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ID PMID Title PublicationDate abstract
15629465 Triptolide suppresses proinflammatory cytokine-induced matrix metalloproteinase and aggrec 2005 Feb 4 A hallmark of rheumatoid- and osteoarthritis (OA) is proinflammatory cytokine-induced degeneration of cartilage collagen and aggrecan by matrix metalloproteinases (MMPs) and aggrecanases (ADAMTS). Effects of the Chinese herb, Tripterygium wilfordii Hook F (TWHF), on cartilage and its anti-arthritic mechanisms are poorly understood. This study investigated the impact of a purified derivative of TWHF, PG490 (triptolide), on cytokine-stimulated expression of the major cartilage damaging proteases, MMP-3, MMP-13, and ADAMTS4. PG490 inhibited cytokine-induced MMP-3, MMP-13 gene expression in primary human OA chondrocytes, bovine chondrocytes, SW1353 cells, and human synovial fibroblasts. Triptolide was effective at low doses and blocked the induction of MMP-13 by IL-1 in human and bovine cartilage explants. TWHF extract and PG490 also suppressed IL-1-, IL-17-, and TNF-alpha-induced expression of ADAMTS-4 in bovine chondrocytes. Thus, PG490 could protect cartilage from MMP- and aggrecanase-driven breakdown. The immunosuppressive, cartilage protective, and anti-inflammatory properties could make PG490 potentially a new therapeutic agent for arthritis.
16214349 Synthesis, molecular modelling and enzymatic evaluation of (+/-)3,5-diphenyl-2-thioxoimida 2006 Feb 15 A series of substituted (+/-)3,5-diphenyl-2-thioxoimidazolin-4-ones was synthesized in order to design new type-2 cyclooxygenase (COX-2) inhibitors. This study has led to molecules which completely inhibit human recombinant COX-2 at 50 microM. Molecular modelling highlighted drug interactions with the active site of both cyclooxygenases and suggested modifications to enhance the selectivity of the compounds. In human blood, COX-2 expression was then induced by LPS, and the inhibitory potency of these drugs was disappointing. This weak activity was attributed to a poor aqueous stability of these imidazolidinones substituted by two aryl in position 3 and 5 (15 min < t(1/2) < 130 min). The improvement of the stability of this heterocycle could generate a novel template to treat COX-associated diseases such as arthritis, rheumatoid polyarthritis and cancer.
17214095 Clinical and immunologic aspects of B chronic lymphocytic leukemia associated with autoimm 2006 Dec BACKGROUND: Autoimmune disorders often develop during the course of B chronic lymphocytic leukemia. The source of the autoantibodies is still uncertain: either uncontrolled production of the malignant B cells or disturbances of the residual normal B and T cells involved in the immune system. OBJECTIVES: To evaluate immunologic parameters in B-CLL associated with autoimmune disorders. As a hypothesis we postulated that in those cases, the malignant B cells might disclose an activated phenotype pattern leading to the production of autoantibodies. METHODS: In the Registry of the Israel Study Group on CLL that includes 964 patients, we found 115 cases showing a single or a complex of autoimmune disorders. We evaluated the lymphocyte morphology, immunoglobulin G and beta-2-microglobulin serum levels and positivity of the CD38 and FMC7 markers, and compared these values with those of a matched CLL population without autoimmune disorder. RESULTS: The main autoimmune disorders encountered were autoimmune hemolytic anemia (55 patients), Evan's syndrome (n=7), Hashimoto's thyroiditis (n=15), vasculitis (n=5) and rheumatoid arthritis (n=4). We found atypical prolymphocytic morphology in 22%, high expression of the activation antigens CD38 and/or FMC7 in 30%, and high level of immunoglobulin G (> 1000 mg/dl) and beta-2-microglobulin in 57% and 78% respectively. When compared with a matched CLL population without an autoimmune disorder, these values were statistically significant. CONCLUSIONS: Our data, which show activated lymphocyte morphology, high levels of IgG and beta-2-microglobulin, and increased expression of CD38 and/or FMC7 in a significant number of cases, suggest that some degree of activation of B cells may lead to the occurrence of an autoimmune disorder in CLL.
