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Short-term mechanical circulatory support (MCS) plays an increasing role in patients in acute cardiogenic shock as a bridge-to-decision strategy for potential left ventricular assist device (LVAD) implantation. Microaxial flow pump (MFP) therapy thereby is gaining increasing importance as a complement to venoarterial extracorporeal membrane oxygenation (VA-ECMO) therapy for left ventricular unloading. The aim of the study was to compare VA-ECMO vs. VA-ECMO + MFP therapy as short-term MCS prior to LVAD implantation. 183 patients with advanced heart failure underwent LVAD implantation at our center between 2010 - 2020. Of these, 34 patients had short-term MCS with VA-ECMO (n=16, group 1) or VA-ECMO + MFP (n=18, group 2) before LVAD implantation. Data were retrospectively analysed. Both groups consisted only of patients in acute cardiogenic shock (INTERMACS profile 1 + 2, age (group 1 vs. group 2: 50.1±9.8 vs. 52.7±7.3 years, p=0.1)). Short-term MCS was performed until LVAD implantation. Time on short-term MCS (6.6±3.8 vs. 8±4.9 days, p=0.4) showed no significant difference between the groups. Implanted permanent devices were HVAD and Heart Mate 3 (HM3) (group 1: HVAD: 88%, HM3: 12%; group 2: HVAD: 55%, HM3: 45%). Procedural characteristics showed no significant differences in terms of access, procedure time or volume management. Rates of in-hospital stroke (5.5 vs. 0%, p=1.0) and major bleeding (0 vs. 0%, p=1.0) were low in both groups. Rate of concomitant temporary RVAD implantation was similar in both groups (43.7 vs. 38.8%, p=1.0). Consecutive right heart failure in the first 3 months occurred in both groups (6,3 vs.5.5%, p=1.0). 30-day (12.5 vs. 17%, p=1.0) and 1-year mortality (31.3 vs. 22.2%, p=0.7) revealed no significant differences between groups. Our study shows a similar outcome after short-term MCS and LVAD implantation in both groups resulting in a 30-day survival of >80% in our high-risk cohorts. The effect of additional MFP needs to be proven in further studies. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Restoration of myocardial blood flow after ischemia triggers an inflammatory response involving toll-like receptors. Toll-like receptor 2 deficiency is associated with a reduced infarct size after myocardial ischemia and reperfusion. Because a marked mortality was observed in C3HeN wild-type mice, which was absent in TLR2 mice, we tested whether cardiac arrhythmias are the underlying pathology and aimed to elucidate how toll-like receptor 2 ligation might prevent lethal arrhythmias. DESIGN: Experimental animal model. SETTING: University hospital research laboratory. SUBJECTS: Male C3HeN mice. INTERVENTIONS: Myocardial ischemia and reperfusion was surgically induced by ligation of the left anterior descending coronary artery for 20 mins followed by 24 hrs of reperfusion. Electrocardiography was continuously recorded during the observation period through an implantable telemetry transmitter to detect cardiac arrhythmias during reperfusion. MEASUREMENTS AND MAIN RESULTS: Toll-like receptor 2 expression was associated with a 51% mortality rate (23 of 45 mice died) after myocardial ischemia and reperfusion. Absence of toll-like receptor 2 improved survival toward 100% (17 of 17 mice survived). Electrocardiography diagnostics in conscious animals and histologic analysis revealed that absence of toll-like receptor 2 signaling prevented the formation of pathologic heart rate turbulence after myocardial ischemia and reperfusion and modulated the density of connexin 43-positive gap junctions in the ischemic area compared with wild-type hearts, indicating arrhythmia as the cause underlying the observed mortality. CONCLUSIONS: The results presented here indicate toll-like receptor 2 as a novel target for the prevention of lethal arrhythmic complications after myocardial ischemia and reperfusion. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To test whether preconditioning with a toll-like receptor (TLR) 2 agonist protects against myocardial ischemia and reperfusion by interfering with chemokine CXCL1 release from cardiomyocytes. DESIGN: C3H mice were challenged with vehicle or synthetic TLR2 agonist Pam3Cys-Ser-Lys4 (Pam3CSK4; 1 mg/kg) 24 hrs before myocardial ischemia (20 mins) and reperfusion (2 hrs or 24 hrs). Infarct size, troponin T release, and leukocyte recruitment were quantified. In murine cardiomyocytes (HL-1), we studied the expression/activation profile of TLR2 in response to stimulation with Pam3CSK4 (0.01-1 mg/mL). Furthermore, we studied the chemokine ligand 1 (CXCL1) response to Pam3CSK4 and ischemia/reperfusion in vivo and in vitro. SETTING: University hospital research laboratory. SUBJECTS: Anesthetized