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B-Zellen spielen eine wichtige Rolle in der Pathogenese der Rheumatoiden Arthritis. Seit dem Jahr 2006 ist der Anti-CD20-Antikörper Rituximab, welcher eine passagere B-Zell-Depletion induziert, zur Therapie der Rheumatoiden Arthritis zugelassen. In dieser Arbeit wurde das variable Kappa- und Lambda-Leichtkettenrepertoire der CD19+CD27+ B-Gedächtniszellen bei einer Patientin mit aktiver Rheumatoider Arthritis vor und nach B-Zell-Depletion durch Rituximab verglichen. Hierzu wurden nach der Einzelzellsortierung von mononuklären Zellen des peripheren Blutes die Rearrangements des Kappa- und Lambda-Leichtkettenrepertoires amplifiziert, sequenziert und analysiert. Die gefundenen Daten sprechen für die Neubildung eines diversen, polyklonalen und hochmutierten Kappa- und Lambda-Leichtkettenrepertoires. Somit ist davon auszugehen, dass nach der CD20+ B-Zell-Depletion ein funktionsfähiges Repertoire entsteht, welches keine Restriktion für die Infektabwehr aufweist.
Although sofosbuvir has been approved for patients with genotypes 2/3 (G2/3), many parts of the world still consider pegylated Interferon alpha (P) and ribavirin (R) as standard of care for G2/3. Patients with rapid virological response (RVR) show response rates >80%. However, SVR (sustained virological response) in non-RVR patients is not satisfactory. Longer treatment duration may be required but evidence from prospective trials are lacking. A total of 1006 chronic HCV genotype 2/3 patients treated with P/R were recruited into a German HepNet multicenter screening registry. Of those, only 226 patients were still HCV RNA positive at week 4 (non-RVR). Non-RVR patients with ongoing response after 24 weeks P-2b/R qualified for OPTEX, a randomized trial investigating treatment extension of additional 24 weeks (total 48 weeks, Group A) or additional 12 weeks (total 36 weeks, group B) of 1.5 \(\mu\)g/kg P-2b and 800-1400 mg R. Due to the low number of patients without RVR, the number of 150 anticipated study patients was not met and only 99 non-RVR patients (n=50 Group A, n=49 Group B) could be enrolled into the OPTEX trial. Baseline factors did not differ between groups. Sixteen patients had G2 and 83 patients G3. Based on the ITT (intention-to-treat) analysis, 68% [55%; 81%] in Group A and 57% [43%; 71%] in Group B achieved SVR (p=0.31). The primary endpoint of better SVR rates in Group A compared to a historical control group (SVR 70%) was not met. In conclusion, approximately 23% of G2/3 patients did not achieve RVR in a real world setting. However, subsequent recruitment in a treatment-extension study was difficult. Prolonged therapy beyond 24 weeks did not result in higher SVR compared to a historical control group.
Farnesol, produced by the polymorphic fungus Candida albicans, is the first quorum-sensing molecule discovered in eukaryotes. Its main function is control of C. albicans filamentation, a process closely linked to pathogenesis. In this study, we analyzed the effects of farnesol on innate immune cells known to be important for fungal clearance and protective immunity. Farnesol enhanced the expression of activation markers on monocytes (CD86 and HLA-DR) and neutrophils (CD66b and CD11b) and promoted oxidative burst and the release of proinflammatory cytokines (tumor necrosis factor alpha [TNF-\(\alpha\)] and macrophage inflammatory protein 1 alpha [MIP-1 \(\alpha\)]). However, this activation did not result in enhanced fungal uptake or killing. Furthermore, the differentiation of monocytes to immature dendritic cells (iDC) was significantly affected by farnesol. Several markers important for maturation and antigen presentation like CD1a, CD83, CD86, and CD80 were significantly reduced in the presence of farnesol. Furthermore, farnesol modulated migrational behavior and cytokine release and impaired the ability of DC to induce T cell proliferation. Of major importance was the absence of interleukin 12 (IL-12) induction in iDC generated in the presence of farnesol. Transcriptome analyses revealed a farnesol-induced shift in effector molecule expression and a down-regulation of the granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor during monocytes to iDC differentiation. Taken together, our data unveil the ability of farnesol to act as a virulence factor of C. albicans by influencing innate immune cells to promote inflammation and mitigating the Th1 response, which is essential for fungal clearance.
