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ID PMID Title PublicationDate abstract
18624351 Deficiency of Act1, a critical modulator of B cell function, leads to development of Sjög 2008 Aug CD40L and B lymphocyte-activating factor (BAFF), members of the TNF superfamily, play critical roles in B cell survival and activation, and in the regulation of humoral immunity. We previously reported that the adaptor molecule Act1 functions as a negative regulator of CD40- and BAFF-mediated B cell survival. Here we demonstrated that mice deficient in Act1 developed systemic autoimmune disease with histological and serological features of human Sjögren's syndrome (SS), in association with systemic lupus erythematosus-like nephritis. Analyses of Act1(-/-)CD40(-/-) and Act1(-/-)BAFF(-/-) double-deficient mice revealed that Act1 regulates different stages of the disease development through its impact on both CD40- and BAFF-mediated pathways. We found that Act1 modulates the survival of autoreactive B cells mainly through its negative regulatory role in BAFF-mediated cell survival, while the effect of Act1 on autoantibody production is likely through modulation of CD40-mediated T cell-dependent antibody response. The impact of Act1 on both BAFF and CD40 pathways establishes Act1-deficient mice as a unique model to study distinct steps of autoimmunity and regulation of self tolerance.
18264709 Modulation of the Fcgamma receptors induced by anti-Ro and anti-La autoantibodies: observa 2008 Jul Only few reports have shown protein expression of the Fcgamma receptors (FcgammaRs) molecules on human salivary gland cells. In this study we investigate a possible upregulation of FcgammaRs following anti-Ro and anti-La autoantibodies treatment. Anti-Ro and anti-La autoantibodies were purified from IgG fractions obtained from 14 patients with primary Sjögren's syndrome (SS), using Sepharose 4B-Ro and Sepharose 4B-La affinity columns. Flow cytometry and RT-PCR were used to study the FCgammaRI, FCgammaRII and FCgammaRIII receptors expression and upregulation by anti-Ro and anti-La on a salivary gland cell line. The present data document that the anti-Ro and anti-La autoantibodies determine an increase of the FcgammaRs expression on salivary gland cells, and provide evidence that both the high affinity FcgammaRI and the low affinity FcgammaRII and FcgammaRIII are overexpressed. Treatment with IgG isolated from healthy donors had no effect on the basal FCgammaRs expression.
18097294 The involvement of the liver in systemic diseases. 2008 Jan The liver has a double blood supply and plays a central role in the metabolism of proteins, carbohydrates, and many medications. In addition, it has a role in the induction of immune tolerance and may also be a target for immune-mediated damage. For these reasons, the liver may be involved in many systemic diseases. In this review, we discuss the involvement of the liver in granulomatous, rheumatologic, malignant, and circulatory diseases. An understanding of the wide spectrum of liver involvement in systemic diseases will aid in both diagnosis and treatment of patients with a wide range of medical conditions.
18328157 Isotype switching and titer variation of anti-Ro/SSA antibodies over time in 100 patients 2008 Jan OBJECTIVE: To correlate the clinical course of the disease with the titer, the isotype profile and the switch of the anti-Ro/SSA antibodies in a cohort of patients affected by UCTD. METHODS: One hundred selected patients with anti-Ro/SSA antibodies detected by counterimmunoelectrophoresis (CIE), and affected by UCTD with a mean follow-up of 7.6 years (SD 4.8 yrs.), were studied. The titer of IgA, IgG and IgM anti-Ro/SSA antibodies was determined in two different sera, obtained at the time of diagnosis and at the last visit, by ELISA with Ro/SSA recombinant proteins as substrate. RESULTS: Thirty-five patients evolved from UCTD to a different connective tissue disease, while 65 showed a stable disease. Anti-Ro/SSA antibodies were detected in 91% and 97% of the patients, at baseline and during follow-up, respectively. IgG dominates the anti-Ro response. The titer of IgA, IgM and IgG anti-Ro/SSA did not differ significantly between the two groups of patients with UCTD. An increasing trend of IgG and IgA anti-Ro/SSA titer could be detected in patients evolving in primary Sjögren's Syndrome (pSS), but only the increase of IgG anti-Ro/SSA was significant (p=0.0235). CONCLUSION: IgG dominates the anti-Ro/SSA response in patients with UCTD. No substantial change of the antibody isotype against Ro/SSA peptides could be observed during follow-up. The titer of IgG anti-Ro/SSA significantly raised in the group of patients evolving in pSS.
