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The CDK inhibitor SNS-032 had previously exerted promising anti-neuroblastoma activity via CDK7 and 9 inhibition. ABCB1 expression was identified as major determinant of SNS-032 resistance. Here, we investigated the role of ABCB1 in acquired SNS-032 resistance. In contrast to ABCB1-expressing UKF-NB-3 sub-lines resistant to other ABCB1 substrates, SNS-032-adapted UKF-NB-3 (UKF-NB-3rSNS- 032300nM) cells remained sensitive to the non-ABCB1 substrate cisplatin and were completely re-sensitized to cytotoxic ABCB1 substrates by ABCB1 inhibition. Moreover, UKF-NB-3rSNS-032300nM cells remained similarly sensitive to CDK7 and 9 inhibition as UKF-NB-3 cells. In contrast, SHEPrSNS-0322000nM, the SNS-032-resistant sub-line of the neuroblastoma cell line SHEP, displayed low level SNS-032 resistance also when ABCB1 was inhibited. This discrepancy may be explained by the higher SNS-032 concentrations that were used to establish SHEPrSNS-0322000nM cells, since SHEP cells intrinsically express ABCB1 and are less sensitive to SNS-032 (IC50 912 nM) than UKF-NB-3 cells (IC50 153 nM). In conclusion, we show that ABCB1 expression represents the primary (sometimes exclusive) resistance mechanism in neuroblastoma cells with acquired resistance to SNS-032. Thus, ABCB1 inhibitors may increase the SNS-032 efficacy in ABCB1-expressing cells and prolong or avoid resistance formation.
The Hepatitis C virus (HCV) infects more than 170 million individuals worldwide and causes challenging HCV-related diseases. Unfortunately, there is no vaccine available. Therefore, a better understanding of the HCV life cycle is urgently needed to develop more effective and better tolerated therapies.
It has been reported that the secretory pathway plays an essential role for the release of HCV, and the SNARE complexes are a central factor controlling intracellular vesicular trafficking. Recently, our group observed that α-taxilin that binds to free syntaxin 4 prevents the SNARE complex formation and exerts an inhibitory effect on the release of HCV particles. Therefore, it was analyzed whether the t-SNARE protein syntaxin 4 is involved in the HCV life cycle.
An increased intracellular amount of syntaxin 4 was found in HCV-positive cells, while the level of syntaxin 4-specific transcripts was decreased as observed in HCV-positive Huh7.5 cells and in HCV-infected primary human hepatocytes (PHH). Since in HCV-positive cells a significant longer half-life of syntaxin 4 was found, the decreased expression is overcompensated, leading to the elevated amount of syntaxin 4. Overexpression of syntaxin 4 increases the amount of secreted infectious viral particles, while silencing of syntaxin 4 expression decreases the number of released viral particles, which indicates that HCV could use the SNARE-dependent secretory pathway for viral release. Confocal immunofluorescence microscopy and co-immunoprecipitation experiments revealed that syntaxin 4 interacts with HCV core and NS5A. To identify the binding domain, various mutants of syntaxin 4 were generated. Based on these mutants, it was found that the H3 domain of syntaxin 4 interacts with core. These data show that the t-SNARE protein syntaxin 4 is an essential cellular factor for HCV morphogenesis and secretion.
HCV induces autophagy, and in HCV-infected cells a major fraction of the de novo synthesized viral particles is not released but intracellularly degraded. Syntaxin 17 is an autophagosomal SNARE required for the fusion of autophagosomes with lysosomes to form autolysosomes and thereby to deliver the enclosed contents for degradation. Therefore, we aim to investigate whether syntaxin 17 is a relevant factor for the HCV life cycle by regulating the fusion between autophagosomes and lysosomes. It was found that HCV-positive cells possess a decreased amount of syntaxin 17, and HCV reduces the intracellular level of syntaxin 17 by NS5A-mediated interruption of c-Raf signaling, which triggers the syntaxin 17 transcription, and by HCV-dependently induced autophagy. Overexpression of syntaxin 17 decreases the intracellular amount of viral particles and reduces the number of released infectious viral particles by favoring the formation of autolysosomes, in which HCV particles can be degraded. Vice versa, inhibition of syntaxin 17 expression by specific siRNAs results in an elevated amount of intracellular viral particles and increases the number of released viral particles by impaired autophagosome-lysosome fusion. Confocal immunofluorescence microscopy analyses show a fraction of core protein in autophagosomes as stained by lysotracker and the autophagy maker p62. These data identify syntaxin 17 as a novel factor controlling the release of HCV and reveal the autophagosome-autolysosome fusion as an essential step affecting the equilibrium between the release of infectious viral particles and lysosomal degradation of intracellular viral particles.
Taken together, these data identify the t-SNARE proteins syntaxin 4 and syntaxin 17 as essential cellular factors for HCV morphogenesis and secretion.
Prognostische Faktoren und das Outcome von Patienten mit einem primären Glioblastom sind in der Fachliteratur gut beschrieben. Im Gegensatz dazu gibt es wenige vergleichbare Informationen zu Patienten mit einem sekundären Glioblastom. Das Ziel dieser Arbeit war es, das Outcome von Patienten mit einem sekundären Glioblastom zu beurteilen und prognostische Faktoren in Be-zug auf das Gesamtüberleben zu identifizieren.
Dazu wurde die interne Datenbank des Universitätsklinikums Frankfurt/Main von Patienten mit Hirntumoren retrospektiv nach klinischen Daten durchsucht. Alle Patienten hatten ein histologisch gesichertes WHO Grad II oder III Gliom und anschließend ein WHO Grad IV sekundäres Glioblastom. Paraffiniertes Hirntumorgewebe wurde auf Mutationen der Isocitrat Dehydrogenase-1 (IDH1) mittels einer immunhistochemischen Färbung mit einem R132H (clone H09) spezifischen Antikörper untersucht. Eine uni- und multivariate statistische Analyse wurde durchgeführt, um Faktoren zu ermitteln, die potentiell das Gesamt-überleben beeinflussen könnten.
Es wurden 45 Patienten mit einem histologisch gesicherten sekundären Glioblastom untersucht. Das mediane Alter betrug 41 Jahre. 14 Patienten unterzogen sich einer radiologisch kompletten Resektion des sekundären Glioblastoms, 31 Patienten wurden subtotal reseziert oder biopsiert. Initial ist bei 37 Patienten ein astrozytärer Tumor nachgewiesen worden und die restlichen Patienten litten an Oligodendrogliomen oder gemischten Gliomen; bei der initialen Diagnose wurden 17 WHO Grad II und 28 WHO Grad III Tumoren fest-gestellt. Die mediane Zeit zwischen Ursprungstumor und dem Auftreten des sekundären Glioblastoms betrug 158,9 Wochen. Das mediane Gesamtüberleben betrug 445 Tage nach der Diagnose eines sekundären Glioblastoms. Mutationen des IDH1 (R132H) Proteins wurden bei 24 Patienten festgestellt und fehlten bei 17 Patienten; bei 4 Patienten konnte keine IDH1 immunhistochemische Färbung durchgeführt werden.
In der univariaten Analyse konnte der Zeitraum zwischen initialer Läsion und dem Progress zu einem sekundären Glioblastom als statistisch signifikanter Einflussfaktor identifiziert werden- Patienten mit einem Zeitraum von mehr als 2 Jahren hatten ein besseres Gesamtüberleben (460 vs. 327 Tage, p = 0,011). Außerdem konnte bei Patienten, die eine kombinierte Radiochemotherapie bekamen, ein besseres Gesamtüberleben nachgewiesen werden als bei Patienten, welche ausschließlich eine Therapieform erhielten (611 vs. 380 Tage, p < 0,001). Weiterhin konnten ein WHO Grad II Ursprungstumor (472 vs. 421 Tage, p = 0,05) und eine Frontalllappenlokalisation des Glioblastoms (472 vs. 425 Ta-ge, p = 0,031) das Überleben steigern.
In der multivariaten Analyse konnte gezeigt werden, dass die Mutation des IDH1 (R132H) Proteins in statistisch signifikanter Weise mit einem längeren Gesamtüberleben assoziiert war (p = 0,012); statistische Signifikanz für ein län-geres Gesamtüberleben bei Patienten mit initial einem WHO Grad II (p = 0,047) und einer Frontallappenlokalisation des Glioblastoms (p = 0,042) stellte sich auch ein. In Bezug auf die Patienten spezifischen Daten wurden zwei Prognosegruppen erstellt; Patienten in der guten Prognosegruppe scheinen einen Benefit von einer totalen Tumorresektion zu haben (p = 0,02), während eine Resektion für die andere Prognosegruppe keine große Rolle spielte (p = 0,926).
Trotz des relativ geringen Erkrankungsalters haben sekundäre Glioblastom Patienten eine schlechte Prognose. Die Ergebnisse dieser Arbeit unterstreichen die Wichtigkeit und den prognostischen Wert der IDH1 Diagnostik, die Notwendigkeit einer kombinierten Radiochemotherapie und eine Risikostratifizierung für eine Prognoseabschätzung anhand der Patienten spezifischen Einflussfaktoren.
