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ID PMID Title PublicationDate abstract
20641247 (99m)Tc-Hydrazinonicotinic acid-Glu-[cyclo(Arg-Gly-Asp-D-Phe-Lys)](2). 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. Antagonists of α(v)β(3) are being studied as antitumor and antiangiogenic agents, and the agonists of α(v)β(3) are being studied as angiogenic agents for coronary angiogenesis (6, 8, 9). A tripeptide sequence consisting of 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 cyclic RGD peptides are composed of five amino acids. Haubner et al. (11) reported that various cyclic RGD peptides exhibit selective inhibition of binding to α(v)β(3) (inhibition concentration (IC(50)), 7–40 nM) but not to integrins α(v)β(5) (IC(50), 600–4,000 nM) or α(IIb)β(3) (IC(50), 700–5,000 nM). Various radiolabeled cyclic RGD peptides have been found to have high accumulation in tumors in nude mice (12). Hydrazinonicotinic acid (HYNIC) is a coupling agent for (99m)Tc labeling of peptides that can achieve high specific activities without affecting the receptor-binding ability of the amino acid sequence. (99m)Tc is bound to the hydrazine group, and other coordination sites can be occupied by one or more coligands. Liu et al. (13) reported the success of radiolabeling the cyclo(Arg-Gly-Asp-D-Phe-Lys) (c(RGDfK)) dimer linked by glutamic acid that was conjugated with HYNIC. Trisodium triphenylphosphine-3,3’,3’’-trisulfonate (TPPTS) and tris(hydroxymethyl)-methylglycine (tricine) as coligands. (99m)Tc-HYNIC-E-[c(RGDfK)](2)(tricine)(TPPTS) showed high tumor accumulation in nude mice bearing human tumor xenografts.
17713973 Phase I evaluation of the safety, pharmacokinetics and pharmacodynamics of CP-481,715. 2007 BACKGROUND AND OBJECTIVES: The chemokine receptor CCR1 is believed to play a role in several inflammatory diseases, primarily by promoting the migration of leukocytes through the endothelial barrier. Thus, a possible strategy for treating inflammatory diseases is inhibition of leukocyte infiltration by antagonising CCR1. Recently, CP-481,715 has been described as a potent and specific antagonist of CCR1. The aims of this study were to assess the safety, pharmacokinetics and pharmacodynamics of CP-481,715 along with drug interactions with ciclosporin. SUBJECTS AND METHODS: This was a phase I randomised, double-blind, placebo-controlled study with CP-481,715 in 78 healthy male volunteers. Subjects were administered escalating CP-481,715 doses of up to 3000 mg with food and after fasting in the single-dose study. In the drug interaction study, which was a single-dose, two-way crossover study, 12 subjects received a 300 mg dose of CP-481,715 as a suspension of polymorph A under fasted conditions, both with and without prior administration of ciclosporin. RESULTS AND CONCLUSIONS: All doses of CP-481,715 were well tolerated, with linear pharmacokinetics up to the 300 mg dose. The pharmacodynamic activity of CP-481,715 was detected ex vivo by demonstrating a dose-related and linear increase in the amount of macrophage inflammatory protein-1alpha, CCL3, required to induce CD11b upregulation. Analysis of vital signs indicated no consistent clinical effects, and statistical analysis of ECG characteristics demonstrated no significant prolongation of the corrected QT interval. A drug-drug interaction study with ciclosporin demonstrated that CP-481,715 clearance was decreased by ciclosporin, consistent with its ability to compete with P-glycoprotein. Phase II studies may be warranted to see if CP-481,715 exhibits efficacy in treating inflammatory diseases such as rheumatoid arthritis, multiple sclerosis or transplant rejection.