17577066 Repeated bacteraemia caused by Streptococcus mutans in a patient with Sjogren's syndrome. 2007 Jul Streptococcus mutans, considered to be a pathogen for dental caries, is known to cause bacteraemia and infective endocarditis. Herein, an unusual case of repeated bacteraemia caused by S. mutans identified in a 71-year-old male is described. The patient visited Itami City Hospital with the major complaint of a fever, and a subsequent clinical examination led to a diagnosis of possible infective endocarditis without specific vegetation formation around the heart valve. A bacteriological examination of blood taken at the first visit showed the presence of S. mutans. Antimicrobial treatment was provided, which successfully eliminated the pathogenic bacteria from the blood. However, the patient returned and was hospitalized twice more with a recurrent fever, and S. mutans was again detected. Analyses of the biological properties of the S. mutans isolates showed that they possessed cariogenic properties and had a low susceptibility to phagocytosis by human polymorphonuclear leukocytes. Since the patient had Sjögren's syndrome, in which a reduction of saliva secretion is a characteristic feature, a great number of dental caries lesions were identified. The findings indicated that S. mutans present in those dental caries lesions caused repeated bacteraemia in this case.
16891656 Parotid gland biopsy compared with labial biopsy in the diagnosis of patients with primary 2007 Feb OBJECTIVE: To assess the value of the parotid biopsy as a diagnostic tool for primary Sjögren's syndrome (pSS), and to compare the parotid biopsy and the labial biopsy with regard to diagnostic value and biopsy-related morbidity. METHODS: In 15 consecutive patients with pSS and 20 controls, the parotid biopsy was assessed as a diagnostic tool based on the presence of lymphocytic foci, benign lymphoepithelial lesions and lymphoid follicles. These new histological criteria were compared with established diagnostic criteria for the labial biopsy in 35 consecutive patients suspected for pSS who underwent simultaneous biopsies from both sites. In addition, both biopsies were compared for morbidity. RESULTS: The first analysis revealed a focus score of >or=1 or lymphocytic infiltrates (not fulfilling the criterion of a focus score of 1) combined with benign lymphoepithelial lesions as diagnostic criteria for pSS. When comparing the parotid biopsy with the labial biopsy sensitivity and specificity were comparable (sensitivity 78%, specificity 86%). Level of pain was comparable and no loss of motor function was observed. No permanent sensory loss was observed after parotid biopsy, while labial biopsy led to permanent sensory loss in 6% of the patients. Malignant lymphoma was detected in one parotid biopsy by chance, without involvement of the labial salivary gland. CONCLUSION: A parotid biopsy has a diagnostic potential comparable with that of a labial biopsy in the diagnosis of pSS, and may be associated with less morbidity.
19089532 Efficacy and safety of rebamipide for the treatment of dry mouth symptoms in patients with 2009 The effects of rebamipide on dry mouth and salivary secretion in Sjögren's syndrome patients were investigated in a double-blind placebo-controlled study. Rebamipide (100 mg TID) or placebo was administered for eight weeks and patient-assessed improvement of dry mouth and increase in salivary secretion measured by the Saxon test were evaluated. At two, four, and eight weeks, dry mouth improvement rates were, respectively, 26.0, 44.0, and 46.9% for rebamipide and 20.0, 27.1, and 39.1% for placebo, and mean increases in salivary secretion were, respectively, 0.14, 0.24, and 0.35 g for rebamipide and 0.03, 0.09, and 0.17 g for placebo, indicating higher values in the rebamipide group for both parameters at all timepoints but no significant differences between the two groups. Analysis by baseline characteristics suggested a statistically significant salivary secretion increasing effect of rebamipide in cases of primary Sjögren's syndrome. No difference in the incidence of adverse events was seen between the two groups, confirming the safety of rebamipide. As a salivary secretion increasing effect was strongly suggested in cases of primary Sjögren's syndrome, further study on the administration of rebamipide for the treatment of dry mouth in patients with Sjögren's syndrome is required.
