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ID PMID Title PublicationDate abstract
16227418 RS3PE syndrome presenting as vascular endothelial growth factor associated disorder. 2005 Nov OBJECTIVES: To characterise serum concentrations of various cytokines and detection by magnetic resonance imaging (MRI) of synovial hypervascularity in patients with remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) syndrome before and after corticosteroid treatment. METHODS: Vascular endothelial growth factor(165) (VEGF(165)), tumour necrosis factor alpha (TNFalpha), and interleukin 1beta (IL1beta) were measured by enzyme linked immunosorbent assay (ELISA) in serum samples from three patients with RS3PE syndrome. As controls, serum samples from 26 healthy volunteers, 12 patients with rheumatoid arthritis, 10 patients with systemic lupus erythematosus, 13 patients with polymyositis/dermatomyositis, 13 patients with vasculitis syndrome, and 6 patients with mixed connective tissue disease were also analysed. Synovial hypervascularity of patients with RS3PE syndrome was estimated by rate of enhancement (E-rate) in a dynamic MRI study. RESULTS: Serum concentrations of VEGF(165) (mean (SD) 2223.3 (156.3) pg/ml) were significantly higher in patients with active RS3PE syndrome than in controls before corticosteroid treatment. TNFalpha and IL1beta levels were similar in patients and controls. Synovial hypervascularity in affected joints and subcutaneous oedema decreased during corticosteroid treatment, in parallel with the fall in serum VEGF(165). CONCLUSIONS: VEGF promotes synovial inflammation and vascular permeability in patients with RS3PE syndrome, suggesting that RS3PE can be classified as a VEGF associated disorder.
16207145 Pharmacogenetics of folate-related drug targets in cancer treatment. 2005 Oct Folate metabolism is the target of two major drug groups: folate antagonists (for example, methotrexate) and thymidylate synthase inhibitors (for example, 5-fluorouracil). These agents are used in the treatment of cancer, as well as for other conditions, such as rheumatoid arthritis. High-dose cancer treatment protocols can induce a state of acute folate depletion which may lead to significant treatment-related toxicity. Polymorphisms in folate-metabolizing enzymes may modify the therapeutic effectiveness and toxicity of these drugs. This review briefly summarizes the drugs targeting the folate pathway and describes common polymorphisms in folate-metabolizing enzymes and transport proteins. Pharmacogenetic studies investigating folate-related drug targets in the treatment of colorectal cancers and hematologic malignancies will subsequently be discussed. Findings to date illustrate a potential for targeting therapy based on patients' genotypes, in order to improve outcomes and reduce toxicity. However, larger, well-designed studies are needed to confirm these early findings.
16167344 Enhanced anti-angiogenic effect of a deletion mutant of plasminogen kringle 5 on neovascul 2005 Dec 15 Kringle 5 (K5), a proteolytic fragment of plasminogen, has been proved to be an angiogenic inhibitor. Previously, we have evaluated the effect of K5 on the vascular leakage and neovascularization in a rat model of oxygen-induced retinopathy. In this study, we expressed K5 and a deletion mutant of K5 (K5 mutant) in a prokaryocyte expression system and purified them by affinity chromatography. K5 mutant was generated by deleting 11 amino acids from K5 while retaining the three disulfide bonds. The anti-angiogenic activity of intact K5 and K5 mutant were compared in endothelial cells and retinal neovascularization rat model. K5 mutant inhibited the proliferation of primary human retinal capillary endothelial cells (HRCEC) in a concentration-dependent manner, with an apparent EC50 of approximate 35 nmol/L, which is twofold more potent than intact K5. In the even higher concentration range, K5 mutant did not inhibit pericytes from the same origin of HRCEC, which suggested an endothelial cell-specific inhibition. K5 mutant had no effect on normal liver cells and Bel7402 hepatoma cells even at high concentration range either. Intravitreal injection of the K5 and mutant in the oxygen-induced retinopathy rat model both resulted in significantly fewer neovascular tufts and nonperfusion area than controls with PBS injection, as shown by fluorescein angiography. Furthermore, K5 mutant exhibited more strong inhibition effect on neovascularization than intact K5 by quantification of vascular cells. These results suggest that this K5 deletion mutant is a more potent angiogenic inhibitor than intact K5 and may have therapeutic potential in the treatment of those disorders with neovascularization, such as solid tumor, diabetic retinopathy, age-related macular degeneration, rheumatoid arthritis, and hyperplasia of prostate.