17636642 WITHDRAWN: Analgesia and non-aspirin, non-steroidal anti-inflammatory drugs for osteoarthr 2007 Jul 18 BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) have been widely used as a pharmacologic treatment to relieve pain for patients with OA of the hip. However, these agents are associated with significant toxicity, particularly in the elderly population (age > 65 years). OBJECTIVES: To review all randomized trials of analgesics and anti-inflammatory therapy in osteoarthritis (OA) of the hip. To determine which non-steroidal, anti-inflammatory drug (NSAID) is the most effective, and which NSAID is the most toxic. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal Group's trials register, the Cochrane Controlled Trials Register and MEDLINE up to August 1994. Reference lists of all trials were also manually searched. SELECTION CRITERIA: All randomized controlled trials comparing non-steroidal anti-inflammatory drugs (NSAIDs) and/or analgesics in patients with Osteoarthritis. The trials selected for inclusion were identified by one reviewer (TT) and rechecked by a second (MH). DATA COLLECTION AND ANALYSIS: Qualitative assessments were performed using a quality scoring system designed for NSAID trials in rheumatoid arthritis. Both the design and analysis aspects of the trials were evaluated, each aspect being rated on a scale of 0 to 8. A quantitative method, which calculates the ratio of improvement produced by one NSAID to that produced by another, was used to rate the relative efficacy of different NSAIDs with respect to pain relief. Toxicity comparisons were made according to the reviewer findings. All quality assessments were carried out independently by two reviewers (TT, BS). All data abstraction was carried out by one reviewer (TT) and rechecked by two other reviewers (BS, GW). A consensus was reached on discrepancies. MAIN RESULTS: Forty-three trials were identified, and of these, 39 evaluated NSAIDs, while four evaluated only analgesics. The median design and analysis scores were two and four respectively. Six NSAIDs were included in at least five trials. Of these, indomethacin was rated more effective in five of its seven comparisons, but more toxic in seven of 12 comparisons. Only five of the 29 (17%) NSAID comparisons found statistically significant differences in efficacy. Of the 43 RCTs identified only 17 had statistical data available for future pooling for this meta-analysis. In the case where data was missing, authors of the trials will be contacted for inclusion of data in future reviews. AUTHORS' CONCLUSIONS: NSAID trials in patients with OA of the hip appear to be weakened by the lack of standardization of case definition of OA, and also by the lack of standardization of outcome assessments. No clear recommendations for the choice of specific NSAID therapy in hip OA can be offered at this time based on this analysis.
17217101 [Regulatory T cells]. 2006 Dec Regulatory T-cells are a subset of T cells that have beene extensively studied in modern immunology. They are important for the maintenance of peripheral tolerance, and have an important role in various clinical conditions such as allergy, autoimmune disorders, tumors, infections, and in transplant medicine. Basically, this population has a suppressive effect on the neighboring immune cells, thus contributing to the local modulation and control of immune response. There are two main populations of regulatory T cells - natural regulatory T cells, which form a distinct cellular lineage, develop in thymus and perform their modulatory action through direct intercellular contact, along with the secreted cytokines; and inducible regulatory T cells, which develop in the periphery after contact with the antigen that is presented on the antigen presenting cell, and their primary mode of action is through the interleukin 10 (IL-10) and transforming growth factor beta (TGF-alpha) cytokines. Natural regulatory T cells are activated through T cell receptor after contact with specific antigen and inhibit proliferation of other T cells in an antigen independent manner. One of the major difficulties in the research of regulatory T cells is the lack of specific molecular markers that would identify these cells. Natural regulatory T cells constitutively express surface molecule CD25, but many other surface and intracellular molecules (HLA-DR, CD122, CD45RO, CD62, CTLA-4, GITR, PD-1, Notch, FOXP3, etc.) are being investigated for further phenotypic characterization of these cells. Because regulatory T cells have an important role in establishing peripheral tolerance, their importance is manifested in a number of clinical conditions. In the IPEX syndrome (immunodysregulation, polyendocrinopathy and enteropathy, X-linked), which is caused by mutation in Foxp3 gene that influences the development and function of regulatory T cells, patients develop severe autoimmune reactions that involve autoimmune endocrine disorders (type 1 diabetes, thyroiditis), respiratory and nutritive allergy, eczema and severe infections. In different types of allergy (pollen allergy, dust mite, nutritive allergens, contact hypersensitivity, etc.) and autoimmune diseases (such as rheumatoid arthritis, multiple sclerosis and type 1 diabetes) a lower number or decreased functional capability of regulatory T cells have been described. In inflammatory conditions and infections, this cell population has an important task in restricting immune response and protecting the host from excessive damage. This ability of regulatory T cells can be used by some pathogens (Epstein Barr virus, Mycobacterium tuberculosis, Leishmania major, etc.) and tumor cells to avoid host response and therefore contribute to the development of some pathological conditions. The knowledge gained on the phenotype and function of regulatory T cells could be useful in many medical conditions. In allergy, autoimmune diseases and in transplant procedures in medicine it would be desirable to increase their function, thus to partially suppress the immune system activity. On the other hand, in some infections and tumors, it would be preferable to decrease the activity of regulatory T cells and boost the function of effector T cells. Regulatory T cells comprise a very active field of immunology, therefore monitoring and modulating of their activity is of great potential significance in a broad spectrum of clinical conditions. By developing and standardizing methods for their monitoring, it would be possible to follow additional parameters of certain clinical conditions and possibly utilize them in therapy.