17161616 The effects of dexamethasone and dehydroepiandrosterone (DHEA) on cytokines and receptor e 2006 Oct Osteoporosis and associated fractures are the most common and debilitating complication of glucocorticoid use. The use of alternative anti-inflammatory agents without the deleterious skeletal effects of glucocorticoids is needed. Dehydroepiandrosterone (DHEA) may have immunomodulatory as well as positive effects on bone. For our further understanding of the mechanisms of action of DHEA, as a steroid-sparing agent, we investigated and compared the effects of dexamethasone (DEX) and DHEA on the regulation of the downstream effector pathway of osteoclastogenesis; RANKL/OPG and a range of inflammatory/pro-resorbing cytokines and receptors using a human clonal osteoblastic cell line. The cells were treated with DEX, DHEA, and androstenedione (ANDI). The mRNA expression of RANKL and OPG was determined by real-time PCR after overnight incubation. The regulation of a broad spectrum of cytokines by DEX and DHEA was also investigated using a human cytokine/growth factor and receptor gene array consisting of 268 cytokine-related cDNAs. To confirm some of the gene expression changes, protein production was measured by ELISA. RANKL expression and RANKL/OPG ratio were increased by DEX. This effect was reversed by co-treatment with both DHEA or ANDI. Several pro-inflammatory/resorptive cytokines including IL-6, IL-4, IFN-gamma, macrophage inhibitory factor (MIF) were down-regulated not only by DEX but also by DHEA. In contrast to DEX, DHEA did not lead to suppression of growth factors including vascular endothelial growth factor (VEGF), fibroblast growth factor-5 (FGF-5), insulin-like growth factor-binding protein3 (IGF-BP3). Several new target genes previously documented to influence bone formation were up-regulated by DHEA such as Notch 2, insulin receptor, thrombin receptor (PAR1). The data suggest that DHEA has immunomodulatory properties without the catabolic effects on bone remodeling, observed with glucocorticoid use. DHEA may thus prove useful as a steroid-sparing agent in the management of inflammatory disorders such as SLE or rheumatoid arthritis. Further in vivo studies are indicated.
17157553 The impact of the implementation of a rehabilitation tool on the contents of the communica 2007 Nov OBJECTIVE: Problems with multidisciplinary team conferences in health care include the exchange of too much (discipline-specific) information. The aim of this study was to investigate the effect of the implementation of a rehabilitation tool on the contents of communication during multidisciplinary team conferences in a rheumatology setting. METHODS: All initial and follow-up team conferences of 25 consecutive patients with rheumatoid arthritis admitted to a day patient care ward were videotaped during a period before (period I) and after (period II) the introduction of a rehabilitation tool. The aims of the rehabilitation tool were to enhance discussions on the co-ordination of care rather than merely exchange of information. This was achieved by providing a framework for the setting and evaluation of common treatment goals and management strategies as well as accompanying electronic and printed records. For every team conference, the duration of time spent on three types of communication was recorded: (1) grounding regarding the patient's health status, (2) the making of practical arrangements by no more than two health professionals, and (3) the co-ordination of common treatment goals or management strategies. Comparisons of the proportions of time spent on the different types of communication between the two periods were done by means of the Mann-Whitney U-test. RESULTS: Apart from the 25 initial team conferences in both periods, 86 and 71 follow-up team conferences were available in periods I and II, respectively. Regarding the initial team conferences, the proportion of time spent on grounding and practical arrangements was significantly smaller in period II than in period I. In addition, the proportion of time spent on common goals or management strategies was significantly greater in period II than in period I. For the follow-up team conferences, the proportion of time spent on practical arrangements was significantly smaller in period II, than in period I. Moreover, the proportions of time spent on the other types of communication did not differ significantly between the two periods. CONCLUSION: The implementation of a rehabilitation tool including a computer application increased the proportion of time spent on the discussion of common treatment goals or management strategies during initial but not during follow-up team conferences in a day patient rheumatology clinic.
