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ID PMID Title PublicationDate abstract
17047890 Improving management of musculoskeletal disorders in primary care: the Joint Adventures Pr 2007 Jul Musculoskeletal disorders represent a large and growing clinical challenge to primary care clinicians. Unfortunately, there appears to be a gap in current training and continuing education to meet this challenge. We used script concordance within a continuing medical education program entitled "Joint Adventures" to assist family physicians to acquire the knowledge, skills, and tools they need to improve their management of musculoskeletal disorders. Program workshops were coordinated through a national continuing education program of the College of Family Physicians of Canada. A group of 54 experts in musculoskeletal disorders including family physicians, rheumatologists, and orthopedists developed cases for six areas of management that were identified by family physicians during a needs survey delivered at a national scientific congress in primary care. Script concordance methodology was used in the Joint Adventures workshop to address knowledge gaps or lack of group consensus in the six areas including (1) diagnosis of osteoarthritis, (2) treatment and management of osteoarthritis, (3) treatment and management of rheumatoid arthritis, (4) diagnosis and treatment of back pain, (5) diagnosis and treatment of fibromyalgia and diagnosis, and (6) treatment of shoulder pain. Each workshop session included 5-30 family physicians, a specialist expert, and a family physician facilitator. Before each session, a group needs assessment was conducted to identify which one or two of the six cases would be used. Perceived knowledge and skill acquisition, self-assessed change in practice, and satisfaction with the program were measured at the conclusion of each session and again at 3 months post program. All programs were delivered from March 2003 to September 2005. Six hundred and fifty family physicians from across Canada completed the program. In general, participants reached concordance with each case. Measures of knowledge and skill acquisition and self-assessed change in practice were significantly improved with high rates of program satisfaction. The Joint Adventures program provided family physicians with knowledge and skills that changed their care of musculoskeletal disorders. This was achieved using consensus that was sensitive to local needs. Further use should be evaluated in other areas of medical practice as well.
16890260 Mosla dianthera inhibits mast cell-mediated allergic reactions through the inhibition of h 2006 Nov 1 In this study, we investigated the effect of the aqueous extract of Mosla dianthera (Maxim.) (AEMD) on the mast cell-mediated allergy model and studied the possible mechanism of action. Mast cell-mediated allergic disease is involved in many diseases such as asthma, sinusitis and rheumatoid arthritis. The discovery of drugs for the treatment of allergic disease is an important subject in human health. AEMD inhibited compound 48/80-induced systemic reactions in mice. AEMD decreased immunoglobulin E-mediated local allergic reactions, passive cutaneous anaphylaxis. AEMD attenuated intracellular calcium level and release of histamine from rat peritoneal mast cells activated by compound 48/80. Furthermore, AEMD attenuated the phorbol 12-myristate 13-acetate (PMA) and calcium ionophore A23187-stimulated TNF-alpha, IL-8 and IL-6 secretion in human mast cells. The inhibitory effect of AEMD on the pro-inflammatory cytokines was nuclear factor-kappaB (NF-kappaB) dependent. AEMD decreased PMA and A23187-induced degradation of IkappaBalpha and nuclear translocation of NF-kappaB. Our findings provide evidence that AEMD inhibits mast cell-derived immediate-type allergic reactions and involvement of pro-inflammatory cytokines and NF-kappaB in these effects.