17114447 IL-10 inhibits lipopolysaccharide-induced CD40 gene expression through induction of suppre 2006 Dec 1 Costimulation between T cells and APCs is required for adaptive immune responses. CD40, an important costimulatory molecule, is expressed on a variety of cell types, including macrophages and microglia. The aberrant expression of CD40 is implicated in diseases including multiple sclerosis, rheumatoid arthritis, and Alzheimer's disease, and inhibition of CD40 signaling has beneficial effects in a number of animal models of autoimmune diseases. In this study, we discovered that IL-10, a cytokine with anti-inflammatory properties, inhibits LPS-induced CD40 gene expression. We previously demonstrated that LPS induction of CD40 in macrophages/microglia involves both NF-kappaB activation and LPS-induced production of IFN-beta, which subsequently activates STAT-1alpha. IL-10 inhibits LPS-induced IFN-beta gene expression and subsequent STAT-1alpha activation, but does not affect NF-kappaB activation. Our results also demonstrate that IL-10 inhibits LPS-induced recruitment of STAT-1alpha, RNA polymerase II, and the coactivators CREB binding protein and p300 to the CD40 promoter, as well as inhibiting permissive histone H3 acetylation (AcH3). IL-10 and LPS synergize to induce suppressor of cytokine signaling (SOCS)-3 gene expression in macrophages and microglia. Ectopic expression of SOCS-3 attenuates LPS-induced STAT activation, and inhibits LPS-induced CD40 gene expression, comparable to that seen by IL-10. These results indicate that SOCS-3 plays an important role in the negative regulation of LPS-induced CD40 gene expression by IL-10.
17052659 Clustering of autoimmune diseases in families with a high-risk for multiple sclerosis: a d 2006 Nov BACKGROUND: Autoimmune mechanisms are thought to have a major role in the pathogenesis of multiple sclerosis. We aimed to identify coexisting autoimmune phenotypes in patients with multiple sclerosis from families with several members with the disease and in their first-degree relatives. METHODS: A total of 176 families (386 individuals and 1107 first-degree relatives) were characterised for a history of other autoimmune disorders. Family-based or case-control analyses were done to assess the association of cytotoxic T-lymphocyte-antigen 4 (CTLA4) and protein tyrosine phosphatase (PTPN22) variants with susceptibility to multiple sclerosis. FINDINGS: 46 (26%) index cases reported at least one coexisting autoimmune disorder. The most common were Hashimoto thyroiditis (10%), psoriasis (6%), inflammatory bowel disease (3%), and rheumatoid arthritis (2%). 112 (64%) families with a history of multiple sclerosis reported autoimmune disorders (excluding multiple sclerosis) in one or more first-degree relatives, whereas 64 (36%) families reported no history of autoimmunity. Similar to index cases, Hashimoto thyroiditis, psoriasis, and inflammatory bowel disease were also the most common disorders occurring in family members. A common variant within CTLA4 was strongly associated with multiple sclerosis in families who had other autoimmune diseases (p=0.009) but not in families without a history of other autoimmune disorders (p=0.90). INTERPRETATION: The presence of various immune disorders in families with several members with multiple sclerosis suggests that the disease might arise on a background of a generalised susceptibility to autoimmunity. This distinct multiple-sclerosis phenotype, defined by its association with other autoimmune diseases, segregates with specific genotypes that could underlie the common susceptibility.
16979123 Protective role of wogonin against lipopolysaccharide-induced angiogenesis via VEGFR-2, no 2006 Nov Wogonin, one of flavonoid derived from particular plants, enriches the property of anti-inflammation. Inflammation-stimulated angiogenesis plays an important role in many pathological diseases, such as rheumatoid arthritis, atherosclerosis, and cancer. The aim of this study was to investigate the suppressive effect of wogonin on lipopolysaccharide (LPS)-induced angiogenesis in human umbilical endothelial cell (HUVEC) cultures. By cell differentiation assays, migration and tube formation activity under LPS treatment were evaluated. Besides, IL-6 neutralizing antibody was added to test the inhibitory effect in the phenotypic alteration. Western blot analysis, ELISA cytokine assay, and quantitative real time-PCR were performed for VEGF, IL-6, VEGF receptors, and IL-6 receptor gene expressions on HUVEC with wogonin treatment. Furthermore, in vivo chorioallantoic membrane (CAM) assay was applied to evaluate the percentage of new vessels formation. The results revealed that wogonin (10(-8)-10(-5) M) inhibited LPS-induced angiogenesis in a concentration-dependent manner. The mRNA and protein expressions of VEGF, VEGFR-2, IL-6, and sIL-6Ralpha were attenuated (P<0.05), but not VEGFR-1. In the LPS-induced CAM model, our data suggested that wogonin (10(-8)-10(-5) M) significantly decreased new vessel formation and vascular network (P<0.05). We conclude that wogonin suppresses both in vitro and in vivo LPS-induced angiogenesis, through VEGFR-2, but not VEGFR-1.