17114481 Macrophage migration inhibitory factor induces macrophage recruitment via CC chemokine lig 2006 Dec 1 Macrophage migration inhibitory factor (MIF) was originally identified for its ability to inhibit the random migration of macrophages in vitro. MIF is now recognized as an important mediator in a range of inflammatory disorders. We recently observed that the absence of MIF is associated with a reduction in leukocyte-endothelial cell interactions induced by a range of inflammatory mediators, suggesting that one mechanism whereby MIF acts during inflammatory responses is by promoting leukocyte recruitment. However, it is unknown whether MIF is capable of inducing leukocyte recruitment independently of additional inflammatory stimuli. In this study, we report that MIF is capable of inducing leukocyte adhesion and transmigration in postcapillary venules in vivo. Moreover, leukocytes recruited in response to MIF were predominantly CD68(+) cells of the monocyte/macrophage lineage. Abs against the monocyte-selective chemokine CCL2 (JE/MCP-1) and its receptor CCR2, but not CCL3 and CXCL2, significantly inhibited MIF-induced monocyte adhesion and transmigration. CCL2(-/-) mice displayed a similar reduction in MIF-induced recruitment indicating a critical role of CCL2 in the MIF-induced response. This hypothesis was supported by findings that MIF induced CCL2 release from primary microvascular endothelial cells. These data demonstrate a previously unrecognized function of this pleiotropic cytokine: induction of monocyte migration into tissues. This function may be critical to the ability of MIF to promote diseases such as atherosclerosis and rheumatoid arthritis, in which macrophages are key participants.
17023270 Viscolin, a new chalcone from Viscum coloratum, inhibits human neutrophil superoxide anion 2006 Nov 1 The mistletoe Viscum coloratum is used in traditional Chinese medicine to treat inflammatory diseases. In this study, a cellular model in isolated human neutrophils, which are important in the pathogenesis of rheumatoid arthritis, chronic obstructive pulmonary disease, and other inflammatory diseases, was established to elucidate the anti-inflammatory functions of V. coloratum. The partially purified extract of V. coloratum (PPE-SVC) potently inhibited formyl-L-methionyl-L-leucyl-L-phenylalanine (FMLP)-induced superoxide anion generation and elastase release in a concentration-dependent manner with IC(50) values of 0.58+/-0.03 and 4.93+/-0.54 microg/ml, respectively. Furthermore, a new chalcone derivative, viscolin (4',4''-dihydroxy-2',3',6',3''-tetramethoxy-1,3-diphenylpropane), was isolated from PPE-SVC. Viscolin was demonstrated to inhibit superoxide anion generation and elastase release, as well as to accelerate resequestration of cytosolic calcium in FMLP-activated human neutrophils. Furthermore, the inhibitory effects of viscolin were reversed by protein kinase A (PKA) inhibitor, suggesting that PKA mediates the viscolin-caused inhibitions. Viscolin induced a substantial increase in cAMP levels, and that occurred through the inhibition of phosphodiesterase (PDE) activity but not an increase in adenylate cyclase function. Consistent with this, viscolin potentiated the PGE(1)-caused inhibition of superoxide anion release and calcium mobilization, as well as elevation of cAMP formation. These results demonstrate that inhibition of inflammatory responses in human neutrophils by viscolin is associated with an elevation of cellular cAMP through inhibition of PDE. Comparable results were also observed by PPE-SVC, indicating that the effect of PPE-SVC is at least partly mediated by viscolin. In summary, viscolin is a novel inhibitor of PDE and might be useful for treatment of neutrophilic inflammation.
16885699 The metabolism of mesalamine and its possible use in colonic diverticulitis as an anti-inf 2006 Aug 5-Aminosalicylic acid (5-ASA) is the mainstay of therapy for inflammatory bowel disease (IBD), particularly ulcerative colitis. 5-ASA is the active moiety in sulfasalazine, which was initially developed for the treatment of rheumatoid arthritis more than 60 years ago, by linking 5-ASA with sulfapyridine Because many of the side effects related to sulfasalazine were found to be due to sulfapyridine, several drugs that contain 5-ASA, and lack the side-effect profile of sulfasalazine, have been developed during the last 2 decades. These drugs have proven to be quite effective in treating mild-to-moderate symptoms of IBD, as well as inducing and maintaining remission. Although they exert anti-inflammatory effects, their exact mechanism of action remains elusive. Nonetheless, their success in treating IBD has led to studies using this class of drugs for novel indications. Several recent studies have evaluated the use of 5-ASA drugs (mesalamine) for the treatment of uncomplicated acute diverticulitis. In this review, we will briefly discuss the development of 5-ASA releasing drugs, their metabolism, side effects, indications, mechanisms of action, and the rationale for the clinical use of mesalamine in colonic diverticulitis.