18626243 Nocardiosis in adult-onset Still's disease and vasculitis syndrome. 2008 Jul Four cases of nocardiosis in patients with adult-onset Still disease and vasculitis syndrome are presented. Three patients developed lung abscesses and 1 case developed a brain abscess. All were treated with high-dose corticosteroids, and 3 were given cyclosporine when they developed nocardiosis. All patients were successfully treated with antibiotics; cyclosporine was discontinued in 2 cases. These cases indicate that systemic nocardiosis can develop in patients with various rheumatologic diseases who are treated with corticosteroid and immunosuppressive drugs such as cyclosporine.
18942337 [Lymphoma of the thyroid in a patient with autoimmune thyroiditis and Sjögren's syndrome- 2008 Aug We present the case of a 74 year old patient suffering from primary Non Hodgkin's lymphoma of the thyroid and Sjogren's syndrome. A massively enlarging goitre, causing breathlessness in a female patient previously treated for autoimmune inflammation of the thyroid (Hashimoto's disease) and Sjogren's syndrome, indicated the need for a fine needle aspiration biopsy (FNA) of the thyroid gland. Non Hodgkin's lymphoma of the thyroid was diagnosed and chemotherapy was begun. After 10 months of cytostatic treatment clinical tests and imaging indicated complete local regression. However, two months after cessation of chemotherapy the patient suffered a relapse of the disease owing to infiltration of the central nervous system. During the course of palliative radiotherapy the patient died. The main purpose for presenting this case was to describe the problem of primary lymphoma of the thyroid in cases of autoimmune disease. As many years of immunisation may lead to carcinogenesis it is important to raise awareness among medical staff with regard to cases of chronic autoimmune disease. In cases of Hashimoto's autoimmune disease of the thyroid, monitoring of the anti-thyroid antibodies is indicated, at least annually, as an increase in the concentration of these antibodies over a period of at least seven years would suggest further development of autoimmune disease. If such conditions are accompanied by tumours of the thyroid, surgery should be considered. It is worth keeping in mind that the thyroid can be a site for extra-lymphatic lymphoma.
16405863 Detection of cleaved alpha-fodrin autoantigen in Sjögren's syndrome: apoptosis and co-loc 2006 Jul Sjögren's syndrome (SS) is a systemic autoimmune disease which targets the exocrine glands and is associated with autoantibodies. The mechanism of salivary gland destruction or autoantibody production is poorly understood but it is increasingly accepted that apoptosis plays a role. OBJECTIVE: The objective of this study is to demonstrate the presence of cleaved alpha-fodrin autoantigen and apoptosis in the salivary glands of patients with primary Sjögren's syndrome. METHODS: 18 patients with primary Sjögren's syndrome provided tissues from a labial salivary gland biopsy. Using terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL) assays to detect DNA fragmentation followed by sequential immunoperoxidase assays in the same patient biopsy to detect cleaved alpha-fodrin, Poly(ADP-ribose) polymerase (PARP), and caspase-3, we show a co-localisation between apoptotic markers and disease. RESULTS: Co-localisation of cleaved alpha-fodrin, PARP and caspase-3 expression was demonstrated primarily in the ducts along with DNA fragmentation in 16/18 salivary gland biopsies from Sjögren's syndrome patients. None of these apoptotic markers was strongly expressed in healthy tissues. CONCLUSION: Apoptotic signals may provide useful therapeutic targets and cleaved alpha-fodrin may prove to be a marker of disease in primary Sjögren's syndrome. Further studies are required to ascertain the specific association of cleaved alpha-fodrin with primary and secondary Sjögren's syndrome.
