Introduction
Bacterial infections are a major problem in medicine, and the rapid and accurate detection of such infections is essential for optimal patient outcome. Bacterial infections can be ...diagnosed by nuclear imaging, but most currently available modalities are unable to discriminate infection from sterile inflammation. Bacteria-targeted positron emission tomography (PET) tracers have the potential to overcome this hurdle. In the present study, we compared three
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F-labelled PET tracers based on the clinically applied antibiotic vancomycin for targeted imaging of Gram-positive bacteria.
Methods
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FFB-NHS and
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FBODIPY-FL-NHS were conjugated to vancomycin. The resulting conjugates, together with our previously developed
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FPQ-VE1-vancomycin, were tested for stability, lipophilicity, selective binding to Gram-positive bacteria, antimicrobial activity and biodistribution. For the first time, the pharmacokinetic properties of all three tracers were compared in healthy animals to identify potential binding sites.
Results
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FFB-vancomycin,
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FBODIPY-FL-vancomycin, and
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FPQ-VE1-vancomycin were successfully synthesized with radiochemical yields of 11.7%, 2.6%, and 0.8%, respectively.
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FFB-vancomycin exhibited poor in vitro and in vivo stability and, accordingly, no bacterial binding. In contrast,
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FBODIPY-FL-vancomycin and
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FPQ-VE1-vancomycin showed strong and specific binding to Gram-positive bacteria, including methicillin-resistant
Staphylococcus aureus
(MRSA), which was outcompeted by unlabeled vancomycin only at concentrations exceeding clinically relevant vancomycin blood levels. Biodistribution showed renal clearance of
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FPQ-VE1-vancomycin and
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FBODIPY-FL-vancomycin with low non-specific accumulation in muscles, fat and bones.
Conclusion
Here we present the synthesis and first evaluation of the vancomycin-based PET tracers
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FBODIPY-FL-vancomycin and
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FPQ-VE1-vancomycin for image-guided detection of Gram-positive bacteria. Our study paves the way towards real-time bacteria-targeted diagnosis of soft tissue and implant-associated infections that are oftentimes caused by Gram-positive bacteria, even after prophylactic treatment with vancomycin.
Abstract
It is important to evaluate how residents, their significant others, and professional caregivers experience life in a nursing home to improve quality of care based on their needs and wishes. ...Narratives are a promising method to assess this experienced quality of care as they enable a rich understanding, reflection, and learning. In the Netherlands, narratives are becoming a more substantial element within the quality improvement cycle of nursing homes. The added value of using narrative methods is that they provide space to share experiences, identify dilemmas in care provision, and provide rich information for quality improvements. The use of narratives in practice, however, can also be challenging as this requires effective guidance on how to learn from this data, incorporation of the narrative method in the organizational structure, and national recognition that narrative data can also be used for accountability. In this article, 5 Dutch research institutes reflect on the importance, value, and challenges of using narratives in nursing homes.
The apparent discrepancy between spectroscopic factors obtained in (e,e′p) and (d,
3He) experiments is investigated. This is performed first for
48Ca(e,e′p) and
48Ca(d,
3He) experiments and then for ...other nuclei. It is shown that the discrepancy disappears if the (d,
3He) experiments are reanalyzed with a nonlocal finite-range DWBA analysis with a bound-state wave function that is obtained from (e,e′p) experiments.
Cross sections for semi-inclusive electroproduction of charged pions (π±) from both proton and deuteron targets were measured for 0.2<x<0.5, 2<Q2<4 GeV2, 0.3<z<1, and Pt2<0.2 GeV2. For Pt<0.1 GeV, we ...find the azimuthal dependence to be small, as expected theoretically. For both π+ and π−, the Pt dependence from the deuteron is found to be slightly weaker than from the proton. In the context of a simple model, this implies that the initial transverse momenta width of d quarks is larger than for u quarks and, contrary to expectations, the transverse momentum width of the favored fragmentation function is larger than the unfavored one.
Bacterial pneumonia remains associated with high morbidity and mortality. The gram-positive pathogen Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. Lipoteichoic ...acid (LTA) is an important proinflammatory component of the gram-positive bacterial cell wall. R-roscovitine, a purine analog, is a potent cyclin-dependent kinase (CDK)-1, -2, -5 and -7 inhibitor that has the ability to inhibit the cell cycle and to induce polymorphonuclear cell (PMN) apoptosis. We sought to investigate the effect of R-roscovitine on LTA-induced activation of cell lines with relevance for lung inflammation in vitro and on lung inflammation elicited by either LTA or viable S. pneumoniae in vivo. In vitro R-roscovitine enhanced apoptosis in PMNs and reduced tumor necrosis factor (TNF)-α and keratinocyte chemoattractant (KC) production in MH-S (alveolar macrophage) and MLE-12/MLE-15 (respiratory epithelial) cell lines. In vivo R-roscovitine treatment reduced PMN numbers in bronchoalveolar lavage fluid during LTA-induced lung inflammation; this effect was reversed by inhibiting apoptosis. Postponed treatment with R-roscovitine (24 and 72 h) diminished PMN numbers in lung tissue during gram-positive pneumonia; this step was associated with a transient increase in pulmonary bacterial loads. R-roscovitine inhibits proinflammatory responses induced by the gram-positive stimuli LTA and S. pneumoniae. R-roscovitine reduces PMN numbers in lungs upon LTA administration by enhancing apoptosis. The reduction in PMN numbers caused by R-roscovitine during S. pneumoniae pneumonia may hamper antibacterial defense.