male mice and murine cardiomyocytes. MEASUREMENTS AND MAIN RESULTS: Preconditioning by Pam3CSK4 reduced infarct size and troponin T release. This was accompanied by a decreased recruitment of leukocytes into the ischemic area and an improved cardiac function. In HL-1 cells, TLR2 activation amplified the expression of the receptor in a time-dependent manner and led to CXCL1 release in a concentration-dependent manner. Preconditioning by Pam3CSK4 impaired CXCL1 release in response to a second inflammatory stimulus in vivo and in vitro. CONCLUSIONS: Preconditioning by TLR2 agonist Pam3CSK4 reduces myocardial infarct size after myocardial ischemia/reperfusion. One of the mechanisms involved is a diminished chemokine release from cardiomyocytes, which subsequently limits leukocyte infiltration. [ABSTRACT FROM AUTHOR]

Abstract Background Bacterial DNA containing motifs of unmethylated CpG dinucleotides (CpG-ODN) initiate an innate immune response mediated by the pattern recognition receptor Toll-like receptor 9 (TLR9). This leads in particular to the expression of proinflammatory mediators such as tumor necrosis factor (TNF-α) and interleukin-1β (IL-1β). TLR9 is expressed in human and murine pulmonary tissue and induction of proinflammatory mediators has been linked to the development of acute lung injury. Therefore, the hypothesis was tested whether CpG-ODN administration induces an inflammatory response in the lung via TLR9 in vivo. Methods Wild-type (WT) and TLR9-deficient (TLR9-D) mice received CpG-ODN intraperitoneally (1668-Thioat, 1 nmol/g BW) and were observed for up to 6 hrs. Lung tissue and plasma samples were taken and various inflammatory markers were measured. Results In WT mice, CpG-ODN induced a strong activation of pulmonary NFκB as well as a significant increase in pulmonary TNF-α and IL-1β mRNA/protein. In addition, cytokine serum levels were significantly elevated in WT mice. Increased pulmonary content of lung myeloperoxidase (MPO) was documented in WT mice following application of CpG-ODN. Bronchoalveolar lavage (BAL) revealed that CpG-ODN stimulation significantly increased total cell number as well as neutrophil count in WT animals. In contrast, the CpG-ODN-induced inflammatory response was abolished in TLR9-D mice. Conclusion This study suggests that bacterial CpG-ODN causes lung inflammation via TLR9.

Background:  Systemic inflammation due to cardiogenic shock is associated with vasoplegia leading to organ hypoperfusion, right heart failure, and poor clinical outcome. Extracorporeal cytokine hemoadsorption emerged to attenuate excessive levels of inflammatory cytokines, potentially improving patient outcomes. Nevertheless, its prognostic impact during high-risk left ventricular assist device (LVAD) implantation remains unknown., Methods:  In total, 40 consecutive patients with advanced heart failure underwent continuous-flow LVAD implantation at our institution between 2018 and 2020. Out of 25 high-risk patients in cardiogenic shock (Interagency Registry for Mechanically Assisted Circulatory Support profile 1 and 2), 9 patients ( CytoSorb group ) underwent LVAD implantation with and 16 patients ( control group ) without simultaneous cytokine hemoadsorption during cardiopulmonary bypass. Besides preoperative patient characteristics, postoperative lactate clearance, vasopressor administration and mean arterial pressure, perioperative complication, and 30-day mortality rates were retrospectively analyzed., Results:  Apart from an increased rate of reoperations within the CytoSorb group, baseline characteristics including the severity of ventricular dysfunction and consecutive signs of end-organ failure were similar in both groups. Preoperative short-term mechanical circulatory support bridging was comparable (66.7 vs. 75%; p  = 0.66) prior to LVAD implantation. Procedural characteristics including intraoperative volume management and postoperative vasopressor administration were similar in both groups. There was no difference regarding postoperative lactate clearance, although postoperative mean arterial pressure was significantly higher in the control group (71.3 vs. 57.4 mm Hg; p  < 0.01). Furthermore, the 30-day mortality rate was significantly higher in the CytoSorb group (33.3 vs. 0.0%; p  = 0.01)., Conclusion:  Extracorporeal cytokine hemoadsorption during high-risk LVAD implantation was not associated with a decrease of postoperative vasopressor support, improved hemodynamics, or an accelerated lactate clearance., Competing Interests: A.M.B declared personal fees from Abbott, Abiomed, AstraZeneca, BerlinHeart, and Medtronic. H.R. declared travel grants from Abbott and Medtronic. Additionally, here are no further disclosures., (Thieme. All rights reserved.)

