Stellenwert von (1-3)-β-D-Glucan zur Vorhersage einer invasiven Pilzinfektion und Assoziation mit dem Schweregrad der Organdysfunktion bei kritisch kranken Patienten mit und ohne Sepsis

Die Diagnostik invasiver fungaler Infektionen (IFI) bei Patienten auf Intensivstation ist schwierig. Wichtig ist aber eine frühzeitige Diagnose zur raschen Therapieeinleitung, um die Mortalität zu senken. Kulturelle Verfahren sind zeitaufwendig und besitzen eine niedrige Sensitivität. Nichtkulturelle Verfahren sind als alleiniges Diagnostikum noch nicht in der Praxis etabliert. Diese Arbeit analysiert prospektiv monozentrisch den Stellenwert von (1-3)-β-D-Glucan (BDG) für den Nachweis einer IFI und stellt Assoziationen mit dem Schweregrad der Organdysfunktion bei kritisch kranken Patienten her. In einem Dreijahres-Zeitraum wurde BDG im Serum von 57 Patienten mit schwerer Sepsis oder septischem Schock (Gruppe 1) und von 61 Patienten nach kardiochirurgischer Operation (Gruppe 2) über sieben Tage und dann wöchentlich bis Tag 28 bestimmt. Die Messung erfolgte kolorimetrisch (MARUHA®-Testkit, Firma WAKO). Die Ergebnisse wurden mit dem Goldstandard (kultureller Candida-Nachweis) verglichen. In Gruppe 1 lagen die BDG-Werte in der ersten Woche um den Cut-Off-Wert von 11 pg/ml, während Patienten der Gruppe 2 über fünf Tage signifikant höhere BDG-Werte aufwiesen, ohne dass jedoch eine IFI vorlag. Bei neun Patienten in der Gruppe 1 war eine IFI nachweisbar. Sensitivität und Spezifität von BDG für den IFI- Nachweis zum Einschlusszeitpunkt betrugen 67 bzw. 50 %, der positive und negative prädiktive Wert 24 bzw. 88 %. Folglich schließt ein negativer BDG-Wert eine IFI nahezu aus. Die BDG-Spiegel über 28 Tage zeigten weder die Schwere der Infektion noch das Outcome an. BDG-Werte von überlebenden und verstorbenen Patienten waren nicht signifikant unterschiedlich. Gesamt-SOFA-Score und Subscores korrelierten nur schwach mit den BDGSpiegeln (Korrelationskoeffizient 0,22). Der Blutkontakt zu Fremdoberflächen wie HLM kann zu falsch hohen BDG-Werten führen können

A Computational Systems Biology Software Platform for Multiscale Modeling and Simulation: Integrating Whole-Body Physiology, Disease Biology, and Molecular Reaction Networks

Today, in silico studies and trial simulations already complement experimental approaches in pharmaceutical R&D and have become indispensable tools for decision making and communication with regulatory agencies. While biology is multiscale by nature, project work, and software tools usually focus on isolated aspects of drug action, such as pharmacokinetics at the organism scale or pharmacodynamic interaction on the molecular level. We present a modeling and simulation software platform consisting of PK-Sim® and MoBi® capable of building and simulating models that integrate across biological scales. A prototypical multiscale model for the progression of a pancreatic tumor and its response to pharmacotherapy is constructed and virtual patients are treated with a prodrug activated by hepatic metabolization. Tumor growth is driven by signal transduction leading to cell cycle transition and proliferation. Free tumor concentrations of the active metabolite inhibit Raf kinase in the signaling cascade and thereby cell cycle progression. In a virtual clinical study, the individual therapeutic outcome of the chemotherapeutic intervention is simulated for a large population with heterogeneous genomic background. Thereby, the platform allows efficient model building and integration of biological knowledge and prior data from all biological scales. Experimental in vitro model systems can be linked with observations in animal experiments and clinical trials. The interplay between patients, diseases, and drugs and topics with high clinical relevance such as the role of pharmacogenomics, drug–drug, or drug–metabolite interactions can be addressed using this mechanistic, insight driven multiscale modeling approach

Tetrathyridiosis in a domestic shorthair cat

Case summary This report describes the clinical and parasitological findings in a domestic shorthair cat with isolated thoracic tetrathyridiosis. The cat was a stray from Malta that had lived in Germany for several years since as an indoor-only cat. Therefore, the process of infection remains very unusual. In this case it must be considered that the cat had been infected years previously while in Malta, and had lived at least 4 years without any clinical signs. It was possible to diagnose this uncommon disease and initiate an effective treatment with fenbendazole, praziquantel and supportive care. Clinical signs, as well as radiographic findings, were regressive with this treatment. Relevance and novel information Tetrathyridiosis is a rare finding in cats, especially in Germany, but it seems to be a potential differential diagnosis of pleural effusion. Mesocestoides corti , which was the causative parasite in this case, has not previously been isolated in Germany. Because tetrathyridiosis is only diagnosed post mortem in most cases, little is known about effective therapeutic options. Furthermore, clinical signs of this disease can be absent for several years and can potentially be triggered by neoplastic conditions or immunosuppression. Tetrathyridiosis seems to be a treatable disease that can be controlled by adequate antiparasitic therapy

Muscle ultrasound for early assessment of critical illness neuromyopathy in severe sepsis