16720634 Etanercept treatment for three months is safe in patients with rheumatological manifestati 2007 Jan OBJECTIVE: The treatment of the rheumatological manifestations associated with hepatitis C virus (HCV) remains difficult. To examine the safety of anti-tumour necrosis factor-alpha treatment, nine patients having rheumatological manifestations associated with HCV were treated with etanercept 25 mg twice a week for 3 months. METHODS: Five patients had a positive viral load at study entry (Group I), four were negative (Group II). Clinical data recorded were: disease duration, painful and swollen joint count, patient global and physician global assessment, the number of 18 specified fibromyalgia tender points and the Health Assessment Questionnaire score. Laboratory studies included checking for the presence of cryoglobulinaemia and transaminase levels. Quantitative HCV viral RNA was performed by real-time polymerase chain reaction (PCR). RESULTS: At 3 months, no patient was found to have evidence of increased hepatic inflammation based on serial serum transaminase levels. In the five patients from Group I with detectable HCV RNA, no significant viral load increase was observed. No reactivation was observed in the four patients from Group II with undetectable HCV RNA. The effect on the clinical rheumatological manifestations was more heterogeneous but appears to be lower than that observed in rheumatoid arthritis. CONCLUSION: In this phase II open short-term study, etanercept appeared to be safe in patients with articular manifestations associated with HCV.
16714221 Fraxetin inhibits the induction of anti-Fas IgM, tumor necrosis factor-alpha and interleuk 2006 Jul The survival of osteoblast cells is one of the determinants of the development of osteoporosis in patients with inflamed synovium, such as in rheumatoid arthritis (RA). By means of alkaline phosphatase (ALP) activity and osteocalcin ELISA assay, we have shown that fraxetin exhibits a significant induction of differentiation in the human osteoblast-like cell line MG-63. In addition, we also assessed whether fraxetin affects inflammatory cytokine-mediated apoptosis in osteoblast cells. TNF-alpha or IL-1beta enhance apoptotic DNA fragmentation in anti-Fas IgM-treated MG-63 cells by increasing Fas receptor expression. However, TNF-alpha or IL-1beta treatment alone does not induce apoptosis. Treatment of MG-63 cells with fraxetin not only inhibited anti-Fas IgM-induced apoptosis, but also blocked the synergetic effect of anti-Fas IgM with TNF-alpha or IL-1beta on cell death. The apoptotic inhibition of fraxetin is associated with inhibition of TNF-alpha and IL-1beta-mediated Fas expression and enhancement of FLIP expression, resulting in a decrease of caspase-8 and caspase-3 activation. These results indicate a potential use of fraxetin in preventing osteoporosis by inhibiting inflammatory cytokine-mediated apoptosis in osteoblast cells.
16806730 Sympathetic nervous system plays an important role in the relationship between immune medi 2006 T helper (Th) lymphocytes have been classified into distinct subsets, Th1 and Th2 on the basis of the cytokines they produce. According to the cross-regulatory properties of Th1 and Th2 cells, one would assume that to be affected by a Th1 type disease increases susceptibility to a Th1 type disease and inhibits a Th2 type disease and vice versa about being affected by a Th2 type disease. However, the pattern of related diseases does not necessarily follow the conventional pattern of inhibitory effects of Th1 and Th2 immune responses on each other. For example, Mycobacteria including BCG, that induce Th1 immune responses; can modulate some Th1 type autoimmune diseases including MS, experimental autoimmune encephalomyelitis (EAE; an animal model for Multiple Sclerosis) and insulin-dependent diabetes mellitus (IDDM) thereby leading to an alleviation of their symptoms. Also BCG precipitates a syndrome similar to systemic lupus erythematosus (SLE), a Th2 type disease; in NOD mice. The coexistence of the major Th2-mediated atopic diseases such as asthma, eczema and allergic rhinitis with the Th1-mediated autoimmune conditions including; coeliac disease (CD), IDDM, rheumatoid arthritis (RA) and psoriasis is another example that is in apparent disagreement with counter-regulatory effects of Th1/Th2 phenotypes. HYPOTHESIS: SNS can be stimulated by pro-inflammatory cytokines, production of which is induced by mycobacteria including BCG. Although these cytokines can inhibit SNS activity in the site of inflammation and secondary lymphoid organs, they increase sympathetic tone in other places. Increased sympathetic tone can induce an anti-inflammatory and Th2 type milieu. This milieu can inhibit MS and IDDM and provide a susceptible environment for starting of SLE. Atopic diseases are Th2 type immune mediated diseases; therefore, they increase the production of Th2 type cytokine and decrease production of pro-inflammatory cytokines in the site of allergic reaction and also in secondary lymphoid organs. Therefore, atopic diseases decrease sympathetic tone in all tissues except in the sites of allergic reaction and secondary lymphoid organs. Decreased sympathetic tone results in a pro-inflammatory milieu and in such an environment, Th1 type autoimmune diseases can affect tissues.
