide boundary lubrication of congruent articular surfaces under conditions of high contact pressure and near zero sliding speed. Lubrication of these surfaces is critical to normal joint function, while different gene expressions of lubricin had been found in the synovium of rheumatoid arthritis (RA) and OA. Moreover, mutations or lacking of lubricin gene have been shown to link to the joint disease such as camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP), synovial hyperplasia and failure of joint function, suggesting an important role of lubricin in the pathogenesis of these joint disease. Recent studies demonstrate that administration with recombinant lubricin in the joint cavity would be effective in the prevention of cartilage degeneration in animal OA models. Therefore, a treatment with lubricin which would protect cartilage in vivo would be desirable. This article reviews recent findings with regard to the possible role of lubricin in the progression of OA, and further discusses lubricin as a novel potential biotherapeutic approaches for the treatment of OA.
20049709 Innate instruction of adaptive immunity revisited: the inflammasome. 2009 May The innate immune system regulates initial responses to pathogen invasion through a set of conserved pattern recognition receptors (PRR). The best-characterized PRRs are the Toll-like receptors, which regulate not only the initial pathogen defense response, but also adaptive immune responses. Thus, insight into the function of PRRs has major implications for our understanding of the physiology of vaccination and the pathophysiology of human disease. Recent advances in our understanding of a new class of pattern recognition receptors--NOD-like receptors (NLR)--have similarly provided insight into both innate and adaptive immunity. In particular, the NLR Nlrp3 (also known as Nalp3 or Cias1) forms an intracellular multimolecular complex with active caspase-1, called an inflammasome, creating a platform for regulating secretion of interleukin-1 (IL-1) family members. Given the important role of IL-1 in inflammatory diseases, from gout to rheumatoid arthritis, the importance of understanding the regulation of such a cytokine cannot be underestimated. In this review, we address new evidence supporting a role for adaptive immune activation by recently identified NLR agonists, with a particular focus on Nlrp3. Basic questions in our understanding of Nlrp3 inflammasome activation are also presented.
20021282 Phospholipase A2 inhibitors as potential therapeutic agents for the treatment of inflammat 2010 Jan IMPORTANCE OF THE FIELD: The various phospholipase A(2) (PLA(2)) types have been implicated in diverse kinds of lipid signaling and inflammatory diseases. Rheumatoid arthritis, lung inflammation, neurological disorders, such as multiple sclerosis, cardiovascular diseases, including atherosclerosis, and cancer are included among the diseases where PLA(2) enzymes are involved. Thus, there is a great interest in developing potent and selective PLA(2) inhibitors and some of them have entered clinical trials. AREAS COVERED IN THIS REVIEW: This review article discusses the role of each PLA(2) class in inflammatory diseases and the advances in the development of inhibitors presented in patent literature from January 2004 to May 2009. WHAT THE READER WILL GAIN: PLA(2)s cluster in four main types: secreted sPLA(2), cytosolic cPLA(2), Ca(2+)-independent iPLA(2) and lipoprotein-associated LpPLA(2). Each of those types has been implicated in diverse kinds of inflammatory diseases. Readers will rapidly gain an overview of the various PLA(2) inhibitors reported in the patent literature in the past 5 years. Furthermore, the readers will learn the difficulties related to the development of PLA(2) inhibitors as new drugs and also the different companies and research groups that are the main players in the field. TAKE HOME MESSAGE: Although the role of each PLA(2) is not yet distinct in different diseases, the development and future use of different PLA(2) inhibitors to treat human disease seems very promising.
20017997 A new gene-based association test for genome-wide association studies. 2009 Dec 15 Genome-wide association studies are widely used today to discover genetic factors that modify the risk of complex diseases. Usually, these methods work in a SNP-by-SNP fashion. We present a gene-based test that can be applied in the context of genome-wide association studies. We compare both strategies, SNP-based and gene-based, in a sample of cases and controls for rheumatoid arthritis.We obtained different results using each strategy. The SNP-based test found the PTPN22 gene while the gene-based test found the PHF19-TRAF1-C5 region. That suggests that no single strategy performs better than another in all cases and that a certain underlying genetic architecture can be delineated more easily with one strategy rather than with another.
