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Zhang R.,University of Kiel | Zhang R.,RI B NT Research Institute of Bioinformatics and Nanotechnology | Eckert T.,Justus Liebig University | Lutteke T.,Justus Liebig University | And 8 more authors.
Current Topics in Medicinal Chemistry | Year: 2016

The Antimicrobial peptides (e.g. defensins, hevein-like molecules and food-protecting peptides like nisin) are able to interact specifically with contact structures on pathogen surfaces. Besides protein receptors, important recognition points for such contacts are provided by pathogen glycan chains or surface lipids. Therefore, structural data concerning surface exposed glycans and lipids are of the highest clinical interest since these recognition functions play a key role when optimising anti-infection therapies. Approaches in nanomedicine and nanopharmacology in which various biophysical techniques such as NMR (Nuclear Magnetic Resonance), AFM (Atomic Force Microscopy), SPR (Surface Plasmon Resonance) and X-ray crystallography can be combined with biochemical and cell-biological methods will lead to improved antimicrobial peptides by this rational drug design approach. Such a strategy is extremely well suited to support clinical studies focussing on an effective fight against multiresistant pathogens. The data sets which are described here can be considered as universal for the design of various antimicrobial drugs against certain pathogens (bacteria, viruses and fungi) which cause severe diseases in humans and animals. Furthermore, these insights are also helpful for progressing developments in the field of food conservation and food preservation. A detailed analysis of the structure-function relationships between antimicrobial peptides and contact molecules on pathogen surfaces at the sub-molecular level will lead to a higher degree of specificity of antimicrobial peptides. © 2016 Bentham Science Publishers.

Ashraf S.,University of Southampton | Nitschke K.,Albert Ludwigs University of Freiburg | Warshow U.M.,Hepatology Research Group | Brooks C.R.,University of Southampton | And 8 more authors.
Hepatology | Year: 2013

CD8+ T-cell responses to hepatitis C virus (HCV) are important in generating a successful immune response and spontaneously clearing infection. Human leukocyte antigen (HLA) class I presents viral peptides to CD8+ T cells to permit detection of infected cells, and tapasin is an important component of the peptide loading complex for HLA class I. We sought to determine if tapasin polymorphisms affected the outcome of HCV infection. Patients with resolved or chronic HCV infection were genotyped for the known G/C coding polymorphism in exon 4 of the tapasin gene. In a European, but not a US, Caucasian population, the tapasin G allele was significantly associated with the outcome of HCV infection, being found in 82.5% of resolvers versus 71.3% of persistently infected individuals (P=0.02, odds ratio [OR]=1.90 95% confidence interval [CI]=1.11-3.23). This was more marked at the HLA-B locus at which heterozygosity of both tapasin and HLA-B was protective (P<0.03). Individuals with an HLA-B allele with an aspartate at residue 114 and the tapasin G allele were more likely to spontaneously resolve HCV infection (P<0.00003, OR=3.2 95% CI=1.6-6.6). Additionally, individuals with chronic HCV and the combination of an HLA-B allele with an aspartate at residue 114 and the tapasin G allele also had stronger CD8+ T-cell responses (P=0.02, OR=2.58, 95% CI-1.05-6.5). Conclusion: Tapasin alleles contribute to the outcome of HCV infection by synergizing with polymorphisms at HLA-B in a population-specific manner. This polymorphism may be relevant for peptide vaccination strategies against HCV infection. (Hepatology 2013;53:881-889). © 2013 by the American Association for the Study of Liver Diseases.