16513876 Association of schizophrenia and autoimmune diseases: linkage of Danish national registers 2006 Mar OBJECTIVE: Individuals with schizophrenia and their relatives tend to have either higher or lower than expected prevalences of autoimmune disorders, especially rheumatoid arthritis, celiac disease, autoimmune thyroid diseases, and type 1 diabetes. The purpose of the study was to estimate the association of schizophrenia with these disorders as well as a range of other autoimmune diseases in a single large epidemiologic study. METHOD: The Danish Psychiatric Register, the National Patient Register, and a register with socioeconomic information were linked to form a data file that included all 7,704 persons in Denmark diagnosed with schizophrenia from 1981 to 1998 and their parents along with a sample of matched comparison subjects and their parents. The data linkage required that the autoimmune disease occur before the diagnosis of schizophrenia. RESULTS: A history of any autoimmune disease was associated with a 45% increase in risk for schizophrenia. Nine autoimmune disorders had higher prevalence rates among patients with schizophrenia than among comparison subjects (crude incidence rate ratios ranging from 1.9 to 12.5), and 12 autoimmune diseases had higher prevalence rates among parents of schizophrenia patients than among parents of comparison subjects (adjusted incidence rate ratios ranging from 1.3 to 3.8). Thyrotoxicosis, celiac disease, acquired hemolytic anemia, interstitial cystitis, and Sjögren's syndrome had higher prevalence rates among patients with schizophrenia than among comparison subjects and also among family members of schizophrenia patients than among family members of comparison subjects. CONCLUSIONS: Schizophrenia is associated with a larger range of autoimmune diseases than heretofore suspected. Future research on comorbidity has the potential to advance understanding of pathogenesis of both psychiatric and autoimmune disorders.
16475026 Low-dose methotrexate inhibits lung metastasis and lengthens survival in rat osteosarcoma. 2005 Lung metastasis is the most crucial event affecting the treatment of osteosarcoma and is dependent on tumor angiogenesis. To improve the prognosis for patients with osteosarcoma, prevention of lung metastasis is essential. Low-dose methotrexate is a useful drug for treating a variety of diseases. Low-dose methotrexate reportedly plays a role in antiangiogenesis for the synovial blood vessels in rheumatoid arthritis. However, whether low-dose methotrexate is correlated with tumor angiogenesis and metastasis is unclear. We investigated the inhibitory effect of methotrexate on lung metastasis in a rat osteosarcoma cell line with high metastatic potential, S-SLM. Two weeks after inoculation of S-SLM cells into male Fischer 344 rats, low-dose methotrexate (1.2 mg/kg once or twice a week) or saline was intraperitonealy injected for 4 weeks and the antimetastatic effect was evaluated. Low-dose methotrexate significantly reduced the number of lung metastatic nodules and the wet weight of the lungs. Immunohistochemical staining showed a decrease in microvessel density in the metastatic nodules. We also evaluated the effect of methotrexate on the proliferation of endothelial cells and S-SLM osteosarcoma cells in vitro. Methotrexate significantly inhibited the proliferation of endothelial cells at a lower concentration than that of S-SLM osteosarcoma cells. These data suggest that low-dose methotrexate inhibited lung metastasis of osteosarcoma through its antiangiogenic activity. Our results indicate that low-dose methotrexate is a promising drug for tumor dormancy therapy in patients with osteosarcoma and lung metastasis.