Evidence about distribution patterns of brain metastases with regard to breast cancer subtypes and its influence on the prognosis of patients is insufficient. Clinical data, cranial computed tomography (CT) and magnetic resonance imaging (MRI) scans of 300 breast cancer patients with brain metastases (BMs) were collected retrospectively in four centers participating in the Brain Metastases in Breast Cancer Registry (BMBC) in Germany. Patients with positive estrogen (ER), progesterone (PR), or human epidermal growth factor receptor 2 (HER2) statuses, had a significantly lower number of BMs at diagnosis. Concerning the treatment mode, HER2-positive patients treated with trastuzumab before the diagnosis of BMs showed a lower number of intracranial metastases (p < 0.001). Patients with a HER2-positive tumor-subtype developed cerebellar metastases more often compared with HER2-negative patients (59.8% vs. 44.5%, p = 0.021), whereas patients with triple-negative primary tumors had leptomeningeal disease more often (31.4% vs. 18.3%, p = 0.038). The localization of Brain metastases (BMs) was associated with prognosis: patients with leptomeningeal disease had shorter survival compared with patients without signs of leptomeningeal disease (median survival 3 vs. 5 months, p = 0.025). A shorter survival could also be observed in the patients with metastases in the occipital lobe (median survival 3 vs. 5 months, p = 0.012). Our findings suggest a different tumor cell homing to different brain regions depending on subtype and treatment. View Full-Text
NOSTRIN belongs to the family of F-BAR proteins, which are multi-domain adaptor proteins that have emerged as important regulators of membrane remodeling and actin dynamics in a variety of vital cellular processes. They have been analyzed structurally and biochemically and overexpression studies have revealed their potential in inducing membrane curvature and tubulation. Several studies have begun to decipher the function of individual proteins, but the understanding of F-BAR protein functions in vivo is still quite limited. The F-BAR protein NOSTRIN is mainly expressed in endothelial cells and has originally been described as interaction partner of the endothelial nitric oxide synthase (eNOS), modulating eNOS subcellular localization. The phenotypic characterization of NOSTRIN knockout mice revealed decreased nitric oxide (NO) and cGMP levels, an increase in systolic blood pressure and an impairment of the acetylcholine-induced, NO-dependent relaxation of aortic rings from mice with global as well as endothelial cell-specific knockout of the NOSTRIN gene (ECKO) . These findings implied that NOSTRIN plays a role in regulating NO production in vivo, but the underlying molecular mechanisms were unclear. Therefore, this study was aimed at addressing the mechanism causing the inhibited vasodilation specifically upon stimulation with acetylcholine in NOSTRIN KO and ECKO mice, and at exploring additional roles of NOSTRIN in the signal transduction of endothelial cells.
The major acetylcholine receptor that mediates vessel relaxation upon stimulation with acetylcholine is the muscarinic acetylcholine receptor subtype M3 (M3R). In the present study NOSTRIN was identified as novel interaction partner of the M3R and important factor for the correct spatial distribution and functionality of the M3R. Moreover, it provides the first example of an F-BAR protein regulating a GPCR. Confocal immunofluorescence microscopy analysis of isolated aortae from NOSTRIN KO and WT mice indicated that NOSTRIN was necessary for the proper subcellular localization of the M3R and targeted it to the plasma membrane. A series of pulldown experiments revealed a direct interaction of NOSTRIN with the M3R. The binding required the SH3 domain of NOSTRIN and the third intracellular loop of the M3R, which has a recognized role in receptor regulation. The interaction of NOSTRIN with the M3R was confirmed by co-localization of NOSTRIN and the M3R upon overexpression in mammalian cells. Expression levels of the M3R as well as eNOS were not affected by the loss of NOSTRIN in accordance with the finding, that NOSTRIN impacts on the acetylcholine/eNOS signaling axis through regulation of the subcellular trafficking of its binding partners.
Furthermore, there were first indications for a role of NOSTRIN in facilitating the carbachol-induced calcium response in M3R-expressing cells, suggesting that NOSTRIN might influence M3R activation. in the absence of NOSTRIN, the function of the M3R in mammalian cells overexpressing the M3R was markedly impaired, resulting in abolition of the calcium response to the M3R agonist carbachol. In accordance, the activated eNOS fraction associated with the Golgi complex was markedly reduced in aorta explants from NOSTRIN knockout and ECKO mice. Moreover, NOSTRIN knockout inhibited the carbachol-induced, activating phosphorylation of eNOS in murine aortae as well as primary mouse lung endothelial cells confirming its role as important regulator of eNOS activity in vivo.
Purpose: A study of real-time adaptive radiotherapy systems was performed to test the hypothesis that, across delivery systems and institutions, the dosimetric accuracy is improved with adaptive treatments over non-adaptive radiotherapy in the presence of patient-measured tumor motion.
Methods and materials: Ten institutions with robotic(2), gimbaled(2), MLC(4) or couch tracking(2) used common materials including CT and structure sets, motion traces and planning protocols to create a lung and a prostate plan. For each motion trace, the plan was delivered twice to a moving dosimeter; with and without real-time adaptation. Each measurement was compared to a static measurement and the percentage of failed points for γ-tests recorded.
Results: For all lung traces all measurement sets show improved dose accuracy with a mean 2%/2 mm γ-fail rate of 1.6% with adaptation and 15.2% without adaptation (p < 0.001). For all prostate the mean 2%/2 mm γ-fail rate was 1.4% with adaptation and 17.3% without adaptation (p < 0.001). The difference between the four systems was small with an average 2%/2 mm γ-fail rate of <3% for all systems with adaptation for lung and prostate.
Conclusions: The investigated systems all accounted for realistic tumor motion accurately and performed to a similar high standard, with real-time adaptation significantly outperforming non-adaptive delivery methods.
BACKGROUND: Polyclonal anti-thymocyte globulins (ATGs) are immunosuppressive drugs widely used in induction of immunosuppression and treatment of acute rejection after solid organ transplantation. We have previously demonstrated that ATGs bind to endothelial cells in vitro, and are able to modulate ECs. The aim of this study was to investigate the binding of ATGs to endothelial cells under in vivo conditions.
MATERIAL AND METHODS: Muscle biopsies from extremities of cynomolgus monkeys were obtained after ischemia/reperfusion at 4°C. ATGs (Thymoglobulin, Sanofi-Aventis, France; 1 mg/kg) were added to the blood 30 min prior to the reperfusion. Biopsies (n=10) of patients undergoing heart transplantation and preoperatively treated with ATGs (Thymoglobulin, Sanofi-Aventis, France; 1.5 mg/kg) as induction therapy were also analyzed 6 hours and 7 days after induction. Binding of ATGs to ECs was analyzed with an anti-rabbit IgG antibody by means of immunohistochemistry.
RESULTS: Binding of ATGs to endothelial cells could be demonstrated in vivo in our animal experiments 4 hours after reperfusion, as well as in the clinical biopsies 6 hours after induction of immunosuppression in heart transplant patients, showing a preferred localization in post-capillary veins. No expression of ATGs on the endothelial surface could be observed after 7 days, suggesting that ATGs may be washed out from the endothelial surface in a time-dependent manner.
CONCLUSIONS: Our results show that ATGs are able to bind to endothelial cells in an experimental model and in clinical practice, supporting preconditioning strategies with ATGs in solid organ transplantation.
Introduction: In the time of increasing resistance and paucity of new drug development there is a growing need for strategies to enhance rational use of antibiotics in German and Austrian hospitals. An evidence-based guideline on recommendations for implementation of antibiotic stewardship (ABS) programmes was developed by the German Society for Infectious Diseases in association with the following societies, associations and institutions: German Society of Hospital Pharmacists, German Society for Hygiene and Microbiology, Paul Ehrlich Society for Chemotherapy, The Austrian Association of Hospital Pharmacists, Austrian Society for Infectious Diseases and Tropical Medicine, Austrian Society for Antimicrobial Chemotherapy, Robert Koch Institute.
Materials and methods: A structured literature research was performed in the databases EMBASE, BIOSIS, MEDLINE and The Cochrane Library from January 2006 to November 2010 with an update to April 2012 (MEDLINE and The Cochrane Library). The grading of recommendations in relation to their evidence is according to the AWMF Guidance Manual and Rules for Guideline Development.
Conclusion: The guideline provides the grounds for rational use of antibiotics in hospital to counteract antimicrobial resistance and to improve the quality of care of patients with infections by maximising clinical outcomes while minimising toxicity. Requirements for a successful implementation of ABS programmes as well as core and supplemental ABS strategies are outlined. The German version of the guideline was published by the German Association of the Scientific Medical Societies (AWMF) in December 2013.
Background: Infection is a main cause of morbidity and mortality after heart surgery, with multi-resistant pathogens increasingly representing a challenge. Daptomycin provides bactericidal activity against gram-positive organisms that are resistant to standard treatment including vancomycin.
Methods: A cohort of cardiac surgical patients, treated with daptomycin for major infection at two tertiary care centers, were retrospectively studied with a particular focus on the type of infection, causative pathogens and co-infections, daptomycin dosage, adverse events and outcome in order to provide evidence for the efficiency and safety of daptomycin in a distinct high-risk patient population.
Results: Sixty-five patients (87.7 % males, 60.4 ± 13.5 years) who had undergone aortic surgery (20.0 %), ventricular assist device (VAD) implantation (21.5 %), combined procedures (21.5 %), coronary artery bypass grafting (12.3 %), isolated valve surgery (15.4 %) and heart transplantation (7.7 %) were diagnosed with catheter-related infection (26.1 %), valve endocarditis (18.8 %), sternal wound (13.0 %), VAD-associated (11.6 %), cardiac implantable electrophysiological device (CIED)-associated (4.1 %), respiratory tract (4.3 %), bloodstream (4.3 %) and other infection (4.3 %). In 13.0 %, no focus of infection was identified though symptoms of severe infection were present. The most frequent pathogens were Staphylococcus epidermidis (30.4 %), Staphylococcus aureus (23.1 %) and Enterococcus species (10.1 %). Daptomycin doses ranging from 3 mg/kg every 48 h to 10 mg/kg every 24 h were administered for 15.4 ± 11.8 days. 87.0 % of the cases were classified as success, 7.2 % as treatment failure and 5.8 as non-evaluable. Adverse events were limited to one case of mild and one case of moderate neutropenia with recovery upon termination of treatment.