15972089 Alexithymia and pain in three chronic pain samples: comparing Caucasians and African Ameri 2005 May OBJECTIVE: African Americans often report greater pain than do Caucasians, but the factors responsible for this discrepancy are not known. We examined whether alexithymia-the trait of difficulty identifying and describing one's feelings and lacking introspection-may contribute to this ethnic group difference. We tested whether the mean level of alexithymia is higher, and whether alexithymia and pain are more highly correlated, among African Americans than among Caucasians in patients with chronic pain disorders. DESIGN: Three cross-sectional, correlational studies were conducted on three separate samples of patients with chronic pain. Analyses examined the full sample and then Caucasians and African Americans separately. SETTING AND PATIENTS: Patients were recruited primarily from treatment settings. Samples were patients with rheumatoid arthritis (N = 155), migraine headaches (N = 160), or systemic lupus erythematosus (N = 123), and each sample included only Caucasians or African Americans. MEASURES: The Toronto Alexithymia Scale-20 assessed global alexithymia and three alexithymia facets. Pain severity, functional disability, or symptoms were also measured on each sample. RESULTS: Similar findings occurred across all three samples. African Americans had only slightly higher mean alexithymia levels than did Caucasians, and this was partly accounted for by socioeconomic differences between groups. More importantly, alexithymia correlated only weakly with pain or symptom severity for each full sample, but the two ethnic groups showed different patterns. Alexithymia correlated positively with pain severity among African Americans, but was uncorrelated with pain among Caucasians, even after covarying for various socioeconomic variables. CONCLUSIONS: Alexithymia is more correlated with pain severity among African Americans with chronic pain disorders than among Caucasians, potentially contributing to the higher pain reports among African Americans.
15917716 Preliminary evidence of genetic anticipation in type 2 diabetes mellitus. 2005 Jun BACKGROUND: The term "anticipation" in genetic diseases refers to earlier age at onset and/or increased severity in successive generations. Several diseases with genetic anticipation include rheumatoid arthritis, Crohn's disease, Schizophrenia, Graves' disease and several other neuropsychiatric disorders. The aim of the present study was to investigate whether genetic anticipation may occur in diabetes. MATERIAL/METHODS: The medical records of 485 subjects with type 2 diabetes, seen in the Diabetes Clinic were screened for subjects with a family history of diabetes and also aware of a definite date of diagnosis for both the subject and their family member. Ninety-six parent-child pairs with a known definite date of diagnosis of type 2 diabetes were identified and the age at onset of diabetes between two parent-child generations was compared. RESULTS: The age at diagnosis of the subjects with positive family history of diabetes was lower than those with no family history of diabetes (48.82+/-12 vs. 56.18+/-13; p<0.001). There was a significant difference in the mean age at diagnosis between the 1(st) generation and 2(nd) generation (57.39 vs. 52.03 years p<0.0001). When the age at diagnosis of the subjects with siblings was compared (38 sibling pairs), there was no significant difference noted (52.21 vs. 50.57; p=0.35). CONCLUSIONS: Patients in the second affected generation seem to acquire the disease at an earlier time in life, indicating strong evidence of anticipation. We conclude that genetic anticipation might occur in type 2 diabetes.