16882533 Nested case-control study of autoimmune disease in an asbestos-exposed population. 2006 Aug OBJECTIVE: To explore the potential association between asbestos exposure and risk of autoimmune disease, we conducted a case-control study among a cohort of 7,307 current and former residents of Libby, Montana, a community with historical occupational and environmental exposure to asbestos-contaminated vermiculite. METHODS: Cases were defined as those who reported having one of three systemic autoimmune diseases (SAIDs): systemic lupus erythematosus, scleroderma, or rheumatoid arthritis (RA). Controls were randomly selected at a 3:1 ratio from among the remaining 6,813 screening participants using frequency-matched age and sex groupings. RESULTS: The odds ratios (ORs) and 95% confidence intervals (CIs) for SAIDs among those >or=65 years of age who had worked for the vermiculite mining company were 2.14 (95% CI, 0.90-5.10) for all SAIDs and 3.23 (95% CI, 1.31-7.96) for RA. In this age group, exposure to asbestos while in the military was also an independent risk factor, resulting in a tripling in risk. Other measures of occupational exposure to vermiculite indicated 54% and 65% increased risk for SAIDs and RA, respectively. Those who had reported frequent contact with vermiculite through various exposure pathways also demonstrated elevated risk for SAIDs and RA. We found increasing risk estimates for SAIDs with increasing numbers of reported vermiculite exposure pathways (p<0.001). CONCLUSION: These preliminary findings support the hypothesis that asbestos exposure is associated with autoimmune disease. Refined measurements of asbestos exposure and SAID status among this cohort will help to further clarify the relationship between these variables.
16874691 Serum amyloid A1 -13 T/C alleles in Turkish familial Mediterranean fever patients with and 2006 May Previously reported studies concerning the effect of homozygosity of the 1.1 allele of the SAA gene found a correlation between this haplotype and susceptibility to amyloidosis in FMF patients. Another report revealed a strong association between SAA1 -13T/C and secondary amyloidosis in the rheumatoid arthritis patient group. In this study, we aimed to determine the effect of SAA1 -13T/C in FMF patients with and without amyloidosis. The study cohort, consisting of 166 patients with FMF was divided into two groups, according to the presence (n=66) or absence (n=100) of renal amyloidosis at study entry. MEFV gene mutation analysis and allelic variant of SAA1 gene -13 T/C was analyzed according to the previously described techniques. SAA1 -13 T allele frequencies were 0.5816, 0.23 and 0.4242 in controls, FMF patients and FMF-amyloidosis patients respectively. The difference between controls vs. FMF patients and FMF-amyloidosis patients were 0.0002 and 0.1673 respectively. It was 0.0071 for FMF-patients vs. FMF-amyloidosis. When 694 M/V homozygous nonamyloid-FMF group was compared with 694 M/V carriers of the FMF-amyloidosis group, the difference was 0.049. When carrying TT allele was considered, the difference between controls vs. FMF patients and FMF-amyloidosis patients were 0.0001 and 0.58. It was 0.0003 for FMF patients vs. FMF-amyloidosis. When 694 M/V homozygous nonamyloid-FMF group was compared with 694 M/V carriers of the FMF-amyloidosis group, the difference was 0.03. Carrying SAA -13T in homozygote state revealed a 7.9 (95% CI 3.6 -17.5) fold risk for the occurrence of amyloidosis when compared with FMF patients without amyloidosis. This was 8.75 (95% CI 3.0 - 25.1) when 694 M/V homozygotes were taken into consideration. Our data revealed that the genotype SAA1 -13T has at least an effect on the development of amyloidosis. As more data on this polymorphism accumulate, we will understand its effect on the pathogenesis of amyloidosis in FMF.
