Fulminant myocarditis managed with pulsatile extracorporeal life support; use of Twin Pulse Life support (T-PLS®)

Fulminant myocarditis frequently results in severe hemodynamic deterioration. High-dose vasopressors or sometimes mechanical circulatory support are required. We report on two cases of fulminant myocarditis successfully treated with pulsatile extracorporeal life support (T-PLS®, Twin Pulse Life support, New heart bio.BHK, Seoul, Korea). With T-PLS, we were able to provide mechanical support to patients until they recovered completely

FBXW7-mediated ERK3 degradation regulates the proliferation of lung cancer cells

Extracellular signal-regulated kinase 3 (ERK3) is an atypical member of the mitogen-activated protein kinase (MAPK) family, members of which play essential roles in diverse cellular processes during carcinogenesis, including cell proliferation, differentiation, migration, and invasion. Unlike other MAPKs, ERK3 is an unstable protein with a short half-life. Although deubiquitination of ERK3 has been suggested to regulate the activity, its ubiquitination has not been described in the literature. Here, we report that FBXW7 (F-box and WD repeat domain-containing 7) acts as a ubiquitination E3 ligase for ERK3. Mammalian two-hybrid assay and immunoprecipitation results demonstrated that ERK3 is a novel binding partner of FBXW7. Furthermore, complex formation between ERK3 and the S-phase kinase-associated protein 1 (SKP1)-cullin 1-F-box protein (SCF) E3 ligase resulted in the destabilization of ERK3 via a ubiquitination-mediated proteasomal degradation pathway, and FBXW7 depletion restored ERK3 protein levels by inhibiting this ubiquitination. The interaction between ERK3 and FBXW7 was driven by binding between the C34D of ERK3, especially at Thr417 and Thr421, and the WD40 domain of FBXW7. A double mutant of ERK3 (Thr417 and Thr421 to alanine) abrogated FBXW7-mediated ubiquitination. Importantly, ERK3 knockdown inhibited the proliferation of lung cancer cells by regulating the G1/S-phase transition of the cell cycle. These results show that FBXW7-mediated ERK3 destabilization suppresses lung cancer cell proliferation in vitro

Terminal spreading depolarization and electrical silence in death of human cerebral cortex

Objective: Restoring the circulation is the primary goal in emergency treatment of cerebral ischemia. However, better understanding of how the brain responds to energy depletion could help predict the time available for resuscitation until irreversible damage and advance development of interventions that prolong this span. Experimentally, injury to central neurons begins only with anoxic depolarization. This potentially reversible, spreading wave typically starts 2 to 5 minutes after the onset of severe ischemia, marking the onset of a toxic intraneuronal change that eventually results in irreversible injury. Methods: To investigate this in the human brain, we performed recordings with either subdural electrode strips (n = 4) or intraparenchymal electrode arrays (n = 5) in patients with devastating brain injury that resulted in activation of a Do Not Resuscitate–Comfort Care order followed by terminal extubation. Results: Withdrawal of life‐sustaining therapies produced a decline in brain tissue partial pressure of oxygen (ptiO2) and circulatory arrest. Silencing of spontaneous electrical activity developed simultaneously across regional electrode arrays in 8 patients. This silencing, termed “nonspreading depression,” developed during the steep falling phase of ptiO2 (intraparenchymal sensor, n = 6) at 11 (interquartile range [IQR] = 7–14) mmHg. Terminal spreading depolarizations started to propagate between electrodes 3.9 (IQR = 2.6–6.3) minutes after onset of the final drop in perfusion and 13 to 266 seconds after nonspreading depression. In 1 patient, terminal spreading depolarization induced the initial electrocerebral silence in a spreading depression pattern; circulatory arrest developed thereafter. Interpretation: These results provide fundamental insight into the neurobiology of dying and have important implications for survivable cerebral ischemic insults. Ann Neurol 2018;83:295–31

Level of professional ethics awareness and medical ethics competency of dental hygienists and dental hygiene students: the need to add ethics items to the Korean Dental Hygienist Licensing Examination