16631730 An orally active reversible inhibitor of cathepsin S inhibits human trans vivo delayed-typ 2006 May 24 Cathepsin S is a major histocompatibility complex (MHC) class II associated invariant chain (Ii) degrading enzyme expressed in antigen presenting cells such as B cells and dendritic cells. This enzyme is essential for MHC class II associated antigen processing and presentation to CD4(+) T cells. Compound I, a selective, reversible and orally bioavailable, inhibitor of cathepsin S, with molecular IC(50)=9 nM, has been recently described. We have tested the effects of compound I in a trans vivo model of delayed-type hypersensitivity. Human peripheral blood mononuclear cells (7-10 x 10(6)) from tetanus-sensitized donors were co-injected with tetanus toxoid (0.25 Lf) into C57Bl/6 mouse footpads. At 24 h, significant footpad swelling (+0.024+/-0.001 cm) characterized by an influx of mouse neutrophils and monocytes was observed. Injection of peripheral blood mononuclear cells alone caused negligible swelling (0.002+/-0.0002 cm). Anti-human MHC class II (HLA-DR, DP, DQ) antibody (5 mg/kg, i.p.) inhibited the swelling 91+/-7%, thus demonstrating a role of human antigen presenting cells in this model. Compound I (10, 30, and 100 mg/kg, p.o.) inhibited the response with an ED50 of approximately 18 mg/kg. Compound III, a less active analogue (molecular IC50>20 microM) had no effect. Furthermore, pretreatment of peripheral blood mononuclear cells with 10 nM compound II, an irreversible inhibitor (molecular IC50=11 nM) inhibited swelling 87+/-4%. These findings support the role of cathepsin S in human delayed-type hypersensitivity. Inhibition of cathepsin S with compound I may be useful in the treatment of human autoimmune diseases like rheumatoid arthritis and multiple sclerosis.
18845662 Transport of diclofenac by breast cancer resistance protein (ABCG2) and stimulation of mul 2009 Jan Diclofenac is an important analgesic and anti-inflammatory drug, widely used for treatment of postoperative pain, rheumatoid arthritis, and chronic pain associated with cancer. Consequently, diclofenac is often used in combination regimens and undesirable drug-drug interactions may occur. Because many drug-drug interactions may occur at the level of drug transporting proteins, we studied interactions of diclofenac with apical ATP-binding cassette (ABC) multidrug efflux transporters. Using Madin-Darby canine kidney (MDCK)-II cells transfected with human P-glycoprotein (P-gp; MDR1/ABCB1), multidrug resistance protein 2 (MRP2/ABCC2), and breast cancer resistance protein (BCRP/ABCG2) and murine Bcrp1, we found that diclofenac was efficiently transported by murine Bcrp1 and moderately by human BCRP but not by P-gp or MRP2. Furthermore, in Sf9-BCRP membrane vesicles diclofenac inhibited transport of methotrexate in a concentration-dependent manner. We next used MDCK-II-MRP2 cells to study interactions of diclofenac with MRP2-mediated drug transport. Diclofenac stimulated paclitaxel, docetaxel, and saquinavir transport at only 50 microM. We further found that the uricosuric drug benzbromarone stimulated MRP2 at an even lower concentration, having maximal stimulatory activity at only 2 microM. Diclofenac and benzbromarone stimulated MRP2-mediated transport of amphipathic lipophilic drugs at 10- and 250-fold lower concentrations, respectively, than reported for other MRP2 stimulators. Because these concentrations are readily achieved in patients, adverse drug-drug interactions may occur, for example, during cancer therapy, in which drug concentrations are often critical and stimulation of elimination via MRP2 may result in suboptimal chemotherapeutic drug concentrations. Moreover, stimulation of MRP2 activity in tumors may lead to increased efflux of chemotherapeutic drugs and thereby drug resistance.