15897309 Increased pentosidine, an advanced glycation end product, in serum and synovial fluid from 2005 Jun BACKGROUND: Pentosidine, an advanced glycation end product, increasingly accumulates in articular cartilage with age, and contributes to the pathogenesis of osteoarthritis (OA). Increased pentosidine concentrations are associated with inflammatory disorders-for example, rheumatoid arthritis. OBJECTIVE: To compare pentosidine serum concentrations in patients with knee OA and in healthy volunteers and to determine a relationship between pentosidine and cartilage oligomeric matrix protein (COMP)-a marker of articular cartilage destruction. METHODS: Paired serum and synovial fluid samples were obtained by arthrocentesis from 38 patients with knee OA and from 38 healthy volunteers. Pentosidine concentration was measured by reverse phase high performance liquid chromatography with fluorescent detection and COMP was determined by sandwich ELISA. RESULTS: Significantly increased serum pentosidine (p<0.01) and COMP (p<0.05) levels were detected in the patients with OA compared with the control group. Serum pentosidine correlated significantly with synovial fluid pentosidine (p<0.001). Pentosidine in synovial fluid (p<0.05) and in serum (p<0.05) correlated significantly with synovial fluid COMP. Pentosidine and COMP concentrations did not correlate significantly with the radiological stage of the disease. CONCLUSION: Increased pentosidine serum concentration in patients with OA and its correlation with the cartilage destruction marker COMP in synovial fluid suggests that pentosidine may be important in OA pathology and is a new potential OA marker.
15893692 Infliximab induces apoptosis of monocytes and T lymphocytes in a human-mouse chimeric mode 2005 Jun Tumor necrosis factor (TNF) antagonism with monoclonal antibodies is an effective therapy for severe Crohn's disease and rheumatoid arthritis. Recent studies have suggested that induction of apoptosis of inflammatory cells contributes to this therapeutic effect. We investigated whether infliximab (a mouse-human IgG1 chimeric anti-TNF monoclonal antibody) could induce apoptosis in vivo in human-mouse chimeras, created by reconstitution of severe combined immunodeficiency/beige mice with THP-1 (human monocytic cell line) or Jurkat cells (human T cell line). Infliximab treatment of chimeric mice depleted spleen and peritoneum from THP-1 cells and Jurkat cells and decreased production of the human cytokines IL-10 and IL-12 in vivo. Cell death was shown to occur already within 1 h of treatment. Infliximab effects were independent of FcgammaR binding or complement activation. Cell death resulted from apoptosis induction in a caspase-dependent pathway, as evidenced by the in vitro protective effect of the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyketone (Z-VAD-FMK). These data provide support for caspase-dependent apoptosis induction being the mechanism of action of infliximab in vivo.
15782314 Cerebral aspergillosis in the critically ill: two cases of successful medical treatment. 2005 May OBJECTIVE: Invasive aspergillosis is associated with a poor prognosis, especially in critically ill patients with cerebral involvement. We present two cases of cerebral invasive aspergillosis successfully treated in the intensive care unit with combination antifungal therapies and without surgery. CASE PRESENTATION: The first patient was a 49-year-old man with rheumatoid arthritis who received corticosteroid and cyclophosphamide treatment and developed pulmonary and cerebral invasive aspergillosis. After failure of voriconazole the patient had a successful outcome with voriconazole and liposomal amphotericin B therapy. The patient returned home after an 8-month hospital stay. The second patient was a 54-year-old woman with pulmonary neoplasia and corticosteroid treatment who developed pulmonary and cerebral invasive aspergillosis. After failure of voriconazole and liposomal amphotericin B therapy the patient had a favorable outcome with liposomal amphotericin B and caspofungin therapy. The patient died 10 months after initial diagnosis of cardiac tamponade unrelated to fungal infection. DISCUSSIONS: These cases illustrate the improving prognosis of invasive aspergillosis due to the availability of new treatments, especially in cases of cerebral involvement. It also demonstrates that the outcome of critically ill patients requiring mechanical ventilation for invasive aspergillosis can be favorable. The treatment of patients with invasive cerebral aspergillosis in the intensive care setting should be encouraged.
15777299 Changes in coagulation-fibrinolysis marker and neutrophil elastase following the use of to 2005 Apr BACKGROUND: To clarify in detail the mechanism underlying the development and exacerbation of deep venous thrombosis (DVT) and/or pulmonary thromboembolism (PTE), we focused on the following factors: the thrombin-antithrombin III complex (TAT), D-dimer and neutrophil elastase (NE). We basically investigated whether NE played an important role in the development of PTE I a mice model. METHODS: Nineteen rheumatoid arthritis (RA) and six osteoarthritis (OA) patients underwent total knee arthroplasty (TKA) with tourniquet, and 13 RA and 12 OA patients underwent TKA without tourniquet in each group. The blood levels of TAT, D-dimer and NE were measured before surgery, immediately after and during the days following surgery. For the induction of experimental PTE due to coagulation of platelets, adenosine diphosphate (ADP) was administrated, and human NE with ADP was also administrated for the development of DVT and/or PTE. RESULTS: The rates of increase in the mean TAT, D-dimer and NE levels in the group with tourniquet were statistically higher than those in the group without tourniquet after surgery. The mortality of the mouse due to PTE increased from 43 to 67% following ADP and human NE administration compared to a single ADP administration. Histological changes of the lungs in the mice receiving NE and ADP injections were characterized by a diffuse and extensive accumulation of platelets and fibrin in alveolar capillaries and other microvessels. CONCLUSION: We suggest that during TKA, the use of tourniquet induces local release of a large amount of NE from neutrophils, inducing the development of DVT and/or PTE and their exacerbation.