16474428 Regulation of cytokine production during phagocytosis of apoptotic cells. 2006 Feb Loss of self-tolerance and expansion of auto-reactive lymphocytes are the basis for autoimmunity. Apoptosis and the rapid clearance of apoptotic cells by phagocytes usually occur as coordinated processes that ensure regulated cellularity and stress response with non-pathological outcomes. Defects in clearance of apoptotic cells would contribute to the generation of self-reactive lymphocytes, which drive autoimmune disorders such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). The IL-12 family of cytokines (IL-12, IL-23, and IL-27) and IL-10 are produced by phagocytic macrophages and play critical roles in the regulation of antigen-presenting cells (APCs) and effector lymphocytes during an immune response to pathogens. Inappropriate expression of these cytokines and their dysregulated activities have been strongly implicated in the pathogenesis of several autoimmune diseases. The production of pro- and anti-inflammatory cytokines by phagocytic APCs is delicately regulated during the ingestion of apoptotic cells as part of an intrinsic mechanism to prevent inflammatory autoimmune reactions. How apoptotic cell-derived signals regulate cytokine production is poorly understood. A recent study by our group demonstrated that phagocytosis of apoptotic cells by activated macrophages results in strong inhibition of IL-12 p35 gene expression by activating a novel transcription repressor, which we named GC-binding protein (GC-BP), through tyrosine dephosphorylation. We are also beginning to understand the molecular mechanisms underlying apoptotic cell-triggered production of IL-10 by phagocytes. These studies will help to elucidate some novel immune regulatory mechanisms and explore the regulation of immune responses to autoantigens with potentials to discover new therapeutic targets for the treatment of autoimmune disorders.
16310808 Effect of thalidomide affecting VEGF secretion, cell migration, adhesion and capillary tub 2006 Apr 25 Angiogenesis, new blood vessel formation, is a multistep process, precisely regulated by pro-angiogenic cytokines, which stimulate endothelial cells to migrate, proliferate and differentiate to form new capillary microvessels. Excessive vascular development and blood vessel remodeling appears in psoriasis, rheumatoid arthritis, diabetic retinopathy and solid tumors formation. Thalidomide [alpha-(N-phthalimido)-glutarimide] is known to be a potent inhibitor of angiogenesis, but the mechanism of its inhibitory action remains unclear. The aim of the study was to investigate the potential influence of thalidomide on the several steps of angiogenesis, using in vitro models. We have evaluated the effect of thalidomide on VEGF secretion, cell migration, adhesion as well as in capillary formation of human endothelial cell line EA.hy 926. Thalidomide at the concentrations of 0.01 microM and 10 microM inhibited VEGF secretion into supernatants, decreased the number of formed capillary tubes and increased cell adhesion to collagen. Administration of thalidomide at the concentration of 0.01 microM increased cell migration, while at 10 microM, it decreased cell migration. Thalidomide in concentrations from 0.1 microM to 10 microM did not change cell proliferation of 72-h cell cultures. We conclude that anti-angiogenic action of thalidomide is due to direct inhibitory action on VEGF secretion and capillary microvessel formation as well as immunomodulatory influence on EA.hy 926 cells migration and adhesion.
16187943 From cellular receptors to transduction-transcription pathways for cytokines: at which lev 2005 Sep An imbalance in cytokine homeostasis is considered to play a major part in the pathogenesis of immuno-inflammatory diseases. Since the identification and cloning of cytokines and their receptors, therapeutic approaches have been developed with the purpose of impeding the interaction between the ligand (cytokine) and its specific receptor, or interactions that involve the use of anti-inflammatory cytokines to switch off inflammation. Although some diseases have been treated successfully with cytokines or anticytokines (i.e., anti-TNF, and to a lesser extent recombinant IL-1 receptor antagonist, in rheumatoid arthritis; IFN-beta in multiple sclerosis), the fact remains that these therapies do not abrogate the concomitant use of steroids or immunosuppressive drugs, and that a significant percentage of patients do not respond to such therapies; these are important limitations. The identification of signalling pathways preferentially used in inflammatory conditions has boosted approaches that target these intracellular mechanisms. This review examines the different therapeutic approaches that may be considered for the treatment of immuno-inflammatory diseases, and discusses the advantages and disadvantages of targeting extracellular or intracellular mechanisms.
