C-reactive protein and albumin kinetics before community-acquired bloodstream infections- A Danish population-based cohort study

aEarly changes in biomarker levels probably occur before bloodstream infection (BSI) is diagnosed. However, this issue has not been fully addressed. We aimed at evaluating the kinetics of C-reactive protein (CRP) and plasma albumin (PA) in the 30 days before community-acquired (CA) BSI diagnosis. From a population-based BSI database we identified 658 patients with at least one measurement of CRP or PA from day-30 (D-30) through day-1 (D-1) before the day of CA-BSI (D0) and a measurement of the same biomarker at D0 or D1. Amongst these, 502 had both CRP and PA measurements which fitted these criteria. CRP and PA concentrations began to change inversely some days before CA-BSI diagnosis, CRP increasing by day-3.1 and PA decreasing by day-1.3. From D-30 to D-4, CRP kinetics (expressed as slopes-rate of concentration change per day) was-1.5 mg/l/day. From D-3 to D1, the CRP slope increased to 36.3 mg/l/day. For albumin, the slope between D-30 to D-2 was 0.1 g/l/day and changed to-1.8 g/l/day between D-1 and D1. We showed that biomarker levels begin to change some days before the CA-BSI diagnosis, CRP 3.1 days and PA 1.3 days before.publishersversionepub_ahead_of_prin

Oral and Fecal Campylobacter concisus Strains Perturb Barrier Function by Apoptosis Induction in HT-29/B6 Intestinal Epithelial Cells

Campylobacter concisus infections of the gastrointestinal tract can be accompanied by diarrhea and inflammation, whereas colonization of the human oral cavity might have a commensal nature. We focus on the pathophysiology of C. concisus and the effects of different clinical oral and fecal C. concisus strains on human HT-29/B6 colon cells. Six oral and eight fecal strains of C. concisus were isolated. Mucus-producing HT-29/B6 epithelial monolayers were infected with the C. concisus strains. Transepithelial electrical resistance (Rt) and tracer fluxes of different molecule size were measured in Ussing chambers. Tight junction (TJ) protein expression was determined by Western blotting, and subcellular TJ distribution was analyzed by confocal laser-scanning microscopy. Apoptosis induction was examined by TUNEL-staining and Western blot of caspase-3 activation. All strains invaded confluent HT-29/B6 cells and impaired epithelial barrier function, characterized by a time- and dose-dependent decrease in Rt either after infection from the apical side but even more from the basolateral compartment. TJ protein expression changes were sparse, only in apoptotic areas of infected monolayers TJ proteins were redistributed. Solely the barrier-forming TJ protein claudin-5 showed a reduced expression level to 66±8% (P<0.05), by expression regulation from the gene. Concomitantly, Lactate dehydrogenase release was elevated to 3.1±0.3% versus 0.7±0.1% in control (P<0.001), suggesting cytotoxic effects. Furthermore, oral and fecal C. concisus strains elevated apoptotic events to 5-fold. C. concisus-infected monolayers revealed an increased permeability for 332 Da fluorescein (1.74±0.13 vs. 0.56±0.17 10−6 cm/s in control, P<0.05) but showed no difference in permeability for 4 kDa FITC-dextran (FD-4). The same was true in camptothecin-exposed monolayers, where camptothecin was used for apoptosis induction

Intestinal Microbiota Shifts towards Elevated Commensal Escherichia coli Loads Abrogate Colonization Resistance against Campylobacter jejuni in Mice

Background: The zoonotic pathogen Campylobacter jejuni is a leading cause of bacterial foodborne enterocolitis in humans worldwide. The understanding of immunopathology underlying human campylobacteriosis is hampered by the fact that mice display strong colonization resistance against the pathogen due to their host specific gut microbiota composition. Methodology/Principal Findings: Since the microbiota composition changes significantly during intestinal inflammation we dissected factors contributing to colonization resistance against C. jejuni in murine ileitis, colitis and in infant mice. In contrast to healthy animals C. jejuni could stably colonize mice suffering from intestinal inflammation. Strikingly, in mice with Toxoplasma gondii-induced acute ileitis, C. jejuni disseminated to mesenteric lymphnodes, spleen, liver, kidney, and blood. In infant mice C. jejuni infection induced enterocolitis. Mice suffering from intestinal inflammation and C. jejuni susceptible infant mice displayed characteristical microbiota shifts dominated by increased numbers of commensal Escherichia coli. To further dissect the pivotal role of those distinct microbiota shifts in abrogating colonization resistance, we investigated C. jejuni infection in healthy adult mice in which the microbiota was artificially modified by feeding live commensal E. coli. Strikingly, in animals harboring supra-physiological intestinal E. coli loads, colonization resistance was significantly diminished and C. jejuni infection induced enterocolitis mimicking key features of human campylobacteriosis. Conclusion/Significance: Murine colonization resistance against C. jejuni is abrogated by changes in the microbiot