15599524 Clinical efficacy of radiation synovectomy in digital joint osteoarthritis. 2005 May PURPOSE: Radiation synovectomy was developed for local treatment of rheumatoid arthritis. In this study, the long-term efficacy of radiation synovectomy was retrospectively evaluated in patients with osteoarthritis (activated arthrosis) of the digital joints using an algofunctional score. METHODS: Fifty-three digital joints in 29 patients (mean age 64.8 years) were treated by intra-articular injection of 169Er citrate. All joints were painful despite pharmacotherapy and showed an elevated blood pool pattern in a pretherapeutic three-phase bone scan, indicative for local synovitis. The patients were asked to classify their complaints with respect to different daily manual activities on a ten-step pain scale from 1 (total disability) to 10 (lack of any impairment) prior to and after treatment, with a mean follow-up of 41 months. Local signs of osteoarthritis such as joint swelling or pain were additionally evaluated and were scored from progression of complaints to excellent improvement based on patient self-evaluation. RESULTS: All patients reported a pronounced improvement in their manual activities. The mean total score of 4.73+/-0.58 for all activities prior to treatment increased significantly to 6.79+/-0.47 after radiation synovectomy (p<0.05). The best results were obtained in the thumb base joints, whereas distal interphalangeal joints were frequently resistant to therapy. CONCLUSION: Radiation synovectomy is highly effective in digital joint osteoarthritis with concomitant local synovitis.
17140160 Increased serum levels of S100A12 in patients with MPO-ANCA-associated glomerulonephritis. 2006 Nov BACKGROUND: Increased serum levels of S100A12, a proinflammatory protein secreted by activated neutrophils, have recently been shown in patients with active inflammatory diseases, such as rheumatoid arthritis and Kawasaki disease. In this study, we investigated serum levels of S100A 12 in patients with small-vessel vasculitis, myeloperoxidase anti-neutrophil cytoplasmic antibodies- (MPO-ANCA) associated pauci-immune glomerulonephritis. METHODS: Serum S100A12 concentrations were measured by a sandwich enzyme-linked immunosorbent assay (ELISA) in 46 patients with MPO-ANCA-associated glomerulonephritis and 29 healthy controls. We analyzed correlations between serum S100A12 levels and a clinical index of vasculitis activity, the Birmingham Vasculitis Activity Score (BVAS), various laboratory parameters, and pathological activity scores in the patients. We also analyzed changes of serum S100A12 levels in 10 patients after treatment. RESULTS: ELISA showed about 4-fold higher levels of serum S100A12 in patients with MPO-ANCA-associated glomerulonephritis than healthy controls. Serum S100A12 levels correlated with the BVAS scores, the peripheral white blood cell count, levels of serum C-reactive protein and creatinine, and pathological activity scores in the patients, but did not correlate with serum MPO-ANCA titers. Serum S100A12 levels after treatment decreased in all the 10 patients examined. CONCLUSION: We demonstrated that increased serum S100A12 levels correlate with clinical, laboratory and pathological parameters of disease activity in patients with MPO-ANCA-associated glomerulonephritis. Serum S100A12 level may be one of the useful markers of disease activity in MPO-ANCA-associated glomerulonephritis.