16177002 Methotrexate prevents renal injury in experimental diabetic rats via anti-inflammatory act 2005 Nov Recent studies suggested the involvement of inflammatory processes in the pathogenesis of diabetic nephropathy. Methotrexate (MTX), a folic acid antagonist, is widely used for the treatment of inflammatory diseases. Recently, it has been shown that treatment with low-dose MTX reduces the cardiovascular mortality in patients with rheumatoid arthritis, suggesting that MTX has anti-atherosclerotic effects via its anti-inflammatory actions. This study was designed to determine the anti-inflammatory effects of this agent on diabetic nephropathy. Diabetes was induced in Sprague-Dawley rats with streptozotocin, and MTX (0.5 or 1.0 mg/kg) was administered once a week for 8 wk. Treatment with MTX reduced urinary albumin excretion, mesangial matrix expansion, macrophage infiltration, expression of TGF-beta and type IV collagen, and intercellular adhesion molecule-1 in glomeruli. MTX also reduced the high glucose-induced NF-kappaB activation in vitro and in vivo. The results indicate that intermittent administration of MTX prevented renal injuries without changes in blood glucose level and BP in experimental diabetic rats. The protective effects of MTX are suggested to be mediated by its anti-inflammatory actions through inhibition of NF-kappaB activation and consequent reduction of intercellular adhesion molecule-1 expression and macrophage infiltration. The results suggest that anti-inflammatory agents might be beneficial for the treatment of diabetic nephropathy.
16076348 Vitamin D for health and in chronic kidney disease. 2005 Jul Vitamin D is taken for granted and is not appreciated for its importance in overall health and well-being. Vitamin D, known as the sunshine vitamin, is appreciated as being important for the prevention of rickets in children. It is now recognized that vitamin D is important for not only the growing skeleton, but for the maintenance of a healthy musculoskeletal system throughout life. Vitamin D deficiency in adults precipitates and exacerbates osteoporosis and causes the painful bone disease osteomalacia. The revelation that vitamin D is biologically inactive and requires sequential hydroxylations in the liver and kidney to form 1,25-dihydroxyvitamin D helps explain why patients with renal failure are often resistant to vitamin D and suffer from secondary hyperparathyroidism and renal osteodystrophy. In addition to its role in maintaining calcium and phosphorus homeostasis, vitamin D is now being recognized as important for maintaining maximum muscle strength and for the prevention of many chronic diseases, including type I diabetes, multiple sclerosis, rheumatoid arthritis, hypertension, cardiovascular heart disease, and many common cancers. Vitamin D status is best determined by the measurement of circulating levels of 25-hydroxyvitamin D. Vigilance for maintaining a 25-hydroxyvitamin D level of at least 20 ng/ml and preferably 30-50 ng/ml has important benefits for both healthy children and adults, as well as children and adults suffering from chronic kidney disease.
15982670 Myricetin inhibits the induction of anti-Fas IgM-, tumor necrosis factor-alpha- and interl 2005 Oct 21 The survival of osteoblast cells is one of the determinants of the development of osteoporosis in patients with inflamed synovium, such as in rheumatoid arthritis (RA). By means of alkaline phosphatase (ALP) activity and osteocalcin ELISA assay, I have shown that myricetin exhibits a significant induction of differentiation in the human osteoblast-like cell line MG-63. In addition, I also assessed whether myricetin affects inflammatory cytokines-mediated apoptosis in osteoblast cells. TNF-alpha or IL-1beta enhances apoptotic DNA fragmentation in anti-Fas IgM-treated MG-63 cells by increasing Fas receptor expression. However, TNF-alpha or IL-1beta treatment alone does not induce apoptosis. Treatment of MG-63 cells with myricetin not only inhibited anti-Fas IgM-induced apoptosis, but also blocked the synergetic effect of anti-Fas IgM with TNF-alpha or IL-1beta on cell death. The apoptotic inhibition of myricetin is associated with inhibition of TNF-alpha and IL-1beta-mediated Fas expression and enhancement of FLIP expression, resulting in a decrease of caspase-8 and caspase-3 activation. These results indicate a potential use of myricetin in preventing osteoporosis by inhibiting inflammatory cytokines-mediated apoptosis in osteoblast cells.