Ultra-Fast and Sensitive Detection of Non-Typhoidal Salmonella Using Microwave-Accelerated Metal-Enhanced Fluorescence (“MAMEF”)

Certain serovars of Salmonella enterica subsp. enterica cause invasive disease (e.g., enteric fever, bacteremia, septicemia, meningitis, etc.) in humans and constitute a global public health problem. A rapid, sensitive diagnostic test is needed to allow prompt initiation of therapy in individual patients and for measuring disease burden at the population level. An innovative and promising new rapid diagnostic technique is microwave-accelerated metal-enhanced fluorescence (MAMEF). We have adapted this assay platform to detect the chromosomal oriC locus common to all Salmonella enterica subsp. enterica serovars. We have shown efficient lysis of biologically relevant concentrations of Salmonella spp. suspended in bacteriological media using microwave-induced lysis. Following lysis and DNA release, as little as 1 CFU of Salmonella in 1 ml of medium can be detected in <30 seconds. Furthermore the assay is sensitive and specific: it can detect oriC from Salmonella serovars Typhi, Paratyphi A, Paratyphi B, Paratyphi C, Typhimurium, Enteritidis and Choleraesuis but does not detect Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Streptococcus pneumoniae, Haemophilus influenzae or Acinetobacter baumanii. We have also performed preliminary experiments using a synthetic Salmonella oriC oligonucleotide suspended in whole human blood and observed rapid detection when the sample was diluted 1∶1 with PBS. These pre-clinical data encourage progress to the next step to detect Salmonella in blood (and other ordinarily sterile, clinically relevant body fluids)

Delineation of the Innate and Adaptive T-Cell Immune Outcome in the Human Host in Response to Campylobacter jejuni Infection

BACKGROUND: Campylobacter jejuni is the most prevalent cause of bacterial gastroenteritis worldwide. Despite the significant health burden this infection presents, molecular understanding of C. jejuni-mediated disease pathogenesis remains poorly defined. Here, we report the characterisation of the early, innate immune response to C. jejuni using an ex-vivo human gut model of infection. Secondly, impact of bacterial-driven dendritic cell activation on T-cell mediated immunity was also sought. METHODOLOGY: Healthy, control paediatric terminal ileum or colonic biopsy tissue was infected with C. jejuni for 8-12 hours. Bacterial colonisation was followed by confocal microscopy and mucosal innate immune responses measured by ELISA. Marked induction of IFNγ with modest increase in IL-22 and IL-17A was noted. Increased mucosal IL-12, IL-23, IL-1β and IL-6 were indicative of a cytokine milieu that may modulate subsequent T-cell mediated immunity. C. jejuni-driven human monocyte-derived dendritic cell activation was followed by analyses of T cell immune responses utilising flow cytometry and ELISA. Significant increase in Th-17, Th-1 and Th-17/Th-1 double-positive cells and corresponding cytokines was observed. The ability of IFNγ, IL-22 and IL-17 cytokines to exert host defence via modulation of C. jejuni adhesion and invasion to intestinal epithelia was measured by standard gentamicin protection assay. CONCLUSIONS: Both innate and adaptive T cell-immunity to C. jejuni infection led to the release of IFNγ, IL-22 and IL-17A; suggesting a critical role for this cytokine triad in establishing host anti-microbial immunity during the acute and effectors phase of infection. In addition, to their known anti-microbial functions; IL-17A and IL-17F reduced the number of intracellular C. jejuni in intestinal epithelia, highlighting a novel aspect of how IL-17 family members may contribute to protective immunity against C. jejuni

R-Allyl Nickel(II) Complexes with Chelating N-Heterocyclic Carbenes: Synthesis, Structural Characterization, and Catalytic Activity

