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ID PMID Title PublicationDate abstract
16764688 Epicutaneous immunization converts subsequent and established antigen-specific T helper ty 2006 Sep Epicutaneous immunization is a potential novel technique for topical vaccine delivery. It targets the immunologically rich milieu of the skin while having the advantage of being a non-invasive immunization procedure. By disrupting the stratum corneum of the epidermis a natural adjuvant effect can be achieved through activation of resident Langerhans cells. This negates the normal need for co-application of noxious adjuvants. Epicutaneous immunization on barrier-disrupted skin induces potent antigen-specific systemic immunity with a strong T helper type 2 (Th2) bias. We show here that epicutaneous immunization enhances the vigour of a subsequent T-cell response to the same antigen. The induced systemic Th2 response prevents the development of Th1 responses induced through injection of antigen in complete Freund's adjuvant (CFA). Prior epicutaneous immunization results in reduced production of antigen-specific interferon-gamma and immunoglobulin G2a (IgG2a) and enhanced interleukin-4, IgG1 and IgE responses to immunization with CFA. Moreover, epicutaneous immunization converts an established Th1 response to a Th2 response, as demonstrated by the specific reduction of interferon-gamma and IgG2a and the enhancement of interleukin-4 and IgE. This Th2 dominance of epicutaneous immunization may have direct therapeutic application as an immune-modulating procedure in Th1-dominant diseases such as autoimmune rheumatoid arthritis, type 1 diabetes, Hashimoto's thyroiditis and multiple sclerosis.
16688677 Treatment of refractory CMV-infection following hematopoietic stem cell transplantation wi 2006 May BACKGROUND: Treatment of cytomegalovirus (CMV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is limited by toxicities of current antiviral drugs and the occurrence of drug resistant strains. Leflunomide, an immunosuppressive agent used for treatment of rheumatoid arthritis, also has activity against CMV by impairing viral assembly. Here we report the control of refractory CMV disease by the combined use of foscarnet and leflunomide. PATIENTS AND RESULTS: A 1S-year-old boy with juvenile myelo-monocytic leukemia (JMML) received an allogeneic HSCT with bone marrow stem cells from a mismatched, unrelated donor (MMUD, recipient and donor CMV-positive). CMV-reactivation two months post transplantation (Tx) could only be controlled by the use of cidofovir. Because of secondary graft failure, the boy received a second HSCT with peripheral blood stem cells (PBSC) of the same donor after overall 6 months. CMV-infection was noticed three weeks later, associated with a considerable rise of both CMV-copy number and pp65-antigen. Since reinduction with cidofovir was ineffective and ganciclovir not warranted due to the history of graft failure, the child then received a combination of foscarnet/leflunomide, leading to a rapid decline of his CMV-copy number and to an afebrile state. Hematological, hepatic or renal toxicities were not observed. CONCLUSION: This case report suggests that leflunomide may be of use in the management of transplant recipients with CMV-infection refractory or intolerant to conventional antiviral therapy.
16687155 Up-regulation of protease-activated receptor-2 by bFGF in cultured human synovial fibrobla 2006 Jul 24 Protease-activated receptors (PARs) have been implicated in the development of acute and chronic inflammatory responses. We have examined the expression of mRNA for PARs and their regulation by growth factors and cytokines in synovial fibroblasts derived from patients with rheumatoid arthritis (RA). Messenger RNA for PAR-1, -2 and -3 was detected in these cells, but not that for PAR-4. Expression of mRNA for PAR-2 was up-regulated by bFGF in a concentration-dependent manner, whereas expression of mRNA for PAR-1 and PAR-3 was not affected. Levels of mRNA encoding PAR-1, PAR-2 and PAR-3 did not increase in response to IL-1beta and TNF-alpha. Expression of mRNA for PAR-2 was maximal 12 h after addition of bFGF, and maximal levels of immunoreactive PAR-2 were reached after 24 h. Furthermore, PAR-2 agonist peptide (SLIGKV-NH(2)), but not the inactive reverse peptide (VKGILS-NH(2)), induced transitory cytosolic Ca(2+) mobilization in cells, and its response was increased by pretreatment with bFGF. An important role could be played by bFGF in the regulation of functional PAR-2 expression in cultured RA synovial fibroblasts.
16684434 Iron and the anaemia of chronic disease: a review and strategic recommendations. 2006 Apr BACKGROUND: The incidence of anaemia is high in many chronic conditions, yet it often receives little attention. SCOPE/METHODS: A panel of international experts with experience in haematology, nephrology, oncology, rheumatology and pharmacy was convened to prepare strategic guidelines. A focused literature search was conducted after key issues had been identified. A series of recommendations was agreed, backed, wherever possible, by published evidence which is included in the annotations. RECOMMENDATIONS: Anaemia is a critical issue for patients with chronic diseases. Healthcare professionals need to recognise that anaemia is a frequent companion of cancer and chronic conditions such as rheumatoid arthritis and heart failure. It reduces patients' quality of life and can increase morbidity and mortality. Anaemia should be considered as a disordered process in which the rate of red cell production fails to match the rate of destruction which leads eventually to a reduction in haemoglobin concentration; this process is common to all chronic anaemias. The aim of anaemia management should be to restore patient functionality and quality of life by restoring effective red cell production. Blood transfusion can elevate haemoglobin concentration in the short term but does nothing to address the underlying disorder; red cell transfusion is, therefore, not an appropriate treatment for chronic anaemia. Patients with anaemia of chronic disease may benefit from iron therapy and/or erythropoiesis stimulating agents (ESAs). Intravenous iron should be considered since this can be given safely to patients with chronic diseases while intramuscular iron causes unacceptable adverse effects and oral iron has limited efficacy in chronic anaemia. CONCLUSION: The management of anaemia calls for the development of a specialist service together with education of all healthcare professionals and transfer of skills from areas of good practice. Improvement in the management of anaemia requires a fundamental change of attitude from healthcare professionals.
16651215 Enlarging retro-odontoid pseudotumor after expanding cervical laminoplasty in the presence 2006 May BACKGROUND CONTEXT: In cranio-vertebral junction, retro-odontoid pseudotumor without evidence of rheumatoid arthritis is a rare condition. PURPOSE: To discuss the mechanism of enlarging retro-odontoid pseudotumor after expanding cervical laminoplasty as a predictable complication. STUDY DESIGN: We report a rare case of an elderly man with non-inflammatory retro-odontoid pseudotumor after cervical expanding laminoplasty. PATIENT SAMPLE: A 76-year-old man presented with progressive quadriparesis of two week's duration caused by enlarging retro-odontoid soft tissue mass after cervical laminoplasty. OUTCOME MEASURES: Pre- and postoperative image, including X-ray and MRI, and the Japanese Orthopaedic Association scores for cervical myelopathy were assessed. METHODS: The patient subsequently underwent resection of the posterior arch of the atlas and posterior fusion from the occiput to C6 using Olerud system without removal of the retro-odontoid soft tissue mass. RESULTS: One year after surgery, the Japanese Orthopaedic Association scores for cervical myelopathy improved from 1 to 10 points, and postoperative MRI showed a mild reduction in the size of the retro-odontoid soft tissue mass. CONCLUSIONS: The kyphotic stability from C3 to C7 after laminoplasty, leading to a compensatory hyperlordosis at the occipitocervical junction, may cause the development of a degenerative osteoarthritic change, resulting in the production of an enlarging mass. Not only posterior compression of spinal cord due to posterior arch of the hyperextended atlas but also anterior compression of spinal cord due to retro-odontoid pseudotumor probably triggered the severe myelopathy. Laminoplasty may be inappropriate in cervical myelopathy with kyphosis.
16508180 Three new and antitumor anthraquinone glycosides from Lasianthus acuminatissimus MERR. 2006 Mar Three new anthraquinone glycosides, lasianthuoside A (1), B (2), and C (3), were isolated from the root of Lasianthus acuminatissimus MERR., The structural elucidation of these anthraquinones was mainly established on the basis of 1D and 2D NMR and HR-MS spectroscopic analysis. Ten known compounds, damnacanthol (4), damnacanthol 11-methyl ether (5), damnacanthol-3-O-beta-D-primeveroside (6), asperuloside (7), asperulosidic acid (8), deacetyl asperulosidic acid (9), a nonglycosidic iridoid (10), 2,6-dimethoxy-4-hydroxyphenol-1-O-beta-D-glucopyranoside (11), tachioside (methoxyhydroquinone-4-O-beta-D-glucopyranoside) (12), and isotachioside (methoxyhydroquinone-1-O-beta-D-glucopyranoside) (13) were also identified for the first time from this plant in the course of the phytochemical and spectroscopic investigation. In addition to this report, a preliminary evaluation of 13 compounds in treating rheumatoid arthritis and antitumor effects of six anthraquinones are presented.