Conclusion: Daptomycin proved safe and effective in major infection in high-risk cardiac surgical patients.
Expression of kidney injury molecule-1 (Kim-1) is rapidly upregulated following tubular injury, constituting a biomarker for acute kidney damage. We examined the renal localization of Kim-1 expression in PKD/Mhm (polycystic kidney disease, Mannheim) (cy/+) rats (cy: mutated allel, +: wild type allel), an established model for autosomal dominant polycystic kidney disease, with chronic, mainly proximal tubulointerstitial alterations. For immunohistochemistry or Western blot analysis, kidneys of male adult heterozygously-affected (cy/+) and unaffected (+/+) littermates were perfusion-fixed or directly removed. Kim-1 expression was determined using peroxidase- or fluorescence-linked immunohistochemistry (alone or in combination with markers for tubule segments or differentiation). Compared to (+/+), only in (cy/+) kidneys, a chronic expression of Kim-1 could be detected by Western blot analysis, which was histologically confined to an apical cellular localization in areas of cystically-transformed proximal tubules with varying size and morphology, but not in distal tubular segments. Kim-1 was expressed by cystic epithelia exhibiting varying extents of dedifferentiation, as shown by double labeling with aquaporin-1, vimentin or osteopontin, yielding partial cellular coexpression. In this model, in contrast to other known molecules indicating renal injury and/or repair mechanisms, the chronic renal expression of Kim-1 is strictly confined to proximal cysts. Its exact role in interfering with tubulo-interstitial alterations in polycystic kidney disease warrants future investigations.
Background: Long noncoding RNAs (lncRNAs) are non-protein coding transcripts regulating a variety of physiological and pathological functions. However, their implication in heart failure is still largely unknown. The aim of this study is to identify and characterize lncRNAs deregulated in patients affected by ischemic heart failure.
Methods: LncRNAs were profiled and validated in left ventricle biopsies of 18 patients affected by non end-stage dilated ischemic cardiomyopathy and 17 matched controls. Further validations were performed in left ventricle samples derived from explanted hearts of end-stage heart failure patients and in a mouse model of cardiac hypertrophy, obtained by transverse aortic constriction. Peripheral blood mononuclear cells of heart failure patients were also analyzed. LncRNA distribution in the heart was assessed by in situ hybridization. Function of the deregulated lncRNA was explored analyzing the expression of the neighbor mRNAs and by gene ontology analysis of the correlating coding transcripts.
Results: Fourteen lncRNAs were significantly modulated in non end-stage heart failure patients, identifying a heart failure lncRNA signature. Nine of these lncRNAs (CDKN2B-AS1/ANRIL, EGOT, H19, HOTAIR, LOC285194/TUSC7, RMRP, RNY5, SOX2-OT and SRA1) were also confirmed in end-stage failing hearts. Intriguingly, among the conserved lncRNAs, h19, rmrp and hotair were also induced in a mouse model of heart hypertrophy. CDKN2B-AS1/ANRIL, HOTAIR and LOC285194/TUSC7 showed similar modulation in peripheral blood mononuclear cells and heart tissue, suggesting a potential role as disease biomarkers. Interestingly, RMRP displayed a ubiquitous nuclear distribution, while H19 RNA was more abundant in blood vessels and was both cytoplasmic and nuclear. Gene ontology analysis of the mRNAs displaying a significant correlation in expression with heart failure lncRNAs identified numerous pathways and functions involved in heart failure progression.
Conclusions: These data strongly suggest lncRNA implication in the molecular mechanisms underpinning HF.
Long noncoding RNAs (lncRNAs) are non-protein coding RNAs regulating gene expression. Although for some lncRNAs a relevant role in hypoxic endothelium has been shown, the regulation and function of lncRNAs is still largely unknown in the vascular physio-pathology. Taking advantage of next-generation sequencing techniques, transcriptomic changes induced by endothelial cell exposure to hypoxia were investigated. Paired-end sequencing of polyadenylated RNA derived from human umbilical vein endothelial cells (HUVECs) exposed to 1% O2 or normoxia was performed. Bioinformatics analysis identified ≈2000 differentially expressed genes, including 122 lncRNAs. Extensive validation was performed by both microarray and qPCR. Among the validated lncRNAs, H19, MIR210HG, MEG9, MALAT1 and MIR22HG were also induced in a mouse model of hindlimb ischemia. To test the functional relevance of lncRNAs in endothelial cells, knockdown of H19 expression was performed. H19 inhibition decreased HUVEC growth, inducing their accumulation in G1 phase of the cell cycle; accordingly, p21 (CDKN1A) expression was increased. Additionally, H19 knockdown also diminished HUVEC ability to form capillary like structures when plated on matrigel. In conclusion, a high-confidence signature of lncRNAs modulated by hypoxia in HUVEC was identified and a significant impact of H19 lncRNA was shown.
Measles virus (MeV) is an aerosol-borne and one of the most contagious pathogenic viruses known. Almost every MeV infection becomes clinically manifest and can lead to serious and even fatal complications, especially under conditions of malnutrition in developing countries, where still 115,000 to 160,000 patients die from measles every year. There is no specific antiviral treatment. In addition, MeV infections cause long-lasting memory B and T cell impairment, predisposing people susceptible to opportunistic infections for years. A rare, but fatal long-term consequence of measles is subacute sclerosing panencephalitis. Fifteen years ago (2001), WHO has launched a programme to eliminate measles by a worldwide vaccination strategy. This is promising, because MeV is a human-specific morbillivirus (i.e. without relevant animal reservoir), safe and potent vaccine viruses are sufficiently produced since decades for common application, and millions of vaccine doses have been used globally without any indications of safety and efficacy issues. Though the prevalence of wild-type MeV infection has decreased by >90 % in Europe, measles is still not eliminated and has even re-emerged with recurrent outbreaks in developed countries, in which effective vaccination programmes had been installed for decades. Here, we discuss the crucial factors for a worldwide elimination of MeV: (1) efficacy of current vaccines, (2) the extremely high contagiosity of MeV demanding a >95 % vaccination rate based on two doses to avoid primary vaccine failure as well as the installation of catch-up vaccination programmes to fill immunity gaps and to achieve herd immunity, (3) the implications of sporadic cases of secondary vaccine failure, (4) organisation, acceptance and drawbacks of modern vaccination campaigns, (5) waning public attention to measles, but increasing concerns from vaccine-associated adverse reactions in societies with high socio-economic standards and (6) clinical, epidemiological and virological surveillance by the use of modern laboratory diagnostics and reporting systems. By consequent implementation of carefully designed epidemiologic and prophylactic measures, it should be possible to eradicate MeV globally out of mankind, as the closely related morbillivirus of rinderpest could be successfully eliminated out of the cattle on a global scale.
Background: Establishing a strong link early on between preclinical coursework and the clinical context is necessary for students to be able to recognize the practical relevance of the curriculum during their preclinical anatomical courses and to transfer knowledge more easily. Our objective was to enhance the clinical relevance of a preclinical anatomy course for second-year medical students of dentistry by implementing an interdisciplinary skills training course on "Palpation of the Head and Neck Muscles" and to measure the learning outcomes.
Methods: For the curricular development of the expanded course module, Kern’s 6-step approach was applied including subjective evaluation. We used a peer-teaching format supported by an e-learning application. A randomized control study measured effects of the two components (skills training, e-module) on learning outcomes. Four learning methods were compared: (1) lecture, (2) lecture + e-module, (3) lecture + skills training, (4) lecture + skills training + e-module. An objective structured clinical examination (OSCE) was used to measure and compare learning outcomes.
Results: The two-way variance analysis demonstrated that participation in the skills training had a statistically significant effect on the OSCE results (p = 0.0007). Students who participated in the skills training did better (φ 107.4 ± 14.4 points) than students who only attended the lecture (φ 88.8 ± 26.2 points). Students who used the e-module but did not attend the skills training earned a slightly but not significantly higher average number of points (φ 91.8 ± 31.3 points) than those who only attended the lecture. The learning outcomes of the skills training were again significantly increased when the training was combined with the e-module (φ 121.8 ± 21.8 points), thus making it the ideal method for achieving the learning objectives defined in this study.
Conclusions: The "Palpation of the Head and Neck Muscles" interdisciplinary skills training course linking basic anatomical knowledge and clinical skills led to clearly improved learning outcomes for both, anatomical knowledge and clinical skills. The additional use of an e-learning tool (e-module) improved the learning effect.
Das idiopathische Parkinsonsyndrom (IPS) wurde durch James Parkinson im Jahr 18171 vornehmlich als neurologische Bewegungsstörung beschrieben. Durch die Verdienste umfassender Forschung und klinischer Diagnostik der letzten Jahrzehnte wird das IPS heute als Syndrom aufgefasst, das neben motorischen auch durch neuropsychiatrische, vegetative und sensible Symptome charakterisiert ist. Eines dieser sogenannten „nicht-motorischen Symptome“ bildet die (milde) kognitive Beeinträchtigung, die jeden vierten nicht-dementen Parkinsonpatienten betrifft2 und die im oft langjährigen Krankheitsverlauf in eine Parkinsondemenz münden kann, an der 8 Jahre nach Krankheitsbeginn bis zu 78% der Parkinsonpatienten leiden.3 Durch die steigende Lebenserwartung der Patienten und die besseren Therapieoptionen der motorischen Komponente eines IPS finden derzeit gerade die nicht-motorischen Symptome sowohl in der Forschung als auch der Klinik zunehmend stärkere Beachtung.