18465456 Immunological alterations in newly diagnosed primary Sjögren's syndrome characterized by 2008 May OBJECTIVES: To describe how certain peripheral immune parameters reflect the inflammatory alterations in patients with primary Sjögren's syndrome (pSS). We determined lymphocyte subpopulations and their state of activation from peripheral blood, evaluating both soluble serum T-helper (Th)1/Th2-type cytokines and intracytoplasmic cytokines. METHODS: Forty-nine patients with newly diagnosed pSS and 40 healthy individuals, all free from immunomodulant or immunosuppressive medication, were studied. Peripheral blood lymphocyte subgroups were quantified by flow cytometry, soluble cytokines were assessed using enzyme-linked immunosorbent assay (ELISA), and intracellular cytokine levels were measured after phorbol myristate acetate (PMA) stimulation by flow cytometry after staining of intracellular cytokines. RESULTS: Patients with primary SS had higher percentages of activated CD3+/CD69+ T cells than controls. When comparing naïve vs. memory subsets of CD4+ and CD8+ T cells, a shift towards the memory phenotype was observed for both. Natural killer (NK) cell and NK T-cell (NKT) percentages and Th0 and Th1 cell numbers were increased in patients compared to controls. Among circulating cytokines, interferon (IFN)-gamma was high, whereas interleukin (IL)-10 was decreased in SS when compared to controls. CONCLUSIONS: SS, considered as a systemic autoimmune disease, is characterized by a complex interplay of various cytokines and immune cells. The skewed T-cell subsets and cytokine imbalance play important roles in an orchestrated proinflammatory cascade.
18413438 Delayed lupus nephritis. 2008 Jul OBJECTIVE: To describe and analyse the clinical and immunological characteristics of a large series of patients with delayed lupus nephritis (LN). METHODS: A cross-sectional study was carried out. Patients with systemic lupus erythematosus (SLE) who developed renal involvement >or=5 years after the first manifestation(s) of the disease (delayed LN, n = 48) were compared with patients with SLE in whom LN developed within 5 years or less after SLE appeared (early-onset LN, n = 187). A control group, the no LN (NLN) group, comprised patients with longstanding SLE (duration of disease >10 years) who had never shown signs of renal involvement (n = 164). RESULTS: The group with delayed LN was positively associated with Sjögren's syndrome, lung involvement and antiphospholipid syndrome as compared with early LN. However, its renal clinical expression and histopathological patterns were similar to those of early-onset LN. The frequency of anti-dsDNA, anti-Sm and anti-RNP antibodies was higher in patients with LN than in the NLN group, as was the frequency of low complement levels. Jaccoud's arthropathy was a protective factor for nephritis. CONCLUSIONS: Delayed LN is not uncommon in patients with SLE. The identified risk factors might aid in its diagnosis and enhance the ability to identify patients at risk for this complication of SLE.
18173916 Epidermal growth factor inhibits Fas-mediated apoptosis in salivary epithelial cells of pa 2007 Nov OBJECTIVES: Cell death is detected in the ducts of labial salivary glands (LSG) of patients with primary Sjögren's syndrome (pSS). However, the counter-mechanism to inhibit the apoptotic process remains unclear. In this study, we studied the ability of epidermal growth factor (EGF) to activate the PI3K-Akt pathway and NF-kB in primary cultured salivary gland epithelial cells (SGEC) of pSS patients. METHODS: SGEC, obtained from 2 female pSS patients, were cultured and used for Hoechst staining and deoxynucleotidyltransferase-mediated dUTP nick end-labeling (TUNEL) assay. The frequency of apoptosis, detected by Hoechst staining, was quantified, and statistical significance was determined through unpaired student's t-test. RESULTS: Following twelve hours of stimulation, both PI3K inhibitors and anti-Fas antibody failed to induce apoptosis in primary cultured SGEC. However, the combination of anti-Fas antibody, along with LY294002 or Bay 11-7082, induced apoptosis which was statistically more significant than apoptosis found in the control cells (p < 0.01). Interestingly, the apoptosis induced by anti-Fas antibody along with LY294002 was clearly inhibited by the addition of 10 ng/ml EGF. Furthermore, the results of the TUNEL assay clearly indicated apoptosis through stimulation with anti-Fas antibody and LY294002 or Bay 11-7082. Furthermore, the apoptosis was completely blocked by the addition of EGF. CONCLUSION: Our results suggest that salivary epithelial cells are protected from Fas mediated apoptosis, through cell survival factors including either the PI3K-Akt pathway or NF-kB.
