Combinations of β-lactam or aminoglycoside antibiotics with plectasin are synergistic against methicillin-sensitive and methicillin-resistant Staphylococcus aureus.

Bacterial infections remain the leading killer worldwide which is worsened by the continuous emergence of antibiotic resistance. In particular, methicillin-sensitive (MSSA) and methicillin-resistant Staphylococcus aureus (MRSA) are prevalent and the latter can be difficult to treat. The traditional strategy of novel therapeutic drug development inevitably leads to emergence of resistant strains, rendering the new drugs ineffective. Therefore, rejuvenating the therapeutic potentials of existing antibiotics offers an attractive novel strategy. Plectasin, a defensin antimicrobial peptide, potentiates the activities of other antibiotics such as β-lactams, aminoglycosides and glycopeptides against MSSA and MRSA. We performed in vitro and in vivo investigations to test against genetically diverse clinical isolates of MSSA (n = 101) and MRSA (n = 115). Minimum inhibitory concentrations (MIC) were determined by the broth microdilution method. The effects of combining plectasin with β-lactams, aminoglycosides and glycopeptides were examined using the chequerboard method and time kill curves. A murine neutropenic thigh model and a murine peritoneal infection model were used to test the effect of combination in vivo. Determined by factional inhibitory concentration index (FICI), plectasin in combination with aminoglycosides (gentamicin, neomycin or amikacin) displayed synergistic effects in 76-78% of MSSA and MRSA. A similar synergistic response was observed when plectasin was combined with β-lactams (penicillin, amoxicillin or flucloxacillin) in 87-89% of MSSA and MRSA. Interestingly, no such interaction was observed when plectasin was paired with vancomycin. Time kill analysis also demonstrated significant synergistic activities when plectasin was combined with amoxicillin, gentamicin or neomycin. In the murine models, plectasin at doses as low as 8 mg/kg augmented the activities of amoxicillin and gentamicin in successful treatment of MSSA and MRSA infections. We demonstrated that plectasin strongly rejuvenates the therapeutic potencies of existing antibiotics in vitro and in vivo. This is a novel strategy that can have major clinical implications in our fight against bacterial infections

Correlation between HIV viral load and aminotransferases as liver damage markers in HIV infected naive patients: a concordance cross-sectional study

Abnormalities in liver function tests could be produced exclusively by direct inflammation in hepatocytes, caused by the human immunodeficiency virus (HIV). Mechanisms by which HIV causes hepatic damage are still unknown. Our aim was to determine the correlation between HIV viral load, and serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) as markers of hepatic damage in HIV naive infected patients

IL28B Genetic Variation Is Associated with Spontaneous Clearance of Hepatitis C Virus, Treatment Response, Serum IL-28B Levels in Chinese Population

<p><b>Background:</b> The interleukin-28B gene (IL28B) locus has been associated with host resistance to hepatitis C virus (HCV) infection and response to PEG-IFN/RBV treatment in western populations. This study was to determine whether this gene variant is also associated with spontaneous clearance of HCV infection, treatment response and IL-28B protein production in Chinese patients.</p> <p><b>Methods:</b> We genotyped IL28B genetic variations (rs12980275, rs8103142, rs8099917 and rs12979860) by pyrosequencing DNA samples from cohorts consisting of 529 subjects with persistent HCV infection, 196 subjects who cleared the infection, 171 healthy individuals and 235 chronic HCV patients underwent IFN/RBV treatment. The expression of IL-28B were measured by ELISA and RT-PCR.</p> <p><b>Results:</b> We found that the four IL28B variants were in complete linkage disequilibrium (r2 = 0.97–0.98). The rs12979860 CC genotype was strongly associated with spontaneously HCV clearance and successful IFN/RBV treatment compared to the CT/TT. IL-28B levels in persistent HCV patients were significantly lower than subjects who spontaneously resolved HCV and healthy controls and were also associated with high levels of ALT (alanine aminotransferase) and AST (aspartate aminotransferase). IL-28B levels were also significantly lower in individuals carrying T alleles than CC homozygous.</p> <p><b>Conclusions:</b> Thus, the rs12979860-CC variant upstream of IL28B gene is associated with spontaneous clearance of HCV, susceptible to IFN/RBV treatment and increased IL-28B levels in this Chinese population.</p&gt

Extreme CD8 T Cell Requirements for Anti-Malarial Liver-Stage Immunity following Immunization with Radiation Attenuated Sporozoites