Kalams S.A.,Infectious Diseases Division | Kalams S.A.,Vanderbilt University | Parker S.D.,University of Alabama at Birmingham | Elizaga M.,Fred Hutchinson Cancer Research Center | And 25 more authors.
Journal of Infectious Diseases | Year: 2013

Background. DNA vaccines have been very poorly immunogenic in humans but have been an effective priming modality in prime-boost regimens. Methods to increase the immunogenicity of DNA vaccines are needed.Methods. HIV Vaccine Trials Network (HVTN) studies 070 and 080 were multicenter, randomized, clinical trials. The human immunodeficiency virus type 1 (HIV-1) PENNVAX®-B DNA vaccine (PV) is a mixture of 3 expression plasmids encoding HIV-1 Clade B Env, Gag, and Pol. The interleukin 12 (IL-12) DNA plasmid expresses human IL-12 proteins p35 and p40. Study subjects were healthy HIV-1-uninfected adults 18-50 years old. Four intramuscular vaccinations were given in HVTN 070, and 3 intramuscular vaccinations were followed by electroporation in HVTN 080. Cellular immune responses were measured by intracellular cytokine staining after stimulation with HIV-1 peptide pools.Results. Vaccination was safe and well tolerated. Administration of PV plus IL-12 with electroporation had a significant dose-sparing effect and provided immunogenicity superior to that observed in the trial without electroporation, despite fewer vaccinations. A total of 71.4% of individuals vaccinated with PV plus IL-12 plasmid with electroporation developed either a CD4+ or CD8+ T-cell response after the second vaccination, and 88.9% developed a CD4+ or CD8+ T-cell response after the third vaccination.Conclusions. Use of electroporation after PV administration provided superior immunogenicity than delivery without electroporation. This study illustrates the power of combined DNA approaches to generate impressive immune responses in humans. © 2013 The Author.

Paquette K.,Infectious Diseases Division | Cheng M.P.,Infectious Diseases Division | Lam C.,Infectious Diseases Division | Quach C.,Infectious Diseases Division | Quach C.,McGill University
Pediatric Emergency Care | Year: 2011

Objectives: Guidelines for the management of febrile infants aged 30 to 90 days presenting to the emergency department (ED) suggest that a lumbar puncture (LP) should be performed routinely if a positive urinalysis is found during initial investigations. The aim of our study was to assess the necessity of routine LPs in infants aged 30 to 90 days presenting to the ED for a fever without source but are found to have a positive urine analysis. Methods: We retrospectively reviewed the records of all infants aged 30 to 90 days, presenting to the Montreal Children's Hospital ED from October 2001 to August 2005 who underwent an LP for bacterial culture, in addition to urinalysis and blood and urine cultures. Descriptive statistics and their corresponding confidence intervals were used. Results: Overall, 392 infants were identified using the microbiology laboratory database. Fifty-seven patients had an abnormal urinalysis. Of these, 1 infant (71 days old) had an Escherichia coli urinary tract infection, bacteremia, and meningitis. This patient, however, was not well on history, and the peripheral white blood cell count was low at 2.9 × 10 9/L. Thus, the negative predictive value of an abnormal urinalysis for meningitis was 98.2%. Conclusions: Routine LPs are not required in infants (30-90 days) presenting to the ED with a fever and a positive urinalysis if they are considered at low risk for serious bacterial infection based on clinical and laboratory criteria. However, we recommend that judicious clinical judgment be used; in doubt, an LP should be performed before empiric antibiotic therapy is begun. Copyright © 2011 by Lippincott Williams & Wilkins.

Florescu D.F.,Infectious Diseases Division | Florescu D.F.,85400 Nebraska Medical Center | Kwon J.Y.,Infectious Diseases Division | Dumitru I.,University of Nebraska Medical Center
Cardiology in Review | Year: 2013

Adenovirus infections have been associated with significant morbidity and mortality in immunocompromised hosts. The clinical significance of adenovirus disease in heart transplantation is not well-defined; in particular, the significance of adenovirus identification in myocardium remains unclear. Although severe adenovirus disease has been described in heart transplant recipients, adenovirus infections seem to be more frequently associated with increased risk of adverse cardiac events, such as rejection, ventricular dysfunction, coronary vasculopathy, need for retransplantation, and graft loss because of death. Cidofovir is currently considered the standard of treatment for adenovirus disease not responding to reduction of immunosuppression. © 2012 Lippincott Williams & Wilkins.

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