17726858 [Myositis with pulmonary fibrosis and eosinophilia]. 2007 Aug 2 A 74-year old female patient suffered from dyspnoea, subfebrile body temperature, myalgias, arthralgias and presented a transitory skin rash. Further findings were an eosinophilia, synovitis, a myositis and pulmonary fibrosis. There was no evidence for a malignancy or an infectious disease. We diagnosed an Anti-Jo-1-Syndrome with a secondary Sjoegren syndrome. Immunsuppressive therapy with steroids, later in addition methotrexate led to improvement of the patient's clinical condition. Above mentioned symptoms and its differential diagnosis are discussed in this article.
17081483 Treatment of hepatitis C cryoglobulinemia: mission and challenges. 2006 Mixed cryoglobulinemia (MC) is a syndrome resulting from cold-insoluble immunoglobulin complexes or cryoglobulins (CGs) that precipitate in the serum of 40% to 50% of patients with chronic hepatitis C virus (HCV) infection. The pathogenesis of cryoglobulinemia likely occurs due to chronic viremia and generation of rheumatoid factor following continuous presentation of antigen-immunoglobulin complexes to B cells. CGs are thought to be responsible for a variety of extrahepatic manifestations associated with HCV, including vasculitis, glomerulonephritis, arthritis, and neuropathies, which occur in approximately 10% of HCV patients with CGs. CGs also are a powerful predictive factor for progressive liver disease and the aggressive reoccurrence of liver disease in HCV-positive patients after liver transplantation. First-line therapy for MC due to HCV infection is antiviral therapy with pegylated interferon-alpha and ribavirin. Viral eradication usually produces marked reduction of physical complications and arrests end organ damage concomitant with clearance of CG. Additional prospective, controlled studies are necessary to determine whether CG influences patient virologic response and/or its durability to antiviral therapy. Immunomodulators such as corticosteroids and cyclophosphamide are efficacious for palliative treatment of the symptomatology of HCV cryoglobulinemia but may enhance viral replication. Consequently, prolonged therapy with immunomodulatory agents should be limited to severe vasculitis or aggressive glomerulonephritis in patients with MC due to HCV who have failed to respond to antiviral therapy. In acute, fulminant presentations, plasmapheresis may provide temporary relief and arrest the rapid progression of the disease so that additional therapy can be initiated.
18241923 The crystal structure of the pathogenic collagen type II-specific mouse monoclonal antibod 2008 Apr Monoclonal anti-collagen type II antibody CIIC1 is an arthritogenic autoantibody, which induces arthritis in mice. We crystallized and solved the structure of CIIC1 Fab molecule. Analysis of structure revealed an interaction between the CDR regions of one Fab to the CH1 domain of another Fab, which resembles an antibody-antigen interaction. ELISA experiments confirmed the cross-reactivity of both the full CIIC1 antibody and a single chain Fv fragment to other anti-collagen antibodies which are of different isotypes and epitope specificity. The rheumatoid factor like reactivity of CIIC1 antibody together with its collagen type II specificity may explain the pathogenicity of this antibody.