15946952 Cell surface expression of CD147/EMMPRIN is regulated by cyclophilin 60. 2005 Jul 29 CD147, also known as extracellular matrix metalloproteinase inducer, is a regulator of matrix metalloproteinase production and also serves as a signaling receptor for extracellular cyclophilins. Previously, we demonstrated that cell surface expression of CD147 is sensitive to cyclophilin-binding drug cyclosporin A, suggesting involvement of a cyclophilin in the regulation of intracellular transport of CD147. In this report, we identify this cyclophilin as cyclophilin 60 (Cyp60), a distinct member of the cyclophilin family of proteins. CD147 co-immunoprecipitated with Cyp60, and confocal immunofluorescent microscopy revealed intracellular co-localization of Cyp60 and CD147. This interaction with Cyp60 involved proline 211 of CD147, which was shown previously to be critical for interaction between CD147 and another cyclophilin, cyclophilin A, in solution. Mutation of this proline residue abrogated co-immunoprecipitation of CD147 and Cyp60 and reduced surface expression of CD147 on the plasma membrane. Suppression of Cyp60 expression using RNA interference had an effect similar to that of cyclosporin A: reduction of cell surface expression of CD147. These results suggest that Cyp60 plays an important role in the translocation of CD147 to the cell surface. Therefore, Cyp60 may present a novel target for therapeutic interventions in diseases where CD147 functions as a pathogenic factor, such as cancer, human immunodeficiency virus infection, or rheumatoid arthritis.
15868610 Methotrexate suppresses inflammatory agonist induced interleukin 6 synthesis in osteoblast 2005 May OBJECTIVE: Interleukin 6 (IL-6) is a pleiotropic cytokine that plays a crucial role in the pathogenesis of rheumatoid arthritis (RA). In bone metabolism, it is known that IL-6 is produced and secreted by osteoblasts, and that IL-6 induces osteoclast formation and stimulates bone resorption. Various bone inflammatory agonists such as tumor necrosis factor-alpha (TNF-alpha), IL-1alpha, prostaglandin D2 (PGD2), PGE2, and PGF2alpha, which play important roles in the pathogenesis of RA, induce IL-6 synthesis in osteoblast-like MC3T3-E1 cells. Low dose methotrexate (MTX) is currently used for treatment of patients with RA. We investigated the effect of MTX on IL-6 synthesis induced by these agents in MC3T3-E1 cells. METHODS: Cultured cells were pretreated with various doses of MTX, and then stimulated by these inflammatory agonists. The IL-6 in the conditioned medium was measured by IL-6 enzyme immunoassay. RESULTS: MTX significantly suppressed IL-6 synthesis stimulated by these agonists in a dose-dependent manner, although MTX alone had no effect on the levels of IL-6. In addition, MTX significantly inhibited the enhancement by IL-17 of TNF-alpha-stimulated IL-6 synthesis. MTX reduced the levels of IL-6 induced by 12-O-tetradecanoylphorbol 13-acetate, a direct activator of protein kinase C (PKC), suggesting that MTX inhibits PKC signals for IL-6 synthesis. CONCLUSION: MTX suppresses IL-6 synthesis stimulated by various inflammatory agonists in osteoblasts.