18487370 Differential suppression of vascular permeability and corneal angiogenesis by nonsteroidal 2008 Sep PURPOSE: Angiogenesis, the formation of new capillary blood vessels, is an essential biological process under physiological conditions, including embryonic development, reproduction, and wound repair. Under pathologic conditions, this process plays a critical role in a variety of diseases such as cancer, rheumatoid arthritis, atherosclerosis, endometriosis, diabetic retinopathy, and age-related macular degeneration. The purpose of this study was to examine the effects of cyclooxygenase inhibitors on basic fibroblast growth factor (bFGF)- and vascular endothelial growth factor (VEGF)-mediated ocular neovascularization and permeability. METHODS: A modified Miles vascular permeability assay was used to examine VEGF-induced vascular hyperpermeability, and the mouse corneal model of angiogenesis was used to compare the efficacy of systemic treatment with different nonsteroidal anti-inflammatory drugs (NSAIDs) on bFGF- and VEGF-induced angiogenesis. RESULTS: The authors demonstrated that systemic application of most NSAIDs, but not acetaminophen, blocked VEGF-induced permeability in mice. However, systemic treatment of mice with NSAIDs resulted in the differential inhibition of bFGF-induced (5%-57%) and VEGF-induced (3%-66%) corneal angiogenesis. The selective COX-2 inhibitors were more effective at suppressing bFGF-induced angiogenesis than VEGF-induced angiogenesis. CONCLUSIONS: Though most NSAIDS are effective at suppressing vascular leak, there exists a differential efficacy at suppressing the angiogenic response of specific cytokines such as bFGF and VEGF.
18408140 The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other 2008 Jun Several sources of information suggest that human beings evolved on a diet with a ratio of omega-6 to omega-3 essential fatty acids (EFA) of approximately 1 whereas in Western diets the ratio is 15/1-16.7/1. Western diets are deficient in omega-3 fatty acids, and have excessive amounts of omega-6 fatty acids compared with the diet on which human beings evolved and their genetic patterns were established. Excessive amounts of omega-6 polyunsaturated fatty acids (PUFA) and a very high omega-6/omega-3 ratio, as is found in today's Western diets, promote the pathogenesis of many diseases, including cardiovascular disease, cancer, and inflammatory and autoimmune diseases, whereas increased levels of omega-3 PUFA (a lower omega-6/omega-3 ratio), exert suppressive effects. In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2-3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial. Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition. A lower ratio of omega-6/omega-3 fatty acids is more desirable in reducing the risk of many of the chronic diseases of high prevalence in Western societies, as well as in the developing countries.
17984097 The D-diastereomer of ShK toxin selectively blocks voltage-gated K+ channels and inhibits 2008 Jan 11 The polypeptide toxin ShK is a potent blocker of Kv1.3 potassium channels, which are crucial in the activation of human effector memory T cells (T(EM)); selective blockers constitute valuable therapeutic leads for the treatment of autoimmune diseases mediated by T(EM) cells, such as multiple sclerosis, rheumatoid arthritis, and type-1 diabetes. The critical motif on the toxin for potassium channel blockade consists of neighboring lysine and tyrosine residues. Because this motif is sufficient for activity, an ShK analogue was designed based on D-amino acids. D-allo-ShK has a structure essentially identical with that of ShK and is resistant to proteolysis. It blocked Kv1.3 with K(d) 36 nm (2,800-fold lower affinity than ShK), was 2-fold selective for Kv1.3 over Kv1.1, and was inactive against other K(+) channels tested. D-allo-ShK inhibited human T(EM) cell proliferation at 100-fold higher concentration than ShK. Its circulating half-life was only slightly longer than that of ShK, implying that renal clearance is the major determinant of its plasma levels. D-allo-ShK did not bind to the closed state of the channel, unlike ShK. Models of D-allo-ShK bound to Kv1.3 show that it can block the pore as effectively as ShK but makes different interactions with the vestibule, some of which are less favorable than for native ShK. The finding that an all-D analogue of a polypeptide toxin retains biological activity and selectivity is highly unusual. Being resistant to proteolysis and nonantigenic, this analogue should be useful in K(+) channel studies; all-d analogues with improved Kv1.3 potency and specificity may have therapeutic advantages.