19908418 Influence of the positioning of a cementless glenoid prosthesis on its interface micromoti 2009 Oct The positioning of the glenoid component in total shoulder arthroplasty is complicated by the limited view during operation. Malalignment and/or motion of the glenoid component with respect to the bone can be a cause of, or contribute to, failure of the implant. The aim of this paper is to determine the effect of the positioning of a cementless glenoid component on the micromotions between the implant and the bone during normal loading after surgery. For this study a three-dimensional finite element model of a complete scapula with a cementless glenoid component was used. In total, eight positions of the upper arm in both abduction and anteflexion were chosen to represent the patient's arm movement postoperatively. A previously published musculoskeletal model was used to determine the joint and muscle forces on the scapula with implant in each arm position. Five different alignments of the glenoid component (neutral, anterior, inferior, posterior, and superior inclinations), two different implantation depths ('optimal' and 'deeper' implantations), and two bone qualities (healthy and rheumatoid arthritis (RA) bone) were considered. Inclinations of 10 degrees with respect to a neutral alignment did not affect the overall interface micromotions in the optimal implantation depth. However, when the implantation depth was 3 mm deeper, anterior and inferior inclinations were more favourable than a neutral alignment and other inclinations. Micromotions in RA bone were always larger than in healthy bone.
19906243 Conference summary and conclusions. A comprehensive approach to predicting and managing mo 2009 Oct The discovery of glucocorticoids and their enormous therapeutic benefits led to the use of these compounds as valuable medications for a wide variety of diseases. In 1950 this effort was ushered in by a landmark event-the awarding of the 1950 Nobel Prize in Physiology and Medicine to Drs. Phillip Hench, Edward Kendall, and Tadeus Reichstein. It was Hench who described and researched the successful use of the glucocorticoid, cortisone, and pituitary adrenocorticotrophic hormones to treat rheumatoid arthritis. Significant scientific discovery preceded Hench and colleagues' efforts, but the revolutionary accumulation of discovery in glucocorticoids since then is one of the unique scientific stories in the history of medicine. The scientific conference upon which this volume is based represents an attempt to convene a state-of-the-science meeting on the current understanding and scientific status of this fascinating, far-reaching, and fast-moving field. This last chapter will summarize the exciting presentations of this 2-day conference.
19857114 Activation signal transduction by proline-rich tyrosine kinase 2 (PYK2) in peripheral bloo 2009 Oct To explore the role of proline-rich tyrosine kinase 2 (PYK2) in systemic lupus erythematosus (SLE), we studied the expression, activation, and function of PYK2 in peripheral blood mononuclear cells (PBMC) from 36 SLE patients. As controls, samples from 19 patients with rheumatoid arthritis and 15 healthy individuals were studied simultaneously. We found a significant increase of both the total PYK2 protein and its activated/phosphorylated form in PBMCs from patients with SLE, particularly those with the complication of nephritis (WHO class IV). There is a clear correlation between the activation of PYK2 and the level of serum complements. In active SLE patients, activation of PYK2 in PBMCs accompanies the increased cell proliferation and the induced expression of co-stimulatory molecules CD40L and CTLA4. These results indicate that phosphorylated PYK2 may induce the expression of CD40L and CTLA4, and subsequently the cell proliferation. PYK2 signaling enhances the autoreactive lymphocyte activation and plays an important role in the pathogenesis of SLE.