16364202 Inhibitory effect of acetylsalicylic acid on matrix metalloproteinase - 2 activity in huma 2005 Oct Matrix metalloproteinases play a major role in the process of angiogenesis, an important feature of diabetes complications, cancer or rheumatoid arthritis. High glucose concentrations were reported to augment metalloproteinase-2 secretion in some cell types. In the present study we investigated the influence of acetylsalicylic acid on metalloproteinase- 2 secretion and expression in endothelial cells cultured for one week in high glucose conditions (25 mM and 33 mM). Metalloproteinase-2 activity was evidenced by gel zymography, the protein was identified by Western blotting, and the gene expression was quantitated by RT-PCR. The results indicated a marked inhibitory effect of acetylsalicylic acid at gene expression level (approximately 43%) and also at secretion level in samples of conditioned media (approximately 30%) and cellular homogenates (approximately 70%). This may suggest that acetylsalicylic acid could have a beneficial effect in preventing the angiogenic process that appears in diabetes complications.
16309946 Regulators of angiogenesis and strategies for their therapeutic manipulation. 2006 Mar Angiogenesis provides a mechanism by which delivery of oxygen and nutrients is adapted to compliment changes in tissue mass or metabolic activity. However, maladaptive angiogenesis is integral to the process of several diseases common in Western countries, including tumor growth, vascular insufficiency, diabetic retinopathy and rheumatoid arthritis. Understanding the process of capillary growth, including the identification and functional analyses of key pro- and anti-angiogenic factors, provides knowledge that can be applied to improve/reverse these pathological states. Initially, angiogenesis research focused predominantly on vascular endothelial growth factor (VEGF) as a main player in the angiogenesis cascade. It is apparent now that participation of multiple angiogenic factors and signal pathways is critical to enable effective growth and maturation of nascent capillaries. The purpose of this review is to focus on recent progress in identifying angiogenesis signaling pathways that show promise as targets for successful induction or inhibition of capillary growth. The strategies applied to achieve these contradictory tasks are discussed within the framework of our existing fundamental knowledge of angiogenesis signaling cascades, with an emphasis on comparing the employment of distinctive tactics in modulation of these pathways. Innovative developments that are presented include: (1) inducing a pleiotropic response via activation or inhibition of angiogenic transcription factors; (2) modulation of nitric oxide tissue concentration; (3) manipulating the kallikrein-kinin system; (4) use of endothelial progenitor cells as a means to either directly contribute to capillary growth or to be used as a vehicle to deliver "suicide genes" to tumor tissue.
16174768 The structural basis of Janus kinase 2 inhibition by a potent and specific pan-Janus kinas 2006 Jan 1 JAK2, a member of the Janus kinase (JAK) family of protein tyrosine kinases (PTKs), is an important intracellular mediator of cytokine signaling. Mutations of the JAK2 gene are associated with hematologic cancers, and aberrant JAK activity is also associated with a number of immune diseases, including rheumatoid arthritis. Accordingly, the development of JAK2-specific inhibitors has tremendous clinical relevance. Critical to the function of JAK2 is its PTK domain. We report the 2.0 A crystal structure of the active conformation of the JAK2 PTK domain in complex with a high-affinity, pan-JAK inhibitor that appears to bind via an induced fit mechanism. This inhibitor, the tetracyclic pyridone 2-tert-butyl-9-fluoro-3,6-dihydro-7H-benz[h]-imidaz[4,5-f]isoquinoline-7-1, was buried deep within a constricted ATP-binding site, in which extensive interactions, including residues that are unique to JAK2 and the JAK family, are made with the inhibitor. We present a structural basis of high-affinity JAK-specific inhibition that will undoubtedly provide an invaluable tool for the further design of novel, potent, and specific therapeutics against the JAK family.
