Molecular imaging is an emerging technology that enables the noninvasive visualization, characterization, and quantification of molecular events within living subjects. Positron emission tomography (PET) is a clinically available molecular imaging tool with significant potential to study pathogenesis of infections in humans., Molecular imaging is an emerging technology that enables the noninvasive visualization, characterization, and quantification of molecular events within living subjects. Positron emission tomography (PET) is a clinically available molecular imaging tool with significant potential to study pathogenesis of infections in humans. PET enables dynamic assessment of infectious processes within the same subject with high temporal and spatial resolution and obviates the need for invasive tissue sampling, which is difficult in patients and generally limited to a single time point, even in animal models. This review presents current state-of-the-art concepts on the application of molecular imaging for infectious diseases and details how PET imaging can facilitate novel insights into infectious processes, ongoing development of pathogen-specific imaging, and simultaneous in situ measurements of intralesional antimicrobial pharmacokinetics in multiple compartments, including privileged sites. Finally, the potential clinical applications of this promising technology are also discussed.

Diabetic foot infections (DFIs) are a common, complex, and costly medical problem with increasing prevalence. Diagnosing DFIs is a clinical challenge due to the poor specificity of the available methods to accurately determine the presence of infection in these patients. However, failure to perform an opportune diagnosis and provide optimal antibiotic therapy can lead to higher morbidity for the patient, unnecessary amputations, and increased healthcare costs. Novel developments in bacteria-specific molecular imaging can provide a non-invasive assessment of the infection site to support diagnosis, determine the extension and location of the infection, guide the selection of antibiotics, and monitor the response to treatment. This is a review of recent research in molecular imaging of infections in the context of DFI. We summarize different clinical and preclinical methods and the translational implications aimed to improve the care of patients with DFI.

Background:Staphylococcus aureus (SA) is a major cause of bacteremia in children. Methicillin-resistant SA (MRSA) is considered a public health threat; however, the differences in the prognosis of children with methicillin-susceptible SA (MSSA) versus MRSA bacteremia are not well defined.Methods:Dat

Aim The use of anaerobic blood cultures in infants suspected of bacteraemia is controversial. Our children's hospital uses both aerobic and anaerobic media, regardless of the risk of anaerobic infection, and the aim of this study was to re-evaluate the use of anaerobic cultures in infants. Methods We collected retrospective data from 2002 to 2016 on all blood cultures taken from infants younger than 90 days in the Hadassah-Hebrew University Medical Centre, Jerusalem, Israel. The incidence and characteristics of infants with positive anaerobic blood cultures were assessed. Results During the study period, 51 035 blood cultures were drawn from 44 304 infants. Of these, 1496 (2.9%) were clinically significant positive cultures. Pathogenic obligatory anaerobic bacteraemia was extremely rare, with only 37 positive cultures (0.07%) from all of the cultures drawn. No specific risk factors for obligatory anaerobic bacteraemia could be defined, but as many as 174 (11.6%) clinically significant isolates were only detected in the anaerobic culture bottle. Conclusion True anaerobic bacteraemia was extremely rare in neonates. Nevertheless, using anaerobic culture media may increase the overall yield of bacterial culture growth by isolating anaerobic-facultative bacteria. This should be weighed up against increasing the volume of blood used for the aerobic culture.

Background:Anaerobic bacteremia is rare in children and current recommendations advocate against the routine use of anaerobic cultures in children. However, the incidence of anaerobic bacteremia and the utility of anaerobic blood cultures in children have not been assessed in recent years. Our pedia

Objectives Neonatal antiphospholipid syndrome (APS) is rare and only few cases have been reported, most of them describing trans-placental passage of penetrable maternal antibodies. The current article aims at defining the clinical and biochemical features of the de novo occurrence of neonatal APS and considerations for long-term treatment. Methods We present a case and review the medical literature using PubMed. Results Including the current report, there are 11 reports of de novo neonatal APS. These include 8 cases of acute ischemic stroke, 2 of venous thrombosis, and 1 of mixed arterial and venous thrombosis. All cases had an additional thrombotic risk factor, either inherited or acquired. Negative maternal history together with low clinical suspicion led to late diagnosis in most cases. In all cases aPL antibodies persisted in the serum throughout the follow-up period. No recurrence of thrombotic events was reported in patients under long-term anticoagulation with either low-molecular-weight heparin (LMWH) or aspirin. There is 1 report of recurrent thrombosis where the patient did not receive anticoagulation. In this case diagnosis was made only retrospectively after recurrence. Conclusions We recommend that de novo APS be considered in all cases of unexplained neonatal thrombosis aiming at early diagnosis and implementation of long-term anticoagulation to prevent recurrent thrombotic events.

Rationale Rescuing adverse myocardial remodeling is an unmet clinical goal and, correspondingly, pharmacological means for its intended reversal are urgently needed. Objectives To harness a newly-developed experimental model recapitulating progressive heart failure development for the discovery of new drugs capable of reversing adverse remodeling. Methods and Results A VEGF-based conditional transgenic system was employed in which an induced perfusion deficit and a resultant compromised cardiac function lead to progressive remodeling and eventually heart failure. Ability of candidate drugs administered at sequential remodeling stages to reverse hypertrophy, enlarged LV size and improve cardiac function was monitored. Arguing for clinical relevance of the experimental system, clinically-used drugs operating on the Renin-Angiotensin-Aldosterone-System (RAAS), namely, the ACE inhibitor Enalapril and the direct renin inhibitor Aliskerin fully reversed remodeling. Remodeling reversal by these drugs was not accompanied by neovascularization and reached a point-of-no-return. Similarly, the PPARγ agonist Pioglitazone was proven capable of reversing all aspects of cardiac remodeling without affecting the vasculature. Extending the arsenal of remodeling-reversing drugs to pathways other than RAAS, a specific inhibitor of 11β-hydroxy-steroid dehydrogenase type 1 (11β HSD1), a key enzyme required for generating active glucocorticoids, fully rescued myocardial hypertrophy. This was associated with mitigating the hypertrophy-associated gene signature, including reversing the myosin heavy chain isoform switch but in a pattern distinguishable from that associated with neovascularization-induced reversal. Conclusions A system was developed suitable for identifying novel remodeling-reversing drugs operating in different pathways and for gaining insights into their mechanisms of action, exemplified here by uncoupling their vascular affects.