19817509 The economic burden of osteoarthritis. 2009 Sep As the most common form of joint disease, osteoarthritis (OA) is associated with an extremely high economic burden. This burden is largely attributable to the effects of disability, comorbid disease, and the expense of treatment. Although typically associated with less severe effects on quality of life and per capita expenditures than rheumatoid arthritis, OA is nevertheless a more costly disease in economic terms because of its far higher prevalence. At the same time, the burden of OA is increasing. While direct and indirect per capita costs for OA have stabilized in recent years, the escalating prevalence of the disease-partly a function of the rapid increase in 2 major risk factors: aging and obesity-has led to much higher overall spending for OA. Approximately one-third of direct OA expenditures are allocated for medications, much of which goes toward pain-related agents. Hospitalization costs comprise nearly half of direct costs, although these expenditures are consumed by only 5% of OA patients who undergo knee or hip replacement surgery. However, while these surgeries are costly, they also appear to be quite cost-effective in the long term. Indirect costs for OA are also high, largely a result of work-related losses and home-care costs. Despite the need for wide-ranging and up-to-date data on the economics of OA treatment to clarify the most effective treatments and the best use of resources, this area of study has received insufficient research attention.
19834761 Systemic sclerosis sine scleroderma and calcinosis cutis: report of a rare case. 2010 Feb Systemic sclerosis sine scleroderma is a rare form of limited cutaneous scleroderma. These patients manifest without cutaneous involvement, but do not differ in its clinical or laboratory features and prognosis from classical systemic sclerosis. In the absence of cutaneous signs/symptoms, its diagnosis is delayed leading to morbidity. The exact prevalence of dystrophic calcification in systemic sclerosis sine scleroderma, though a feature of systemic sclerosis, is not known. Development of dystrophic calcification further aggravates patient's woes. This paper describes systemic sclerosis sine scleroderma in a 17-year-old girl diagnosed initially as seronegative juvenile rheumatoid arthritis. She developed progressively increasing disk-like masses of calcinosis over the gluteal regions, knee, elbow, and ankle joints fixed to the overlying skin associated with malaise, anorexia, and weight loss. There was no Raynaud's phenomenon, dysphagia, dyspnoea, sclerodermatous skin, sclerodactyly, telangectasias, or muscle tenderness/weakness. Digital pitted scars, elevated anticentromere antibody values, esophageal hypomotility, and fluffy calcification in subdermal soft tissues in gluteal regions and around wrist, hip, knees, heels, and ankle joints (without affecting the underlying structures) were detected. Therapy with diltiazem and magnesium/aluminum antacids was useful in resolving calcinosis.
19796950 Posterior C1 lateral mass and C2 pedicle screw internal fixation for atlantoaxial instabil 2009 Dec From January 1999 to May 2005, 25 patients (15 males and 10 females; age range, 18-70 years; mean, 42 years) who demonstrated clinical and radiographic evidence of atlantoaxial instability underwent C1 lateral mass and C2 pedicle screw internal fixation with or without fusion at our Orthopedic Unit. The cause of instability was: 13 patients, traumatic fracture; three patients, rheumatoid arthritis; two patients, rotatory subluxation; two patients, congenital malformation; five patients, failed previous surgery. A mean follow-up of 16 months was obtained (range, 4-48 months). Mean operative time was 107 minutes (range, 80-141 minutes). No patient received a blood transfusion. No patient experienced worsening neurological function related to the procedure postoperatively or at follow-up. No other postoperative complication was observed. All patients were relieved from axial pain. Screw placement and reduction were achieved satisfactorily in all patients. Each patient showed evidence of solid fusion after 12 months by plain radiography and dynamic films. During follow-up, no complications were observed related to the bone graft or the screw rod. We suggest that C1 lateral mass and C2 pedicle screw internal fixation is a reliable method to repair atlantoaxial instability.