16155443 Toxic neuropathy. 2005 Oct PURPOSE OF REVIEW: This paper examines recent research on toxic neuropathy and potential therapeutic developments. It also summarizes reports of new agents reported to cause peripheral neuropathy. RECENT FINDINGS: Gene therapy with vasoactive endothelial growth factor, neurotrophic substances such as nerve growth factor and neurotrophin-3 are reported to reverse or protect against neurotoxicity in animal models. The neuroprotective effects of more established therapeutic agents like vitamin E, tacrolimus (FK 506) and erythropoietin hold promise for the immediate future. Cisplatin and high-dose pyridoxine are used more frequently to produce robust models of peripheral neuropathy in animals. Statins do appear to cause peripheral neuropathy. The incidence is low, however, and compared to its benefits in terms of cardiovascular protection, relatively innocuous. The profile of thalidomide neuropathy is becoming clearer as the indications for this drug increases. The incidence of thalidomide neuropathy is high, up to three quarters in some series, and although the information on dose dependency is variable, lower cumulative doses appear to be less toxic. Like thalidomide bortezomib, a novel proteosome inhibitor, is reportedly effective in the treatment of multiple myeloma and is associated with peripheral neuropathy. Oxaliplatin and epothilone are emerging anticancer drugs with neurotoxic potential. Similarly, leflunomide, a new disease modifying-agent approved for the treatment of rheumatoid arthritis, is reported to cause neuropathy. SUMMARY: The study of toxic neuropathy is not only enhancing our knowledge of the mechanisms of neurotoxicity but also the neurobiology of peripheral neuropathy in general; and is likely to reveal avenues for therapeutics.
16076916 Glycemic monitoring in diabetics with sickle cell plus beta-thalassemia hemoglobinopathy. 2005 Sep OBJECTIVE: To report a case of diabetes management in a patient with a hemoglobinopathy that caused her clinician to seek a different measure of glycemic control, fructosamine, rather than glycosylated hemoglobin (HbA1c). CASE SUMMARY: A 53-year-old African American woman presented with a past medical history of type 2 diabetes, hypertension, seizure disorder, rheumatoid arthritis, and sickle cell disease plus beta-thalassemia. She reported fasting blood glucose values ranging broadly from 50 to 320 mg/dL, yet her HbA1c result remained steady in a low range of <6%. A measure of fructosamine returned elevated at 340 micromol/L (reference range 200-300). DISCUSSION: We believe that this patient's hemoglobinopathy resulted in falsely low levels of HbA1c, and we substantiate this interpretation with the patient's self-monitored blood glucose values from home that appeared higher and inconsistent with the HbA1c results. Although few reports on using the measure of fructosamine appear in the literature, this patient's high fructosamine result supports fructosamine as the more appropriate measure of glycemic control. CONCLUSIONS: Serum fructosamine levels may be considered as an appropriate laboratory measurement when monitoring long-term glycemic control in patients with type 2 diabetes mellitus and sickle cell disease.
15951022 FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid 2005 Dec FTY720 is the first of a new immunomodulator class: sphingosine 1-phosphate (S1P) receptor agonist. In 1994, an immunosuppressive natural product, ISP-I (myriocin), was isolated from the culture broth of Isaria sinclairii, a type of vegetative wasp. The chemical modification of ISP-I yielded a new compound, FTY720, which has more potent immunosuppressive activity and less toxicity than ISP-I does. FTY720 has been shown to be highly effective in experimental allotransplantation models and autoimmune disease models. A striking feature of FTY720 is the induction of a marked decrease in peripheral blood T- and B-cells at doses that show immunosuppressive activity in these models. Reportedly, FTY720 is rapidly converted to FTY720-phosphate (FTY720-P) by sphingosine kinase 2 in vivo, and FTY720-P acts as a potent agonist at S1P receptors. Recently, it has been suggested that FTY720-P internalizes S1P1 on lymphocytes and thereby inhibits the migration of lymphocytes toward S1P. Thus, it is likely that the reduction of circulating lymphocytes by FTY720 is due to the inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid tissues and thymus. Because FTY720 displays a novel mechanism of action that has not been observed with other immunosuppressive agents and shows a synergism with cyclosporin A (CsA) and tacrolimus, it is presumed that FTY720 provides a useful tool for the prevention of transplant rejection and a new therapeutic approach for autoimmune diseases including multiple sclerosis and rheumatoid arthritis.
15868402 Poly(ADP-ribosyl)ation in relation to cancer and autoimmune disease. 2005 Apr Carcinogenesis involves multiple steps and pathways with functional alterations in a variety of genes. There is accumulating evidence that a deficiency of poly(ADP-ribose) polymerase (PARP)-1 leads to DNA repair defects, genomic instability, failure of induction of cell death and modulation of gene transcription. PARP-1 also supports the growth of tumor cells in certain situations. Genetic analyses of the PARP-1 gene have demonstrated alterations in neoplasms, and a mutation affecting the conserved amino acid E251 in germ cell tumors, as well as an association of a single-nucleotide polymorphism V762A with risk of prostate cancer. Recent development of a selective inhibitor of poly(ADP-ribose) glycohydrolase (PARG), the enzyme primarily responsible for degradation of poly(ADP-ribose), and PARG-deficient animals should facilitate studies of the relationship of poly(ADP-ribose) with carcinogenesis. Inhibitors of PARP have also suggested roles in the pathogenesis of autoimmune disease, and a promoter haplotype of PARP-1 confers a higher risk of rheumatoid arthritis. Further analysis of PARP-1, PARG and other PARP family genes should extend our understanding of the pathogenesis of cancer and autoimmune diseases. Furthermore, there is potential for sensitization to chemo- and radiation therapy of cancers as well as the treatment of autoimmune disease with development of stronger PARP inhibitors.
15864078 Does fish oil supplementation in pregnancy reduce the risk of allergic disease in infants? 2005 Jun PURPOSE OF REVIEW: Parallel increases in many inflammatory diseases over the last 40 years suggest that common environmental changes are promoting inflammatory immune responses and/or inhibiting the processes that normally keep these in check. One key change during this period has been declining intakes of anti-inflammatory dietary factors, including omega-3 polyunsaturated fatty acids (n-3 PUFA). As allergic diseases often first manifest in early infancy, prevention strategies need to be targeted early, even in utero. This review will examine recent evidence for the use of fish oil during this early period as a primary prevention strategy for allergic disease. RECENT FINDINGS: N-3 PUFA have well documented anti-inflammatory effects in vitro and have also been demonstrated to have health benefits in a range of chronic inflammatory diseases, including cardiovascular disease, rheumatoid arthritis and diabetes, supporting their role in modulating inflammation in vivo. Although the effects of fish oil supplementation in established allergic disease are less convincing, there is accumulating evidence that dietary n-3 PUFA may have greater effects before allergic responses are established. SUMMARY: Supplementation of the maternal diet in pregnancy with n-3 PUFA may provide a non-invasive intervention with significant potential to prevent the development of allergic and possibly other immune-mediated diseases.
15838377 Depletion of B cells by a humanized anti-CD20 antibody PRO70769 in Macaca fascicularis. 2005 May PRO70769 is a humanized IgG1 monoclonal antibody against the CD20 molecule that is present on normal and malignant B cells. PRO70769 is being evaluated for treatment of B-cell-mediated diseases and is in a phase 1 trial for rheumatoid arthritis. As part of the preclinical toxicology evaluation, B-cell depletion profiles and safety of PRO70769 were assessed in cynomolgus monkeys. Animals were administered drug (IV) on days 1 and 15 with 10, 50, or 100 mg/kg PRO70769 and killed 2 weeks after the second dose and after a 3-month recovery period. In a parallel study, animals were not necropsied but instead were retreated with a second cycle of PRO70769 administered under an identical regimen. PRO70769 suppressed B cells in the blood to undetectable levels and significantly reduced B cells in lymphoid tissues. Splenic B cells were depleted to a greater extent compared with lymph node B cells. A second cycle of treatment resulted in a greater extent of depletion in lymphoid tissues compared with the depletion observed after one cycle of treatment; however, residual B cells in lymphoid tissues were still detectable, even at the highest dose. The rate of B-cell recovery in peripheral blood appeared similar between one and two cycles of treatment. Upon depletion there was a change in the profile of lymph node B-cell subsets. After recovery, B-cell subsets were reconstituted to normal levels. Depletion of CD20-expressing cells and lymphoid follicular atrophy were the only treatment-related effects.