Objectives: Implantation of implantable cardioverter defibrillators (ICD) reduces the risk of all-cause mortality in symptomatic heart failure (HF) patients with severe left ventricular (LV) dysfunction. Nevertheless, the prognostic impact of ICD therapy in continuous flow left ventricular assist device (LVAD) recipients remains controversial., Methods: 162 consecutive HF patients, who underwent LVAD implantation at our institution between 2010 and 2019, were categorized according to the presence ( n  = 94, ICD-group ) or absence ( n  = 68, Control-group) of ICDs. Apart from clinical baseline and follow-up parameters, adverse events (AEs) related to ICD therapy and overall survival rates were retrospectively analyzed., Results: Out of 162 consecutive LVAD recipients 79 patients (48.8%) were preoperatively categorized as Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile ≤2. The prevalence of severe HF symptoms and preoperative use of short-term circulatory support devices (54.4% vs. 13.8%, p  < 0.001) was higher within the Control-group, although baseline severity of LV and RV dysfunction was similar. Apart from an increased prevalence of perioperative right heart failure (RHF) within the Control-group (45.6% vs. 17.0%; p  < 0.001), procedural characteristics and perioperative outcome were similar. Overall-survival during a median follow-up of 14 (3.0-36.5) months was similar within both groups ( p  = 0.46). During the first 2 years after LVAD implantation 53 ICD-related AEs occurred within the ICD-group. Thereof, lead-dysfunction occurred in 19 patients and unplanned ICD-reintervention in 11 patients. Furthermore, in 18 patients appropriate shocks without loss of consciousness occurred, whereas inappropriate shocks occurred in 5 patients., Conclusion: ICD therapy in LVAD recipients was not associated with a survival benefit or reduced morbidity after LVAD implantation. Conservative ICD-programming seems to be justified to avoid ICD-related complications and "awake shocks" after LVAD implantation., Competing Interests: TT declared consulting activity for Medtronic and Boston Scientific, as well as speaker honorarium from Medtronic. YY and SP declared consulting activity for Medtronic and Philips Medical. HR declared travel grants and speaker honoraria from Abbott and Abiomed. AB declared consulting activity for Abiomed, as well as travel grants and speaker honoraria from Abbott and Abiomed., (© 2023 Pausch, Mersmann, Bhadra, Barten, Tönnis, Yildirim, Pecha, Reichenspurner and Bernhardt.)

Study Objective: We explored the feasibility of a Clinical Decision Support System (CDSS) to guide evidence-based perioperative anticoagulation., Design: Prospective randomised clinical management simulation multicentre study., Setting: Five University and 11 general hospitals in Germany., Participants: We enrolled physicians (anaesthesiologist (n = 73), trauma surgeons (n = 2), unknown (n = 1)) with different professional experience., Interventions: A CDSS based on a multiple-choice test was developed and validated at the University Hospital of Frankfurt (phase-I). The CDSS comprised European guidelines for the management of anticoagulation in cardiology, cardio-thoracic, non-cardio-thoracic surgery and anaesthesiology. Phase-II compared the efficiency of physicians in identifying evidence-based approach of managing perioperative anticoagulation. In total 168 physicians were randomised to CDSS (PERI-KOAG) or CONTROL., Measurements: Overall mean score and association of processing time and professional experience were analysed. The multiple-choice test consists of 11 cases and two correct answers per question were required to gain 100% success rate (=22 points)., Main Results: In total 76 physicians completed the questionnaire (n = 42 PERI-KOAG; n = 34 CONTROL; attrition rate 54%). Overall mean score (max. 100% = 22 points) was significantly higher in PERI-KOAG compared to CONTROL (82 ± 15% vs. 70 ± 10%; 18 ± 3 vs. 15 ± 2 points; P = 0.0003). A longer processing time is associated with significantly increased overall mean scores in PERI-KOAG (≥33 min. 89 ± 10% (20 ± 2 points) vs. <33 min. 73 ± 15% (16 ± 3 points), P = 0.0005) but not in CONTROL (≥33 min. 74 ± 13% (16 ± 3 points) vs. <33 min. 69 ± 9% (15 ± 2 points), P = 0.11). Within PERI-KOAG, there is a tendency towards higher results within the more experienced group (>5 years), but no significant difference to less (≤5 years) experienced colleagues (87 ± 10% (19 ± 2 points) vs. 78 ± 17% (17 ± 4 points), P = 0.08). However, an