Objective—Proangiogenic therapy is a promising avenue for the treatment for chronic heart failure and a potentially powerful modality for reversing adverse cardiac remodeling. There is a concern, however, that adverse remodeling might enter an irreversible stage, and become refractory to treatments. The present study aims to determine whether neovascularization therapy is feasible at end stage heart failure and its capacity to reverse adverse cardiac remodeling during progressive disease stages.Methods and Results—Using a conditional transgenic mouse system for generating escalating levels of myocardium-specific vascular deficit and resultant stepwise development of heart remodeling, we show that left ventricular dilatation and fibrosis precede ventricular hypertrophy, but that interstitial fibrosis is progressive and eventually results in heart failure. Vascular endothelial growth factor–mediated neovascularization was efficient even at the end stage of disease, and rescued compromised contractile function. Remarkably, remodeling was also fully reversed by neovascularization during early and late stages. Adverse remodeling could not be rescued, however, at the end stage of the disease, thus defining a point of no return and indentifying a critical level of fibrosis as the key determinant to be considered in intended reversal.Conclusion—The study supports the notion of a restricted golden time for remodeling reversal but not for vascular endothelial growth factor–induced neovascularization, which is feasible even during advanced disease stages.

A transgenic mouse model for conditional induction of long-term hibernation via myocardium-specific expression of a VEGF-sequestering soluble receptor allowed the dissection of the hibernation process into an initiation and a maintenance phase. The hypoxic initiation phase was characterized by peak levels of K(ATP) channel and glucose transporter 1 (GLUT1) expression. Glibenclamide, an inhibitor of K(ATP) channels, blocked GLUT1 induction. In the maintenance phase, tissue hypoxia and GLUT1 expression were reduced. Thus, we employed a combined “-omics” approach to resolve this cardioprotective adaptation process. Unguided bioinformatics analysis on the transcriptomic, proteomic and metabolomic datasets confirmed that anaerobic glycolysis was affected and that the observed enzymatic changes in cardiac metabolism were directly linked to hypoxia-inducible factor (HIF)-1 activation. Although metabolite concentrations were kept relatively constant, the combination of the proteomic and transcriptomic dataset improved the statistical confidence of the pathway analysis by 2 orders of magnitude. Importantly, proteomics revealed a reduced phosphorylation state of myosin light chain 2 and cardiac troponin I within the contractile apparatus of hibernating hearts in the absence of changes in protein abundance. Our study demonstrates how combining different “-omics” datasets aids in the identification of key biological pathways: chronic hypoxia resulted in a pronounced adaptive response at the transcript and the protein level to keep metabolite levels steady. This preservation of metabolic homeostasis is likely to contribute to the long-term survival of the hibernating myocardium.

A key energy-saving adaptation to chronic hypoxia that enables cardiomyocytes to withstand severe ischemic insults is hibernation, i.e., a reversible arrest of contractile function. Whereas hibernating cardiomyocytes represent the critical reserve of dysfunctional cells that can be potentially rescued, a lack of a suitable animal model has hampered insights on this medically important condition. We developed a transgenic mouse system for conditional induction of long-term hibernation and a system to rescue hibernating cardiomyocytes at will. Via myocardium-specific induction (and, in turn, deinduction) of a VEGF-sequestering soluble receptor, we show that VEGF is indispensable for adjusting the coronary vasculature to match increased oxygen consumption and exploit this finding to generate a hypoperfused heart. Importantly, ensuing ischemia is tunable to a level at which large cohorts of cardiomyocytes are driven to enter a hibernation mode, without cardiac cell death. Relieving the VEGF blockade even months later resulted in rapid revascularization and full recovery of contractile function. Furthermore, we show that left ventricular remodeling associated with hibernation is also fully reversible. The unique opportunity to uncouple hibernation from other ischemic heart phenotypes (e.g., infarction) was used to determine the genetic program of hibernation; uncovering hypoxia-inducible factor target genes associated with metabolic adjustments and induced expression of several cardioprotective genes. Autophagy, specifically self-digestion of mitochondria, was identified as a key prosurvival mechanism in hibernating cardiomyocytes. This system may lend itself for examining the potential utility of treatments to rescue dysfunctional cardiomyocytes and reverse maladaptive remodeling.

Nud1p, a protein homologous to the mammalian centrosome and midbody component Centriolin, is a component of the budding yeast spindle pole body (SPB), with roles in anchorage of microtubules and regulation of the mitotic exit network during vegetative growth. Here we analyze the function of Nud1p during yeast meiosis. We find that a nud1-2 temperature-sensitive mutant has two meiosis-related defects that reflect genetically distinct functions of Nud1p. First, the mutation affects spore formation due to its late function during spore maturation. Second, and most important, the mutant loses its ability to distinguish between the ages of the four spindle pole bodies, which normally determine which SPB would be preferentially included in the mature spores. This affects the regulation of genome inheritance in starved meiotic cells and leads to the formation of random dyads instead of non-sister dyads under these conditions. Both functions of Nud1p are connected to the ability of Spc72p to bind to the outer plaque and half-bridge (via Kar1p) of the SPB.