15780119 BCA-1/CXCL13 expression is associated with CXCR5-positive B-cell cluster formation in acut 2005 Apr BACKGROUND: Recent studies showed a crucial role for B cells in acute renal allograft rejection. It remains largely unknown, however, which mechanisms lead to the B-cell recruitment into the allograft. The chemokine CXCL13 and its corresponding receptor CXCR5 play a central role in B-cell trafficking to secondary lymphatic tissue and ectopic B-cell clusters in rheumatoid arthritis. We therefore investigated the potential role of CXCL13 and CXCR5 in formation of B-cell clusters in renal transplant rejection. METHODS: Serial immunohistochemical staining for CXCL13, CXCR5, and CD20 was carried out in protocol biopsies of 23 patients obtained between day 4 and day 9 after renal transplantation. Intragraft mRNA expression of CXCL13 was assessed by real-time polymerase chain reaction (PCR) analysis. RESULTS: Of 23 kidney biopsies obtained between days 4 and 9 after renal transplantation, 13 revealed an acute rejection. Four of these patients showed a substantial infiltration of the transplant with cluster-forming B cells. By immunohistochemistry CXCL13 and the corresponding receptor CXCR5 were exclusively detected in areas of B-cell clusters. Intrarenal CXCL13 mRNA expression was 27-fold higher in transplants with B-cell clusters compared to rejecting allografts without B-cell accumulation (P= 0.011). CONCLUSION: We describe a striking colocalization of CXCL13 expression with CXCR5- and CD20-positive B cells in renal transplants undergoing rejection. This is the first study demonstrating a potential role of CXCL13 and its specific receptor CXCR5 in recruitment of B cells in renal allograft rejection.
15703453 Anti-caspase-8 autoantibody response in silicosis patients is associated with HLA-DRB1, DQ 2005 Jan We reported previously the autoantibodies directed to caspase-8 among patients with silicosis, systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) , and in healthy individuals. In this study, we analyzed the correlation between anti-caspase-8 autoantibody responses and HLA class II alleles in silicosis patients. The frequencies of HLA-DRB1*0406 were significantly higher in antibody positive patients (16.67%) than in control individuals (3.03%, p=0.0006). The lysine (K) at position 71 as in DRB1*0406 has been reported to be associated with rheumatoid arthritis (RA) and insulin dependent diabetes mellitus (IDDM). The haplotype HLA-DR4; DQB1*0302 was detected in 4 of 12 antibody positive patients. RA, IDDM, or pemphygus vulgaris link to the haplotype. The frequencies of DQB1*0401 were significantly lower in antibody positive patients (0%) than that in controls (13.33%, p=0.0390). The aspartic acid at position 57 in the DQB1 molecule as in DQB1*0401 is reported to play a role in the resistance to IDDM. The frequency of DPB1*0601 in antibody positive patients (5.88%) was significantly higher than that in controls (0.56%, p=0.0003). DPB1*0601 is reported to be a risk factor among RA patients, and glutamate at position 69 of the DPB1 molecule may be involved. Repeated and continuous screening of autoantibodies seems to be necessary among workers in contact with Si-related substances for the detection of immunological disorders in the early stage.