15723634 Neurotransmitters and chemokines regulate tumor cell migration: potential for a new pharma 2005 The migration of tumor cells is a prerequisite for tumor cell invasion and metastasis development, which accounts for over 90% of cancer mortality. Therefore a major focus of current tumor biological research is the study of those factors that regulate tumor cell migration. Those chemokines and neurotransmitters that bind to G-protein coupled receptors (also known as serpentine receptors) are the most prominent of these factors. Neurotransmitters have been identified that have not only a stimulatory (e.g. norepinephrine) effect, but an inhibitory effect (e.g. GABA) as well. This is an especially fortuitous development, because many known agonists and antagonists of neurotransmitter receptors are currently being successfully used in the treatment of other pathological conditions (e.g. beta-blockers in the treatment of cardiovascular diseases). Likewise, chemokine receptor antagonists, which are under development for the treatment of HIV or rheumatoid arthritis, may be effective tools for the inhibition of chemokine-driven tumor cell migration as well. A further approach to inhibit tumor cell migration arises from the investigation of the relevant signal transduction pathways. The PKC alpha, for example, is a key enzyme in the regulation of tumor cell migration, but not of leukocyte migration. It thus offers a selective target opportunity for specific pharmacological agents to interfere with tumor cell migration. In this review we therefore summarize the current findings on those serpentine receptors involved in the neurotransmitter- and chemokine-regulated tumor cell migration, on the underlying signal transduction pathways, and on the opportunities to inhibit tumor cell migration and ultimately metastasis development with pharmaceutical agents.
17140435 Testing the proficiency to distinguish locations with elevated plantar pressure within and 2006 Dec 1 BACKGROUND: Identification of locations with elevated plantar pressures is important in daily foot care for patients with rheumatoid arthritis, metatarsalgia and diabetes. The purpose of the present study was to evaluate the proficiency of podiatrists, pedorthists and orthotists, to distinguish locations with elevated plantar pressure in patients with metatarsalgia. METHODS: Ten podiatrists, ten pedorthists and ten orthotists working in The Netherlands were asked to identify locations with excessively high plantar pressure in three patients with forefoot complaints. Therapists were instructed to examine the patients according to the methods used in their everyday clinical practice. Regions could be marked through hatching an illustration of a plantar aspect. A pressure sensitive platform was used to quantify the dynamic bare foot plantar pressures and was considered as 'Gold Standard' (GS). A pressure higher than 700 kPa was used as cut-off criterion for categorizing peak pressure into elevated or non-elevated pressure. This was done for both patient's feet and six separate forefoot regions: big toe and metatarsal one to five. Data were analysed by a mixed-model ANOVA and Generalizability Theory. RESULTS: The proportions elevated/non-elevated pressure regions, based on clinical ratings of the therapists, show important discrepancies with the criterion values obtained through quantitative plantar pressure measurement. In general, plantar pressures in the big toe region were underrated and those in the metatarsal regions were overrated. The estimated method agreement on clinical judgement of plantar pressures with the GS was below an acceptable level: i.e. all intraclass correlation coefficient's equal or smaller than .60. The inter-observer agreement for each discipline demonstrated worrisome results: all below .18. The estimated mutual agreements showed that there was virtually no mutual agreement between the professional groups studied. CONCLUSION: Identification of elevated plantar pressure through clinical evaluation is difficult, insufficient and may be potentially harmful. The process of clinical plantar pressure screening has to be re-evaluated. The results of this study point towards the merit of quantitative plantar pressure measurement for clinical practice.