Die motorische Symptomatik des IPS wird vorrangig durch die Degeneration dopaminerger Neuronen in bestimmten Strukturen des Hirnstamms hervorgerufen.4 Die Entwicklung kognitiver Symptome ist komplexer und umfasst vermutlich neben der (genannten) dopaminergen Degeneration die Beeinträchtigung weiterer Neurotransmitter sowie degenerative Prozesse an anderer Stelle des ZNS.5 Insbesondere die Atrophie von frontalem, parietalem und (medio-) temporalem Cortex scheint mit der Parkinsondemenz assoziiert.6–8 Auch gleichzeitig auftretende histopathologische Prozesse, die für die Alzheimer-Demenz charakteristisch sind, werden diskutiert.9
Der Hippocampus, eine Struktur des Mediotemporallappens, leistet einen bedeutenden Beitrag zum deklarativen räumlichen Gedächtnis und zum Arbeitsgedächtnis sowie zur Verarbeitung von Emotionen, sodass er beim normalen Altern, aber auch vielen Erkrankungen, eine wichtige Rolle einnimmt.10–12 Vor allem bei der Alzheimer-Demenz ist der Hippocampus eine sehr früh von der Atrophie betroffene Struktur.13 In den letzten Jahren mehren sich die Hinweise, dass dies auch bei der Parkinsondemenz der Fall ist.14–16 Aus diesem Grund wird im Folgenden ein besonderes Augenmerk auf diese Struktur gelegt.
Die vorliegende Studie setzt sich mit der Fragestellung auseinander, ob und inwiefern sich Parkinsonpatienten mit unterschiedlich ausgeprägten kognitiven Einschränkungen in den Volumina ausgewählter Hirnstrukturen – darunter die corticale graue und weiße 8 Substanz, der Hippocampus und die Hirnventrikel – sowie in den neuropsychologischen Domänen Gedächtnis, Exekutivfunktionen und Aufmerksamkeit, Sprache und visuell-räumliche Funktionen unterscheiden. Außerdem wird untersucht, ob zwischen den Hirnvolumina und dem Grad der kognitiven Einschränkung ein Zusammenhang besteht. Hierzu werden Parkinsonpatienten ohne Demenz (PD), Parkinsonpatienten mit milder kognitiver Beeinträchtigung (PD-MCI) und Patienten mit Parkinsondemenz (PDD) neuropsychologisch untersucht und magnetresonanztomographische Aufnahmen des Gehirns erstellt. Die mit einem automatisierten Messprogramm ermittelten Hirnvolumina werden in Korrelation zu Testungen des Gedächtnisses, der Exekutive und Aufmerksamkeit, der Sprache und visuell-räumlicher Funktionen gesetzt.
Die Arbeit gliedert sich wie folgt: Zum besseren Verständnis der kognitiven Symptomatik werden im ersten Kapitel die nicht-kognitiven Symptome des IPS charakterisiert sowie der aktuelle Wissensstand über Kognition beim IPS wiedergegeben. Anschließend werden die technischen Grundlagen der Magnetresonanztomographie und Methoden zur Auswertung struktureller MRT-Bilder erläutert. Darauf aufbauend wird die Fragestellung konkretisiert, bevor im zweiten Teil der Arbeit die Vorstellung des Studiendesigns, die Präsentation der Ergebnisse und im letzten Teil die Diskussion erfolgen.
Herb induced liver injury (HILI) and drug induced liver injury (DILI) share the common characteristic of chemical compounds as their causative agents, which were either produced by the plant or synthetic processes. Both, natural and synthetic chemicals are foreign products to the body and need metabolic degradation to be eliminated. During this process, hepatotoxic metabolites may be generated causing liver injury in susceptible patients. There is uncertainty, whether risk factors such as high lipophilicity or high daily and cumulative doses play a pathogenetic role for HILI, as these are under discussion for DILI. It is also often unclear, whether a HILI case has an idiosyncratic or an intrinsic background. Treatment with herbs of Western medicine or traditional Chinese medicine (TCM) rarely causes elevated liver tests (LT). However, HILI can develop to acute liver failure requiring liver transplantation in single cases. HILI is a diagnosis of exclusion, because clinical features of HILI are not specific as they are also found in many other liver diseases unrelated to herbal use. In strikingly increased liver tests signifying severe liver injury, herbal use has to be stopped. To establish HILI as the cause of liver damage, RUCAM (Roussel Uclaf Causality Assessment Method) is a useful tool. Diagnostic problems may emerge when alternative causes were not carefully excluded and the correct therapy is withheld. Future strategies should focus on RUCAM based causality assessment in suspected HILI cases and more regulatory efforts to provide all herbal medicines and herbal dietary supplements used as medicine with strict regulatory surveillance, considering them as herbal drugs and ascertaining an appropriate risk benefit balance.
The most frequently used parameters to describe the barrier properties of endothelial cells (ECs) in vitro are (i) the macromolecular permeability, indicating the flux of a macromolecular tracer across the endothelium, and (ii) electrical impedance of ECs grown on gold-film electrodes reporting on the cell layer's tightness for ion flow. Due to the experimental differences between these approaches, inconsistent observations have been described. Here, we present the first direct comparison of these assays applied to one single cell type (human microvascular ECs) under the same experimental conditions. The impact of different pharmacological tools (histamine, forskolin, Y-27632, blebbistatin, TRAP) on endothelial barrier function was analyzed by Transwell(®) tracer assays and two commercial impedance devices (xCELLigence(®), ECIS(®)). The two impedance techniques provided very similar results for all compounds, whereas macromolecular permeability readings were found to be partly inconsistent with impedance. Possible reasons for these discrepancies are discussed. We conclude that the complementary combination of both approaches is highly recommended to overcome the restrictions of each assay. Since the nature of the growth support may contribute to the observed differences, structure-function relationships should be based on cells that are consistently grown on either permeable or impermeable growth supports in all experiments.
Positive Effekte körperliche Aktivität als komplementäre Therapie in der Onkologie wurden in den letzten Jahren in zahlreichen Studien aufgezeigt. Hierbei zeigte sich ein Anstieg der körperlichen Fitness und Muskelmasse, eine Steigerung der Lebensqualität, eine Reduktion des Fatigue-Syndroms, aber auch eine verbesserte Therapieverträglichkeit sowie einer Rezidiv-Prophylaxe (Backman et al., 2014; Meyerhardt et al., 2006; Segal et al., 2001). Daraufhin wurden Empfehlungen für körperliche Aktivität im Rahmen der onkologischen Therapie ausgesprochen, welche 150 Minuten moderate körperliche Aktivität pro Woche umfassen. Diese Empfehlungen basieren auf entitätsunspezifische Studienkollektive mit meist Tumorstadium I und II. Eine Vielzahl an Studien verdeutlichen, dass gerade Patienten in fortgeschrittenen Tumorstadien mit zahlreichen therapie- sowie tumorbedingten Nebenwirkungen zu kämpfen haben und dadurch ein stärkerer Abbau der körperlichen Fitness, der Muskulatur, aber auch der funktionellen Eigenschaften vorzufinden ist. Hierbei stellen Patienten mit fortgeschrittenen gastrointestinalen Tumoren (GIT) ein stark belastetes Kollektiv dar, da 80 Prozent dieser Patienten eine Tumorkachexie erleiden. Zusätzliche wurde in einer Querschnittsuntersuchung aufgezeigt, dass Patienten mit fortgeschrittenen GIT bereits vor Therapiestart einen deutlich verminderten körperlichen und funktionellen Status im Vergleich zu Mammakarzinom-Patientinnen und Gesunden aufweisen (Stuecher et al., 2016). In der vorliegenden randomisiert kontrollierten Untersuchung wurde erstmals ein heimbasiertes Training ohne Supervision zur Steigerung der körperlichen Aktivität bei Patienten mit fortgeschrittenen GIT durchgeführt und dieses mit einer leitliniengetreuen onkologischen Therapie ohne komplementäre Bewegungstherapie verglichen. Dabei wurden der körperliche und funktionelle Status sowie die Aktivitäten des täglichen Lebens verglichen.
Zweiundvierzig Patienten mit fortgeschrittenen GIT (UICC ≥ III, 67,1 ± 6,8 Jahre, 45,2 % weiblich) wurden vor ihrer geplanten first-line Chemotherapie (CT) in die zweiarmige randomisiert kontrollierte Studie eingeschlossen. Eine der Gruppen (I) erhielt, entsprechend der ACSM-Guidelines für onkologische Patienten, die Vorgabe ein wöchentliches Laufprogramm mit einem Umfang von 150 Minuten moderater Intensität pro Woche. Die zweite Gruppe diente als Kontrollgruppe (K) und erhielt am Ende der Studiendauer entsprechende Empfehlungen. Die Interventionsdurchführung wurde mittels Trainingstagebuch und Pedometer begleitet. Vor Beginn (T0), nach zwei CT-zyklen (T1) sowie nach zwölf Wochen (T2) wurde der funktionelle und körperliche Status sowie die Alltagsbewältigung der Patienten erfasst.