19747139 Selective matrix metalloproteinase inhibitors for cancer. 2009 The matrix metalloproteinases are a family of nearly 30 enzymes that are intimately involved in tissue remodeling. Disease processes associated with the matrix metalloproteinases are generally related to imbalance between the inhibition and activation of matrix metalloproteinases resulting in excessive degradation of the extracellullar matrix. These include osteoarthritis, rheumatoid arthritis, tumor metastasis and congestive heart failure. Despite massive research and development efforts, there are only two drugs launched on the market: periostat (doxycycline), a tetracycline used for periodontal disease and glucosemine sulfate, for osteoarthritis. Possible reasons for the low success rate of matrix metalloproteinase inhibitors in the clinic are mainly from unwanted side effects caused by their lack of selectivity, since inhibition of collagenase-1 may be responsible for the musculoskeletal side effects observed clinically with broad-spectrum inhibitors. Considering these data, many efforts were directed to developing a more selective second generation of inhibitors against the specific matrix metalloproteinases believed to be involved in the different pathologies. This review mainly focuses on selective matrix metalloproteinase inhibitors development on matrix metalloproteinases in terms of antitumor since the late 90s, in terms of synthetic compounds of low molecular mass incorporating specific zinc-binding groups, natural products and their derivatives. Through these methods, new hope is emerging in the form of synthetic and natural matrix metalloproteinase inhibitors for the prevention and treatment of cancer.
19717244 Vitamin D: in the evolution of human skin colour. 2010 Jan The natural selection hypothesis suggests that lighter skin colour evolved to optimise vitamin D production. Some authors question if vitamin D deficiency leads to sufficient health problems to act as a selection pressure. This paper reviews the numerous effects of vitamin D deficiency on human health and argues that vitamin D deficiency is sufficient to pose as a potent selection pressure for lighter skin colour. Vitamin D deficiency manifesting as rickets and osteomalacia are sufficient to impair reproductive success, but additionally, animal studies and some clinical observations suggest that vitamin D may have more direct impact on human fertility. Vitamin D deficiency may lead to a whole host of clinical conditions which impair health and increase mortality rates: increase susceptibility to bacterial and viral infections; rickets, osteomalacia and osteoporosis, with increased risk of falls and fractures; increased risk of cancers; hypertension and cardiovascular disease; maturity onset diabetes; autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel disease and Type 1 diabetes; and gum disease. We submit that at higher latitudes, lighter skin colour evolved to facilitate vitamin D production under conditions of low ultra-violet B radiation in order to avoid a plethora of ill health, reproductive difficulties and early mortality.
19689369 Cot/Tpl-2 protein kinase as a target for the treatment of inflammatory disease. 2009 Cot/Tpl-2/MAP3K8 is a serine/threonine protein kinase that is essential for lipopolysaccharide (LPS)-induced activation of the MEK/ERK pathway in macrophages as demonstrated in Cot/Tpl-2-deficient mice. Cot/Tpl-2 kinase activation plays an integral role in the production of pro-inflammatory cytokines such as TNF and IL-1beta in this immune cell type. Elevated levels of these cytokines have been clinically implicated as mediators of a number of autoimmune diseases, in particular, the pain and joint destruction of rheumatoid arthritis. By inference, pharmaceutical agents that inhibit Cot/Tpl-2 kinase have the potential to be novel and effective therapies for the treatment of these diseases. This review will describe the physiological regulation and importance of Cot/Tpl-2 in inflammation as well as the landscape of small molecules that have been reported as Cot/Tpl-2 inhibitors.
19621776 [A case of hypertrophic pachymeningitis treated successfully with antibiotics: the remarka 2009 Jul A 70-year-old man had hyperemia of the right cornea associated with a high serum C-reactive protein value. MRI of the head revealed hypertrophic pachymeningitis associated with a mass in the right cavernous sinus. The hypertrophic dura showed iso-intensity on T1 -weighted image, and very low intensity on T2-weighted image, and was markedly enhanced with gadolinium. In contrast, the mass in the right cavernous sinus was only slightly enhanced. Intravenous administration of some antibiotics (piperacillin sodium, ampicillin sodium/ sulbactam sodium, ampicillin sodium, cefozopran hydrochloride) was begun, but minocycline hydrochloride, which was subsequently administrated, proved remarkably effective in relieving symptoms and decreasing the serum C-reactive protein value, although other antibiotics showed little or no effect. MRI performed 9 days after initiation of minocycline therapy showed remarkable relief from hypertrophy of the dura compared with a scan obtained before admission. Although hypertrophic pachymeningitis in this case may have been associated with infection by bacteria that were especially sensitive to minocycline, the drug is believed to have anti-inflammatory and immunosuppressive effects similar to those of steroids used to relieve the symptoms of rheumatoid arthritis or Takayasu arteritis. We suspect that hypertrophic pachymeningitis in this patient may have been idiopathic or associated with an autoimmune disease, and may therefore have been relieved by the anti-inflammatory and immunosuppressive effects of minocycline in a manner similar to the Seffect of steroids on similar types of hypertrophic pachymeningitis.