association between professional experience and success rate in CONTROL has not been shown (71 ± 8% vs. 70 ± 13%, 16 ± 2 vs. 15 ± 3 points; P = 0.66)., Conclusions: CDSS significantly improved the identification of evidence-based treatment approaches. A precise usage of CDSS is mandatory to maximise efficiency., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The Virtual Brain (TVB) is now available as open-source services on the cloud research platform EBRAINS (ebrains.eu). It offers software for constructing, simulating and analysing brain network models including the TVB simulator; magnetic resonance imaging (MRI) processing pipelines to extract structural and functional brain networks; combined simulation of large-scale brain networks with small-scale spiking networks; automatic conversion of user-specified model equations into fast simulation code; simulation-ready brain models of patients and healthy volunteers; Bayesian parameter optimization in epilepsy patient models; data and software for mouse brain simulation; and extensive educational material. TVB cloud services facilitate reproducible online collaboration and discovery of data assets, models, and software embedded in scalable and secure workflows, a precondition for research on large cohort data sets, better generalizability, and clinical translation., Competing Interests: Declaration of competing interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Functional mitral regurgitation (FMR) is a common finding of advanced heart failure with detrimental effects. The prognostic impact of uncorrected FMR prior to left ventricular assist device (LVAD) implantation remains controversial., Methods: Between 2016 and 2019 77 patients underwent continuous-flow LVAD implantation at our institution. 34 patients showed FMR ≥ 2 (MR-group), whereas 43 patients showed FMR < 2 (Control-group). Data was retrospectively analyzed. Primary composite endpoint comprised freedom from death, stroke, pump-thrombosis, major bleeding and right heart failure (RHF) after 1 year., Results: Baseline characteristics, including the severity of left and right ventricular dysfunction, and periprocedural results were comparable. The overall survival during a mean follow up of 24.9 months was 55.9% in the MR-group versus 58.1% in the Control-group (p = 0.963), whereas 1-year event-free survival was 35.3% in the MR-group compared to 44.2% in the Control-group (p = 0.404). RHF within the first postoperative year occurred more frequently in the MR-group (35.3% vs. 11.6%; p = 0.017). Furthermore, RV function was significantly reduced in comparison to baseline values in the MR-group. 12 months after surgery, 74% of patients in the MR-group were classified as NYHA III in comparison to 24% of patients in the Control-group (p < 0.001)., Conclusions: Preoperative uncorrected FMR prior to LVAD implantation did not affect overall survival, nevertheless it was associated with an impaired RV function and increased incidence of right heart failure during follow-up. Furthermore, preoperative FMR ≥ 2 was associated with persistent symptoms of heart failure., (© 2022. The Author(s).)

Effective antibiotic therapy of cerebral infections such as meningitis or ventriculitis is hindered by low penetration into the cerebrospinal fluid (CSF). Because continuous infusion of meropenem and vancomycin and routine therapeutic drug monitoring (TDM) have been proposed to optimize antimicrobial exposure in ventriculitis patients, an individualized dosing strategy was implemented in our department. We present a retrospective analysis of meropenem and vancomycin concentrations in serum and CSF in the first nine ventriculitis patients treated with continuous infusion and TDM-guided dose optimization aiming at 20-30 mg/L. Median initial dosing was 8.8 g/24 h meropenem and 4.25 g/24 h vancomycin, respectively, resulting in median serum concentrations of 21.3 mg/L for meropenem and 24.5 mg/L for vancomycin and CSF concentrations of 3.4 mg/L for meropenem and 1.7 mg/L for vancomycin. Median CSF penetration was 15% for meropenem and 7% for vancomycin. With initial dosing, all but one patient achieved CSF concentrations above 1 mg/L. Dose adjustment according to TDM ensured sufficient CSF concentrations in all patients within 48 h of treatment. Given the limited penetration, continuous infusion of meropenem and vancomycin based on renal function and TDM-guided dose optimization appears a reasonable approach to attain sufficient CSF concentrations in ventriculitis patients.