17088646 Osteopetroses and immunodeficiencies in humans. 2006 Dec PURPOSE OF REVIEW: This review focuses on human and murine pathologies involving both osteoclasts and immune cells. These diseases have been relevant to the discovery of novel interactions and pathways shared between these two types of cells. RECENT FINDINGS: Interactions between immune cells and osteoclasts were originally shown in murine models by gene targeting of molecules involved in the early steps of osteoclast differentiation, since receptor activator of nuclear factor kappa-B ligand (RANKL), RANK and TNFR-associated factor 6 knockout mice bore abnormalities of both bone resorption and immune system. Subsequently, osteoclast stimulation by RANKL secreted by lymphocytes in autoimmune diseases, such as rheumatoid arthritis, was found. More recently, the identification of immunoreceptor tyrosine-based activation motif receptors and adaptors important for both dendritic cells and osteoclast function has established a link between innate and adaptive immunity and bone. Finally, osteoclasts are also important for hematopoietic stem-cell mobilization, providing a further level of regulation of lymphoid cells. SUMMARY: These findings open up a new field of research, osteoimmunology, which will unravel previously unsuspected links between bone remodelling and the immune response.
17086610 Higher prevalence of fibromyalgia in patients infected with human T cell lymphotropic viru 2006 Nov OBJECTIVE: . Inflammatory rheumatic conditions including rheumatoid arthritis and Sjögren's syndrome have been reported in individuals infected with human T cell lymphotropic virus type I (HTLV-I). Other chronic lymphotropic virus infections such as hepatitis C and human immunodeficiency virus are associated with fibromyalgia (FM). There are no reports about the association between HTLV-I infection and FM. We evaluated the association between FM and HTLV-I infection. METHODS: We conducted a case-control study with prevalent cases. Ex-blood donation candidates with HTLV-I infection from a blood bank cohort, and healthy blood donors as a control group, were submitted to rheumatologic evaluation to compare the prevalence of FM. The following covariables were also evaluated: other rheumatic diseases, age, sex, personal income, level of education, and depression. RESULTS: One hundred individuals with HTLV-I infection and 62 non-infected blood donors were studied. Thirty-eight (38%) HTLV-I infected individuals and 3 (4.8%) individuals from the control group presented the diagnosis of FM (OR 12.05, 95% CI 3.53-41.17). Other rheumatic diseases were also more prevalent in the infected group (37% vs 12.9%; OR 3.80, 95% CI 1.63-8.86). In multivariate analysis adjusted by the covariables, the association between HTLV-I and FM was statistically significant (OR 9.14, 95% CI 2.42-34.52). CONCLUSION: Our study shows a greater prevalence of FM in HTLV-I infected individuals, suggesting that FM may be associated with this viral infection.
17011767 The role of SAP and the SLAM family in autoimmunity. 2006 Dec The signaling lymphocyte activation molecule (SLAM) family of receptors and their associated signaling adaptors play a pivotal role in the regulation of various stages of cellular immunity. They regulate lymphocyte-lymphocyte interactions involved in both cell-mediated and humoral immune responses. Recent evidence indicates that members of this family of receptors and signaling intermediates are also involved in autoimmunity. These include strictly correlative studies showing increased expression of various family members in immune effectors involved in rheumatoid arthritis and in inflammatory bowel disease, as well as more direct evidence (from various knockout strains of mice) for their role in autoimmune processes such as experimental allergic encephalomyelitis and lupus. Additional studies defining naturally occurring polymorphic variations in the SLAM family show a direct role in initiating the break in tolerance that is an essential step in the progression towards autoimmunity.