In this pilot study, we exemplify differences between a septic and a colonizing GBS strain during their interaction with Endothelial Cells by evaluating cytokine levels, surface and apoptosis-related molecules. These preliminary results indicate that in vitro infection using an exemplary septic GBS strain results in diminished activation of the innate immune response.
RNAseq analysis of Aspergillus fumigatus in blood reveals a just wait and see resting stage behavior
(2015)
Background:
Invasive aspergillosis is started after germination of Aspergillus fumigatus conidia that are inhaled by susceptible individuals. Fungal hyphae can grow in the lung through the epithelial tissue and disseminate hematogenously to invade into other organs. Low fungaemia indicates that fungal elements do not reside in the bloodstream for long.
Results:
We analyzed whether blood represents a hostile environment to which the physiology of A. fumigatus has to adapt. An in vitro model of A. fumigatus infection was established by incubating mycelium in blood. Our model allowed to discern the changes of the gene expression profile of A. fumigatus at various stages of the infection. The majority of described virulence factors that are connected to pulmonary infections appeared not to be activated during the blood phase. Three active processes were identified that presumably help the fungus to survive the blood environment in an advanced phase of the infection: iron homeostasis, secondary metabolism, and the formation of detoxifying enzymes.
Conclusions:
We propose that A. fumigatus is hardly able to propagate in blood. After an early stage of sensing the environment, virtually all uptake mechanisms and energy-consuming metabolic pathways are shut-down. The fungus appears to adapt by trans-differentiation into a resting mycelial stage. This might reflect the harsh conditions in blood where A. fumigatus cannot take up sufficient nutrients to establish self-defense mechanisms combined with significant growth.
Regulation Tumornekrosefaktor (TNF) Rezeptor assoziierter Signalwege durch das Adapterprotein TRAF1
(2015)
TWEAK ist ein zu der TNF-Superfamilie (Tumor Necrosis Factor) zugehöriges Zytokin, welches in Form löslicher und membranständiger Moleküle vorkommt. Beide Formen des Liganden können an den Rezeptor (Fn14) binden. Viele verschiedene intrazelluläre Signalwege werden durch den Fn14 aktiviert, beispielweise Erk1/2, JNK, Jun und STAT3, vor allem jedoch das NFkB. Lösliches und membranständiges TWEAK zeigen eine ähnliche Aktivierungseffizienz bezüglich des alternativen NFkB-Signalwegs, wohingegen membranständiges TWEAK weit besser als lösliches TWEAK den klassischen NFkB-Signalweg aktiviert. In der vorliegenden Arbeit wurde zunächst die TWEAK-vermittelte Induzierbarkeit von verschiedenen Zielgenen des NFkB-Systems untersucht. Lösliches TWEAK zeigte einen weit schwächeren aktivierenden Effekt auf den klassischen NFkB-Signalweg als TNF, das ein sehr guter Aktivator des klassischen NFkB-Systems ist (Abb. 5, 6). Nichtsdestotrotz war TWEAK imstande eine stärkere TRAF1-Induktion als TNF herbeizuführen (Abbildung 7, 8). TRAF1 ist ein durch NFkB-System stark reguliertes Gen. Um posttranskriptionelle TRAF1-Modifikationen als Ursache für die unerwartet gute TRAF1-Induktion durch lösliches TWEAK auszuschließen, wurde die TRAF1-Expression nach Proteasom- und Caspasen-Inhibition untersucht (Abbildung 9). Dies ergab keinen Hinweis auf einen Einfluss dieser Prozessen auf der TRAF1-Expression.