20641743 (68)Ga-1,4,7,10-Tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo(Arg-Gly-Asp-D-P 2004 Integrins are a family of heterodimeric glycoproteins on cell surfaces that mediate diverse biological events involving cell–cell and cell–matrix interactions (1). Integrins consist of an α and a β subunit and are important for cell adhesion and signal transduction. The α(v)β(3) integrin is the most prominent receptor affecting tumor growth, tumor invasiveness, metastasis, tumor-induced angiogenesis, inflammation, osteoporosis, and rheumatoid arthritis (2-7). Expression of the α(v)β(3) integrin is strong on tumor cells and activated endothelial cells, whereas expression is weak on resting endothelial cells and most normal tissues. The α(v)β(3) antagonists are being studied as antitumor and antiangiogenic agents and the agonists are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). The peptide sequence Arg-Gly-Asp (RGD) has been identified as a recognition motif used by extracellular matrix proteins (vitronectin, fibrinogen, laminin, and collagen) to bind to a variety of integrins, including α(v)β(3). Various radiolabeled antagonists have been introduced for imaging of tumors and tumor angiogenesis (10). Most of the cyclic RGD peptides are composed of five amino acids. Various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (50% inhibition concentration (IC(50)), 7–40 nM) but not to α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM) integrins (11). Various radiolabeled cyclic RGD peptides and peptidominetics have been found to have high accumulation in tumors in mice (12, 13). Out of these developments [(18)F]Galacto-c(RGDfK) has been evaluated in a number of clinical studies for imaging of α(v)β(3) in cancer patients (14-19). Decristoforo et al. (20) reported the development of (68)Ga-1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid-cyclo(Arg-Gly-Asp-D-Phe-Lys) ((68)Ga-DOTA-c(RGDfK)) for positron emission tomography (PET) imaging of α(v)β(3) receptors in nude mice bearing melanoma tumors.
19476137 [Morbidity of the elderly in inpatient rheumatology clinic]. 2008 Apr BACKGROUND: The improvement of life expectation in our country explains at least in part the increase of the proportion of the elderly in hospitalized patients. AIM: The aim of this study was to identify the main diseases leading to hospitalization of the aged in a rheumatology department, to establish their clinical profiles and to evaluate the quality of their management. METHODS: Retrospective chart review about the elderly (age > or =65 years) admitted in the rheumatology department of the Charles Nicolle Hospital during a 2-year-period [January 2003-December 2004]. RESULTS: Among the 831 patients admitted to our inpatient clinic during that period, 86 were 65-year-old or more representing 10% of the total. Mean age was 71.2 years [65-88]. The sex ratio was 1/3. A history of a mean of two associated diseases [0-5] was noted. They were dominated by hypertension (50%) and diabetes (26.7%). Almost 1/3 of the elders had a surgical history. Gastro-intestinal troubles have been noted in only 19% of cases. The main cause of hospitalization was a diagnosis exploration (77.6%). The remainings were admitted for therapeutic adjustment. The disease was evolving since in mean 16 months (15 days-15 years). The mean duration of hospitalization was 21.2 days (4-60). The pathologies involved were varied dominated by degenerative rheumatisms (26.7%) with a predilection to lumbar spine, systemic diseases: 18 cases (20.9%) with 13 cases of rheumatoid arthritis, and malignant bone diseases (18.7%). At least two rheumatic diseases were found together in 49 patients (57%). The clinical findings were atypical in almost half cases (42.4%) in such aged patients. Besides drugs prescribed for non rheumatic diseases, our patients took a mean of 3.4 drugs (1-8) as symptomatic, adjuvant or etiologic treatment. The treatment observance was good in 74.4% of cases. Iatrogenic incidents occurred in 14 cases (16.2%). The outcome was favorable in 68.9% of cases. Twelve of our patients necessitated a third help. Half of our patients (54%) were controlled in our outpatient clinic 1-2 months after their issue, 12 have been hospitalized for the same disease, 8 deceased, and 19 have been lost. CONCLUSIONS: The management of the elderly patients in hospitalization must be multidisciplinary. It should take into account the clinical and therapeutic particularities of such a population. Prevention remains the best guarantee for a good quality of life and to decrease social and economic costs.