17964900 Effectiveness of multidisciplinary rehabilitation services in postacute care: state-of-the 2007 Nov OBJECTIVES: To summarize the efficacy of postacute rehabilitation and to outline future research strategies for increasing knowledge of its effectiveness. DATA SOURCES: English-language systematic reviews that examined multidisciplinary therapy-based rehabilitation services for adults, published in the last 25 years and available through Cochrane, Medline, or CINAHL databases. We excluded multidisciplinary biopsychosocial rehabilitation programs and mental health services. STUDY SELECTION: Using the search term rehabilitation, 167 records were identified in the Cochrane database, 1163 meta-analyses and reviews were identified in Medline, and 226 in CINAHL. The Medline and CINAHL search was further refined with 3 additional search terms: therapy, multidisciplinary, and interdisciplinary. In summary, we used 12 reviews to summarize the efficacy of multidisciplinary, therapy-based postacute rehabilitation; the 12 covered only 5 populations. DATA EXTRACTION: Two reviewers extracted information about study populations, sample sizes, study designs, the settings and timing of rehabilitation, interventions, and findings. DATA SYNTHESIS: Based on systematic reviews, the evidence for efficacy of postacute rehabilitation services across the continuum was strongest for stroke. There was also strong evidence supporting multidisciplinary inpatient rehabilitation for patients with rheumatoid arthritis, moderate to severe acquired brain injury, including traumatic etiologies, and for older adults. Heterogeneity limited our ability to conclude a benefit or a lack of a benefit for rehabilitation in other postacute settings for the other conditions in which systematic reviews had been completed. The efficacy of multidisciplinary rehabilitation services has not been systematically reviewed for many of the diagnostic conditions treated in rehabilitation. We did not complete a summary of findings from individual studies. CONCLUSIONS: Given the limitations and paucity of systematic reviews, information from carefully designed nonrandomized studies could be used to complement randomized controlled trials in the study of the effectiveness of postacute rehabilitation. Consequently, a stronger evidence base would become available with which to inform policy decisions, guide the use of services, and improve patient access and outcomes.
17920532 Sinomenine inhibits activation of rat retinal microglia induced by advanced glycation end 2007 Dec 5 Diabetic retinopathy involves an inflammatory response in the retina characterized by an increase in inflammatory cytokines and activation of microglia. The degree of microglia activation may influence the extent of retina injury following an inflammatory stimulus. Cytokines, released by activated microglia, regulate the influx of inflammatory cells to the damaged area. Thus, therapeutic strategy to reduce cytokine expression in microglia would be neuroprotective. Sinomenine, an alkaloid isolated from the stem and root of Sinomenium acutum, has long been recognized as an anti-inflammatory drug for rheumatoid arthritis and also inhibits macrophage activation. In this study, we activated retinal microglia in culture with advanced glycation end products (AGEs) treatment and attempted to determine whether sinomenine could reduce the production of cytokines from the activated microglia at both gene and protein levels. Changes in inflammatory cytokines, TNF alpha, IL-1 beta and IL-6, were measured by semi-quantitative RT-PCR and enzyme-linked immunosorbent assay (ELISA) both in the presence and absence of AGEs. The effect of sinomenine on levels of reactive oxygen species (ROS) and the nuclear translocation of NF-kB p65 were studied with a laser confocal scanning microscope. AGEs treatment induced a significant release of TNF alpha, IL-1 beta, and IL-6 from retinal microglia. Sinomenine could inhibit release of these cytokines. Sinomenine attenuated ROS production in a dose-dependent fashion and reduced the nuclear translocation of NF-kB p65 in AGEs-activated retinal microglia in culture.
17377159 NALP1 in vitiligo-associated multiple autoimmune disease. 2007 Mar 22 BACKGROUND: Autoimmune and autoinflammatory diseases involve interactions between genetic risk factors and environmental triggers. We searched for a gene on chromosome 17p13 that contributes to a group of epidemiologically associated autoimmune and autoinflammatory diseases. The group includes various combinations of generalized vitiligo, autoimmune thyroid disease, latent autoimmune diabetes in adults, rheumatoid arthritis, psoriasis, pernicious anemia, systemic lupus erythematosus, and Addison's disease. METHODS: We tested 177 single-nucleotide polymorphisms (SNPs) spanning the 17p13 linkage peak for association with disease and identified a strong candidate gene. We then sequenced DNA in and around the gene to identify additional SNPs. We carried out a second round of tests of association using some of these additional SNPs, thus elucidating the association with disease in the gene and its extended promoter region in fine detail. RESULTS: Association analyses resulted in our identifying as a candidate gene NALP1, which encodes NACHT leucine-rich-repeat protein 1, a regulator of the innate immune system. Fine-scale association mapping with the use of DNA from affected families and additional SNPs in and around NALP1 showed an association of specific variants with vitiligo alone, with an extended autoimmune and autoinflammatory disease phenotype, or with both. Conditional logistic-regression analysis of NALP1 SNPs indicated that at least two variants contribute independently to the risk of disease. CONCLUSIONS: DNA sequence variants in the NALP1 region are associated with the risk of several epidemiologically associated autoimmune and autoinflammatory diseases, implicating the innate immune system in the pathogenesis of these disorders.