Purpose This study aimed to evaluate the level of professional ethics awareness and medical ethics competency in order to assess the potential need for ethics items to be included on the Korean Dental Hygienist Licensing Examination. Methods In total, 358 clinical dental hygienists and dental hygiene students completed a structured questionnaire to evaluate their level of ethical awareness and medical ethics competency. The sub-factors of medical ethics were classified into relationships with patients, medical and social relations, and individual specialized fields. Results Only 32.1% of participants indicated that they had taken a course on professional ethics in the university curriculum, but 95.2% of respondents considered professional ethics to be important. The overall score for medical ethics competency was average (3.37 out of 5). The score for relationships with patients was 3.75 points, followed by medical and social relations (3.19 points) and individual specialized fields (3.16 points). The level of professional ethics awareness was higher among participants who had taken a course on professional ethics than among those who had not done so or who did not remember whether they had done so. Conclusion Dental hygienists were aware of the importance of professional ethics, but their medical ethics competency was moderate. Therefore, medical ethics should be treated as a required subject in the university curriculum, and medical ethics competency evaluations should be strengthened by adding ethics items to the Korean Dental Hygienist Licensing Examination

Long non-coding RNA ChRO1 facilitates ATRX/DAXX-dependent H3.3 deposition for transcription-associated heterochromatin reorganization.

Constitutive heterochromatin undergoes a dynamic clustering and spatial reorganization during myogenic differentiation. However the detailed mechanisms and its role in cell differentiation remain largely elusive. Here, we report the identification of a muscle-specific long non-coding RNA, ChRO1, involved in constitutive heterochromatin reorganization. ChRO1 is induced during terminal differentiation of myoblasts, and is specifically localized to the chromocenters in myotubes. ChRO1 is required for efficient cell differentiation, with global impacts on gene expression. It influences DNA methylation and chromatin compaction at peri/centromeric regions. Inhibition of ChRO1 leads to defects in the spatial fusion of chromocenters, and mislocalization of H4K20 trimethylation, Suv420H2, HP1, MeCP2 and cohesin. In particular, ChRO1 specifically associates with ATRX/DAXX/H3.3 complex at chromocenters to promote H3.3 incorporation and transcriptional induction of satellite repeats, which is essential for chromocenter clustering. Thus, our results unveil a mechanism involving a lncRNA that plays a role in large-scale heterochromatin reorganization and cell differentiation.Individual Basic Researcher Program [2018R1D1A1B070 48056 to E.-J.C., 2017R1D1A1B03035883 to J.P.]; Advanced Research Center Program [NRF-2010-0029359 to E.-J.C.]; National Creative Research Laboratory Program [2012R1A3A2048767 to H.-D.Y.]; NRF-2012-Fostering Core Leaders of the Future Basic Science Program through the National Research Foundation of Korea [2012H1A8003093 to J.P.]

Implikationen für (1.) die Evaluierung der Intaktheit der elektrischen Blut- Hirn-Schranke und (2.) die Detektion der spreading