Bei einer Dropoutrate von 36 Prozent konnten 28 (K: 15; I; 13) Patienten die Studie komplett durchlaufen. Die mittlere Adhärenzrate lag bei 81,3 Prozent. Im Untersuchungszeitraum konnten die folgenden sign. Veränderungen (p< 0,05) der einzelnen Parameter gezeigt werden. Die posturale Stabilität (COPLänge) konnte sowohl ein Gruppeneffekt, als auch ein Zeiteffekt nachgewiesen werden. Die Interventionsgruppe verbesserte sich im Zeitraum T0-T1 (-71,47mm) sowie im Gesamtzeitraum T0-T2 (-74,13 mm), wohingegen die Kontrollgruppe sich im Gesamtzeitraum T0-T2 (+72,83) verschlechterte. Die Gruppen unterschieden sich daher sowohl in den Zeiträumen T0-T1 ((K)+38,61; (I)-71,47 mm) sowie T0-T2 ((K)+72,83; (I) -74,13mm). Bezüglich des körperlichen Status konnte sich die Interventionsgruppe von T1-T2 (+4,03 kg) sowie von T0-T2 (+4,04 kg) verbessern, sodass sich die Gruppen zwischen den Zeitpunkten T1-T2 ((K) -0,49; (I)+4,03 kg) und T0-T2 ((K) 0,19; 4,04 kg) unterschieden. Der iADL-Fragebogen erbrachte eine Verbesserung der Interventionsgruppe im Gesamtmesszeitraum T0-T2 (+0,12), daraus resultierte ein zusätzlicher Gruppenunterschied in diesem Zeitraum ((K) -0,89; (I) +0,12). Der Ernährungszustand zeigte auch einen unterschiedlichen Verlauf der beiden Gruppen. Zwischen T1-T2 ((K) -0,59; + 1,74) sowie T0-T2 ((K) -0,55; (I) +2,39) unterschieden sich die Gruppen.
Obgleich es für einige Patienten schwierig war die Laufintervention gemäß den Empfehlungen durchzuführen, weisen die Teilnehmer der Interventionsgruppe sowohl in den Parametern des körperlichen, als auch des funktionellen Status Verbesserungen auf. Demnach scheint ein durchschnittlicher Umfang von zwei Stunden moderater körperlicher Aktivität während einer Tumortherapie ausreichend zu sein. Es veranschaulicht, dass eine komplementäre Bewegungstherapie in der onkologischen Therapie bei Patienten mit fortgeschrittenen GIT sinnvoll ist und sowohl einen Benefit in der Körperzusammensetzung, als auch der funktionellen Eigenschaften mitsichbringt. Dies hat wiederum einen positiven Einfluss auf die Alltagsbewältigung. Da einige Barrieren das Laufprogramm der Patienten einschränkten oder gar zum Laufabbruch führten, sollte versucht werden diese zu mindern. Hierbei sind vor allem klima- und wetterbedingte Barrieren ein möglicher Ansatzpunkt, da Nebenwirkungen kaum vermeidbar sind. Dennoch sollten die Patienten auch nach nebenwirkungsbedingten Laufpausen motiviert werden das Programm weiterzuführen. Diese Studie gibt zudem erste Hinweise, dass durch eine komplementäre Bewegungstherapie mit moderater körperlicher Aktivität die Toxizität der CT bei Patienten mit fortgeschrittenen GIT vermindert werden kann. Da der klinische Benefit, welcher in einigen Studien anderer Tumorentitäten postuliert wurde, in dieser Untersuchung nicht objektiv erfasst wurde, wäre dies ein möglicher Ansatzpunkt für Folgestudien.
Hintergrund: Die Delegation ärztlicher Leistungen an nichtärztliches medizinisches Fachpersonal wird in Deutschland vor dem Hintergrund eines absehbaren Hausärztemangels bei gleichzeitig wachsendem Bedarf an hausärztlichen Betreuungsleistungen seit einiger Zeit diskutiert. Inzwischen wurden unterschiedliche Qualifikationsmodelle für Medizinische Fachangestellte (MFA) (z.B. die Versorgungs-assistentin in der Hausarztpraxis, VERAH) konzipiert und implementiert, die für eine Delegation von Leistungen qualifizieren. VERAH sind v.a. in Baden-Württemberg in Hausarztpraxen tätig, da deren Einsatz dort im Rahmen der Hausarztzentrierten Versorgung (HzV) seit 2008 finanziell honoriert wird. Dabei ist es den Praxen freigestellt, wie sie das VERAH-Konzept und damit auch die Delegation umsetzen. Auch gesetzliche Vorgaben zur Delegation lassen erheblichen Spielraum bei der Umsetzung. Erschwerend kommt hinzu, dass weiterhin Unklarheit darüber besteht, welche Leistungsübertragung als „Delegation“ und welche eher als „Substitution“ zu verstehen ist.
Zielrichtung der Arbeit: Ziel dieser publikationsbasierten Dissertation ist eine Darstellung der Formen und Graduierungen von Delegation, d.h. der tatsächlichen Umsetzung von Leistungsübertragung in der Hausarztpraxis am Beispiel der VERAH in Baden-Württemberg. Es können Empfehlungen für das Gelingen der Delegation aus der Analyse von Ergebnissen auf Patienten-, Praxis- und Teamebene abgeleitet werden.
Resultate: Diese Dissertation basiert auf sechs Publikationen, die im Rahmen von zwei Projekten zur Evaluation des VERAH-Einsatzes in der HzV in Baden-Württemberg entstanden. Die Evaluationen basieren auf einem Mixed Methods-Design, d.h. auf der Analyse von querschnittlich erhobenen quantitativen Daten sowie qualitativen Daten zu verschiedenen Fragen des VERAH-Einsatzes.
Es existiert ein breites Spektrum an Formen und Graduierungen der Delegation in Hausarztpraxen, die am HzV-Modell teilnehmen. VERAH übernehmen einerseits supplementäre (zusätzliche) ärztliche Tätigkeiten, wie z.B. Geriatrisches Assessment oder Impfberatungen, aber auch komplementäre (ergänzende) Tätigkeiten wie z.B. die Beratung der Angehörigen zu Hilfeleistungen im Gesundheitssystem. Vor allem im Rahmen von Hausbesuchen üben VERAH auch substituierende (ersetzende) Funktionen
aus. Auf Patientenseite sind gerade ältere, multimorbide und pflegebedürftige Patienten Empfänger delegierter Leistungen. Sie erhalten eine umfassende Betreuung und werden beim Erhalt ihrer häuslichen Selbständigkeit unterstützt. Die Patienten sehen in der VERAH eine zusätzliche Vertrauensperson in der Praxis und akzeptieren sie als kompetente Ansprechpartnerin. Die Hausärzte profitieren durch die Delegation von Tätigkeiten an VERAH, indem sie entlastet werden und Zeit für wichtige medizinische Aufgaben gewinnen. Für VERAH stellt die Delegation eine Erweiterung ihrer Tätigkeits- und Kompetenzbereiche dar und kann insofern als ein Schritt zur Professionalisierung des nichtärztlichen Personals einer Hausarztpraxis gelten.
Viele Faktoren, die zum Gelingen einer Umsetzung der Delegation beitragen, können vom hausärztlichen Team selbst beeinflusst werden. Darunter fallen das Engagement der MFA, die Qualifikation, zeitliche Flexibilität, ausreichend Gestaltungsspielraum, Grad der Autonomie, Abgrenzung des Verantwortungsbereiches und auch adäquates Equipment. Entsprechend richten sich die hier formulierten Empfehlungen meist an die Praxis, aber auch an den Gesetzgeber.
Bedeutung für die übergeordnete Fragestellung: Die Ergebnisse dieser Arbeit zeigen, dass mit dem VERAH-Konzept erste Ansätze einer teambasierten Versorgung vorhanden sind, und dass sich die Analyse dieses Konzeptes eignet, um Desiderata für die Zukunft von Delegation (haus-)ärztlicher Leistungen an nichtärztliches Personal formulieren zu können. Teambasierte Ansätze bedürfen, wie auch internationale Beispiele verdeutlichen, einer Weiterentwicklung der bestehenden Delegationskonzepte in deutschen Hausarztpraxen. Idealerweise mündet eine mit Delegation einhergehende Aufgaben- und Rollenneuverteilung in einer Betreuungsform, in der alle Teammitglieder entsprechend ihrer Qualifikation an der Versorgung der Patienten in der Hausarztpraxis beteiligt sind. Daher kommt die Einbindung von Pflegekräften in die hausärztliche Versorgung genauso in Frage, wie auch speziell ausgebildete VERAH/MFA. In jedem Fall sollte über Schritte der Professionalisierung nichtärztlicher Berufsgruppen nachgedacht werden. Ob sich in Deutschland, wie in den USA und in Kanada, aus diesen Delegationskonzepten im Laufe der Zeit Substitution (im Sinne der Verantwortungsübertragung an nichtärztliche Berufsgruppen) entwickelt, bleibt abzuwarten. Die Ergebnisse der Dissertation zeigen, dass es mit der gegenwärtigen Umsetzung der Delegation an VERAH zu einer Erweiterung des Leistungsspektrums in den Hausarztpraxen kommen kann; eine Ausweitung der Delegation sollte jedoch zeitnah vorangetrieben werden.
Es war kein Aprilscherz, als das »Time Magazine« am 1. April 2013 auf der Titelseite ankündigte, wie man Krebs heilen kann. Anlass war die Gründung einer Initiative zur besseren Vernetzung von klinischen Forschern und Grundlagenwissenschaftlern, um so neue Therapieansätze wie »Checkpoint-Inhibitoren« bei malignem Melanom (schwarzem Hautkrebs), auch auf andere Krebserkrankungen übertragen zu können. Checkpoint-Inhibitoren sind der erste echte Durchbruch in der Therapie von fortgeschrittenen Krebserkrankungen.
Organspenden retten und verlängern Leben : Prof. Dr. Ingeborg Hauser im Interview mit Dr. Anne Hardy
(2016)
Der 21. Mai 2015 ist für Claudia und Timothy Pillar ein besonderer Tag. Seitdem verbindet das Paar mehr als die Erlebnisse einer fast vierzigjährigen Ehe und ein gemeinsamer Sohn. Tim Pillar hat seiner Frau eine Niere gespendet und ihr damit wieder ein (fast) normales Leben ermöglicht. Inzwischen spricht sie von ihrer Krankheit in der Vergangenheitsform.