17307753 Role of APRIL (TNFSF13) polymorphisms in the susceptibility to systemic lupus erythematosu 2007 May OBJECTIVES: A polymorphism of APRIL, c.199G > A (Gly67Arg), has been reported to be associated with systemic lupus erythematosus (SLE) in Japanese. To identify the causative polymorphism, we screened for polymorphisms of APRIL as well as TWEAK (TNFSF12), a closely located gene that generates a fusion protein TWE-PRIL by intergenic splicing. Association of APRIL and TWEAK with rheumatoid arthritis (RA) was examined in parallel. METHODS: Polymorphisms were screened by direct sequencing. Association was analysed by case-control analysis using 266 SLE, 298 RA and 208 healthy individuals. Allele-specific difference in the mRNA level was examined using RNA difference plot analysis. Serum APRIL level was measured by ELISA. RESULTS: The protective effect of APRIL c.199A/A homozygotes in SLE was replicated (odds ratio 0.50, 95% confidence interval 0.30-0.83, P = 0.0073; pooled P = 0.0001, Pcorr = 0.007). In addition, association of c.287A > G (Asn96Ser, P = 0.0064, allele frequency) and c.*263C > T (3' untranslated region, P = 0.025, allele frequency) was detected. c.199G-c.287A (67Gly-96Asn) haplotype was found to confer risk for SLE, while c.199A-c.287G (67Arg-96Ser) was protective. Association of TWEAK was observed neither for SLE nor RA. APRIL mRNA was increased in SLE-associated c.*263T allele. In addition, serum APRIL was undetectable in all six healthy controls homozygous for the protective c.199A-c.287G haplotype (P = 0.015). CONCLUSIONS: In addition to replicating the protective role of APRIL c.199A/A, two additional SNPs in APRIL were found to be associated with SLE. Presence of a protective haplotype and a risk haplotype was demonstrated. The mechanism of association was suggested to be altered expression at the protein and mRNA levels.
17127278 Role of TWEAK and Fn14 in tumor biology. 2007 Jan 1 The tumor necrosis factor (TNF) superfamily member TNF-like weak inducer of apoptosis (TWEAK) was initially described in a 1997 publication co-authored by investigators from the biotechnology company Biogen (now Biogen-Idec) and the University of Geneva. Four years later, researchers at the biotechnology company Immunex (now part of Amgen) reported the cloning and characterization of the human TWEAK receptor. A sequence database search revealed that the predicted TWEAK receptor amino acid sequence was identical to that of fibroblast growth factor-inducible 14 (Fn14), a small transmembrane protein described one year earlier in a publication from investigators at the American Red Cross Holland Laboratory. Recent studies have revealed that the TWEAK-Fn14 ligand-receptor pair likely plays an important role in a variety of cellular processes and in the pathogenesis of several human diseases, including atherosclerosis, stroke, rheumatoid arthritis and cancer. In this paper, we first summarize the general properties of these two proteins and then review the available data implicating TWEAK and Fn14 in multiple aspects of tumor biology.
16835316 Attractin, a dipeptidyl peptidase IV/CD26-like enzyme, is expressed on human peripheral bl 2006 Sep The ectoenzyme dipeptidyl peptidase IV (DP IV; CD26) was shown to play a crucial role in T cell activation. Several compounds inhibiting DP IV-like activity are currently under investigation for the treatment of Type 2 diabetes, rheumatoid arthritis, colitis ulcerosa, psoriasis, multiple sclerosis, and other diseases. In the present study, we show that human peripheral blood monocytes express a DP IV-like enzyme activity, which could be inhibited completely by the synthetic DP IV inhibitor Lys[Z(NO(2))]-thiazolidide. DP IV immunoreactivity was not detectable on monocytes, and DP IV transcript levels of monocytes were near the detection limit of quantitative polymerase chain reaction. However, monocytes exhibit a strong mRNA expression of the multifunctional DP IV-like ectoenzyme attractin and were highly positive for attractin in flow cytometric analysis. Fluorescence microscopy clearly demonstrated that attractin is located on the cell surface of monocytes. Attractin immunoprecipitates hydrolyzed Gly-Pro-pNA, indicating that monocyte-expressed attractin possesses DP IV-like activity. Inhibitor kinetic studies with purified human plasma attractin revealed that Lys[Z(NO(2))]-thiazolidide not only inhibits DP IV but also attractin (50% inhibition concentration=8.45 x 10(-9) M). Studying the influence of this inhibitor on monocyte functions, we observed a clear reduction of cell adhesion to fibronectin-coated culture plates in the presence of Lys[Z(NO(2))]-thiazolidide. Moreover, this inhibitor significantly modulates the production of interleukin-1 (IL-1) receptor antagonist, IL-6, and transforming growth factor-beta1 in lipopolysaccharide-stimulated monocyte cultures. In summary, here, we demonstrate for the first time expression of attractin on monocytes and provide first data suggesting that drugs directed to DP IV-like enzyme activity could affect monocyte function via attractin inhibition.