We have shown previously that during myocardial ischemia/reperfusion (MI/R), toll-like receptor 2 (TLR2) signaling regulates connexin 43 (Cx43) subcellular localization and function and dampens arrhythmia formation. We aimed to identify sites capable of TLR2-dependent redox modification within Cx43. Post-ischemic TLR2 -/- or wild-type (WT) mouse hearts were analyzed by OxICAT. Cx43 was mutated to exclude redox modification and transfected into HL-1 cardiomyocytes (CM) that were challenged with a TLR2 agonist. We identified Cys260 of Cx43 to be susceptible to reversible oxidation MI/R; TLR2 -/- leads to reduced H 2 O 2 production in post-ischemic isolated mitochondria and subsequently reduced oxidation of Cx43 at Cys260. Cx43 was dephosphorylated in WT, while phosphorylation was preserved in TLR2 -/- . Mutation of Cx43 (C260A) and lentiviral transfection in HL-1 CM accelerated pacemaker activity and reduced activity after TLR2 ligand stimulation. We here provide evidence for TLR2-dependent reversible oxidation of Cx43 at Cys260, which led to decreased Cx43 phosphorylation and affected CM pacemaker frequency and intercellular communication.

Acute kidney injury remains an important cause of renal dysfunction. In this context, Toll-like receptors have been demonstrated to play a critical role in the induction of innate and inflammatory responses. Among these, Toll-like receptor 2 (TLR2) is constitutively expressed in tubular epithelial cells (TECs) of the kidney and is also known to mediate ischaemia reperfusion (IR) injury. Adult male C57BL/6JRj mice were randomized into seven groups (n = 8): a non-operative control group (CTRL) and six interventional groups in which mice were subjected to a 30 min. bilateral renal ischaemia. Immediately before reperfusion, mice were treated either with saline or with TLR2 antibody (clone T2.5) and harvested after ischaemia and reperfusion for 3, 24 and 48 hr. Analysed kidney homogenates of TLR2 antibody-treated mice displayed significantly decreased levels of TLR2 protein after 3 hr of IR compared to saline-treated mice. Accordingly, the degree of AKT phosphorylation was significantly decreased after 3 hr of IR compared to saline-treated animals. TUNEL staining revealed significantly higher apoptosis rates in TLR2 antibody-treated animals compared to saline-treated mice after 3 and 24 hr of IR. Further, a positive correlation between TLR2 protein expression and phosphorylation of AKT as well as a negative correlation with the number of TUNEL-positive cells could be observed. Inhibition of TLR2 and its signalling pathway by a single application of TLR2 antibody results in reduced phosphorylation of AKT and consecutively increased apoptosis., (© 2017 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background: We present a case of stress-induced cardiomyopathy (Takotsubo cardiomyopathy) caused by a venous air embolism during a craniotomy performed in the sitting position., Case Description: A 69-year-old woman was admitted to the neurosurgical department and scheduled for elective resection of a cerebellar metastasis in the sitting position. After craniotomy and opening of the posterior fossa, a venous air embolism was detected via transesophageal echocardiography. The patient immediately presented with cardiac decompensation with signs of takotsubo or stress-induced cardiomyopathy., Conclusions: Intensivists and anesthesiologists in the operating room and in intensive care units need to be aware of stress-induced cardiomyopathy as a probably underdiagnosed disease entity, especially as management differs significantly from other forms of cardiogenic shock. Diagnosis can be accomplished quickly by bedside echocardiography, emphasizing the need for availability of this tool and the integration of stress-induced cardiomyopathy in diagnostic algorithms in the intensive care unit., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Rupture of an intracranial aneurysm usually presents with an acute onset and requires multidisciplinary intensive care treatment and the overall death and disability rates are high. The ABO blood type is known to play an important role in hemostasis, thrombosis, and vascular NO response. The aspect of ABO blood type in onset, clinical progress, and outcome after subarachnoid hemorrhage (SAH) is largely unexplored. We conducted this study to elucidate the association of ABO blood type with the occurrence and outcome of aneurysmal SAH., Methods: In our retrospective study, 470 patients with aneurysmal SAH treated at our institution were included. We performed a χ 2 test for comparison between blood types and World Federation of Neurosurgical Societies admission status, cerebral vasospasm, delayed infarction, associated intracerebral hemorrhage and Fisher grade for analysis for their association with SAH., Results: No significant difference between blood type and the reviewed variables for SAH outcome were identified: World Federation of Neurosurgical Societies admission status (odds ratio, 1.12; 95% confidence interval [CI], 0.7-1.6; P = 0.56); SAH-associated intracerebral hemorrhage (odds ratio, 0.81; 95% CI, 0.5-1.3; P = 0.36); cerebral vasospasm (odds ratio, 1.08; 95% CI, 0.7-1.6; P = 0.71); DCI (odds ratio, 1.23; 95% CI, 0.8-1.8; P = 0.30); Fisher grade (odds ratio, 1.13; 95% CI, 0.7-1.6; P = 0.19)., Conclusions: Although a possible relationship between the ABO blood