Sie hören Stimmen, vermuten Botschaften in bedeutungslosen Ereignissen oder fühlen sich ferngesteuert: Die Symptome von Menschen mit einer schizophrenen Störung galten bisher als »uneinfühlbar«, da für Außenstehende nicht nachvollziehbar. Aktuelle neurowissenschaftliche Modelle helfen, die Verwechslung von »eigen« und »fremd« aufzuklären.
Obesity is associated with an increased risk of heart failure. Little is known about the impact of dietary changes on the cardiac sequelae in obese patients. Twenty-one obese subjects underwent a 12-week low calorie fasting phase of a formula diet. Transthoracic two-dimensional speckle-tracking echocardiography was performed to obtain systolic left ventricular strain before and after weight loss. Body mass index decreased significantly from 38.6 ± 6.2 to 31.5 ± 5.3 kg/m(2), and the total percentage fat loss was 19%. Weight reduction was associated with a reduction in blood pressure and heart rate. Left ventricular longitudinal global peak systolic strain was in the lower normal range (-18.7 ± 3.2%) before weight loss and was unchanged (-18.8 ± 2.4%) after 12 weeks on diet with substantial weight loss. Also, no significant change in global radial strain after weight loss was noted (41.1 ± 22.0 versus 43.9 ± 23.3, p = 0.09). Left atrial and ventricular dimensions were in normal range before fasting and remained unchanged after weight loss. In our study obesity was associated with normal systolic left ventricular function. A 12-week low calorie diet with successful weight loss can reduce blood pressure and heart rate. Systolic left ventricular function and morphology were not affected by rapid weight reduction.
Most research on human fear conditioning and its generalization has focused on adults whereas only little is known about these processes in children. Direct comparisons between child and adult populations are needed to determine developmental risk markers of fear and anxiety. We compared 267 children and 285 adults in a differential fear conditioning paradigm and generalization test. Skin conductance responses (SCR) and ratings of valence and arousal were obtained to indicate fear learning. Both groups displayed robust and similar differential conditioning on subjective and physiological levels. However, children showed heightened fear generalization compared to adults as indexed by higher arousal ratings and SCR to the generalization stimuli. Results indicate overgeneralization of conditioned fear as a developmental correlate of fear learning. The developmental change from a shallow to a steeper generalization gradient is likely related to the maturation of brain structures that modulate efficient discrimination between danger and (ambiguous) safety cues.
This position paper is the second ESCMID Consensus Document on this subject and aims to provide intensivists, infectious disease specialists, and emergency physicians with a standardized approach to the management of serious travel-related infections in the intensive care unit (ICU) or the emergency department. This document is a cooperative effort between members of two European Society of Clinical Microbiology and Infectious Diseases (ESCMID) study groups and was coordinated by Hakan Leblebicioglu and Jordi Rello for ESGITM (ESCMID Study Group for Infections in Travellers and Migrants) and ESGCIP (ESCMID Study Group for Infections in Critically Ill Patients), respectively. A relevant expert on the subject of each section prepared the first draft which was then edited and approved by additional members from both ESCMID study groups. This article summarizes considerations regarding clinical syndromes requiring ICU admission in travellers, covering immunocompromised patients.
Objective: The aim of this study was to assess the potential risk of gadobutrol-enhanced magnetic resonance imaging (MRI) in patients with moderate to severe renal impairment for the development of nephrogenic systemic fibrosis (NSF).
Materials and Methods: We performed a prospective, international, multicenter, open-label study in 55 centers. Patients with moderate to severe renal impairment scheduled for any gadobutrol-enhanced MRI were included. All patients received a single intravenous bolus injection of gadobutrol at a dose of 0.1 mmol/kg body weight. The primary target variable was the number of patients who develop NSF within a 2-year follow-up period.
Results: A total of 908 patients were enrolled, including 586 with moderate and 284 with severe renal impairment who are at highest risk for developing NSF. The mean time since renal disease diagnosis was 1.83 and 5.49 years in the moderate and severe renal impairment cohort, respectively. Overall, 184 patients (20.3%) underwent further contrast-enhanced MRI with other gadolinium-based contrast agents within the 2-year follow-up. No patient developed symptoms conclusive of NSF.
Conclusions: No safety concerns with gadobutrol in patients with moderate to severe renal impairment were identified. There were no NSF cases.
In this meeting report, particularly addressing the topic of protection of the cardiovascular system from ischemia/reperfusion injury, highlights are presented that relate to conditioning strategies of the heart with respect to molecular mechanisms and outcome in patients’ cohorts, the influence of co-morbidities and medications, as well as the contribution of innate immune reactions in cardioprotection. Moreover, developmental or systems biology approaches bear great potential in systematically uncovering unexpected components involved in ischemia–reperfusion injury or heart regeneration. Based on the characterization of particular platelet integrins, mitochondrial redox-linked proteins, or lipid-diol compounds in cardiovascular diseases, their targeting by newly developed theranostics and technologies opens new avenues for diagnosis and therapy of myocardial infarction to improve the patients’ outcome.
Under physiological conditions, endothelial cells and the endothelial nitric oxide (NO) synthase (eNOS) are the main source of NO in the cardiovascular system. However, several other cell types have also been implicated in the NO-dependent regulation of cell function, including erythrocytes. NO derived from red blood cells has been proposed to regulate erythrocyte membrane fluidity, inhibit platelet activation and induce vasodilation in hypoxic areas, but these proposals are highly controversial. In the current issue of Cell Communication and Signaling, an elegant study by Gambaryan et al., assayed NO production by erythrocytes by monitoring the activation of the platelet intracellular NO receptor, soluble guanylyl cyclase, and its downstream kinase protein kinase G. After systematically testing different combinations of erythrocyte/platelet suspensions, the authors found no evidence for platelet soluble guanylyl cyclase/protein kinase G activation by erythrocytes and conclude that erythrocytes do not release biologically active NO to inhibit platelet activation.
Left ventricular non-compaction cardiomyopathy and left ventricular assist device: a word of caution
(2016)
BACKGROUND: In patients with left ventricular non-compaction (LVNC), implantation of a left ventricular assist device (LVAD) may be performed as a bridge to transplantation. In this respect, the particular characteristics of the left ventricular myocardium may represent a challenge.
CASE PRESENTATION: We report a patient with LVNC who required urgent heart transplantation for inflow cannula obstruction nine months after receiving a LVAD. LVAD parameters, echocardiography and examination of the explanted heart suggested changes of left ventricular configuration brought about by LVAD support as the most likely cause of inflow cannula obstruction.
CONCLUSIONS: We conclude that changes experienced by non-compacted myocardium during LVAD support may give rise to inflow cannula obstruction and flow reduction. Presence of LVNC mandates tight surveillance for changes in LV configuration and LVAD flow characteristics and may justify urgent transplantation listing status.
The aim of this clinical trial was to evaluate the impact of all-trans retinoic acid (ATRA) in combination with chemotherapy and to assess the NPM1 status as biomarker for ATRA therapy in younger adult patients (18-60 years) with acute myeloid leukemia (AML). Patients were randomized for intensive chemotherapy with or without open-label ATRA (45 mg/m2, days 6-8; 15 mg/m2, days 9-21). Two cycles of induction therapy were followed by risk-adapted consolidation with high-dose cytarabine or allogeneic hematopoietic cell transplantation. Due to the open label character of the study, analysis was performed on an intention-to-treat (ITT) and a per-protocol (PP) basis. One thousand one hundred patients were randomized (556, STANDARD; 544, ATRA) with 38 patients treated vice versa. Median follow-up for survival was 5.2 years. ITT analyses revealed no difference between ATRA and STANDARD for the total cohort and for the subset of NPM1-mutated AML with respect to event-free (EFS; p = 0.93, p = 0.17) and overall survival (OS; p = 0.24 and p = 0.32, respectively). Pre-specified PP analyses revealed better EFS in NPM1-mutated AML (p = 0.05) and better OS in the total cohort (p = 0.03). Explorative subgroup analyses on an ITT basis revealed better OS (p = 0.05) in ATRA for genetic low-risk patients according to ELN recommendations. The clinical trial is registered at clinicaltrialsregister.eu (EudraCT Number: 2004-004321-95).
Cl(-) plays a crucial role in neuronal function and synaptic inhibition. However, the impact of neuronal morphology on the diffusion and redistribution of intracellular Cl(-) is not well understood. The role of spines in Cl(-) diffusion along dendritic trees has not been addressed so far. Because measuring fast and spatially restricted Cl(-) changes within dendrites is not yet technically possible, we used computational approaches to predict the effects of spines on Cl(-) dynamics in morphologically complex dendrites. In all morphologies tested, including dendrites imaged by super-resolution STED microscopy in live brain tissue, spines slowed down longitudinal Cl(-) diffusion along dendrites. This effect was robust and could be observed in both deterministic as well as stochastic simulations. Cl(-) extrusion altered Cl(-) diffusion to a much lesser extent than the presence of spines. The spine-dependent slowing of Cl(-) diffusion affected the amount and spatial spread of changes in the GABA reversal potential thereby altering homosynaptic as well as heterosynaptic short-term ionic plasticity at GABAergic synapses in dendrites. Altogether, our results suggest a fundamental role of dendritic spines in shaping Cl(-) diffusion, which could be of relevance in the context of pathological conditions where spine densities and neural excitability are perturbed.