19603292 [Restless legs syndrome. Features and impact on sleep]. 2009 May INTRODUCTION: Restless legs syndrome (RLS) is a chronic neurological disorder that has a negtive influence on sleep. We describe clinical spectrum, polysomnogram and impact on sleep of patients' series with RLS. METHODS: We studied 49 patients with RLS. We analyse socio- demographic information, clinical features, therapy and impact on sleep. We realized differents questionnaire: Index of Severity of Sleep, Epworth Scale, Index-RLS, Questionnaire Quality of Life-RLS and Questionnaire from limitation of laboral productivity. RESULTS: Mean age is 60.33+/-14.27 with similar distribution enter gender. They presented a positive family history in 36,73% with predominant in early onset of symptoms. Secondary causes more frequent associated were rheumatoid arthritis, iron-deficiency, uremia, pregnancy and polineuropathy. Significative prevalence of insomnia (73,43%) and periodic limb movement disorder (51,02%), obstructive sleep apnea syndrome (22,45%) and hipersomnia (22,45 %). Pharmacological treatment more used were dopaminergic drugs. We didn't find significant stadistic differences enter clinical feature and therapy, so tendency to better quality of life with dopaminergic drugs. CONCLUSIONS: It's an neurological disorder with important delay in diagnosis. Early detection is needed because important impact on sleep efficiency and quality of life, and improvement with therapy, solely dopaminergic drugs.
19550224 Internal fixation versus arthroplasty for displaced femoral neck fractures: what is the ev 2009 Jul A review of the current evidence for internal fixation versus hemiarthroplasty versus primary total hip arthroplasty for displaced femoral neck fractures was undertaken. At the meta-analysis level no difference in postoperative pain, function, or quality of life can yet be demonstrated. A significant difference in mortality has also not been found, but a trend towards higher mortality after primary arthroplasty is possible. Internal fixation (IF) has less morbidity, but a higher risk of revision and less cost-effectiveness. Independent adjudication for IF technique is rare in studies and bias towards higher revision rates due to technical failure is an issue. Randomized trials comparing IF with arthroplasty remain underpowered in specific subgroups of patients, in which IF revision rates could be acceptable. In hemiarthroplasty the data suggest minimal differences in outcome between the prosthesis types. The cementless Austin-Moore prosthesis is out-dated. Currently a cemented unipolar or bipolar, depending on costs, hemi-arthroplasty is the treatment of choice for an elderly patient with functional limitations before the fracture. The role of modern, uncemented hemiarthroplasty designs are uncertain until more data are published. Total hip arthroplasty (THA) should be considered in any active older patient with a displaced femoral neck fracture. Patients with concomitant osteoarthritis, rheumatoid arthritis, or renal failure do poorly with other treatment options and should be treated with THA. Randomized trials have shown THA to be a cost-effective treatment with lower revision rates than IF. THA may also appear to be superior to hemiarthroplasty in specific subgroups, but larger trials are needed to confirm this observation.
19536154 Novel association of the CD226 (DNAM-1) Gly307Ser polymorphism in Wegener's granulomatosis 2009 Sep Recently, there has been increasing evidence that a non-synonymous exchange (Gly307Ser) in the gene for CD226 is linked to several autoimmune diseases including type 1 diabetes, multiple sclerosis (MS), rheumatoid arthritis and Grave's disease. Here we present evidence that this polymorphism also predisposes to Wegener's granulomatosis (WG), an autoimmune condition belonging to the group of ANCA (antineutrophil cytoplasmic autoantibody)-associated vasculitides. We found a significant association of the 307Ser allele in separate panels of 520 Northern German (P=0.016, odds ratio (OR)=1.20) and 122 Southern German (P=0.020, OR=1.37) WG cases compared with 1226 healthy controls. The importance of this single-nucleotide polymorphism in the etiopathology of ANCA-associated vasculitides is supported by similar effect sizes that we found in British WG cases (n=105) and German patients with Churg-Strauss syndrome (n=119), which, however, miss significance level because of the relatively small cohorts available for these rare disorders. Finally, we confirm the association with MS in a cohort of 422 German patients (P=0.011, OR=1.23).