Direct current (DC) potentials are slow electrical potentials measured in the extracellular space which reflect biophysicochemical phenomena in neurons and astrocytes such as spreading depolarization (SD) or ictal epileptic events (IEE). It is nevertheless assumed that DC potentials can also arise at the blood-brain barrier (BBB). For example, the latter may apply to CO2-dependent DC shifts, which I further investigated in rats in study 1. To start with, I found that one of the major supporting arguments for this hypothesis is invalid, namely the DC change following intracarotideal dehydrocholate (DHC) application, because intracarotideal DHC causes not only BBB opening but also middle cerebral artery thrombosis with focal cerebral ischemia. Intracarotideal DHC is thus not a suitable model to study isolated BBB opening. Nevertheless, I then applied a number of neuronal/astrocytic channel blockers topically to the brain. They should have altered the CO2-dependent DC shift if it were of neuronal/astrocytic origin, but they failed to do so. Moreover, the typical CO2-dependent DC shift was lacking in brain slices, which lack an intact BBB, whereas DC shifts of SDs or IEEs are preserved. This further supported the origin of the CO2-dependent DC shift at the BBB. Using pH- and K+-selective microelectrodes in vivo, we then found further evidence that the CO2-dependent DC shift is specifically generated by the proton gradient across the BBB. Thus, it seems to be a marker for the closed paracellular pathway, which maintains the ion gradients across the BBB under physiological conditions. Using this tool, we then provided functional evidence for previous results with electron microscopy for the first time that the BBB opens in a hierarchical manner under pathological conditions. First, the transcellular pathway allows macromolecules such as albumin to pass. Only later, the paracellular pathway opens for small molecules such as protons or potassium. In the second study, we investigated the detection of SDs using DC/alternating current (AC)-scalp-electroencephalography (EEG) simultaneously with invasive DC/AC-electrocorticography (ECoG) in patients with aneurysmal subarachnoid hemorrhage (aSAH). DC/AC-ECoG is the gold standard to measure SDs. However, we also found correlates of both DC and AC changes of SDs in the scalp-EEG. This may offer a non-invasive approach to detect SDs in patients in the future, but the tool requires further refinement. In the third study, we investigated hemodynamic responses to SDs and IEEs in an aSAH patient using DC /AC-ECoG and laser-Doppler flowmetry. We found that hypoemic responses occurred not only during SDs but also during IEEs. Interestingly, these hypoemic responses showed a spatial association with increased BBB permeability, indicating a possible relationship between BBB dysfunction and abnormal hemodynamic responses to SDs and IEEs.Direct current (DC) Potentiale sind langsame elektrische Potentiale im Extrazellulärraum, die neuronal/astrozytäre Phänomene wie spreading depolarization (SD) oder ictal epileptic events (IEE) anzeigen. DC Potentiale könnten aber auch an der Bluthirnschranke (BBB) entstehen. Dies wird z.B. für das CO2-abhängige DC Potential diskutiert. In Studie 1 habe ich diese Hypothese weiter untersucht. Zunächst musste ich feststellen, dass ein wichtiges Argument dafür, nämlich die DC Potentialänderung nach intrakarotidealer Gabe von Dehydrocholat (DHC), nicht stichhaltig ist, weil keine isolierte Öffnung der BBB sondern eine fokale zerebrale Ischämie durch DHC induziert wird. Im Anschluss applizierte ich jedoch eine Reihe von neuronalen/astrozytären Kanalinhibitoren in vivo, die das CO2-abhängige DC Potential beeinflussen sollten, würde es in Neuronen oder Astrozyten generiert werden. Dies war jedoch nicht der Fall. Außerdem zeigen Hirnschnitte, denen eine intakte BBB fehlt, die typischen DC Potentiale von SD und IEEs, das typische CO2-abhängige DC Potential konnten wir jedoch nicht nachweisen. Auch dies unterstützt seine Entstehung an der BBB. Messungen mit pH- und K+-sensitiven Mikroelektroden in vivo unterstützten zudem die Annahme, dass das CO2-abhängige DC Potential durch den Protonengradienten an der BBB entsteht. Somit wäre es ein Marker für den physiologischerweise geschlossenen, parazellulären Passageweg, der für die Aufrechterhaltung der Ionengradienten über die BBB verantwortlich ist. Mit diesem Marker konnten wir dann zum ersten Mal ein funktionelles Argument für Befunde früherer elektronenmikroskopischer Studien liefern, dass sich die BBB unter pathologischen Bedingungen in hierarchischer Weise öffnet. Zuerst öffnet sich der transzelluläre Passageweg für Makromoleküle wie Albumin, erst später der parazelluläre Passageweg für kleine Moleküle wie Protonen oder Kalium. In der zweiten Studie untersuchten wir die Detektion von SDs mittels DC/alternating current (AC)-scalp- Elektroenzephalografie (EEG) parallel zur invasiven DC/AC-Elektrokortikografie (ECoG) in Patienten mit aneurysmatischer Subarachnoidalblutung (aSAH). Die DC /AC-ECoG ist der Goldstandard zur SD-Messung. Jedoch fanden wir auch Korrelate der DC- und AC-Veränderung in der scalp-EEG. Dies könnte in Zukunft zu einer nicht-invasiven, klinischen Methode der SD-Detektion weiterentwickelt werden. In der dritten Studie analysierten wir hämodynamische Antworten auf SDs und IEEs in einem Patienten mit aSAH anhand DC/AC-ECoG und Laser-Doppler Flussmessung. Nicht nur bei SDs sondern auch bei IEEs traten hypoämische Antworten auf, die einen räumlichen Zusammenhang mit erhöhter BBB- Permeabilität aufwiesen. