The Implementation of Brazil Sustainable Urban Mobility Policy

Institute of Transport and Logistics Studies. Faculty of Economics and Business. The University of Sydne

Soluble IL-18 receptor complex: a new star in the firmament of rheumatoid arthritis diagnosis?

Contains fulltext : 97538.pdf (publisher's version ) (Open Access)It has long been recognized that laboratory tests are useful in the diagnosis of disease and to monitor treatment outcome. Their performance has become even more demanding with the development of personalized medicine. In patients with rheumatoid arthritis (RA) the standard biochemical tests measure serological markers of disease, such as C-reactive protein, and RA-associated auto-antibodies, such as rheumatoid factor and anti-citrullinated protein antibodies. The information obtained from these markers does not, however, provide a complete picture of the disease and treatment efficacy. New biomarkers based on cytokine receptor complexes are promising for RA theragnostics

Inflammation-responsive promoters for fine-tuned gene therapy in rheumatoid arthritis.

Item does not contain fulltextThe inflamed joints of rheumatoid arthritis (RA) patients are ideally suited for gene therapy applications that induce local production of potent anti-inflammatory biologicals. The precise and absolute targeting needed when treating cancer is not necessary in RA. However, the challenge is to regulate transgene expression to meet variable physiological demands during the intermittent course of the disease in RA patients. Thus, a biosensing system with an inducible transcriptional switch that allows robust but adjustable transgene expression is required. Inflammation-inducible promoters are likely candidates to achieve precise control of transgene expression by physiologically driven processes. Acute-phase proteins, pro-inflammatory cytokines, heatshock proteins and hypoxia-responsive genes are all related to the pathogenesis of RA, and their promoters can be exploited for disease-inducible transgene expression. With this, gene therapy enters a new era, that of temporal control of the therapeutic transgene expression. In addition to the reversible transcriptional switch, the ideal expression system also contains an amplification loop for high transgene expression and a drug-controllable switch to allow intervention by the physician. The merging of these modalities may provide a flexible system to fine-tune transgene expression, which is a prerequisite for the implementation of gene therapy in RA

Effect of interleukin 1 and leukaemia inhibitory factor on chondrocyte metabolism in articular cartilage from normal and interleukin-6-deficient mice: Role of nitric oxide and IL-6 in the suppression of proteoglycan synthesis

Contains fulltext : 25725___.PDF (publisher's version ) (Open Access

Anticytokine treatment of established type II collagen-induced arthritis in DBA/1 mice: a comparative study using anti-TNFalpha, anti-IL-1alpha/beta, and IL-1Ra

Contains fulltext : 23084.PDF (publisher's version ) (Open Access

Gene therapy for rheumatoid arthritis. Lessons from animal models, including studies on interleukin-4, interleukin-10, and interleukin-1 receptor antagonist as potential disease modulators.

Item does not contain fulltextEvidence from animal models convincingly supports the fact that gene therapy can be an advantageous strategy in the treatment of chronic destructive RA. In this article, we review the state of the art in anticytokine gene transfer into the synovial arthritic joint with the emphasis on IL-1Ra, IL-4, and IL-10 effects on CIA in mice. In CIA, only high and continuous release of IL-1Ra protein systemically by mini-osmotic pumps could prevent disease onset and was curative in mice. Local gene transfer seemed to be the obvious way to reach the high local levels that are demanded for protection. It was shown that local IL-1Ra overexpression reduced arthritis incidence and severity as well as tissue destruction. In line with observations about neutralizing antibodies and soluble receptors, gene therapy with TNF soluble receptors provided anti-inflammatory activity in early arthritis but not in advanced arthritis. The limited efficacy at later stages and poor protection against destruction imply that the combination of gene constructs for TNF and IL-1 inhibitors is the obvious direction for future therapy. Apart from targeting of proinflammatory cytokines, adenoviral overexpression of IL-10 and IL-4 may have therapeutic applicability. Local injection of AdIL-10 in the knee joint was effective at the site, but also highly reduced spreading to ipsilateral sites. High local dosages caused suppression in contralateral sites as well. The reports on the anti-inflammatory effect of AdIL-4 are conflicting; however, all present data showed that IL-4 overexpression provides impressive protection against cartilage and bone erosion. Apart from the local effects in the injected joint, it is becoming more and more clear that local treatment also affects arthritis in nearby joints. This is an intriguing general finding, which may enlarge the therapeutic applicability of gene transfer in human arthritis. Proving the feasibility of gene therapy in experimental arthritis, most research efforts are now focused on improving local gene delivery by enhanced viral infection of synovial cells, using RGD-modified adenovirus, or achieving prolonged persistence and regulated expression with AAV. Elegant future alternatives are the application of in vitro engineered T cells as a vehicle capable of specific homing to joint tissues. The feasibility of viral transduction of chondrocytes to obtain a tissue-specific approach to treat articular cartilage damage in arthritis needs further attention