16983006 What is meant by a "flare" in atopic dermatitis? A systematic review and proposal. 2006 Sep OBJECTIVE: To make preliminary recommendations for defining a flare of atopic dermatitis (AD) in clinical research based on a systematic review of the literature and experience in running clinical trials. DATA SOURCES: A sensitive electronic search of MEDLINE biographic database was conducted on April 19, 2005, using the following search terms: flare$, exacerbation$, relaps$, remission$, worse$, and *recurrence. The search was restricted to all prospective studies of AD in humans, using the Cochrane search terms for AD and prospective studies. In addition, we searched the literature on 3 chronic intermittent diseases (asthma, rheumatoid arthritis, and multiple sclerosis) to gain insight as to how other disciplines had tackled the definition of flares. DATA SYNTHESIS: A total of 401 citations were reviewed, of which 16 articles (15 studies) were relevant. All were clinical trials. The definitions of disease flare or relapse in retrieved articles could be categorized into 3 broad themes: (1) composite definitions that include at least 2 different factors (eg, symptoms, severity duration, or treatment) (4 studies); (2) score thresholds or changes in severity scores (8 studies); and (3) behavioral definitions, such as the use of rescue therapy (3 studies). Only 1 investigative group (3 studies) used the same definition. None of the included studies were primarily designed to develop a definition of "flare." Evidence from other disciplines suggested at least 2 measures-totally controlled weeks and well-controlled weeks from asthma research-that could be used successfully in AD research. CONCLUSIONS: Defining an AD flare is a complex process, and this review has highlighted the need for standardization in defining measures of long-term disease control. We propose that a flare of AD be simply defined as an episode requiring escalation of treatment or seeking additional medical advice. Consideration should also be given to totally controlled weeks and well-controlled weeks to assess overall disease activity in patients with AD. Together, these definitions are intuitive, simple to use, and easy to understand. Future work is required to test the applicability of these recommendations in a variety of research settings.
16982001 The association of comorbidities, utilization and costs for patients identified with low b 2006 Sep 18 BACKGROUND: Existing studies have examined the high prevalence of LBP along with the high treatment costs of patients with low back pain (LBP). Various factors have been shown to be correlated or predictive of chronic or episodic LBP including the characteristics of the initial episode, pain, comorbid conditions, psychosocial issues, and opiate use. This study replicates and extends earlier studies by examining the association of patient characteristics including baseline comorbidities with patterns of healthcare service use and cost. METHODS: This is a retrospective analysis of measures of comorbidities, healthcare use, and cost for patients identified with LBP, stratified by the number of LBP episodes. Administrative data associated with outpatient and hospital based care for the years 1996 through 2001, were used to identify adult patients with LBP. LBP patients continuously enrolled for 12 months prior and 24 months after their initial LBP event were included in the study. A LBP episode was identified as the number of 30-day periods where a patient had one or more healthcare events with a diagnosis consistent with LBP. Chi-square and multivariate regression analyses were employed to estimate the variation in utilization and costs. RESULTS: Of 16,567 patients enrolled, 67% were identified with only one LBP episode and 4.5% had > or =6. The prevalence of comorbidities, analgesic use, and healthcare service use, varied by the number of back pain episodes. Diabetes, rheumatoid arthritis, anxiety, psychotic illness, depression, use of opiates and NSAIDs were associated with significant incremental increases in costs (P < .003). CONCLUSION: Physical and mental health co-morbidities and measures of analgesic use were associated with chronicity, healthcare utilization and costs. Given the association of comorbidities and cost for patients with LBP, management approaches that are effective across chronic illnesses may prove to be beneficial for high cost patients identified with LBP.
16927044 Methotrexate, azathioprine, cyclosporine, and risk of fracture. 2006 Aug We studied the fracture risk associated with use of methotrexate, azathioprine, and cyclosporine. The study was designed as a case-control study. All patients with a fracture (n = 124,655) in the year 2000 in Denmark served as cases. Information on fractures and confounders was retrieved from the National Hospital Discharge Register and a number of other national registers. For each case, three age- and gender-matched controls were randomly drawn from the general population (n = 373,962). Exposure was use of the drugs and a number of covariates including other immunosuppressive drugs, corticosteroids, any cancer, Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, liver and kidney disease, prior fracture, and alcoholism. Azathioprine was associated with an increase in overall fracture risk, but besides this, none of the drugs was significantly associated with overall fracture risk or risk of hip, spine, or forearm fracture. Liver [odds ratio (OR) = 1.55, 95% confidence interval (CI) 1.42-1.69] and kidney (OR = 1.26, 95% CI 1.16-1.37) diseases were significantly associated with increased risk of fractures. Azathioprine was associated with an increase in overall fracture risk but not in the risk of spine, hip, or forearm fractures. Methotrexate and cyclosporine were not associated with fracture risk. It thus seems that the underlying disease for which the treatment is administered may be responsible for much of the increase in fracture risk rather than the drugs used to treat the disorder in question.
16884693 Antioxidant effect of bisphosphonates and simvastatin on chondrocyte lipid peroxidation. 2006 Sep 22 The objective of this study was to evaluate the effect of bisphosphonates (BPs) and simvastatin on chondrocyte lipid peroxidation. For this purpose, a flow cytometrical method using C11-BODIPY(581/591) was developed to detect hydroperoxide-induced lipid peroxidation in chondrocytes. Tertiary butylhydroperoxide (t-BHP) induced a time and concentration dependent increase in chondrocyte lipid peroxidation. Addition of a Fe2+/EDTA complex to t-BHP or hydrogen peroxide (H2O2) clearly enhanced lipid peroxidation. The lipophilic simvastatin demonstrated a small inhibition in the chondrocyte lipid peroxidation. None of three tested BPs (clodronate, pamidronate, and risedronate) had an effect on chondrocyte lipid peroxidation induced by t-BHP. However, when Fe2+/EDTA complex was added to t-BHP or H2O2, BPs inhibited the lipid peroxidation process varying from 25% to 58%. This study demonstrates that BPs have antioxidant properties as iron chelators, thereby inhibiting the chondrocyte lipid peroxidation. These findings add evidence to the therapeutic potential of bisphosphonates and statins in rheumatoid arthritis.
16880931 Immunomodulatory effects of Pseudomonas aeruginosa quorum sensing small molecule probes on 2006 Feb Pseudomonas aeruginosa produces the quorum sensing signalling molecule N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL). This natural product not only coordinates production of virulence factors by the bacterium, but also has immunomodulatory effects on the host organism. Immunomodulatory small molecules are valuable for immunology research and are potential therapeutics for autoimmune diseases such as rheumatoid arthritis, and immunosuppressive drugs following organ transplants. We describe the total synthesis of OdDHL using solid-supported reagents and scavengers, which has the potential to be used for automated analogue synthesis. OdDHL and four analogues were tested for their ability to activate or inhibit release of the pro-inflammatory mediators tumour necrosis factor alpha (TNFalpha) and nitric oxide (NO) from equine or murine macrophages (immune cells). Two of the analogues showed substantial immunomodulatory activity with these macrophages. One analogue showed differing species selectivity, being a potent antagonist in mouse cells, but a partial agonist in horse-derived macrophages. These compounds have the therapeutic potential to be used for protecting animals from bacterial septic shock.
16855135 Stress system activity, innate and T helper cytokines, and susceptibility to immune-relate 2006 Jun Associations between stress and health outcomes have now been carefully documented, but the mechanisms by which stress specifically influences disease susceptibility and outcome remain poorly understood. Recent evidence indicates that glucocorticoids (GCs) and catecholamines (CAs), the major stress hormones, inhibit systemically IL-12, TNF-alpha, and INF-gamma, but upregulate IL-10, IL-4, and TGF-beta production. Thus, during an immune and inflammatory response, the activation of the stress system, through induction of a Th2 shift may protect the organism from systemic "overshooting" with T helper lymphocyte 1 (Th1)/proinflammatory cytokines. In certain local responses and under certain conditions, however, stress hormones may actually facilitate inflammation, through induction of IL-1, IL-6, IL-8, IL-18, TNF-alpha, and CRP production, and through activation of the corticotropin-releasing hormone (CRH)/substance P(SP)-histamine axis. Autoimmunity, chronic infections, major depression, and atherosclerosis are characterized by a dysregulation of the pro/anti-inflammatory and Th1/Th2 cytokine balance. Thus, hyperactive or hypoactive stress system, and a dysfunctional neuroendocrine-immune interface associated with abnormalities of the "systemic anti-inflammatory feedback" and/or "hyperactivity" of the local proinflammatory factors may contribute to the pathogenesis of these diseases. Conditions that are associated with significant changes in stress system activity, such as acute or chronic stress, cessation of chronic stress, pregnancy and the postpartum period, or rheumatoid arthritis (RA) through modulation of the systemic or local pro/anti-inflammatory and Th1/Th2 cytokine balance, may suppress or potentiate disease activity and/or progression. Thus, stress hormones-induced inhibition or upregulation of innate and Th cytokine production may represent an important mechanism by which stress affects disease susceptibility, activity, and outcome of various immune-related diseases.