Autophagy can act either as a tumor suppressor or as a survival mechanism for established tumors. To understand how autophagy plays this dual role in cancer, in vivo models are required. By using a highly heterogeneous C. elegans germline tumor, we show that autophagy-related proteins are expressed in a specific subset of tumor cells, neurons. Inhibition of autophagy impairs neuronal differentiation and increases tumor cell number, resulting in a shorter life span of animals with tumors, while induction of autophagy extends their life span by impairing tumor proliferation. Fasting of animals with fully developed tumors leads to a doubling of their life span, which depends on modular changes in transcription including switches in transcription factor networks and mitochondrial metabolism. Hence, our results suggest that metabolic restructuring, cell-type specific regulation of autophagy and neuronal differentiation constitute central pathways preventing growth of heterogeneous tumors.
Lactate is an essential component of carbon metabolism in mammals. Recently, lactate was shown to signal through the G protein coupled receptor 81 (GPR81) and to thus modulate inflammatory processes. This study demonstrates that lactate inhibits pro-inflammatory signaling in a GPR81-independent fashion. While lipopolysaccharide (LPS) triggered expression of IL-6 and IL-12 p40, and CD40 in bone marrow-derived macrophages, lactate was able to abrogate these responses in a dose dependent manner in Gpr81-/- cells as well as in wild type cells. Macrophage activation was impaired when glycolysis was blocked by chemical inhibitors. Remarkably, lactate was found to inhibit LPS-induced glycolysis in wild type as well as in Gpr81-/- cells. In conclusion, our study suggests that lactate can induce GPR81-independent metabolic changes that modulate macrophage pro-inflammatory activation.
Preserving a patient’s own teeth—even in a difficult situation—is nowadays preferable to surgical intervention and therefore promotes development of suitable dental repair materials. Biodentine®, a mineral trioxide aggregate substitute, has been used to replace dentine in a bioactive and biocompatible manner in both the dental crown and the root. The aim of our study was to evaluate the influence of Biodentine® on pulp fibroblasts in vitro. For this study, one to five Biodentine® discs with a diameter of 5.1mm were incubated in DMEM. To obtain Biodentine® suspensions the media were collected and replaced with fresh medium every 24h for 4 days. Primary pulp cells were isolated from freshly extracted wisdom teeth of 20–23 year old patients and incubated with the Biodentine® suspensions. Proliferation, cell morphology, cell integrity and cell viability were monitored. To evaluate the effect of Biodentine® on collagen type I synthesis, the secretion of the N-terminal domain of pro-collagen type I (P1NP) and the release of transforming growth factor-β1 (TGF-β1) were quantified. None of the Biodentine® suspensions tested influenced cell morphology, proliferation or cell integrity. The cell viability varied slightly depending on the suspension used. However, the concentrations of P1NP of all pulp fibroblast cultures treated for 24h with the moderate to high Biodentine® concentration containing suspensions of day 1 were reduced to 5% of the control. Furthermore, a significant TGF-β1 reduction was observed after treatment with these suspensions. It could be shown that Biodentine® is biocompatible. However, dissolved particles of the moderate to high concentrated Biodentine® suspensions 24h after mixing induce a significant reduction of TGF-β1 release and reduce the secretion of collagen type I of primary pulp fibroblasts.
Combined diabetes-obesity syndromes severely impair regeneration of acute skin wounds in mouse models. This study assessed the contribution of subcutaneous adipose tissue to exacerbated wound inflammatory conditions. Genetically obese (ob/ob) mice showed an increased expression of positive transcriptional effectors of adipocyte differentiation such as Krüppel-like factor (KLF)-5 and peroxisome proliferator-activated receptor (PPAR)-γ and an associated expression of leptin and fatty acid-binding protein (FABP)-4, but also CXCL2 in isolated subcutaneous fat. This observation in obese mice is in keeping with differentially elevated levels of KLF-5, PPAR-γ, leptin, FABP-4 and CXCL2 in in vitro-differentiated 3T3-L1 adipocytes. Notably, CXCL2 expression restrictively appeared upon cytokine (IL-1β/TNF-α) stimulation only in mature, but not immature 3T3-L1 adipocytes. Of importance, the critical regulator of adipocyte maturation, PPAR-γ, was merely expressed in the final phase of in-vitro induced adipocyte differentiation from 3T3-L1 pre-adipocytes. Consistently, the PPAR-γ agonist rosiglitazone suppressed cytokine-induced CXCL2 release from mature adipocytes, but not from early 3T3-L1 adipocyte stages. The inhibitory effect of PPAR-γ activation on CXCL2 release appeared to be a general anti-inflammatory effect in mature adipocytes, as cytokine-induced cyclooxygenase (Cox)-2 was simultaneously repressed by rosiglitazone. In accordance with these findings, oral administration of rosiglitazone to wounded obese mice significantly changed subcutaneous adipocyte morphology, reduced wound CXCL2 and Cox-2 expression and improved tissue regeneration. Thus, our data suggest that PPAR-γ might provide a target to suppress inflammatory signals from mature adipocytes, which add to the prolonged wound inflammation observed in diabetes-obesity conditions.
Background: Antiangiogenic treatment of glioblastomas with Bevacizumab lacks predictive markers. Myoinositol (MI) is an organic osmolyte, with intracellular concentration changes depending on the extracellular osmolality. Since Bevacizumab markedly reduces tumor edema and influences the tumor microenvironment, we investigated whether the MI concentration in the tumor changes during therapy.
Methods: We used 1H-magnetic resonance spectroscopy to measure the MI concentrations in the tumor and contralateral control tissue of 39 prospectively recruited patients with recurrent glioblastomas before and 8–12 weeks after starting therapy. 30 patients received Bevacizumab and 9 patients were treated with CCNU/VM26 as control. We performed a survival analysis to evaluate MI as a predictive biomarker for Bevacizumab therapy.
Results: MI concentrations increased significantly during Bevacizumab therapy in tumor (p < .001) and control tissue (p = .001), but not during CCNU/VM26 treatment. For the Bevacizumab cohort, higher MI concentrations in the control tissue at baseline (p = .021) and higher differences between control and tumor tissue (delta MI, p = .011) were associated with longer survival. A Kaplan-Meier analysis showed a median OS of 164 days for patients with a deltaMI < 1,817 mmol/l and 275 days for patients with a deltaMI > 1,817 mmol/l. No differences were observed for the relative changes or the post treatment concentrations. Additionally calculated creatine concentrations showed no differences in between subgroups or between pre and post treatment measurements.
Conclusion: Our data suggest that recurrent glioblastoma shows a strong metabolic reaction to Bevacizumab. Further, our results support the hypothesis that MI might be a marker for early tumor cell invasion. Pre-therapeutic MI concentrations are predictive of overall survival in patients with recurrent glioblastoma treated with Bevacizumab.
This study evaluated the interferon-free, oral combination of deleobuvir (non-nucleoside HCV NS5-RNA-polymerase inhibitor) and faldaprevir (HCV NS3/4A-protease inhibitor) with ribavirin in patients with HCV genotype-1b and moderate (Child-Pugh B [CPB], n = 17) or mild hepatic impairment (Child-Pugh A [CPA], n = 18). Patients received faldaprevir 120 mg and deleobuvir (600 mg [CPA], 400 mg [CPB]) twice-daily with weight-based ribavirin for 24 weeks. Baseline characteristics were similar between groups. Among CPA patients, 13/18 completed treatment; discontinuations were for adverse events (AEs, n = 1), lack of efficacy (n = 3) and withdrawal (n = 1). Among CPB patients, 8/17 completed treatment; discontinuations were for AEs (n = 6), withdrawal (n = 1) and ‘other’ (n = 2). Sustained virologic response at post-treatment Week 12 (SVR12) was achieved by 11 (61%) CPA patients (95% confidence interval: 38.6%–83.6%) and 9 (53%) CPB patients (95% confidence interval: 29.2%–76.7%), including most CPA (11/16) patients with Week 4 HCV RNA <25 IU.mL-1 (target detected or not detected) and most CPB (8/9) patients with Week 4 HCV RNA <25 IU.mL-1 (target not detected); 0/4 CPB patients with Week 4 HCV RNA <25 IU.mL-1 (target detected) achieved SVR12. The most common AEs in both groups were nausea, diarrhoea and vomiting. Serious AEs were observed in 9 (53%) CPB patients and 1 (6%) CPA patient. Plasma trough concentrations of deleobuvir and faldaprevir were not substantially different between the CPA and CPB groups. In conclusion, in this small study the safety and efficacy profiles for 24 weeks of treatment with faldaprevir+deleobuvir+ribavirin in patients with mild or moderate hepatic impairment were consistent with the safety and efficacy profile of this regimen in non-cirrhotic patients. Faldaprevir+deleobuvir+ribavirin resulted in SVR12 in 53–61% of patients: proportions achieving SVR4 but not SVR12 were higher than in non-cirrhotic patients and overall response rates were lower than rates reported with other all-oral regimens in patients with cirrhosis.
BACKGROUND: Evaluation of latest generation automated attenuation-based tube potential selection (ATPS) impact on image quality and radiation dose in contrast-enhanced chest-abdomen-pelvis computed tomography examinations for gynaecologic cancer staging.
METHODS: This IRB approved single-centre, observer-blinded retrospective study with a waiver for informed consent included a total of 100 patients with contrast-enhanced chest-abdomen-pelvis CT for gynaecologic cancer staging. All patients were examined with activated ATPS for adaption of tube voltage to body habitus. 50 patients were scanned on a third-generation dual-source CT (DSCT), and another 50 patients on a second-generation DSCT. Predefined image quality setting remained stable between both groups at 120 kV and a current of 210 Reference mAs. Subjective image quality assessment was performed by two blinded readers independently. Attenuation and image noise were measured in several anatomic structures. Signal-to-noise ratio (SNR) was calculated. For the evaluation of radiation exposure, CT dose index (CTDIvol) values were compared.