16864010 Penicillamine and nephrotic syndrome. 2006 Aug BACKGROUND: Penicillamine (PA) treatment may be associated with a wide spectrum of adverse effects. There are many case reports and small series of PA-induced nephrotic syndrome (NS). In addition to our patient, in this study, we review all the cases of NS due to PA treatment in the English literature. METHODS: A retrospective Medline search was done for the years 1963-2004 using the terms "penicillamine" and "proteinuria" or "penicillamine" and "nephrotic". Cases were also located through article references. Cases were included in our review only if they had enough clinical and laboratory data and if the NS was considered by the authors to be mainly or solely due to PA treatment. Diagnosis of the patient, dose and duration of PA treatment, maximal amount of proteinuria, kidney function, urine analysis, serological markers, clinical data, kidney biopsy results, treatment, and course of proteinuria were documented. RESULTS: Sixty-three patients met our criteria. The female/male ratio was 40:23. Seventy-five percent of the patients had rheumatoid arthritis (RA). Mean age at diagnosis of NS was 44 (+/-S.D. 14) years. Mean dose of PA at diagnosis was 1.09 (+/-S.D. 0.413) g. Mean duration of PA treatment prior to proteinuria was 7.6 (+/-S.D. 3.90) months and mean duration of PA treatment until diagnosis of NS was 11.9 (+/-S.D. 18.8) months. Peak level of proteinuria was 10.79 (+/-S.D. 9.436) g. Some 33% of the patients developed mild to moderate renal failure at the time of diagnosis of NS, and one patient developed acute renal failure. Fifty-five percent of the patients had membranous glomerulonephritis and 27% had minimal change disease. Twelve patients were treated with corticosteroids (CS) at a dose ranging from 40 to 90 mg/day. In the overwhelming majority of patients, the proteinuria decreased significantly or disappeared within 7 months after stopping PA treatment. Patients treated with CS had a faster response. Five patients died, two of them from the CS-treated group, due to sepsis. CONCLUSION: The mean duration of PA treatment prior to the development of NS is nearly 1 year (5 months after the development of proteinuria). The most common histopathological finding is membranous glomerulonephritis. Most patients will have a significant reduction in, or disappearance of, proteinuria within 7 months after stopping PA treatment. The decrease in proteinuria is faster with CS treatment.
16842204 Chemistry and biology of anti-inflammatory marine natural products: molecules interfering 2006 The majority of the anti-inflammatory drugs routinely used nowadays are COX (cyclo-oxygenase) inhibitors. The important role of this enzyme, once known as prostaglandin synthase, in inflammation came a consequence of the discovery by the Nobel prize winner John Vane with his path-breaking discovery that aspirin and similar drugs exert their action by blocking the biosynthesis of the prostaglandin group of lipid mediators. (John R. Vane, Nobel Lecture, December 8, 1982 and references cited therein) In the last five years it has become clear that there are two such enzymes involved. One of the "cyclo-oxygenases", called COX1 is responsible for making prostaglandins, which among other things, protect the stomach and kidney from damage. It is now clear that inhibition of COX1 accounts for the unwanted side effects of aspirin-like drugs such as gastric irritation and renal damage. The other enzyme, COX2, is induced by inflammatory stimuli and it is prostaglandins made by this enzyme that contribute to the inflammation in diseases such as rheumatoid arthritis. However, concerning inflammation-related targets, one should not limit the interest to COX and PLA2 enzymes. In recent years, it has steadily become more clear, that modulation in the expression of genes underlies most cellular responses, and inflammation is certainly not an exception in this sense. It does not come as surprise that molecules showing ability to interfere with factors involved in the modulation of genes expression, such as NF-kB, have also to be considered potential anti-inflammatory agents. Also in this respect, marine natural products (MNP) have brought a collection of novel molecular entities displaying ability to target COX1/COX2, NF-kappaB or acting through molecular mechanisms yet-to-be-discovered. Following, the marine natural products accounted for within this review will be grouped on the basis of their bio-molecular targets. Chemical synthesis of particular relevant molecules will be also discussed, especially in those cases where the natural products can be considered as lead compounds for the development of simplified derivatives or analogues of potential pharmaceutical interest.