Osteoporosis and osteoarthritis are two sides of the same coin paid for obesity

Item does not contain fulltextObesity is characterized by adipose tissue expansion and chronic low-grade inflammation. Among the inflammatory mediators related to obesity development are the adipokines. These cytokines are released from fatty tissues and act in an autocrine, paracrine, or endocrine manner. Adipocytes influence the comorbidities of obesity such as osteoporosis (OP) and osteoarthritis (OA). It is still controversial as to whether OP is associated with either a low or high body mass index, but it is quite clear that the latter condition increases the risk for OA development. Bone marrow adipocytes (BMAs) have the same precursors of osteoblasts, which are the primary cells involved in bone formation, and the amount of BMAs appears to be inversely related to bone mineral density. Although adipokines released by these adipocytes influence bone loss progress, their exact role remains controversial. Differently, the infrapatellar fat pad (IPFP) is indicated to protect the function of joint regarding OA. However, there is relatively limited information about the secretion of adipokines and other inflammatory mediators by the IPFP. Despite some inconsistencies, nutritional interventions targeting obesity may also benefit patients with OP and OA. The association among obesity, OP, and OA is quite complex, and many factors need to be explored that are mainly related to the role of adipokines derived locally rather than from visceral and subcutaneous adipose tissue. Also, nutritional intervention may affect fatty tissue mass and secretion of inflammatory mediators that may, at least in part, influence other tissues in the organism such as bone and articular cartilage. The aim of this review was to present the latest knowledge about the interrelationship between obesity and OA or OP and to discuss whether a dietary intervention for obesity will hold promise for patients with OA or OP

Role of Interleukin-1, Tumor Necrosis Factor alpha and Interleukin-6 in cartilage proteoglycan metabolism and destruction: effect of in situ blocking in murine antigen- and zymosan-induced arthritis

Contains fulltext : 21074.PDF (publisher's version ) (Open Access

Resolving inflammation by TAM receptor activation

The control of inflammation is strictly regulated to ensure the adequate intensity and duration of an inflammatory response, enabling the removal of the trigger factors and the restoration of the integrity of the tissues and their functions. This process is coordinated by anti-inflammatory and pro-resolving mediators that regulate the cellular and molecular events necessary to restore homeostasis, and defects in this control are associated with the development of chronic and autoimmune diseases. The TAM family of receptor tyrosine kinases-Tyro3, Axl, and MerTK-plays an essential role in efferocytosis, a key process for the resolution of inflammation. However, new studies have demonstrated that TAM receptor activation not only reduces the synthesis of pro-inflammatory mediators by different cell types in response to some stimuli but also stimulates the production of anti-inflammatory and pro-resolving molecules that control the inflammation. This review provides a comprehensive view of TAM receptor family members as important players in controlling inflammatory responses through anti-inflammatory and pro-resolving actions

Gene therapy works in animal models of rheumatoid arthritis...so what!

Contains fulltext : 49934.pdf (publisher's version ) (Closed access)Rheumatoid arthritis (RA) is a systemic disease with polyarticular manifestation of chronic inflammation in the knees and small joints of hand and feet. The current systemic anti-tumor necrosis factor (TNF)-alpha therapies with biologics ameliorate disease in 60% to 70% of RA patients. However, biologics must be given systemically in relatively high dosages to achieve constant therapeutic levels in the joints, and side effects have been reported. To this end, local gene delivery can provide an alternative approach to achieve high, long-term expression of biologics, optimizing the therapeutic efficacy and minimizing systemic exposure. Evidence from animal models convincingly supports the application of local gene therapy in rheumatoid arthritis, but preclinical studies remain necessary to evaluate the merge of cell-specific targeting, viral vector development, and disease-regulated transgene expression to optimize efficacy and safety