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    • March marked Multiple Sclerosis MS

    2018-10-23

    March 2–8 marked Multiple Sclerosis (MS) Awareness Week in the United States MS is a chronic, often debilitating disease of the central caged compounds (CNS), affecting more than 2 million people worldwide. As recently as 25years ago, a diagnosis of MS came with no hope for course-altering treatment options, and researchers had only a very limited understanding of the mechanistic underpinnings of disease onset or progression.
    Despite the long and hard battle against tuberculosis (TB), WHO estimated that 9 million people developed the disease in 2013, and nearly 1.5 million people died of TB (). To make matters worse, drug-resistance is a growing threat, and 3 out of 9 million TB cases are either not diagnosed, or not notified to TB control programs. But there is some good news from the perspective of new tool introduction. Slowly but surely, the landscape of TB technologies is changing (). We now have a variety of new TB diagnostics, including rapid molecular tests (e.g. Xpert MTB/RIF, Cepheid Inc., USA) for detection as well as drug susceptibility testing (DST) (). We also have new TB drugs (e.g. bedaquiline and delamanid) on the market, and new TB drug regimens are expected within the next 2–3years. These are major, exciting developments in the fight against a very ancient scourge. This article reviews the current best diagnostic tools available for TB diagnosis and monitoring, and describes the most important gaps, and translational challenges for developing innovative products that can meet the needs (). As shown in the Table, there are critical unmet needs that range from a simple, triage test for use in the community, to DST tools that can detect a range of mutations for several important drugs that will make up future drug regimens (). For the next-generation DST tools, a big translational challenge is the paucity of good data on the correlation of mutations with phenotypic DST results and clinical outcomes and the association with cross-resistance (). This is particularly important to make sure that we have companion diagnostics for emerging TB drug regimens (). The translational challenges associated with DST are reviewed elsewhere (). For the development of rapid triage tests, non-sputum based tests for active TB, highly predictive LTBI tests, and an accurate test for cure, we need validated biomarkers. Although considerable efforts are being made to identify biomarkers that can meet some of these needs, progress has been slow, and the translational challenges have been reviewed elsewhere ().
    Sepsis is a common, costly and lethal condition with high mortality and substantial long-term disability in survivors. With high rates of sepsis at the extremes of age (premature infants and the elderly), growth of both of these populations will lead to an increase in sepsis burden in years to come. Development of targeted sepsis therapies, of which there are currently none, is a priority. In recent years, our group and others have described high levels of circulating cell-free hemoglobin (Hb) in the majority of patient with sepsis () and have shown that higher levels are associated with poor clinical outcomes. Pre-clinical studies have begun to dissect the molecular mechanisms of the damaging effects of cell-free Hb in sepsis, most of which have focused on the endothelium () or macrophages () and not on neutrophils. In this issue of the journal, the study by brings us one step closer to understanding the pathophysiologic role of circulating cell-free Hb in sepsis. The authors show that oxidized Hb, specifically methemoglobin (metHb), is a damage-associated molecular pattern (DAMP) that signals through the Toll-like receptor (TLR) 2/NF-κB pathway to generate neutrophil reactive oxygen species, induce neutrophil apoptosis and increase expression of proinflammatory cytokines. Importantly, the effects of metHb were synergistic with lipoteichoic acid (LTA), a cell wall component of that also signals through TLR2. The effects of metHb in neutrophils were attenuated in the presence of other immune cells indicating modulation of metHb effects in a complex immune environment.