16547141 Essential role for hematopoietic prostaglandin D2 synthase in the control of delayed type 2006 Mar 28 Hematopoietic prostaglandin D(2) synthase (hPGD(2)S) metabolizes cyclooxygenase-derived prostaglandin (PG) H(2) to PGD(2), which is dehydrated to cyclopentenone PGs, including 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). PGD(2) acts through two receptors (DP1 and DP2/CRTH2), whereas 15d-PGJ(2) can activate peroxisome proliferator-activated receptors or inhibit a range of proinflammatory signaling pathways, including NF-kappaB. Despite eliciting asthmatic and allergic reactions through the generation of PGD(2), it is not known what role hPGD(2)S plays in T helper (Th)1-driven adaptive immunity. To investigate this question, the severity and duration of a delayed type hypersensitivity reaction was examined in hPGD(2)S knockout and transgenic mice. Compared with their respective controls, knockouts displayed a more severe inflammatory response that failed to resolve, characterized histologically as persistent acute inflammation, whereas transgenic mice had little detectable inflammation. Lymphocytes isolated from inguinal lymph nodes of hPGD(2)S(-/-) animals showed hyperproliferation and increased IL-2 synthesis effects that were rescued by 15d-PGJ(2), but not PGD(2), working through either of its receptors. Crucially, 15d-PGJ(2) exerted its suppressive effects through the inhibition of NF-kappaB activation and not through peroxisome proliferator-activated receptor signaling. In contrast, lymph node cultures from transgenics proliferated more slowly and synthesized significantly less IL-2 than controls. Therefore, contrary to its role in driving Th2-like responses, this report shows that hPGD(2)S may act as an internal braking signal essential for bringing about the resolution of Th1-driven delayed type hypersensitivity reactions. Consequently, hPGD(2)S-derived cyclopentenone PGs may protect against inflammatory diseases, where T lymphocytes play a pathogenic role, as in rheumatoid arthritis, atopic eczema, and chronic rejection.
16374254 Caspase activation and apoptosis induction by adalimumab: demonstration in vitro and in vi 2006 Jan BACKGROUND: Adalimumab is a fully human monoclonal antibody to tumor necrosis factor (TNF), which was recently introduced as a therapy for Crohn's disease and rheumatoid arthritis. Besides neutralization, induction of apoptosis of monocytes/macrophages and T cells is thought to be an important mechanism of action of the anti-tumor necrosis factor monoclonal antibody infliximab, at least in Crohn's disease therapy. AIM: To study caspase activation and the induction of apoptosis by adalimumab and the effect of a caspase inhibitor in vivo. METHODS: For in vitro studies, THP-1 cells (human monocytic cell line) were incubated with adalimumab, infliximab, or human immunoglobulin G, and annexin V + propidium iodide, Apo2.7, and 7-amino actinomycin-D were used to study apoptosis on the cell membrane, mitochodrial, and DNA level, respectively. Active caspase-3 was detected by intracellular staining. For in vivo studies, a chimeric human-mouse model was used, in which THP-1 cells were injected intraperitoneally in SCID-Beige mice followed by treatment with adalimumab, infliximab, or human immunoglobulin G. Effects of a pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp-fluoromethyketone on apoptosis induction were evaluated. RESULTS: In vitro analysis revealed that apoptosis could be induced in THP-1 cells by both adalimumab and infliximab. Activation of caspase-3 after incubation with adalimumab was demonstrated by intracellular staining. In addition, in the chimeric mouse model, a higher percentage of residual THP-1 cells were apoptotic, and lower cell numbers were recovered in the adalimumab- or infliximab-treated mouse. Apoptosis induction by adalimumab could be abrogated through in vivo pretreatment of mice with the pan-caspase inhibitor. CONCLUSIONS: Adalimumab, besides neutralizing tumor necrosis factor, also induces apoptosis of transmembrane tumor necrosis factor-positive THP-1 cells by activating intracellular caspases. This activity is likely to be important for the clinical effect of this biodrug.