Yosra BEDOUI obtained her degree of doctor of pharmacy in 2014 at Monastir University, Tunisia. She is currently in her third year of her PhD at the University of La Reunion, France. She is working at the UMR PIMIT. Her thesis is devoted to the evaluation of the immunomodulatory and anti-viral role of methotrexate in the context of chronic arthritis induced by Chikungunya virus infection. Her interests are focused on the study of the physiopathological mechanisms of chronic arthritis induced by Chikungunya virus and the immunomodulatory effects of methotrexate treatment.
Abstract Methotrexate (MTX), the first line disease modifying anti-rheumatic drug in rheumatoid arthritis (RA) therapy, has been used successfully to treat patients with rheumatoid-like arthritis post-Chikungunya virus (CHIKV) infection (1). However, mechanisms by which MTX exerts its therapeutic effect are poorly understood. The eicosanoid prostaglandin (PG) E2 is one of the most important mediators of inflammation and contributes to several pathogenic features of arthritis such as pain and bone destruction (2,3). The proinflammatory cytokines IL-1β and TNFα, which play a pivotal role in initiating and driving RA, are known to enhance PGE2 production (4). We herein used a model of primary human synovial fibroblasts (HSF) infected with CHIKV or stimulated by the synthetic molecule polyriboinosinic:polyribocytidylic acid (PIC) to mimic chronic viral infection (5) and assessed the potential pharmacological effects of MTX. By quantitative RT-PCR, we found that PIC but not CHIKV increased the mRNA level of group IVA cytosolic phospholipase A2 (cPLA2α) (6) , a central enzyme in AA-derived eicosanoid production. Similarly, PIC but not CHIKV upregulated mRNA expression of the microsomal prostaglandin E2 synthase 1 (mPGES-1) (7) enzyme involved in PGE2 synthesis. In contrast, we found that PIC and CHIKV enhanced mRNA expression of cyclooxygenase 2 (COX-2) (4) , a major PGE2 biosynthetic enzyme. Moreover, PIC and CHIKV decreased mRNA expression of the PGE2 degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) (8) and this effect was not modulated by MTX. As controls, we found that IL-1β as well as TNFα stimulated mRNA levels of PLA2, COX-2, mPGES-1 and all these effects were inhibited by dexamethasone (DXM). DXM, in contrast, upregulated mRNA expression of the PGE2 degrading enzyme (15-PGDH). These original data argue for a therapeutic activity of MTX independently of PGE2 regulated response and through novel mechanisms which remain to be explored.
Biography Maannashon Prabaharan is an intercalating student who has interests in pharmacology, and its uses in clinical practice. This paper vocalizes his opinions about the current clinical scenario regarding sepsis (Levy et al. 2018), and potential future changes that could be implemented in all aspects of clinical care.
Abstract Sepsis is caused by the host’s over-response to an infection, which leads to organ failure. This affects many areas of the body, including the cardiovascular, renal, GI and pulmonary systems. Sepsis has high mortality rates, with survivors being affected by complications, including cognitive decline and increased cardiovascular events. Current methods for diagnosing sepsis include the use of physical biomarkers such as heart rate (HR), and serological biomarkers such as C-Reactive Protein (CRP) and Procalcitonin (PCT). Clinical trials were found through literature searches using the PubMed and Ovid databases. The cumulative evidence suggests that other serological biomarkers such as presepsin, Pentraxin-3 (PTX3) and micro-RNA have potential for future clinical use. Heart rate variability (HRV) is a newer physical biomarker that has good evidence for diagnosing sepsis patients. The Surviving Sepsis Campaign has annual updates on guidelines for clinicians in treating sepsis. The latest guidelines have included the empirical use of broad-spectrum antimicrobials to be given immediately, as part of a ‘1-hour bundle’, which does have disadvantages. The growing evidence suggests of a trend in increasing antimicrobial resistance, therefore, new alternatives should be found. This text has evidence for alternative methods, such as the use of antimicrobial stewardship (responsible use of antibiotics) and bacteriophages (viruses which infect and destroy bacteria). Recent innovations in technology over the past decade have been integrated into clinical practice, and there is great hope for the near future with new research into predictive algorithms and consumer technology in treating patients. This review aims to summarise the current developments that have occurred in the diagnosis, treatment and management of septic patients. This review also aims to show the reader what future developments hold for improving the quality of sepsis management.