group and the clinical course of patients with SAH was hypothesized, our study showed no significant influence of patient's ABO blood type on cerebral vasospasm onset, SAH-associated intracerebral hemorrhage, or delayed infarction., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Sepsis is burdened by high mortality due to uncontrolled inflammatory response to pathogens. Increased caspase 1 activation causing maturation of IL1β/18 remains a therapeutic challenge in sepsis. SHARPIN (shank-associated regulator of G-protein signaling homology domain-interacting protein), a component of the LUBAC (linear ubiquitin chain-assembly complex), regulates inflammation, with unknown effects on caspase 1 activation. Mice lacking Casp1, Casp11, or both in a Sharpin-deficient background were generated, exposed to lipopolysaccharide-induced endotoxemia, and injected with caspase 1 inhibitor. We monitored survival, Il1β/18, and caspase 1/11 levels in plasma and organs and deciphered mechanisms of SHARPIN-dependent caspase 1 inhibition. A correlation between LUBAC and active caspase 1 was found in blood mononuclear cells from septic patients. SHARPIN bound caspase 1 and disrupted p20/p10 dimer formation, the last step of caspase 1 processing, thereby inhibiting enzyme activation and maturation of IL1β/18 in a LUBAC-independent manner. In septic patients, LUBAC-independent decline in SHARPIN correlated with enhancement of active caspase 1 in circulating mononuclear cells. Septic Sharpin-deficient mice displayed enrichment in mature Il1β/18 and active caspase 1, and shortened survival. Inhibition of caspase 1 reduced levels of Il1β/18 and splenic cell death, and prolonged survival in septic Sharpin-deficient mice. Our findings identify SHARPIN as a potent in vivo caspase 1 inhibitor and propose the caspase 1-SHARPIN interaction as a target in sepsis., (Copyright © 2016 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background: Due to demographic changes, the number of patients with traumatic brain injury carrying a cardiac resynchronization therapy device is increasing. One of the common complications of subdural hematoma (SDH) is epilepsy, whereas one of the most frequent early complications after cardiac resynchronization therapy device implantation is lead dislocation. The latter might then cause unintended skeletal muscle stimulation that might be misinterpreted in seizure-prone patients., Case Description: An 86-year-old female patient with an initially conservatively treated SDH on the right side presented with a tonic muscle contraction in her left arm 2 weeks after the trauma not responding to antiepileptic therapy. A computed tomography scan revealed residual hematoma on the right side with regular, time-dependent resorption. The muscle contraction was misdiagnosed as a focal epileptic state leading to evacuation of the chronic SDH. Additionally, routine postoperative chest radiographs were performed. Postoperatively, the tonic muscle contraction in her arm persisted. Chest radiographs revealed a dislocation of the left ventricular electrode, which appeared retracted into the left subclavian vein, next to the plexus brachialis. After deactivating the electrode, the alleged focal state ceased., Conclusions: In case of refractory treatment of epilepsy, dislocation of pacemaker electrodes is a, most certainly, rare but possible differential diagnosis. Confirmation of electrode position and function is easily and quickly feasible and will help prevent futile seizure-directed therapy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The Virtual Brain (TVB; thevirtualbrain.org) is a neuroinformatics platform for full brain network simulation based on individual anatomical connectivity data. The framework addresses clinical and neuroscientific questions by simulating multi-scale neural dynamics that range from local population activity to large-scale brain function and related macroscopic signals like electroencephalography and functional magnetic resonance imaging. TVB is equipped with a graphical and a command-line interface to create models that capture the characteristic biological variability to predict the brain activity of individual subjects. To enable researchers from various backgrounds a quick start into TVB and brain network modeling in general, we developed an educational module: TVB-EduPack. EduPack offers two educational functionalities that seamlessly integrate into TVB's graphical user interface (GUI): (i) interactive tutorials introduce GUI elements, guide through the basic mechanics of software usage and develop complex use-case scenarios; animations, videos and textual descriptions transport essential principles of computational neuroscience and brain modeling; (ii) an automatic script generator records model parameters and produces input files for TVB's Python programming interface; thereby, simulation configurations can be exported as scripts that allow flexible customization of the modeling process and self-defined batch- and post-processing applications while benefitting from the full power of the Python language and its toolboxes. This article covers the implementation of TVB-EduPack and its integration into TVB architecture. Like TVB, EduPack is an open source community project that lives from the participation and contribution of its users. TVB-EduPack can be obtained as part of TVB from thevirtualbrain.org.