Mittels des IKK2-spezifischen Inhibitor TPCA-1 wurde die TWEAK-vermittelte TRAF1-Induktion Zelltyp-abhängig gehemmt, wohingegen die TNF-vermittelte Induktion von TRAF1 in allen Zelllinien vollständig inhibiert wurde (Abbildung 13). Versuche mit dem NEDD8-aktivierenden Enzym (NAE) Inhibitor MLN4924, resultierten in einer totalen Inhibition der TRAF1-Expression in allen TWEAK- und TNF-stimulierten Zellen (Abbildung 14). Diese Befunde sprechen dafür, dass bei der TWEAK-vermittelten TRAF1-Expression beide Zweige des NFkB-Signalwegs Zelltyp-abhängig beteiligt sind.
Die Oligomerisierung der Liganden der TNF-Familie verstärkt oft ihre Aktivität. Oligomerisiertes TWEAK imitiert die biologische Aktivität von membranständigem TWEAK. Lösliches TWEAK wurde mit einem anti-Flag Antikörper oligomerisiert und die TRAF1-Induktion durch den alternativen NFkB-Signalweg wurde analysiert
Oligomerisiertes TWEAK aktivierte Zelltyp-unabhängig den klassischen NFkB-Signalweg stärker als lösliches TWEAK, wohingegen kein Effekt auf die TRAF1-Induktion oder auf die Aktivierung den alternativen NFkB-Signalweg festgestellt wurde (Abbildung 11, 12). TWEAK ist imstande die TRAF2-vermittelte CD40-Induktion des klassischen NFkB-Signalwegs zu hemmen (Abbildung 16, 17). Um den Beitrag von TWEAK-Induziertem TRAF1 zur CD40-Inhibition zu herauszufinden, wurden TRAF1-stabil transfizierte 786O- und U2OS-Zellen hergestellt (Abbildung 19). Die CD40-Induzierte IkBa-Degradation und IL8/6 Produktion war in den TRAF1-Transfektanten als auch in mit löslichem TWEAK vorbehandelte Zellen stark inhibiert (Abbildung 21, 22), wobei die CD40-Expression und CD40/CD40L-Interaktion unverändert blieb (Abbildung 20). Diese Ergebnisse sprechen für einen wichtigen Beitrag des Adaptorprotein TRAF1 in der TWEAK-vermittelte Inhibition der CD40-induzierte Aktivierung des klassischen NFkB-Signalwegs.
Background
“Tako-Tsubo cardiomyopathy” (TTC) is a syndrome characterized by left ventricular (LV) wall motion abnormalities, usually without coronary artery disease, mimicking the diagnosis of acute coronary syndrome. It most often affects post-menopausal women and TTC tends to run a benign course with very low rates of recurrence, complications or mortality. The condition is also called “stress-induced cardiomyopathy” because acute physical or emotional stress appears to be frequently related to its onset. The pathogenic role of premorbid or comorbid psychiatric illnesses has been discussed controversially. For the first time, we present a case of fourfold recurrent TTC with severe complications in a pre-menopausal woman. Furthermore, a long history of flaring posttraumatic stress symptoms anteceded the first event.
Case presentation
A 43-year old, pre-menopausal Caucasian woman was hospitalized with symptoms of acute coronary syndrome. Clinical examination revealed hypokinetic wall motion in the apical ventricular region with no signs of coronary artery disease and diagnosis of TTC was established. She experienced recurrence three times within the following ten months, which led to thrombembolism and myocardial scarring among others. The circumstances of chronic distress were striking. 16 years ago she miscarried after having removed a myoma according to her doctor’s suggestion. Since then, she has suffered from symptoms of posttraumatic distress which peaked annually at the day of abortion. Chronic distress became even more pronounced after the premature birth of a daughter some years later. The first event of TTC occurred after a family dispute about parenting.
Conclusion
This is the first case report of fourfold TTC in a pre-menopausal woman. From somatic perspectives, the course of the disease with recurrences and complications underlines the fact that TTC is not entirely benign. Furthermore, it is the first case report of long lasting symptoms of traumatic stress anteceding TTC. Close connections between adrenergic signaling and late onset of clinical stress symptoms are well known in the psychopathology of traumatization. Although larger clinical trials are needed to elucidate possible interactions of premorbid psychiatric illnesses and TTC, cardiologists should be vigilant especially in cases of recurrent TTC.
