Generation of a Convalescent Model of Virulent Francisella tularensis Infection for Assessment of Host Requirements for Survival of Tularemia

Francisella tularensis is a facultative intracellular bacterium and the causative agent of tularemia. Development of novel vaccines and therapeutics for tularemia has been hampered by the lack of understanding of which immune components are required to survive infection. Defining these requirements for protection against virulent F. tularensis, such as strain SchuS4, has been difficult since experimentally infected animals typically die within 5 days after exposure to as few as 10 bacteria. Such a short mean time to death typically precludes development, and therefore assessment, of immune responses directed against virulent F. tularensis. To enable identification of the components of the immune system that are required for survival of virulent F. tularensis, we developed a convalescent model of tularemia in C57Bl/6 mice using low dose antibiotic therapy in which the host immune response is ultimately responsible for clearance of the bacterium. Using this model we demonstrate αβTCR+ cells, γδTCR+ cells, and B cells are necessary to survive primary SchuS4 infection. Analysis of mice deficient in specific soluble mediators shows that IL-12p40 and IL-12p35 are essential for survival of SchuS4 infection. We also show that IFN-γ is required for survival of SchuS4 infection since mice lacking IFN-γR succumb to disease during the course of antibiotic therapy. Finally, we found that both CD4+ and CD8+ cells are the primary producers of IFN-γand that γδTCR+ cells and NK cells make a minimal contribution toward production of this cytokine throughout infection. Together these data provide a novel model that identifies key cells and cytokines required for survival or exacerbation of infection with virulent F. tularensis and provides evidence that this model will be a useful tool for better understanding the dynamics of tularemia infection

Anti-inflammatory Components from Functional Foods for Obesity

Obesity, defined as excessive fat accumulation that may impair health, has been described throughout human history, but it has now reached epidemic proportions with the WHO estimating that 39% of the world’s adults over 18 years of age were overweight or obese in 2016. Obesity is a chronic low-grade inflammatory state leading to organ damage with an increased risk of common diseases including cardiovascular and metabolic disease, non-alcoholic fatty liver disease, osteo-arthritis and some cancers. This inflammatory state may be influenced by adipose tissue hypoxia and changes in the gut microbiota. There has been an increasing focus on functional foods and nutraceuticals as treatment options for obesity as drug treatments are limited in efficacy. This chapter summarises the importance of anthocyanin-containing fruits and vegetables, coffee and its components, tropical fruit and food waste as sources of phytochemicals for obesity treatment. We emphasise that preclinical studies can form the basis for clinical trials to determine the effectiveness of these treatments in humans

Reasons for Not Intensifying Medications: Differentiating “Clinical Inertia” from Appropriate Care

BACKGROUND: Clinical inertia has been defined as inaction by physicians caring for patients with uncontrolled risk factors such as blood pressure. Some have proposed that it accounts for up to 80% of cardiovascular events, potentially an important quality problem. However, reasons for so-called clinical inertia are poorly understood. OBJECTIVE: To derive an empiric conceptual model of clinical inertia as a subset of all clinical inactions from the physician perspective. METHODS: We used Nominal Group panels of practicing physicians to identify reasons why they do not intensify medications when seeing an established patient with uncontrolled blood pressure. MEASUREMENTS AND MAIN RESULTS: We stopped at 2 groups (N = 6 and 7, respectively) because of the high degree of agreement on reasons for not intensifying, indicating saturation. A third group of clinicians (N = 9) independently sorted the reasons generated by the Nominal Groups. Using multidimensional scaling and hierarchical cluster analysis, we translated the sorting results into a cognitive map that represents an empirically derived model of clinical inaction from the physician\u27s perspective. The model shows that much inaction may in fact be clinically appropriate care. CONCLUSIONS/RECOMMENDATIONS: Many reasons offered by physicians for not intensifying medications suggest that low rates of intensification do not necessarily reflect poor quality of care. The empirically derived model of clinical inaction can be used as a guide to construct performance measures for monitoring clinical inertia that better focus on true quality problems

In search of a new paradigm for protective immunity to TB

Author ManuscriptClinical trials of vaccines against Mycobacterium tuberculosis are well under way and results are starting to come in. Some of these results are not so encouraging, as exemplified by the latest Aeras-422 and MVA85A trials. Other than empirically determining whether a vaccine reduces the number of cases of active tuberculosis, which is a daunting prospect given the chronic nature of the disease, we have no way of assessing vaccine efficacy. Therefore, investigators seek to identify biomarkers that predict vaccine efficacy. Historically, focus has been on the production of interferon-γ by CD4(+) T cells, but this has not been a useful correlate of vaccine-induced protection. In this Opinion article, we discuss recent advances in our understanding of the immune control of M. tuberculosis and how this knowledge could be used for vaccine design and evaluation.The authors are supported by the following grants from the US National Institutes of Heath (NIH) and US National Institute of Allergy and Infectious Diseases (NIAID): R21AI100766, R01AI085669, R01AI098637, and R01AI10672