RESULTS: Diagnostic image quality was obtained in all patients. The median CTDIvol (6.1 mGy, range 3.9-22 mGy) was 40 % lower when using the algorithm compared with the previous ATCM protocol (median 10.2 mGy · cm, range 5.8-22.8 mGy). A reduction in potential to 90 kV occurred in 19 cases, a reduction to 100 kV in 23 patients and a reduction to 110 kV in 3 patients of our experimental cohort. These patients received significantly lower radiation exposure compared to the former used protocol.
CONCLUSION: Latest generation automated ATPS on third-generation DSCT provides good diagnostic image quality in chest-abdomen-pelvis CT while average radiation dose is reduced by 40 % compared to former ATPS protocol on second-generation DSCT.
Multimodal therapy of glioblastoma (GBM) reveals inter-individual variability in terms of treatment outcome. Here, we examined whether a miRNA signature can be defined for the a priori identification of patients with particularly poor prognosis.
FFPE sections from 36 GBM patients along with overall survival follow-up were collected retrospectively and subjected to miRNA signature identification from microarray data. A risk score based on the expression of the signature miRNAs and cox-proportional hazard coefficients was calculated for each patient followed by validation in a matched GBM subset of TCGA. Genes potentially regulated by the signature miRNAs were identified by a correlation approach followed by pathway analysis.
A prognostic 4-miRNA signature, independent of MGMT promoter methylation, age, and sex, was identified and a risk score was assigned to each patient that allowed defining two groups significantly differing in prognosis (p-value: 0.0001, median survival: 10.6 months and 15.1 months, hazard ratio = 3.8). The signature was technically validated by qRT-PCR and independently validated in an age- and sex-matched subset of standard-of-care treated patients of the TCGA GBM cohort (n=58). Pathway analysis suggested tumorigenesis-associated processes such as immune response, extracellular matrix organization, axon guidance, signalling by NGF, GPCR and Wnt. Here, we describe the identification and independent validation of a 4-miRNA signature that allows stratification of GBM patients into different prognostic groups in combination with one defined threshold and set of coefficients that could be utilized as diagnostic tool to identify GBM patients for improved and/or alternative treatment approaches.
Background: Erythema migrans represents an early cutaneous and most common manifestation of Lyme borreliosis. Recommendations regarding pharmacological agents, dose and duration of treatment are subject of intense debate. This review aims to explore differences in efficacy and safety between pharmacological treatments and control treatment.
Methods: To identify relevant studies, we will conduct a systematic literature search. We will include randomised controlled trials (RCTs) and non-RCTs. Eligible comparative studies need to (1) consider patients with a diagnosis of erythema migrans resulting from Lyme borreliosis and (2) compare different pharmacological agents against each other, against any other non-pharmacological treatment, placebo or no treatment. Two review authors will independently assess included studies for risk of bias according to the methods of the Cochrane Handbook for Systematic Reviews of Interventions and related to specific study designs. We will address patient-relevant outcomes including clinical remission of cutaneous symptoms, any treatment-related adverse events, quality of life and progressive symptoms such as neuroborreliosis or Lyme carditis and flu-like symptoms. Provided that the identified trials are comparable in terms of clinical issues, combined estimates will be provided. Estimations of treatment effects will be calculated based on a random effects model. Heterogeneity will be evaluated based on I (2) and chi-square test. In case of significant heterogeneity, a pooled estimate will not be provided, but heterogeneity will be investigated on the basis of methodological and clinical study aspects. We plan subgroup analysis to reveal potential differences in the effect estimates between patient populations and treatment specifications. We will consider risk of bias using sensitivity analyses to decide whether to rely on the pooled estimates. The quality of a body of evidence for individual outcomes will be assessed using the GRADE approach.
Discussion: Benefits and harms of pharmacological treatment in erythema migrans have not yet been adequately assessed. This systematic review will evaluate and summarise available evidence addressing benefits and harms of different pharmacological treatments. In addition, this summary of clinical evidence will inform decision-making between clinicians and patients and will play an important part in patient care.
Systematic review registration: PROSPERO: CRD42016037932.
Aus Wissen wird Gesundheit : das Magazin des Universitätsklinikums Frankfurt. Ausgabe 04/2016
(2016)
Aus Wissen wird Gesundheit : das Magazin des Universitätsklinikums Frankfurt. Ausgabe 03/2016
(2016)
The physiological role of amyloid precursor protein (APP) has been extensively investigated in the rodent hippocampus. Evidence suggests that APP plays a role in synaptic plasticity, dendritic and spine morphogenesis, neuroprotection and—at the behavioral level—hippocampus-dependent forms of learning and memory. Intriguingly, however, studies focusing on the role of APP in synaptic plasticity have reported diverging results and considerable differences in effect size between the dentate gyrus (DG) and area CA1 of the mouse hippocampus. We speculated that regional differences in APP expression could underlie these discrepancies and studied the expression of APP in both regions using immunostaining, in situ hybridization (ISH), and laser microdissection (LMD) in combination with quantitative reverse transcription polymerase chain reaction (RT-qPCR) and western blotting. In sum, our results show that APP is approximately 1.7-fold higher expressed in pyramidal cells of Ammon’s horn than in granule cells of the DG. This regional difference in APP expression may explain why loss-of-function approaches using APP-deficient mice revealed a role for APP in Hebbian plasticity in area CA1, whereas this could not be shown in the DG of the same APP mutants.
Background: Immunosuppression with calcineurin inhibitors remains the mainstay of treatment after kidney transplantation; however, long-term use of these drugs may be associated with nephrotoxicity. In this regard, the current approach is to optimise available immunosuppressive regimens to reduce the calcineurin inhibitor dose while protecting renal function without affecting the efficacy. The ATHENA study is designed to evaluate renal function in two regimens: an everolimus and reduced calcineurin inhibitor-based regimen versus a standard treatment protocol with mycophenolic acid and tacrolimus in de novo kidney transplant recipients.
Method/Design: ATHENA is a 12-month, multicentre, open-label, prospective, randomised, parallel-group study in de novo kidney transplant recipients (aged 18 years or older) receiving renal allografts from deceased or living donors. Eligible patients are randomised (1:1:1) prior to transplantation to one of the following three treatment arms: everolimus (starting dose 1.5 mg/day; C0 3–8 ng/mL) with cyclosporine or everolimus (starting dose 3 mg/day; C0 3–8 ng/mL) with tacrolimus or mycophenolic acid (enteric-coated mycophenolate sodium at 1.44 g/day or mycophenolate mofetil at 2 g/day) with tacrolimus; in combination with corticosteroids. All patients receive induction therapy with basiliximab. The primary objective is to demonstrate non-inferiority of renal function (eGFR by the Nankivell formula) in one of the everolimus arms compared with the standard group at month 12 post transplantation. The key secondary objective is to assess the incidence of treatment failure, defined as biopsy-proven acute rejection, graft loss, or death, among the treatment groups. Other objectives include assessment of the individual components of treatment failure, incidence and severity of viral infections, incidence and duration of delayed graft function, incidence of indication biopsies, slow graft function and wound healing complications, and overall safety and tolerability. Exploratory objectives include evaluation of left ventricular hypertrophy assessed by the left ventricular mass index, evolution of human leukocyte antigen and non-human leukocyte antigen antibodies, and a cytomegalovirus substudy.
Discussion: As one of the largest European multicentre kidney transplant studies, ATHENA will determine whether a de novo everolimus-based regimen can preserve renal function versus the standard of care. This study further assesses a number of clinical issues which impact long-term outcomes post transplantation; hence, its results will have a major clinical impact.
Trial registration: Clinicaltrials.gov: NCT01843348, date of registration – 18 April 2013; EUDRACT number: 2011-005238-21, date of registration – 20 March 2012
Targeted redox inhibition of protein phosphatase 1 by Nox4 regulates eIF2α‐mediated stress signaling
(2016)
Phosphorylation of translation initiation factor 2α (eIF2α) attenuates global protein synthesis but enhances translation of activating transcription factor 4 (ATF4) and is a crucial evolutionarily conserved adaptive pathway during cellular stresses. The serine–threonine protein phosphatase 1 (PP1) deactivates this pathway whereas prolonging eIF2α phosphorylation enhances cell survival. Here, we show that the reactive oxygen species‐generating NADPH oxidase‐4 (Nox4) is induced downstream of ATF4, binds to a PP1‐targeting subunit GADD34 at the endoplasmic reticulum, and inhibits PP1 activity to increase eIF2α phosphorylation and ATF4 levels. Other PP1 targets distant from the endoplasmic reticulum are unaffected, indicating a spatially confined inhibition of the phosphatase. PP1 inhibition involves metal center oxidation rather than the thiol oxidation that underlies redox inhibition of protein tyrosine phosphatases. We show that this Nox4‐regulated pathway robustly enhances cell survival and has a physiologic role in heart ischemia–reperfusion and acute kidney injury. This work uncovers a novel redox signaling pathway, involving Nox4–GADD34 interaction and a targeted oxidative inactivation of the PP1 metal center, that sustains eIF2α phosphorylation to protect tissues under stress.
Copeptin is the C-terminal end of pre-provasopressin released equimolar to vasopressin into circulation and recently discussed as promising cardiovascular biomarker amendatory to established markers such as troponins. Vasopressin is a cytokine synthesized in the hypothalamus. A direct release of copeptin from the heart into the circulation is implied by data from a rat model showing a cardiac origin in hearts put under cardiovascular wall stress. Therefore, evaluation of a potential release of copeptin from the human heart in acute myocardial infarction (AMI) has been done.