Background:
While HIV, AIDS and atypical Mycobacterium infections are closely linked, the use of Integrase-Inhibitor based cART, notably raltegravir-based regimens is more widespread. RAL should be double-dosed to 800 mg semi-daily in situation of rifampicin co-medication, because RAL is more rapidly metabolized due to rifampicin-induced Uridine-5'-diphosph-gluronosyl-transferase (UGT1A1). Recently, it was speculated that chewed RAL might lead to increased absorption, which might compensate the inductive effect of rifampicin-rapid metabolized RAL, as part of cost-saving effects in countries with high-tuberculosis prevalence and less economic power.
Methods:
We report measurement of raltegravir pharmacokinetics in a 34-year AIDS-patient suffering from disseminated Mycobacterium avium infection with necessity of parenteral rifampicin treatment. RAL levels were measured with HPLC (internal standard: carbamazepine, LLQ 11 ng/ml, validation with Valistat 2.0 program (Arvecon, Germany)). For statistical analysis, a two-sided Wilcoxon signed rank test for paired samples was used.
Results:
High intra-personal variability in raltegravir serum levels was seen. Comparable C\(_{max}\) concentrations were found for 800 mg chewed and swallowed RAL, as well as for 400 mg chewed and swallowed RAL. While C\(_{max}\) seems to be more dependent from overall RAL dosing than from swallowed or chewed tablets, increased AUC(12) is clearly linked to higher RAL dosages per administration. Anyway, chewed raltegravir showed a rapid decrease in serum levels.
Conclusions:
We found no evidence that chewed 400 mg semi-daily raltegravir in rifampicin co-medication leads to optimized pharmacokinetics. There is need for more data from randomized trials for further recommendations.
Objectives
Liver biopsies are the current gold standard in non-alcoholic steatohepatitis (NASH) diagnosis. Their invasive nature, however, still carries an increased risk for patients' health. The development of non-invasive diagnostic tools to differentiate between bland steatosis (NAFL) and NASH remains crucial. The aim of this study is the evaluation of investigated circulating microRNAs in combination with new targets in order to optimize the discrimination of NASH patients by non-invasive serum biomarkers.
Methods
Serum profiles of four microRNAs were evaluated in two cohorts consisting of 137 NAFLD patients and 61 healthy controls. In a binary logistic regression model microRNAs of relevance were detected. Correlation of microRNA appearance with known biomarkers like ALT and CK18-Asp396 was evaluated. A simplified scoring model was developed, combining the levels of microRNA in circulation and CK18-Asp396 fragments. Receiver operating characteristics were used to evaluate the potential of discriminating NASH.
Results
The new finding of our study is the different profile of circulating miR-21 in NASH patients (p<0.0001). Also, it validates recently published results of miR-122 and miR-192 to be differentially regulated in NAFL and NASH. Combined microRNA expression profiles with CK18-Asp396 fragment level scoring model had a higher potential of NASH prediction compared to other risk biomarkers (AUROC = 0.83, 95% CI = 0.754-0.908; p<0.001). Evaluation of score model for NAFL (Score = 0) and NASH (Score = 4) had shown high rates of sensitivity (91%) and specificity (83%).
Conclusions
Our study defines candidates for a combined model of miRNAs and CK18-Asp396 levels relevant as a promising expansion for diagnosis and in turn treatment of NASH.
A 21 year old MSM patient with newly diagnosed HIV infection was hospitalized in our department after ingestion of an overdose of his antiretroviral therapy (ART) comprising dolutegravir (DTG - Tivicay\(^{®}\)) and tenofovir disaproxil fumarate/emtricitabine (Truvada\(^{®}\)) in suicidal intention. On admission, the patient did not show any clinical signs of intoxication and laboratory findings were unremarkable. After 6 hours of intensive care monitoring, the patient was referred to a psychiatric clinic. 5 days after the day of intoxication, serum creatinine levels increased to high normal values (1.2 mg/dl). However, levels never exceeded the upper threshold. 8 and 12 weeks later, serum creatinine normalized to levels measured prior to the intoxication. No other adverse events occurred, and the patient does not suffer from permanent impairments.