Background. Pneumonia is frequently caused by gram-negative pathogens, among which Klebsiella pneumoniae prominently features. Recognition of pathogen-associated molecular patterns by Toll-like ...receptors (TLRs) is important fpr an appropriate immune response during infection. TLR signaling can proceed via 2 distinct routes that are dependent on the adaptor proteins Myeloid differentiation primary response gene (88) (MyD88) and TIR-domaincontaining adaptor-inducing interferon-β (TRIF). The aim of the study was to determine the relative contribution of MyD88 and TRIF signaling in resident and hematopoietic cells to host defense during pneumonia. Methods. Bone marrow chimeras of MyD88 deficient/wild type and TRIF mutant/wild type mice were created and infected with K. pneumoniae via the airways. Results. MyD88 in both resident and hematopoietic cells contributed to survival and antibacterial defense in late-stage infection, whereas only TRIF in hematopoietic cells was protective. On the other hand, resident MyD88 and hematopoietic TRIF contributed to distant cellular injury. Resident MyD88 was pivotal for early chemokine release and neutrophil recruitment in the bronchoalveolar space. Conclusions. MyD88-and TRIF-dependent signaling has a differential contribution to host defense in different cell types that changes from early-to late-stage gram-negative pneumonia.
A measurement of beam-helicity asymmetries for single-hadron production in deep-inelastic scattering is presented. Data from the scattering of 27.6 GeV electrons and positrons off gaseous hydrogen ...and deuterium targets were collected by the HERMES experiment. The asymmetries are presented separately as a function of the Bjorken scaling variable, the hadron transverse momentum, and the fractional energy for charged pions and kaons as well as for protons and anti-protons. These asymmetries are also presented as a function of the three aforementioned kinematic variables simultaneously.
Background. Guidelines for treatment of human immunodeficiency virus type 1 (HIV-1) infection consider lamivudine and emtricitabine to be interchangeable components in first-line combination ...antiretroviral therapy (cART). The evidence for their clinical equivalence in cART is inconsistent. The primary aim of this study was to evaluate the virological responses to lamivudine and emtricitabine in recommended cART. Methods. This was an observational study using data from the AIDS Therapy Evaluation in the Netherlands (ATHENA) nationwide HIV cohort. The virological responses to lamivudine and emtricitabine were compared by multivariable adjusted logistic regression and Cox proportional hazard models. Sensitivity analyses included propensity score-adjusted models. Results. Therapy-naive HIV-1–infected patients without baseline resistance (N = 4740) initiated lamivudine or emtricitabine with efavirenz/tenofovir or nevirapine/tenofovir. The use of lamivudine was associated with more virological failure at week 48 compared to emtricitabine with efavirenz/tenofovir (10.8% vs 3.6%; adjusted odds ratio AOR, 1.78; 95% confidence interval CI, 1.11–2.84) and nevirapine/tenofovir (27% vs 11%; AOR, 2.09; 95% CI, 1.25–3.52) in on-treatment analysis. Propensity score-adjusted models and intent-to-treat sensitivity analyses gave comparable results. The adjusted hazard ratio of virological failure at week 240 using lamivudine instead of emtricitabine was 2.35 (95% CI, 1.61–3.42) with efavirenz and 2.01 (95% CI, 1.36–2.98) with nevirapine. The inclusion of lamivudine or emtricitabine in cART did not influence the time to virological suppression within 48 weeks or the probability of virological rebound after successful virological suppression. Conclusions. The use of emtricitabine instead of lamivudine as part of cART was associated with better virological responses. These findings are relevant for settings with extensive use of lamivudine and for settings where generic lamivudine will be available.
Backward-angle meson electroproduction above the resonance region, which was previously ignored, is anticipated to offer unique access to the three quark plus sea component of the nucleon wave ...function. In this Letter, we present the first complete separation of the four electromagnetic structure functions above the resonance region in exclusive ω electroproduction off the proton, ep→e′pω, at central Q2 values of 1.60, 2.45 GeV2, at W=2.21 GeV. The results of our pioneering −u≈−umin study demonstrate the existence of a unanticipated backward-angle cross section peak and the feasibility of full L/T/LT/TT separations in this never explored kinematic territory. At Q2=2.45 GeV2, the observed dominance of σT over σL, is qualitatively consistent with the collinear QCD description in the near-backward regime, in which the scattering amplitude factorizes into a hard subprocess amplitude and baryon to meson transition distribution amplitudes: universal nonperturbative objects only accessible through backward-angle kinematics.
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