16800067 [Metal-metal-backed polyethylene cemented hip arthroplasty: mid-term results]. 2006 Apr PURPOSE OF THE STUDY: Metal-on-metal bearings in total hip arthroplasty may, in theory, provide an effective answer to osteolysis in active patients. The purpose of this retrospective study was to evaluate the results of a consecutive series of Metasul total hip arthroplasties with a cemented socket. MATERIAL AND METHODS: The series was composed of 28 total hip arthroplasties in 23 patients (13 women and 10 men). The mean age at operation was 44 +/- 8.3 years (range 22-59 years). The initial diagnosis was osteoarthritis (14 hips), osteonecrosis of the femoral head (11 hips) and rheumatoid arthritis (3 hips). Cemented cups with a metal articulation surface molded into the polyethylene were used. The cup was articulated with a 28-mm metallic head. Cemented stems were used in 27 hips, whereas a hydroxyapatite coated stem was implanted in one hip. RESULTS: One hip required revision for deep infection five months postoperatively. One patient (one hip) was lost to follow-up. Twenty-six hips were evaluated at an average 31-month follow-up (range 12-47 months). All hips were rated excellent or very good. Radiographically, seven hips (27%) had a progressive acetabular radiolucent line, including three complete radiolucent lines. The latter always were located at the bone-cement interface. No implant migration was noted. In these cases, the mean socket diameter was lower than for the rest of the cohort (p < 0.001). DISCUSSION AND CONCLUSION: Progression of acetabular radiolucent lines remains of concern in this series of Metasul artificial hips. It is hypothesized that the diminution of polyethylene thickness has led to an increased rigidity of the socket, resulting in a higher rate of constraints at the bone-cement interface. Special attention must be given to these hips.
16796743 Evidence for the association of the SLC22A4 and SLC22A5 genes with type 1 diabetes: a case 2006 Jun 23 BACKGROUND: Type 1 diabetes (T1D) is a chronic, autoimmune and multifactorial disease characterized by abnormal metabolism of carbohydrate and fat. Diminished carnitine plasma levels have been previously reported in T1D patients and carnitine increases the sensitivity of the cells to insulin. Polymorphisms in the carnitine transporters, encoded by the SLC22A4 and SLC22A5 genes, have been involved in susceptibility to two other autoimmune diseases, rheumatoid arthritis and Crohn's disease. For these reasons, we investigated for the first time the association with T1D of six single nucleotide polymorphisms (SNPs) mapping to these candidate genes: slc2F2, slc2F11, T306I, L503F, OCTN2-promoter and OCTN2-intron. METHODS: A case-control study was performed in the Spanish population with 295 T1D patients and 508 healthy control subjects. Maximum-likelihood haplotype frequencies were estimated by applying the Expectation-Maximization (EM) algorithm implemented by the Arlequin software. RESULTS: When independently analyzed, one of the tested polymorphisms in the SLC22A4 gene at 1672 showed significant association with T1D in our Spanish cohort. The overall comparison of the inferred haplotypes was significantly different between patients and controls (chi2 = 10.43; p = 0.034) with one of the haplotypes showing a protective effect for T1D (rs3792876/rs1050152/rs2631367/rs274559, CCGA: OR = 0.62 (0.41-0.93); p = 0.02). CONCLUSION: The haplotype distribution in the carnitine transporter locus seems to be significantly different between T1D patients and controls; however, additional studies in independent populations would allow to confirm the role of these genes in T1D risk.