19061007 A comparison of vitamin A and leucovorin for the prevention of methotrexate-induced micron 2008 Dec INTRODUCTION: Methotrexate, a folate antagonist, is a mainstay treatment for childhood acute lymphoblastic leukemia. It is also widely used in a low dose formulation to treat patients with rheumatoid arthritis. In rats, methotrexate is known to induce micronuclei formation, leading to genetic damage, while vitamin A is known to protect against such methotrexate-induced genetic damage. Leucovorin (folinic acid) is generally administered with methotrexate to decrease methotrexate-induced toxicity. OBJECTIVES: We aimed to determine whether vitamin A and leucovorin differed in their capacity to prevent formation of methotrexate-induced micronuclei in rat bone marrow erythrocytes. The present study also aimed to evaluate the effect of combined treatment with vitamin A and leucovorin on the formation of methotrexate-induced micronuclei. METHODS: Male and female Wistar rats (n=8) were injected with 20 mg/kg methotrexate (single i.p. dose). The control group received an equal volume of distilled water. The third and fourth groups of rats received vitamin A (5000 IU daily dose for 4 successive days) and leucovorin (0.5 mg/kg i.p. dose for 4 successive days), respectively. The fifth and sixth groups of rats received a combination of vitamin A and a single dose of methotrexate and a combination of leucovorin and methotrexate, respectively. The last group of rats received a combination of leucovorin, vitamin A and single dose of methotrexate. Samples were collected at 24 hours after the last dose of the treatment into 5% bovine albumin. Smears were obtained and stained with May-Grunwald and Giemsa. One thousand polychromatic erythrocytes were counted per animal for the presence of micronuclei and the percentage of polychromatic erythrocyte was determined. RESULTS: Comparison of methotrexate-treated rats with the control group showed a significant increase in the percentage of cells with micronuclei and a significant decrease polychromatic erythrocyte percentage. Combined methotrexate and vitamin A therapy and combined methotrexate and leucovorin therapy led to significant decreases in the micronuclei percentage and an increase in polychromatic erythrocyte percentage when compared to rats treated with methotrexate alone. Leucovorin was found to be more effective than vitamin A against the formation of methotrexate-induced micronuclei. CONCLUSIONS: Both vitamin A and leucovorin provided significant protection against genetic damage induced by methotrexate.
18973838 High oxygen tension prolongs the survival of osteoclast precursors via macrophage colony-s 2009 Jan The oxygen tension affects the function, differentiation, and transformation of various cells, including bone cells. In pathological conditions such as rheumatoid arthritis (RA), rapidly destructive arthropathy, and primary or metastatic tumors, severe bone destruction or osteolysis occurs. Abundant blood vessels are often observed around these destructive lesions. At such sites, we have confirmed the increased production of reactive oxygen species (ROS) induced by a high oxygen tension and/or oxidative stress, as well as numerous osteoclasts detectable by immunohistochemistry. These findings suggest that osteoclasts are influenced by the high oxygen tension in pathological bone lesions because the zone around blood vessels has a relatively high oxygen tension. In this study, we investigated the effects of oxygen tension on osteoclastogenesis by culturing human CD14-positive cells (osteoclast precursors) with or without osteoblast-like supporting cells (Saos-4/3 cells) under a normal oxygen tension (20% O(2)) or a high oxygen tension (40% O(2)). A high oxygen tension markedly prolonged the duration of osteoclast precursor formation in the presence of supporting cells, and also markedly and persistently increased the production of macrophage colony stimulating factor (M-CSF) by supporting cells. Furthermore, we found an increase of cells expressing M-CSF and cells positive for tartrate-resistant acid phosphatase (TRAP) in hypervascular destructive bone lesions of RA patients where ROS were also abundant.