INTRODUCTION: Muscle ultrasound is emerging as a promising tool in the diagnosis of neuromuscular diseases. The current observational study evaluates the usefulness of muscle ultrasound in patients with severe sepsis for assessment of critical illness polyneuropathy and myopathy (CINM) in the intensive care unit. METHODS: 28 patients with either septic shock or severe sepsis underwent clinical neurological examinations, muscle ultrasound, and nerve conduction studies on days 4 and 14 after onset of sepsis. 26 healthy controls of comparable age underwent clinical neurological evaluation and muscle ultrasound only. RESULTS: 26 of the 28 patients exhibited classic electrophysiological characteristics of CINM, and all showed typical clinical signs. Ultrasonic echogenicity of muscles was graded semiquantitatively and fasciculations were evaluated in muscles of proximal and distal arms and legs. 75% of patients showed a mean echotexture greater than 1.5, which was the maximal value found in the control group. A significant difference in mean muscle echotexture between patients and controls was found at day 4 and day 14 (both p < 0.001). In addition, from day 4 to day 14, the mean grades of muscle echotexture increased in the patient group, although the values did not reach significance levels (p = 0.085). Controls revealed the lowest number of fasciculations. In the patients group, fasciculations were detected in more muscular regions (lower and upper arm and leg) in comparison to controls (p = 0.08 at day 4 and p = 0.002 at day 14). CONCLUSIONS: Muscle ultrasound represents an easily applicable, non-invasive diagnostic tool which adds to neurophysiological testing information regarding morphological changes of muscles early in the course of sepsis. Muscle ultrasound could be useful for screening purposes prior to subjecting patients to more invasive techniques such as electromyography and/or muscle biopsy. TRIAL REGISTRATION: German Clinical Trials Register, DRKS-ID: DRKS00000642

C-Terminal Alpha-1 Antitrypsin Peptide: A New Sepsis Biomarker with Immunomodulatory Function

Systemic inflammatory response syndrome (SIRS) is a life threatening condition and the leading cause of death in intensive care units. Although single aspects of pathophysiology have been described in detail, numerous unknown mediators contribute to the progression of this complex disease. The aim of this study was to elucidate the pathophysiological role of CAAP48, a C-terminal alpha-1 antitrypsin fragment, that we found to be elevated in septic patients and to apply this peptide as diagnostic marker for infectious and noninfectious etiologies of SIRS. Incubation of human polymorphonuclear neutrophils with synthetic CAAP48, the SNP-variant CAAP47, and several control peptides revealed intense neutrophil activation, induction of neutrophil chemotaxis, reduction of neutrophil viability, and release of cytokines. We determined the abundance of CAAP48 in patients with severe sepsis, severe SIRS of noninfectious origin, and viral infection. CAAP48 levels were 3-4-fold higher in patients with sepsis compared to SIRS of noninfectious origin and allowed discrimination of those patients with high sensitivity and specificity. Our results suggest that CAAP48 is a promising discriminatory sepsis biomarker with immunomodulatory functions, particularly on human neutrophils, supporting its important role in the host response and pathophysiology of sepsis

Different Roles of Mitochondria in Cell Death and Inflammation: Focusing on Mitochondrial Quality Control in Ischemic Stroke and Reperfusion

Mitochondrial dysfunctions are among the main hallmarks of several brain diseases, including ischemic stroke. An insufficient supply of oxygen and glucose in brain cells, primarily neurons, triggers a cascade of events in which mitochondria are the leading characters. Mitochondrial calcium overload, reactive oxygen species (ROS) overproduction, mitochondrial permeability transition pore (mPTP) opening, and damage-associated molecular pattern (DAMP) release place mitochondria in the center of an intricate series of chance interactions. Depending on the degree to which mitochondria are affected, they promote different pathways, ranging from inflammatory response pathways to cell death pathways. In this review, we will explore the principal mitochondrial molecular mechanisms compromised during ischemic and reperfusion injury, and we will delineate potential neuroprotective strategies targeting mitochondrial dysfunction and mitochondrial homeostasis

Prevalence of specific IgG-antibodies against Toxoplasma gondii in domestic turkeys determined by kinetic ELISA based on recombinant GRA7 and GRA8.

International audienceThe protozoan parasite Toxoplasma (T.) gondii is one of the most common zoonotic infectious agents worldwide. Besides its sexual reproduction in cats, T. gondii can also infect a wide spectrum of other warm-blooded animals. These include animals used for human consumption such as pigs or chickens. Nevertheless, the role of turkeys for the epidemiology of T. gondii infections has not been studied thoroughly. We have established a kinetic ELISA (KELA) for the detection of T. gondii-specific IgG antibodies in turkey serum samples. The test is based on the recombinant dense granule antigens GRA7 and GRA8. These proteins were used as an antigen mixture at a concentration of 0.13 μg per well. The overall sensitivity of the assay was between 92.6% and 100% and the specificity ranged from 78.1% to 100%, depending on the method used to calculate these parameters. Using this KELA we examined 1913 turkey serum samples from 14 turkey farms from different areas of Germany. From these sera, 387 produced a signal in the KELA, corresponding to a true seroprevalence of up to 20.2%. The seropositivity rate in individual fattening cycles at individual farms ranged from 0.0% to 77.1%, whereas the rates were highly variable within the individual farms and individual fattening cycles. Consequently, conditions of animal husbandry could not be associated with particular seroprevalence rates. Although seropositivity cannot be linked directly to infectious tissue cysts in the muscle tissue of commercially produced turkey meat, we state that there is a potential risk of being infected by consuming turkey meat products that were not heat treated