Ruxolitinib Supplier Future considerations must be given to

Future considerations must be given to host-pathogen interactions that can also influence drug susceptibility. (1) Animals, including primates, often tolerate drugs differently than humans (pharmacokinetic parameters such as drug clearance, volume of distribution, and half-life can result in unanticipated changes in antimicrobial efficacy) (Ambrose et al., 2007; Deziel et al., 2005). (2) Bacterial community composition can compromise antibiotic efficacy (antibiotic deactivation or biofilm production provides passive resistance for all microbes within a polymicrobial environment) (Vega and Gore, 2014; Sorg et al., 2016). (3) Antimicrobial selection is based on drug concentrations achieved in plasma, but concentrations achieved in different tissues and sites of infection may be greater or less depending on the drug\'s properties (pH at the infection site or within an organelle can dictate lipid solubility of the drug or its distribution in cells and tissues) (Logan et al., 2012). (4) Antibiotic resistance may be inadvertently triggered by diet, underlying conditions in the patient, or by clinical interventions that may disrupt drug efficacy (ascorbic Ruxolitinib Supplier treatment of urinary tract infections to lower urine pH) (Carlsson et al., 2001). (5) Many patients that develop multidrug-resistant infections have co-morbidities, immunosuppressive therapy and/or the presence of invasive medical devices that impact susceptibility to indicated pathogens (Paterson and Bonomo, 2005).
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Introduction Early detection of common (e.g., herpesvirus) and new emerging viruses (e.g., Zika virus) infections is extremely important for control of disease transmission, prompt initiation of treatment and prevention of infection-related complications. Human herpesvirus 8 (HHV-8; KSHV, Kaposi sarcoma-associated herpesvirus) is a member of the gamma-herpes virus family that evolved to maintain life-long latent infections in the human host (Levy, 1997; Luppi and Torelli, 1996; Mesri et al., 2010). KSHV is a causative factor for Kaposi sarcoma, primary effusion lymphoma, and some subtypes of multicentric Castleman disease (Ganem, 2010). Unlike the other members of the gamma-herpes virus family, wide variation is seen in the seroprevalence of KSHV, which is generally high in African and Mediterranean regions (20%–80%), and low in non-endemic areas such as the United States and Northern Europe (1.5%–7%) (Rohner et al., 2014; Stiller et al., 2014). These geographical variations in KSHV/HHV-8 seroprevalence and the incidence of classic Kaposi sarcoma (KS) remain largely unexplained. Most cases of KS reported outside endemic areas are in immunosuppressed patients (e.g., HIV-infected patients, and post-transplant recipients) (Osmond et al., 2002). In the last two decades, modern techniques (e.g., real-time PCR or RT-qPCR, ELISA) have improved identification of viral infections. However, there is no agreement on a standard assay to detect the presence of KSHV infection and thus estimate its prevalence (Bhutani et al., 2015). Although the current method of choice is to detect antibodies produced in the patients after being infected by KSHV, the seroprevalence of KSHV varies greatly geographically and the true prevalence of KSHV infection may be underestimated (Mesri et al., 2010; Stiller et al., 2014). MicroRNAs (miRNAs) are short non-coding RNAs (ncRNAs) that post-transcriptionally regulate gene expression, thereby affecting multiple cellular processes, and miRNAs can serve as biomarkers for prognosis of different diseases including malignancies (Ambros, 2003; Calin et al., 2002; Calin et al., 2005; Fabbri et al., 2011). Previous studies led to the discovery of virally encoded miRNAs that play important roles in regulating the latent-lytic switch of gamma-Herpesviruses infections (Mesri et al., 2010; Zhu et al., 2013). Viral miRNAs can modulate both viral and host cellular gene expression during infections without generating antigenic viral proteins that can be detected by the host immune system (Skalsky and Cullen, 2010). Changes in cellular and viral miRNAs expression levels in the circulation (plasma or serum) showed specific patterns in various diseases (e.g., malignancies, sepsis, atherosclerosis) (Boss et al., 2011; Fabris and Calin, 2016; Ferrajoli et al., 2015; Giza et al., 2016; Herman et al., 2015; Tudor et al., 2014; Zhang et al., 2012). These miRNAs remain in circulation in a stable form, being highly resistant to acute changes in pH, endogenous RNase activity, and variations in temperature (Shah and Calin, 2013). Furthermore, several mature miRNAs, derived from 12 precursor miRNAs in the latency locus of the KSHV genome, play important roles in KSHV-induced cell transformation (Cai et al., 2005; Samols et al., 2005). Moreover, we previously reported that higher plasma levels of KSHV miRNAs are associated with a worse clinical outcome in patients with sepsis (Tudor et al., 2014). We hypothesized that, since viral DNA/messenger RNA/proteins cannot be detected in all infected individuals, detection of miRNAs encoded by viruses may represent a more sensitive assay to determine the true prevalence of certain viral infections, including latent KSHV infection. Therefore, we compared the results of measurement of plasma miRNA by RT-qPCR to serological testing for KSHV in four groups of Caucasian patients from US and Romania to determine the relative effectiveness of the two methods to measure and detect evidence of occult KSHV infection.