Antimicrobial treatment regimens against bacterial pathogens are designed using the drug's minimum inhibitory concentration (MIC) measured at a bacterial density of 5.7 log10(colony-forming units (CFU)/mL) in vitro. However, MIC changes with pathogen density, which varies among infectious diseases and during treatment. Incorporating this into treatment design requires realistic mathematical models of the relationships. We compared the MIC–density relationships for Gram-negative Escherichia coli and non-typhoidal Salmonella enterica subsp. enterica and Gram-positive Staphylococcus aureus and Streptococcus pneumonia (for n = 4 drug-susceptible strains per (sub)species and 1–8 log10(CFU/mL) densities), for antimicrobial classes with bactericidal activity against the (sub)species: β-lactams (ceftriaxone and oxacillin), fluoroquinolones (ciprofloxacin), aminoglycosides (gentamicin), glycopeptides (vancomycin) and oxazolidinones (linezolid). Fitting six candidate mathematical models to the log2(MIC) vs. log10(CFU/mL) curves did not identify one model best capturing the relationships across the pathogen–antimicrobial combinations. Gompertz and logistic models (rather than a previously proposed Michaelis–Menten model) fitted best most often. Importantly, the bacterial density after which the MIC sharply increases (an MIC advancement-point density) and that density's intra-(sub)species range evidently depended on the antimicrobial mechanism of action. Capturing these dependencies for the disease–pathogen–antimicrobial combination could help determine the MICs for which bacterial densities are most informative for treatment regimen design.
Immune cell-mediated attack on the liver is a defining feature of autoimmune hepatitis and hepatic allograft rejection. Despite an assortment of diagnostic tools, invasive biopsies remain the only method for identifying immune cells in the liver. We evaluated whether PET imaging with radiotracers that quantify immune activation (F-FDG and F-1-(2'-deoxy-2'-fluoro-arabinofuranosyl)cytosine [F-FAC]) and hepatocyte biology (F-2-deoxy-2-fluoroarabinose [F-DFA]) can visualize and quantify liver-infiltrating immune cells and hepatocyte inflammation, respectively, in a preclinical model of autoimmune hepatitis. Mice treated with concanavalin A (ConA) to induce a model of autoimmune hepatitis or vehicle were imaged withF-FDG, F-FAC, andF-DFA PET. Immunohistochemistry, digital autoradiography, and ex vivo accumulation assays were used to localize areas of altered radiotracer accumulation in the liver. For comparison, mice treated with an adenovirus to induce a viral hepatitis were imaged with F-FDG,F-FAC, and F-DFA PET.F-FAC PET was performed on mice treated with ConA and vehicle or with ConA and dexamethasone. Biopsy samples of patients with autoimmune hepatitis were immunostained for deoxycytidine kinase. Hepatic accumulation ofF-FDG and F-FAC was 173% and 61% higher, respectively, and hepatic accumulation ofF-DFA was 41% lower, in a mouse model of autoimmune hepatitis than in control mice. Increased hepatic F-FDG accumulation was localized to infiltrating leukocytes and inflamed sinusoidal endothelial cells, increased hepaticF-FAC accumulation was concentrated in infiltrating CD4 and CD8 cells, and decreased hepatic F-DFA accumulation was apparent in hepatocytes throughout the liver. In contrast, viral hepatitis increased hepaticF-FDG accumulation by 109% and decreased hepatic F-DFA accumulation by 20% but had no effect on hepaticF-FAC accumulation (nonsignificant 2% decrease). F-FAC PET provided a noninvasive biomarker of the efficacy of dexamethasone for treating the autoimmune hepatitis model. Infiltrating leukocytes in liver biopsy samples from patients with autoimmune hepatitis express high levels of deoxycytidine kinase, a rate-limiting enzyme in the accumulation ofF-FAC. Our data suggest that PET can be used to noninvasively visualize activated leukocytes and inflamed hepatocytes in a mouse model of autoimmune hepatitis.
F-FDG measures glucose consumption and is an integral part of cancer management. Most cancer types upregulate their glucose consumption, yielding elevated 18 F-FDG PET accumulation in those cancer cells. The biochemical pathway through which 18 F-FDG accumulates in cancer cells is well established. However, beyond well-known regulators such as c-Myc, PI3K/PKB, and HIF1a, the proteins and signaling pathways that cancer cells modulate to activate the facilitated glucose transporters and hexokinase enzymes that drive elevated 18 F-FDG accumulation are less well understood. Understanding these signaling pathways could yield additional biologic insights from 18 F-FDG PET scans and could suggest new uses of 18 F-FDG PET in the management of cancer. Work over the past 5 years, building on studies from years prior, has identified new proteins and signaling pathways that drive glucose consumption in cancer. Here, we review these recent studies and discuss current limitations to our understanding of glucose consumption in cancer.
Drug-induced liver failure is a significant indication for a liver transplant, and unexpected liver toxicity is a major reason that otherwise effective therapies are removed from the market. Various methods exist for monitoring liver injury but are often inadequate to predict liver failure. New diagnostic tools are needed. We evaluate in a preclinical model whetherF-2-deoxy-2-fluoroarabinose (F-DFA), a PET radiotracer that measures the ribose salvage pathway, can be used to monitor acetaminophen-induced liver injury and failure. Mice treated with vehicle, 100, 300, or 500 mg/kg acetaminophen for 7 or 21 h were imaged with F-FDG andF-DFA PET. Hepatic radiotracer accumulation was correlated to survival and percentage of nonnecrotic tissue in the liver. Mice treated with acetaminophen and vehicle or -acetylcysteine were imaged withF-DFA PET. F-DFA accumulation was evaluated in human hepatocytes engrafted into the mouse liver. We show that hepatic F-DFA accumulation is 49%-52% lower in mice treated with high-dose acetaminophen than in mice treated with low-dose acetaminophen or vehicle. Under these same conditions, hepaticF-FDG accumulation was unaffected. At 21 h after acetaminophen treatment, hepatic F-DFA accumulation can distinguish mice that will succumb to the liver injury from those that will survive it (6.2 vs. 9.7 signal to background, respectively). HepaticF-DFA accumulation in this model provides a tomographic representation of hepatocyte density in the liver, with a between hepaticF-DFA accumulation and percentage of nonnecrotic tissue of 0.70. PET imaging with F-DFA can be used to distinguish effective from ineffective resolution of acetaminophen-induced liver injury with-acetylcysteine (15.6 vs. 6.2 signal to background, respectively). Human hepatocytes, in culture or engrafted into a mouse liver, have levels of ribose salvage activity similar to those of mouse hepatocytes. Our findings suggest that PET imaging withF-DFA can be used to visualize and quantify drug-induced acute liver injury and may provide information on the progression from liver injury to hepatic failure.
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