Irrespective of geo- or heliocentric presuppositions, the functioning of sundials is based on the observation of moving shadows or light spots. Even though the cast shadow was often simply used to indicate the time, it could also remind the users of the ephemerality of earthly things or function as an index of planetary movements. This article examines the various ways in which early modem sundials visually interpret the moving shadow or light spot. The instruments address the shadow in inscriptions, integrate it into their design (e.g., in cruciform dials) or even manipulate its course (as in the so-called Horologium Ahaz). Both the crucifix and the Ahaz dials not only refer to astronomical miracles but actually restage them. Even though by means of the horologium it was not possible to explain the Old Testament miracle of the shadow moving backward, adepts were able to recreate it on a terrestrial scale.

TheVirtualBrain (TVB) is a neuroinformatics Python package representing the convergence of clinical, systems, and theoretical neuroscience in the analysis, visualization and modeling of neural and neuroimaging dynamics. TVB is composed of a flexible simulator for neural dynamics measured across scales from local populations to large-scale dynamics measured by electroencephalography (EEG), magnetoencephalography (MEG) and functional magnetic resonance imaging (fMRI), and core analytic and visualization functions, all accessible through a web browser user interface. A datatype system modeling neuroscientific data ties together these pieces with persistent data storage, based on a combination of SQL and HDF5. These datatypes combine with adapters allowing TVB to integrate other algorithms or computational systems. TVB provides infrastructure for multiple projects and multiple users, possibly participating under multiple roles. For example, a clinician might import patient data to identify several potential lesion points in the patient's connectome. A modeler, working on the same project, tests these points for viability through whole brain simulation, based on the patient's connectome, and subsequent analysis of dynamical features. TVB also drives research forward: the simulator itself represents the culmination of several simulation frameworks in the modeling literature. The availability of the numerical methods, set of neural mass models and forward solutions allows for the construction of a wide range of brain-scale simulation scenarios. This paper briefly outlines the history and motivation for TVB, describing the framework and simulator, giving usage examples in the web UI and Python scripting.

We present The Virtual Brain (TVB), a neuroinformatics platform for full brain network simulations using biologically realistic connectivity. This simulation environment enables the model-based inference of neurophysiological mechanisms across different brain scales that underlie the generation of macroscopic neuroimaging signals including functional MRI (fMRI), EEG and MEG. Researchers from different backgrounds can benefit from an integrative software platform including a supporting framework for data management (generation, organization, storage, integration and sharing) and a simulation core written in Python. TVB allows the reproduction and evaluation of personalized configurations of the brain by using individual subject data. This personalization facilitates an exploration of the consequences of pathological changes in the system, permitting to investigate potential ways to counteract such unfavorable processes. The architecture of TVB supports interaction with MATLAB packages, for example, the well known Brain Connectivity Toolbox. TVB can be used in a client-server configuration, such that it can be remotely accessed through the Internet thanks to its web-based HTML5, JS, and WebGL graphical user interface. TVB is also accessible as a standalone cross-platform Python library and application, and users can interact with the scientific core through the scripting interface IDLE, enabling easy modeling, development and debugging of the scientific kernel. This second interface makes TVB extensible by combining it with other libraries and modules developed by the Python scientific community. In this article, we describe the theoretical background and foundations that led to the development of TVB, the architecture and features of its major software components as well as potential neuroscience applications.

Genetic or pharmacological ablation of toll-like receptor 2 (TLR2) protects against myocardial ischemia/reperfusion injury (MI/R). However, the endogenous ligand responsible for TLR2 activation has not yet been detected. The objective of this study was to identify HMGB1 as an activator of TLR2 signalling during MI/R. C57BL/6 wild-type (WT) or TLR2(-/-)-mice were injected with vehicle, HMGB1, or HMGB1 BoxA one hour before myocardial ischemia (30 min) and reperfusion (24 hrs). Infarct size, cardiac troponin T, leukocyte infiltration, HMGB1 release, TLR4-, TLR9-, and RAGE-expression were quantified. HMGB1 plasma levels were measured in patients undergoing coronary artery bypass graft (CABG) surgery. HMGB1 antagonist BoxA reduced cardiomyocyte necrosis during MI/R in WT mice, accompanied by reduced leukocyte infiltration. Injection of HMGB1 did, however, not increase infarct size in WT animals. In TLR2(-/-)-hearts, neither BoxA nor HMGB1 affected infarct size. No differences in RAGE and TLR9 expression could be detected, while TLR2(-/-)-mice display increased TLR4 and HMGB1 expression. Plasma levels of HMGB1 were increased MI/R in TLR2(-/-)-mice after CABG surgery in patients carrying a TLR2 polymorphism (Arg753Gln). We here provide evidence that absence of TLR2 signalling abrogates infarct-sparing effects of HMGB1 blockade.