16859308 Exploration of a binding mode of benzothiazol-2-yl acetonitrile pyrimidine core based deri 2006 Jul C-Jun N-terminal kinase (JNK) is a therapeutic target for inhibitors which may provide clinical benefit in the pathogenesis of rheumatoid arthritis (RA) as well as in various apoptosis-related disorders. The benzothiazol-2-yl acetonitrile derivatives, recently reported by Pascale et al. (J. Med. Chem. 2005, 48, 4596-4607), are the first generation JNK inhibitors of this class. To understand inhibitory mechanisms and elucidate pharmacophoric properties of these derivatives molecular docking and 3D-QSAR studies were performed on a set of 44 compounds. Ligand Fit module of Cerius2 (4.9) was employed to locate the binding orientations of all the compounds within the JNK-3 ATP binding site. A good correlation (r2=0.810) between the calculated binding free energies (-PMF score) and the experimental inhibitory activities suggests that the identified binding conformations of these potential inhibitors are reliable. Based on the binding conformations, robust and highly predictive 3D-QSAR models were developed with conventional r2 0.886 and 0.802, full cross-validation r2 0.980 and 0.788, and predictive r2 0.965 and 0.968 for MFA and MSA, respectively. The interaction mode was demonstrated taking into consideration inhibitor conformation, hydrogen bonding, and electrostatic interaction. The 3D-QSAR model built in this study will provide clear guidelines for a novel inhibitor design based on the benzothiazole derivatives against JNK-3 for the treatment of inflammatory disorders.
16755239 The incidence of fibromyalgia and its associated comorbidities: a population-based retrosp 2006 Jun BACKGROUND: The epidemiology of fibromyalgia is poorly defined. The incidence of fibromyalgia has not been determined using a large population base. Previous studies based on prevalence data demonstrated that females are 7 times more likely to have fibromyalgia than males and that the peak age for females is during the childbearing years. OBJECTIVE: We have calculated the incidence rate of fibromyalgia in a large, stable population and determined the strength of association between fibromyalgia and 7 comorbid conditions. METHODS: We conducted a retrospective cohort study of a large, stable health insurance claims database (62,000 nationwide enrollees per year). Claims from 1997 to 2002 were examined using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes to identify fibromyalgia cases (ICD code 729.1) and 7 predetermined comorbid conditions. RESULTS: A total of 2595 incident cases of fibromyalgia were identified between 1997 and 2002. Age-adjusted incidence rates were 6.88 cases per 1000 person-years for males and 11.28 cases per 1000 person-years for females. Females were 1.64 times (95% confidence interval = 1.59-1.69) more likely than males to have fibromyalgia. Patients with fibromyalgia were 2.14 to 7.05 times more likely to have one or more of the following comorbid conditions: depression, anxiety, headache, irritable bowel syndrome, chronic fatigue syndrome, systemic lupus erythematosus, and rheumatoid arthritis. CONCLUSION: Females are more likely to be diagnosed with fibromyalgia than males, although to a substantially smaller degree than previously reported, and there are strong associations for comorbid conditions that are commonly thought to be associated with fibromyalgia.
16697465 A human monoclonal IgG1 potently neutralizing the pro-inflammatory cytokine GM-CSF. 2007 Feb The pro-inflammatory cytokine GM-CSF is aberrantly produced in many autoimmune and chronic inflammatory human diseases. GM-CSF neutralization by antibodies has been shown to have a profound therapeutic effect in animal models of rheumatoid arthritis, inflammatory lung diseases, psoriasis and multiple sclerosis. Moreover, the absence of GM-CSF in null mutant mice ameliorates or prevents certain of these diseases. Here we describe the biophysical and biological properties of a human anti-GM-CSF IgG1 antibody designated MT203, which was derived by phage display guided selection. MT203 bound with picomolar affinity to an epitope on human and macaque GM-CSF involved in high-affinity receptor interaction. As a consequence, the antibody potently prevented both GM-CSF-induced proliferation of TF-1 cells with a sub-nanomolar IC50 value and the production of the chemokine IL-8 by U937 cells. MT203 neutralized equally well recombinant (r) human (h) GM-CSF from Escherichia coli and yeast, and also normally glycosylated GM-CSF secreted by human lung epithelial cells in response to IL-1beta stimulation. Furthermore, MT203 significantly reduced both survival and activation of peripheral human eosinophils as may be required for effective treatment of inflammatory lung diseases. The antibody did not show a detectable loss of neutralizing activity after 5 days in human serum at 37 degrees C. Based on its favorable properties, MT203 has been selected for development as a novel anti-inflammatory human monoclonal antibody with therapeutic potential in a multitude of human autoimmune and inflammatory diseases.