The N-heterocyclic carbene (NHC) nickel complexes [(L)Ni(NHC)][BArF4] (ArF = 3,5-bis(trifluoromethyl)- phenyl; L = allyl (1), methylallyl (2); NHC = 1-(2-picolyl)-3-methylimidazol-2-ylidene (a), 1-(2-picolyl)-3-isopropylimidazol-2-ylidene (b), 1-(2-picolyl)-3-n-butylimidazol-2-ylidene (c), 1-(2-picolyl)-3-phenylimidazol-2-ylidene (d), 1-(2-picolyl)-3- methylbenzoimidazol-2-ylidene (e), 1-(2-picolyl)-4,5-dichloro-3-methylimidazol-2-ylidene (f)) have been obtained in high yields and characterized by NMR spectroscopy. Furthermore, 1d was unambiguously characterized by single-crystal X-ray crystallography. Complexes 1a−f/2a−f have shown catalytic activity toward dimerization and hydrosilylation of styrenes. In particular, 1a proved to be the most efficient catalyst in the dimerization of styrene derivatives in the absence of cocatalyst. Also, complexes 1a,d showed high selectivity and moderate to good yields in hydrosilylation reactions

Screening and Treatment of Vitamin D Deficiency on Hospital Admission: Is There a Benefit for Medical Inpatients?

BACKGROUND: Whether screening and treatment of vitamin D deficiency improves clinical outcomes in medical inpatients remains unclear. We performed a systematic search and summarized the evidence from observational and randomized, controlled studies (RCTs) on the influence of vitamin D deficiency and its treatment on patient outcomes. METHODS: The MEDLINE and EMBASE databases were searched in January 2015 using the terms "vitamin D deficiency," "vitamin D," "mortality," "inpatient," "length of stay," "hospitalization," "accidental falls," "quality of life," "activities of daily living," and "intensive care units." RESULTS: Of 239 potential studies, 29 observational studies and 5 RCTs were included. Observational studies revealed an association between vitamin D deficiency and adverse patient outcomes, such as mortality, higher incidence and severity of infections, and increased duration of hospital stay, in the inpatient and geriatric patient population. The RCT data, however, are inconclusive regarding beneficial effects of vitamin D supplementation for reduction of mortality and length of hospital stay, as well as fall prevention. CONCLUSIONS: Despite evidence of associations in observational studies, high-quality evidence from interventional trials on the benefits of vitamin D supplementation in inpatients is currently lacking. On the basis of the available evidence, general vitamin D screening and supplementation for the medical inpatient population in an acute care setting cannot be recommended

Cefuroxime compared to piperacillin/tazobactam as empirical treatment of Escherichia coli bacteremia in a low Extended-spectrum beta-lactamase (ESBL) prevalence cohort

Sara Th&oslash;nnings,1,2 Filip Jans&aring;ker,1,3 Kim Oren Gradel,4,5 Bjarne Styrishave,2 Jenny Dahl Knudsen11Department of Clinical Microbiology, Copenhagen University Hospital, Hvidovre, Denmark; 2Toxicology Laboratory, Analytical BioSciences, Department of Pharmacy, University of Copenhagen, Copenhagen, Denmark; 3Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark; 4Center for Clinical Epidemiology, Odense University Hospital, Odense, Denmark; 5Research Unit of Clinical Epidemiology, Institute of Clinical Research, University of Southern Denmark, Odense, DenmarkObjectives: On January 18, 2010, a part of the capital region of Denmark shifted the empirical treatment of febrile conditions from cefuroxime to piperacillin/tazobactam. We compare empirical treatment with piperacillin/tazobactam versus cefuroxime for Escherichia coli bacteremia with regard to 14 days mortality, in a low prevalence cohort of Extended-spectrum beta-lactamase-producing E. coli.Methods: From January 18, 2010 to December 31, 2012, we conducted a retrospective cohort study including patients with E. coli bacteremia from six university hospitals in Copenhagen, Denmark. Clinical and laboratory information was obtained from a bacteremia research database, including information on comorbidity, and we used Cox proportional hazard analysis to asses all-cause 14 days mortality.Results: A total of 568 patients receiving either cefuroxime (n=377) or piperacillin/tazobactam (n=191) as empirical therapy were included. In the Cox proportional hazard model, cefuroxime treatment was significantly associated with death (mortality rate ratio 3.95, CI 1.12&ndash;13.90). Other variables associated with death were health care related infection (MRR 3.20, CI 1.67&ndash;6.15), hospital-acquired infection (MRR 2,17, CI 1.02&ndash;4.62), admission at intensive care unit (MRR 20.45, 5.31&ndash;78.82), and combination therapy with ciprofloxacin (MRR 2.14, CI 0.98&ndash;4.68).Conclusion: Empiric cefuroxime treatment of E. coli bacteremia was significantly associated with higher 14 days mortality in comparison with piperacillin/tazobactam.Keywords: piperacillin/tazobactam, cefuroxime, E. coli, bacteremia, mortalit