Charles L Grant Epub 18

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Introduction: Ciprofloxacin, levofloxacin, and moxifloxacin belong to the fluoroquinolone class of antibiotics and are amongst the most commonly prescribed antibiotics. In 2018 and 2019, Food and Drug Administration (FDA) and the European Medicine Agency (EMA) requested that manufacturers harmonize FQ safety information related to neuropsychiatric, aortic dissection, and long-term disability. The authors hypothesize that FDA and EMA epidemiologists support a strong association between these drugs and the three toxicities. Areas covered: Studies of FQ-associated neuropsychiatric toxicity, long-term disability, and aortic ruptures/dissections. Clinical sources include FDA Advisory Committee documents, a 2014 Citizen Petition filed with the FDA requesting safety information additions to FQ labels for neuropsychiatric toxicities (partially granted in 2018), an under-review Citizen Petition under review by the FDA requesting a FQ Risk Evaluation and Mitigation Strategy, and safety notifications from the EMA. Expert opinion: FDA and the EMA report state that neuropsychiatric toxicity, long-term disability, and aortic dissections//aneurysms occur with all FQs. Disability and neuropsychiatric toxicity can occur after one dose or several months after FQs. United States' and European' regulators warn physicians not to prescribe FQs for uncomplicated acute urinary tract infection, sinusitis, or bronchitis, unless other possible choices are tried first, as risks outweigh benefits in these settings.

D.A. Tuveson reports receiving commercial research grants from ONO and Fibrogen, has ownership interest (including stock, patents, etc.) in Leap Therapeutics and Surface Oncology, and is a consultant/advisory board member for Leap Therapeutics, Surface Oncology, MabImmune, and Bethyl Antibodies. No potential conflicts of interest were disclosed by the other authors.

To date, he has authored over 90 peer-reviewed publications and three book chapters. He has received funding from several sources including a OREF program development grant, a new investigator grant, a VA research grant, an AAHKS research grant, and several resident development grants from the Orthopedic Research and Education Foundation. He routinely lectures at local, regional, national and internationally.

A major focus of my research is on the autoimmune aspects of Type 1 or insulin-dependent diabetes, using the nonobese diabetic (NOD) mouse as a primary model. In humans and the NOD mouse, insulin-dependent diabetes is inherited. Autoantibodies to insulin and islet cells are produced, and T lymphocytes invade the islets in the pancreas. T-cell invasion or insulitis is associated with destruction of the insulin-secreting beta cells. In the NOD mouse, insulitis begins at 4-6 weeks of age; however, the mice do not spontaneously become diabetic until 3 to 6 months of age, at which time sufficient beta cells have been destroyed to result in the loss of insulin secretion. Other investigators have shown that the insulin receptor (IR) can function as a chemotactic receptor capable of directing cell movement in response to a gradient of insulin. Published data from my laboratory has shown that flow cytometry-sorted T lymphocytes, from diabetic NOD mice expressing a high density of insulin receptors (IR+ T cells), aggressively transfer insulitis and diabetes, while T cells with low to negative IR expression (IR- T cells) are capable of neither. An association of IR+ T cells with an increased risk for diabetes would provide a new target for drug therapy. Furthermore, chemotactic signaling and metabolic signaling are mediated by distinct parts of the insulin receptor and could, therefore, be selectively targeted for therapeutic intervention prior to diabetes onset. Current research in my laboratory involves the development of a flag-tagged, T cell-specific, IR transgenic mouse on a background that does not spontaneously become diabetic to determine whether movement of T cells into an islet can be based on IR expression. We have been successful in two of the transgenic models and now wish to make a transgenic mouse that has IR expression on the surface of Tregs to prevent the development of type 1 diabetes. We will be using Cre-Lox transgenic mice systems to reach this goal. There are areas of translational research associated with this work on high density IR expression using peripheral blood from human diabetic patients. The recent NIH/NIDDK grant (2014-18) supports this research.

Dr. McInerney has served on over 30 grant review panels for NIH for NIDDK, NCI, NIAID, NIDCR-ODCS, NIDCR, NIAMSD, SEP in IMM. She has also reviewed grants for Diabetes UK, Diabetes Action Research and Education Foundation, where she is on the Medical Advisory Board; USDA/NIFA; Wright State University; Michigan Diabetes Research and Training Center; and Ohio University. 2b1af7f3a8