440 research outputs found

    Down Selection of Polymerized Bovine Hemoglobins for Use as Oxygen Releasing Therapeutics in a Guinea Pig Model

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    Editor's Highlight: The development of hemoglobin-based oxygen carriers (HBOCs) as a replacement for whole-blood transfusions has been impeded by their systemic toxicity. This paper presents data from a series of HBOCs, demonstrating one candidate that meets predetermined safety criteria. This approach may allow the development of an acceptable blood substitute for human us

    Accepting higher morbidity in exchange for sacrificing fewer animals in studies developing novel infection-control strategies.

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    Preventing bacterial infections from becoming the leading cause of death by the year 2050 requires the development of novel, infection-control strategies, building heavily on biomaterials science, including nanotechnology. Pre-clinical (animal) studies are indispensable for this development. Often, animal infection outcomes bear little relation to human clinical outcome. Here, we review conclusions from pathogen-inoculum dose-finding pilot studies for evaluation of novel infection-control strategies in murine models. Pathogen-inoculum doses are generally preferred that produce the largest differences in quantitative infection outcome parameters between a control and an experimental group, without death or termination of animals due to having reached an inhumane end-point during the study. However, animal death may represent a better end-point for evaluation than large differences in outcome parameters or number of days over which infection persists. The clinical relevance of lower pre-clinical outcomes, such as bioluminescence, colony forming units (CFUs) retrieved or more rapid clearance of infection is unknown, as most animals cure infection without intervention, depending on pathogen-species and pathogen-inoculum dose administered. In human clinical practice, patients suffering from infection present to hospital emergency wards, frequently in life-threatening conditions. Animal infection-models should therefore use prevention of death and recurrence of infection as primary efficacy targets to be addressed by novel strategies. To compensate for increased animal morbidity and mortality, animal experiments should solely be conducted for pre-clinical proof of principle and safety. With the advent of sophisticated in vitro models, we advocate limiting use of animal models when exploring pathogenesis or infection mechanisms

    Hemophagocytic syndrome caused by primary herpes simplex virus 1 infection: report of a first case

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    Introduction: Hemophagocytic syndrome represents a severe hyperinflammatory condition by activated macrophages. Leading viral triggering agents are Epstein-Barr virus (EBV), cytomegalovirus (CMV), and adenovirus. Materials and methods: We present a patient with Wegener's granulomatosis on azathioprine and prednisone medication, who developed a life-threatening hemophagocytic syndrome. Positive plasma polymerase chain reaction (PCR) with negative serology revealed a primary, disseminated infection with herpes simplex virus-1 as the triggering pathogen. After treatment with acyclovir, high-dose steroids, immunoglobulins, and etoposide, the patient recovered. Conclusion: Early diagnosis of potentially underlying infections of hemophagocytic syndrome influences the therapeutic approach. It is important to consider a variety of infectious agents, particularly in immunosuppressed individuals. The reported case emphasizes the importance of screening for herpes simplex virus

    ICDs at higher age and clinical risk factors

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    Background The implantable cardioverter defibrillator (ICD) is effective in preventing sudden cardiac death. However, in elderly patients (aged 75 years or older) the role of ICDs is still not well-defined and controversial. Methods We retrospectively analysed all clinical and survival data of all ICD patients who were ≥75 years at the date of implantation in the Erasmus MC, Rotterdam, the Netherlands and the University Hospital, Basel, Switzerland. Kaplan- Meier survival analysis was performed, and mortality predictors were identified. Mortality of the cohort was compared with a random sample of patients aged 60-70 years originating from the same database and to an age- and sex-matched cohort of Dutch persons. Results The study cohort consisted of 179 patients aged 75 years or older who were implanted between February 1999 and July 2008. The median follow-up time was 2.0 (IQR 2.8) years. Survival rates after 1, 2 and 3 years were 87, 82, 75 %, respectively. Survival was similar for primary and secondary prevention. Mortality in this study population could be predicted by combining four clinical risk factors: QRS duration >120 ms, NYHA class > II, renal failure and atrial fibrillation (AF). Survival was worse compared with the group of ICD patients aged 60-70 years and to the age- and sex-matched group of elderly persons. However, survival was not significantly worse when comparing elderly ICD patients without additional risk factors to the general population. Conclusions Elderly patients still have an acceptable survival probability independent of prevention indication, certainly if there are no additional clinical risk factors. The presence or absence of additional clinical risk factors should be taken into account when making the decision for imp

    Haptoglobin preserves the CD163 hemoglobin scavenger pathway by shielding hemoglobin from peroxidative modification

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    Detoxification and clearance of extracellular hemoglobin (Hb) have been attributed to its removal by the CD163 scavenger receptor pathway. However, even low-level hydrogen peroxide (H(2)O(2)) exposure irreversibly modifies Hb and severely impairs Hb endocytosis by CD163. We show here that when Hb is bound to the high-affinity Hb scavenger protein haptoglobin (Hp), the complex protects Hb from structural modification by preventing alpha-globin cross-links and oxidations of amino acids in critical regions of the beta-globin chain (eg, Trp15, Cys93, and Cys112). As a result of this structural stabilization, H(2)O(2)-exposed Hb-Hp binds to CD163 with the same affinity as nonoxidized complex. Endocytosis and lysosomal translocation of oxidized Hb-Hp by CD163-expressing cells were found to be as efficient as with nonoxidized complex. Hp complex formation did not alter Hb's ability to consume added H(2)O(2) by redox cycling, suggesting that within the complex the oxidative radical burden is shifted to Hp. We provide structural and functional evidence that Hp protects Hb when oxidatively challenged with H(2)O(2) preserving CD163-mediated Hb clearance under oxidative stress conditions. In addition, our data provide in vivo evidence that unbound Hb is oxidatively modified within extravascular compartments consistent with our in vitro findings

    S-system theory applied to array-based GNSS ionospheric sensing

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    The GPS carrier-phase and code data have proven to be valuable sources of measuring the Earth’s ionospheric total electron content (TEC). With the development of new GNSSs with multi frequency data, many more ionosphere-sensing combinations of different precision can be formed as input of ionospheric modelling. We present the general way of interpreting such combinations through an application of S-system theory and address how their precision propagates into that of the unbiased TEC solution. Presenting the data relevant to TEC determination, we propose the usage of an array of GNSS antennas to improve the TEC precision and to expedite the rather long observational time-span required for high-precision TEC determination
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