Current pharmaceutical design
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Neuropathic pain is characterized by complicated combination of positive (e.g., hyperalgesia and allodynia) and negative (e.g., hypoesthesia and hypoalgesia) symptoms, and is often refractory to conventional pharmacological agents, including morphine. Although the molecular mechanisms for positive symptoms are extensively studied, those for negative symptoms are poorly understood. There is convincing evidence that altered gene expression within peripheral and central nervous systems is a key mechanism for neuropathic pain; however, its transcriptional mechanisms are poorly understood. ⋯ Importantly, there is emerging evidence that a variety of genes undergo epigenetic regulation via DNA methylation and histone modifications within peripheral and central nervous systems, thereby contributing to the alterations in both pain sensitivity and pharmacological efficacy in neuropathic pain. In this review, we will highlight the epigenetic gene regulation underlying neuropathic pain, especially focusing on the negative symptoms. Moreover, we will discuss whether epigenetic mechanisms can serve as a potential target to treat neuropathic pain.
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The cardiovascular system exhibits significant daily rhythms in physiologic processes (heart rate, blood pressure, cardiac contractility and function), and molecular gene and protein expression. An increasing number of clinical and experimental studies demonstrate the circadian system is an important underlying mechanism that coordinates these rhythmic processes for the health of the cardiovascular system. ⋯ We also discuss therapeutic applications of circadian rhythms for the cardiovascular system. Cardiovascular disease is a leading cause of death worldwide, and applying circadian biology to cardiology (and indeed medicine in general) provides a new translational approach to benefit patients clinically.
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The confinement of critically ill patients in intensive care units (ICU) imposes environmental constancy throughout both day and night (continuous light, noise, caring activities medications, etc.), which has a negative impact on human health by inducing a new syndrome known as circadian misalignment, circadian disruption or chronodisruption (CD). This syndrome contributes to poor sleep quality and delirium, and may impair septic states frequently observed in critically ill patients. ⋯ Delirium, the most serious condition because it has a severe effect on prognosis and increases mortality, as well as sleep impairment and sepsis, all three of them linked to disorganization of the circadian system in critically ill patients, will be revised considering the functional organization of the circadian system, the main input and output signals that synchronize the clock, including a brief description of the molecular circadian clock machinery, the non-visual effects of light, and the ICU light environment. Finally, the potential usefulness of increased light/dark contrast and melatonin treatment in this context will be analyzed, including some practical countermeasures to minimize circadian disruption and improve circadian system chronoenhancement, helping to make these units optimal healing environments for patients.
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Staphylococci, in particular Staphylococcus aureus and Staphylococcus epidermidis, are a leading cause of healthcare-associated infections. Patients who have a medical device inserted are at particular risk of an infection with these organisms as staphylococci possess a wide range of immune evasion mechanisms, one of which being their ability to form biofilm. Once embedded in a biofilm, bacteria are inherently more resistant to treatment with antibiotics. ⋯ Several obstacles need to be overcome in the further development of these and other novel anti-biofilm agents. Most notably, although in vitro investigation has progressed over recent years, the need for biofilm models to closely mimic the in vivo situation is of paramount importance followed by controlled clinical trials. In this review we highlight the issues associated with staphylococcal colonisation of medical devices and potential new treatment options for the prevention and control of these significant infections.
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Rheumatoid Arthritis (RA) is a chronic, inflammatory, autoimmune disease affecting diarthrodial joints and extra-articular tissues; in the absence of an effective treatment, it is characterized by persistent symmetrical and erosive synovitis which leads to structural joint damage and lifelong disability. Several autoantibodies have been associated with RA such as rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA). B cells have been shown to play a crucial role in the pathogenesis of RA by producing autoantibodies and promoting synovial inflammation through antigen presentation, T cells activation and cytokines production [1]. ⋯ Consequently, to date a "trial-and-error" approach is used in the prescription of biologics in RA, which has the obvious disadvantage of potentially exposing patients to drugs that they may not respond, with potential unnecessary side-effects, delaying use of an effective treatment and causing a significant economic burden to society. Therefore, identifying pre-treatment predictors of response with a customized stratification approach would be of invaluable importance in RA, also in consideration of the large number of biologics in development targeting novel pathways currently being tested in clinical trials. In this manuscript, we review existing data and provide future perspectives with regard to the role of synovial histopathology as a potential prognostic biomarker for patient stratification in RA, in particular regarding the use of specific biologic therapies.