15678923 A cross-sectional study of primary biliary cirrhosis in Japan: utilization of clinical dat 2005 Jan BACKGROUND: There have not been many reports regarding primary biliary cirrhosis (PBC) in Asia. We conducted a cross-sectional study of PBC in Japan. METHODS: In fiscal year 1999, 9,761 patients with symptomatic PBC were registered to receive public financial aid from the Ministry of Health, Labour and Welfare of Japan. For our cross-sectional study we chose 5,805 patients whose clinical data had been written between 1999 and 2000, and statistically analyzed the data, including sex, age, major symptoms, and laboratory data. RESULTS: Our study estimated that the male-to-female ratio was 1:8.0. The median ages of male and female patients were 59 and 60 years, respectively. The major symptoms and physical findings were as follows: pruritus 53.3%, jaundice 11.3%, xanthomas 5.8%, splenomegaly 38.1%, and esophageal varices 19.1%. Antimitochondrial antibody (AMA) was positive in 86.6%, but its positive rate was lower among Japanese patients than among those in western countries. IgM levels were higher among AMA-positive patients than among AMA-negative patients. Regarding Sjogren's syndrome, rheumatoid arthritis, chronic thyroiditis, and scleroderma, patients had lower frequencies of complicated autoimmune diseases than those in western countries. CONCLUSIONS: The male-to-female ratio, frequencies by age group, symptoms and physical findings among patients with PBC were consistent with previous reports in Japan and from other countries. However, positivity of AMA and the frequency of complicated autoimmune diseases were lower among patients in Japan than among those in western countries.
15662292 Mechanism of action of paracetamol. 2005 Jan Paracetamol (acetaminophen) is generally considered to be a weak inhibitor of the synthesis of prostaglandins (PGs). However, the in vivo effects of paracetamol are similar to those of the selective cyclooxygenase-2 (COX-2) inhibitors. Paracetamol also decreases PG concentrations in vivo, but, unlike the selective COX-2 inhibitors, paracetamol does not suppress the inflammation of rheumatoid arthritis. It does, however, decrease swelling after oral surgery in humans and suppresses inflammation in rats and mice. Paracetamol is a weak inhibitor of PG synthesis of COX-1 and COX-2 in broken cell systems, but, by contrast, therapeutic concentrations of paracetamol inhibit PG synthesis in intact cells in vitro when the levels of the substrate arachidonic acid are low (less than about 5 mumol/L). When the levels of arachidonic acid are low, PGs are synthesized largely by COX-2 in cells that contain both COX-1 and COX-2. Thus, the apparent selectivity of paracetamol may be due to inhibition of COX-2-dependent pathways that are proceeding at low rates. This hypothesis is consistent with the similar pharmacological effects of paracetamol and the selective COX-2 inhibitors. COX-3, a splice variant of COX-1, has been suggested to be the site of action of paracetamol, but genomic and kinetic analysis indicates that this selective interaction is unlikely to be clinically relevant. There is considerable evidence that the analgesic effect of paracetamol is central and is due to activation of descending serotonergic pathways, but its primary site of action may still be inhibition of PG synthesis. The action of paracetamol at a molecular level is unclear but could be related to the production of reactive metabolites by the peroxidase function of COX-2, which could deplete glutathione, a cofactor of enzymes such as PGE synthase.
15642335 Leptin, from fat to inflammation: old questions and new insights. 2005 Jan 17 Leptin is 16 kDa adipokine that links nutritional status with neuroendocrine and immune functions. Initially thought to be a satiety factor that regulates body weight by inhibiting food intake and stimulating energy expenditure, leptin is a pleiotropic hormone whose multiple effects include regulation of endocrine function, reproduction, and immunity. Leptin can be considered as a pro-inflammatory cytokine that belongs to the family of long-chain helical cytokines and has structural similarity with interleukin-6, prolactin, growth hormone, IL-12, IL-15, granulocyte colony-stimulating factor and oncostatin M. Because of its dual nature as a hormone and cytokine, leptin links the neuroendocrine and the immune system. The role of leptin in the modulation of immune response and inflammation has recently become increasingly evident. The increase in leptin production that occurs during infection and inflammation strongly suggests that leptin is a part of the cytokine network which governs the inflammatory-immune response and the host defense mechanisms. Leptin plays an important role in inflammatory processes involving T cells and has been reported to modulate T-helper cells activity in the cellular immune response. Several studies have implicated leptin in the pathogenesis of autoimmune inflammatory conditions, such as experimental autoimmune encephalomyelitis, type 1 diabetes, rheumatoid arthritis, and intestinal inflammation. Very recently, a key role for leptin in osteoarthritis has been demonstrated: leptin indeed exhibits, in concert with other pro-inflammatory cytokines, a detrimental effect on articular cartilage by promoting nitric oxide synthesis in chondrocytes. Here, we review the recent advances regarding leptin biology with a special focus on those actions relevant to the role of leptin in the pathophysiology of inflammatory processes and immune responses.