16697735 Therapeutic action of ghrelin in a mouse model of colitis. 2006 May BACKGROUND & AIMS: Ghrelin is a novel growth hormone-releasing peptide with potential endogenous anti-inflammatory activities ameliorating some pathologic inflammatory conditions. Crohn's disease is a chronic debilitating disease characterized by severe T helper cell (Th)1-driven inflammation of the colon. The aim of this study was to investigate the therapeutic effect of ghrelin in a murine model of colitis. METHODS: We examined the anti-inflammatory action of ghrelin in the colitis induced by intracolonic administration of trinitrobenzene sulfonic acid. Diverse clinical signs of the disease were evaluated, including weight loss, diarrhea, colitis, and histopathology. We also investigated the mechanisms involved in the potential therapeutic effect of ghrelin, such as inflammatory cytokines and chemokines, Th1-type response, and regulatory factors. RESULTS: Ghrelin ameliorated significantly the clinical and histopathologic severity of the trinitrobenzene sulfonic acid-induced colitis; abrogating body weight loss, diarrhea, and inflammation; and increasing survival. The therapeutic effect was associated with down-regulation of both inflammatory and Th1-driven autoimmune response through the regulation of a wide spectrum of inflammatory mediators. In addition, a partial involvement of interluekin-10/transforming growth factor-beta1-secreting regulatory T cells in this therapeutic effect was demonstrated. Importantly, the ghrelin treatment was therapeutically effective in established colitis and avoided the recurrence of the disease. CONCLUSIONS: Our data demonstrate novel anti-inflammatory actions for ghrelin in the gastrointestinal tract, ie, the capacity to deactivate the intestinal inflammatory response and to restore mucosal immune tolerance at multiple levels. Consequently, ghrelin administration represents a novel possible therapeutic approach for the treatment of Crohn's disease and other Th1-mediated inflammatory diseases, such as rheumatoid arthritis and multiple sclerosis.
16273109 Autoimmune-associated lymphoid tyrosine phosphatase is a gain-of-function variant. 2005 Dec A SNP in the gene PTPN22 is associated with type 1 diabetes, rheumatoid arthritis, lupus, Graves thyroiditis, Addison disease and other autoimmune disorders. T cells from carriers of the predisposing allele produce less interleukin-2 upon TCR stimulation, and the encoded phosphatase has higher catalytic activity and is a more potent negative regulator of T lymphocyte activation. We conclude that the autoimmune-predisposing allele is a gain-of-function mutant.
16221721 FcgammaRIIa-131R allele and FcgammaRIIIa-176V/V genotype are risk factors for progression 2005 Nov BACKGROUND: Fcgamma receptors (FcgammaRs) may play an important role in positive and negative regulation of immune cell responses and immune complex (IC) clearance. Mesangial IgG deposition and circulating IgG/IgA-IC in sera are observed in patients with IgA nephropathy (IgAN). Therefore, the pathological roles of IgG-IC in IgAN have been discussed. On the other hand, several studies have identified FcgammaR polymorphisms (FcgammaRIIa, FcgammaRIIIa and FcgammaRIIIb) that determine susceptibility to autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis. The objective of the present study was to clarify whether FcgammaR polymorphisms influence susceptibility to IgAN, clinical features or severity in patients with IgAN. METHODS: Japanese patients with IgAN (n = 124) and healthy controls (n = 100) were genotyped for FcgammaR polymorphisms (FcgammaRIIa-131H or R, FcgammaRIIIa-176F or V and FcgammaRIIIb-NA1 or -NA2). The genotyping of these polymorphisms was performed using allele-specific polymerase chain reaction (PCR) methods. Associations among FcgammaR polymorphisms and susceptibility, age of onset, levels of serum immunoglobulins, intensity of glomerular IgG deposition and pathological severity were analysed. RESULTS: These three FcgammaR polymorphisms showed no significant differences in genotype and allele frequencies between the IgAN patients and healthy controls. Each FcgammaR polymorphism had no influence on age of onset, serum levels of IgG and glomerular IgG deposition in IgAN. However, FcgammaRIIa-131R (R/R or H/R) or FcgammaRIIIa-176V homozygous carriers (V/V) showed significantly more severe injury than FcgammaRIIa-131H homozygous (H/H) (P < 0.03) or FcgammaRIIIa-176F carriers (F/F or F/V) (P < 0.03), respectively. CONCLUSION: The present study shows that polymorphisms of FcgammaRIIa and FcgammaRIIIa influence the severity of IgAN in Japanese patients but not the incidence, suggesting that IgG-IC may play important roles in the progression and prognosis of this disease via FcgammaRs.