19531016 Novel MK2 inhibitors by fragment screening. 2009 Aug Inhibitors of MAPKAP kinase 2 (MK2) are expected to attenuate the p38alpha signal transduction pathway in macrophages in a similar way to p38alpha inhibitors and to have a lower propensity for toxic side effects that have slowed the clinical development of the latter. Therefore, novel MK2 inhibitors may find therapeutic application in acute and chronic, TNFalpha-mediated inflammatory conditions like rheumatoid arthritis and others. Herein we have applied fragment screening, using physiologically relevant bioassays and fragment binding mode mapping by protein-observed NMR spectroscopy to the discovery of novel efficient chemical starting points for MK2.
19527731 Aggregation-prone motifs in human immunoglobulin G. 2009 Aug 14 Therapeutic antibodies of many different IgG subclasses (IgG1, IgG2 and IgG4) are used in the treatment of various cancers, rheumatoid arthritis and other inflammatory and infectious diseases. These antibodies are stored for long durations under high concentrations as required in the disease treatment. Unfortunately, these antibodies aggregate under these storage conditions, leading to a decrease in antibody activity and raising concerns about causing an immunological response. Thus, there is a tremendous need to identify the aggregation-prone regions in different classes of antibodies. We use the SAP (spatial-aggregation-propensity) technology based on molecular simulations to determine the aggregation-prone motifs in the constant regions of IgG1 classes of antibodies. Mutations engineered on these aggregation-prone motif regions led to antibodies of enhanced stability. Fourteen aggregation-prone motifs are identified, with each motif containing one to seven residues. While some of these motifs contain residues that are neighbors in primary sequence, others contain residues that are far apart in primary sequence but are close together in the tertiary structure. Comparison of the IgG1 sequence with those of other subclasses (IgG2, IgG3 and IgG4) showed that these aggregation-prone motifs are largely preserved among all IgG subclasses. Other broader classes of antibodies (IgA1, IgD, IgE and IgM), however, differed in these motif regions. The aggregation-prone motifs identified were therefore common to all IgG subclasses, but differ from those of non-IgG classes. Moreover, since the motifs identified are in the constant regions, they are applicable for all antibodies within the IgG class irrespective of the variable region. Thus, the motif regions identified could be modified on all IgGs to yield antibodies of enhanced stability.
19523143 Multiple sclerosis association study with the TENR-IL2-IL21 region in a Spanish population 2009 Sep Polymorphisms from the TENR-IL2-IL21 block in the 4q27 chromosome were recently associated with type 1 diabetes, celiac disease, rheumatoid arthritis and psoriasis. We undertook this study to investigate the potential role of polymorphisms rs3136534, rs6822844 and rs2069762 (-330 T/G IL2) in multiple sclerosis (MS) (805 patients of Spanish Caucasian origin and 952 health controls). We did not find evidence for association with any single nucleotide polymorphisms (SNPs) tested. Allele and genotype frequencies of the SNPs, which were studied, were similar in DRB1*15-positive or DRB1*15-negative patients. After stratification of MS patients by clinical course, a weak association was observed with rs2069762 G allele and haplotype bearing this allele with secondary progressive MS, although these cases represent 22% of the MS cases. Our results did not show major influence of TENR-IL2-IL21 locus on susceptibility or disease progression in MS. However, we could not exclude completely the effect in MS for this region. Additional studies, using much larger sample sizes and analysis of additional polymorphisms in the gene and its flanking region, will be required to ascertain their contributions to MS susceptibility.