Radiation-attenuated Plasmodium sporozoites (RAS) are the only vaccine shown to induce sterilizing protection against malaria in both humans and rodents. Importantly, these “whole-parasite” vaccines are currently under evaluation in human clinical trials. Studies with inbred mice reveal that RAS-induced CD8 T cells targeting liver-stage parasites are critical for protection. However, the paucity of defined T cell epitopes for these parasites has precluded precise understanding of the specific characteristics of RAS-induced protective CD8 T cell responses. Thus, it is not known whether quantitative or qualitative differences in RAS-induced CD8 T cell responses underlie the relative resistance or susceptibility of immune inbred mice to sporozoite challenge. Moreover, whether extraordinarily large CD8 T cell responses are generated and required for protection following RAS immunization, as has been described for CD8 T cell responses following single-antigen subunit vaccination, remains unknown. Here, we used surrogate T cell activation markers to identify and track whole-parasite, RAS-vaccine-induced effector and memory CD8 T cell responses. Our data show that the differential susceptibility of RAS-immune inbred mouse strains to Plasmodium berghei or P. yoelii sporozoite challenge does not result from host- or parasite-specific decreases in the CD8 T cell response. Moreover, the surrogate activation marker approach allowed us for the first time to evaluate CD8 T cell responses and protective immunity following RAS-immunization in outbred hosts. Importantly, we show that compared to a protective subunit vaccine that elicits a CD8 T cell response to a single epitope, diversifying the targeted antigens through whole-parasite RAS immunization only minimally, if at all, reduced the numerical requirements for memory CD8 T cell-mediated protection. Thus, our studies reveal that extremely high frequencies of RAS-induced memory CD8 T cells are required, but may not suffice, for sterilizing anti-Plasmodial immunity. These data provide new insights into protective CD8 T cell responses elicited by RAS-immunization in genetically diverse hosts, information with relevance to developing attenuated whole-parasite vaccines

Undetectable phospho-STAT1 in peripheral blood mononuclear cells from patients with chronic hepatitis C who do not respond to interferon-alpha therapy

SUMMARY. The a-defensin genes promoter regions contain a putative nuclear factors of activated T cells (NFAT)-binding site and it is known that hepatitis C virus (HCV) core protein activates the interleukin (IL)-2 gene transcription through the NFAT pathway. The aims of this study were to investigate if HCV affects the a-defensin expression in peripheral human mononuclear cells (PBMCs) and to evaluate the existence of a correlation between a-defensins and liver damage in patients with chronic hepatitis C. Ninety patients with chronic hepatitis C, 30 with chronic hepatitis B and 25 healthy controls were enrolled. a-Defensins were identified and quantified in PBMCs by mass spectrometry, enzymelinked immunosorbent assay, antibacterial activity and mRNA levels. PBMCs from three patients and controls were stimulated with HCV core protein, hepatitis B virus core antigen and the a-defensin mRNAs level was quantified. We found that HCV core protein activates in vitro the a-defensin transcription. a-Defensin levels in patients with chronic hepatitis C (mean ± SD ¼ 1.103 ± 0.765 ng/106 cells), chronic hepatitis B (0.53 ± 0.15) and healthy controls (0.217 ± 0.09) resulted significantly different (P < 0.001). In patients with chronic hepatitis C, the a-defensin levels and antibacterial activity correlate with the liver fibrosis. Our data suggest that HCV induces a-defensin expression. The high linear correlation of a-defensin levels with advancing fibrosis makes the measure of these peptides a reliable marker to evaluate fibrosis stage. Keywords: a-defensin, chronic hepatitis, hepatitis C vir

A case of myiasis in man due to Wohlfahrtia magnifica (Schiner) recorded near Rome.

n this report the case of a 14-year-old Italian boy is described in whom scratching wounds of the scalp were invaded by maggots of the dipterous Wohlfahrtia magnifica (Schiner)

Development of hepatotoxicity in HIV patients switching at least one protease inhibitor

In order to evaluate the occurrence of hepatotoxicity in patients treated with antiretroviral therapy (ART) who switch protease inhibitor (PI), and the role of viral hepatitis in its development, we performed a retrospective study on 182 HIV patients treated with ART for 24 months. The presence of hepatitis viruses and alanine transaminase levels were evaluated. Hepatotoxicity developed in a low number of subjects without co-infection, but was significantly higher in co-infected patients (14/51 versus 62/131, P = 0.01). Ritonavir was associated with higher rates of severe hepatotoxicity in the co-infected group. Patients presenting any problems related to ART, including the development of hepatotoxicity, continued therapy by switching PI. The occurrence of hepatotoxicity with second/third choice PIs, including ritonavir, remained stable. Our results suggest that switching PI does not increase the occurrence of drug-related liver toxicity