16189447 Frameless stereotactic image-guided C1-C2 transarticular screw fixation for atlantoaxial i 2005 Oct OBJECTIVE: We retrospectively studied 20 adults who underwent C1-C2 transarticular screw (TAS) fixation utilizing frameless stereotaxy. METHODS: The study group comprised 13 men and 7 women, with a mean age of 63 years (range 12-87 years). All patients demonstrated clinical and radiographic evidence of C1-C2 instability. The cause of the instability was trauma in 11 patients, rheumatoid arthritis in 6 patients, failed prior surgery in 2 patients, and congenital malformation in 1 patient. All patients underwent stabilization with C1-C2 TASs using image-guided frameless stereotaxy. RESULTS: There were no new or worsening neurologic symptoms reported at 18-month follow-up. Motor weakness improved in seven of nine patients, myelopathy in seven of seven, and gait in three of six patients in whom these deficits were present preoperatively. Postoperative complications included one surgical site abscess, one cutaneous pressure ulcer, and one iliac crest donor site infection. Of 36 screws placed, 33 (92%) were well positioned. Normal C1-C2 alignment was achieved in 17 of 20 (85%) patients. In 4 of 20 cases, screw implant, which was thought to be anatomically difficult, if not impossible, on the basis of routine magnetic resonance or computed tomography imaging, was actually accomplished successfully using surgical navigation. CONCLUSIONS: C1-C2 TAS placement is a safe and accurate surgical technique that may improve neurologic function. Use of intraoperative navigation can facilitate achieving difficult surgical trajectories that match the patient's anatomy, thus allowing TAS implant in patients who otherwise would not be candidates for this type of internal fixation.
16079149 Reactive site mutations in tissue inhibitor of metalloproteinase-3 disrupt inhibition of m 2005 Sep 23 Tissue inhibitor of metalloproteinase-3 (TIMP-3) is a dual inhibitor of the matrix metalloproteinases (MMPs) and some adamalysins, two families of extracellular and cell surface metalloproteinases that function in extracellular matrix turnover and the shedding of cell surface proteins. The mechanism of inhibition of MMPs by TIMPs has been well characterized, and since the catalytic domains of MMPs and adamalysins are homologous, it was assumed that the interaction of TIMP-3 with adamalysins is closely similar. Here we report that the inhibition of the extracellular region of ADAM-17 (tumor necrosis factor alpha-converting enzyme (TACE)) by the inhibitory domain of TIMP-3 (N-TIMP-3) shows positive cooperativity. Also, mutations in the core of the MMP interaction surface of N-TIMP-3 dramatically reduce the binding affinity for MMPs but have little effect on the inhibitory activity for TACE. These results suggest that the mechanism of inhibition of ADAM-17 by TIMP-3 may be distinct from that for MMPs. The mutant proteins are also effective inhibitors of tumor necrosis factor alpha (TNF-alpha) release from phorbol ester-stimulated cells, indicating that they provide a lead for engineering TACE-specific inhibitors that may reduce side effects arising from MMP inhibition and are possibly useful for treatment of diseases associated with excessive TNF-alpha levels such as rheumatoid arthritis.
15639649 The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but 2005 Feb Low-dose methotrexate (MTX) is an established and highly effective treatment for severe psoriasis and rheumatoid arthritis; however, its mechanism of action remains unclear. We investigated the effects of low-dose MTX on antigen-stimulated peripheral blood mononuclear cells and explored through which cellular pathways these effects are mediated. We show that MTX caused a dose-dependent suppression of T cell activation and adhesion molecule expression, and this was not due to lymphocyte apoptosis. The suppression of intercellular adhesion molecule (ICAM)-1 was adenosine and folate-dependent, while MTX suppression of the skin-homing cutaneous lymphocyte-associated antigen (CLA) was adenosine-independent. The effect of MTX on CLA, but not ICAM-1, required the constant presence of MTX in cultures. Thus, the suppression of T cell activation and T cell adhesion molecule expression, rather than apoptosis, mediated in part by adenosine or polyglutamated MTX or both, are important mechanisms in the anti-inflammatory action of MTX.