Aims: Inflammation and Toll-like receptor (TLR) signalling have been linked to the development of cardiac hypertrophy following transverse aortic constriction (TAC). In the present study, we investigated whether pre-treatment with the synthetic TLR9 ligands 1668-thioate or 1612-thioate modulates the progression of TAC-induced cardiac inflammation and hypertrophy., Methods and Results: C57BL/6N-mice were pre-treated with 1668-thioate, 1612-thioate (0.25 nmol/g, i.p.), or phosphate-buffered saline 16 h prior to TAC or sham surgery. Heart-weight/body-weight ratio (HW/BW), cardiomyocyte cell size, cellular macrophage accumulation, myofibroblast differentiation, and collagen deposition were investigated for up to 28 days. Cardiac function was monitored using a pressure-volume catheter and M-mode echocardiography. Inflammatory gene expression in the heart was analysed via gene array, while the time course of mRNA expression of key inflammatory mediators was assessed via RT-qPCR. TAC increased the HW/BW ratio and cardiomyocyte cell size and induced macrophage accumulation, myofibroblast differentiation, and collagen deposition. These changes were accompanied by cardiac inflammation and a significant loss of left ventricular function. Pre-treatment with cytosine-phosphate-guanine (CpG)-containing 1668-thioate attenuated the inflammatory response, the progression of cardiac hypertrophy, and cardiac remodelling, which resulted in a prolonged preservation of left ventricular function. These changes were induced to a smaller extent by the use of the non-CG-containing oligodeoxynucleotide 1612-thioate., Conclusion: Pre-treatment with 1668-thioate attenuated cardiac hypertrophy following pressure overload, possibly by modifying the hypertrophy-induced inflammatory response, thereby reducing cardiac growth and fibrosis as well as delaying loss of cardiac function.

Background: The perioperative morbidity and mortality of abdominal aortic aneurysm repair is linked to systemic inflammation. Important triggers of the latter are Toll-like receptors (TLRs), which play a central role in innate immunity. Ischemia/reperfusion (I/R) injury can be influenced by either TLR stimulation before I/R (preconditioning) or TLR dysfunction (deficiency or polymorphism). The influence of TLR2 stimulation or deficiency on systemic cytokine release and organ damage after aortic cross clamping has not been evaluated yet., Methods: Wild type (WT) and TLR2-deficient mice were subjected to 1 h ischemia and 2 or 4 h reperfusion of the infrarenal aorta. One group of WT mice was preconditioned with the synthetic TLR2 agonist Pam(3)Cys-Ser-Lys(4) (Pam(3)CSK(4)). Sham-operated animals without I/R served as controls. Plasma levels of interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, granulocyte macrophage-colony stimulating factor, tumor necrosis factor-α, alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH), and creatinine were measured., Results: I/R injury caused by transient clamping of the infrarenal aorta led to a time-dependent increase of all measured cytokines except IL-4, IL-5, and granulocyte macrophage-colony stimulating factor. This was accompanied by elevated markers of organ damage (ALT, AST, and LDH) except creatinine. Preconditioning with Pam(3)CSK(4) led to lower plasma concentrations of all cytokines, with the exception of anti-inflammatory IL-10 which was significantly upregulated. Furthermore, ALT, AST, and LDH plasma concentrations were lower in the preconditioning group. TLR2-deficient mice similarly showed reduced signs of systemic inflammation and organ damage, although less distinctive. IL-2, IL-6, IL-12, ALT, and LDH were time dependently lower compared with WT mice. IL-10 concentration was higher in TLR2-deficient mice compared with WT., Conclusions: Both, preconditioning via TLR2 and TLR2 deficiency, ameliorate systemic inflammation and organ damage during I/R injury caused by clamping of the infrarenal aorta. Compared with untreated WT animals, Pam(3)CSK(4) preconditioned and TLR2-deficient mice showed lower concentrations of pro-inflammatory cytokines, whereas anti-inflammatory IL-10 was elevated in both groups. This was accompanied by reduced organ dysfunction parameters., (Copyright © 2012 Elsevier Inc. All rights reserved.)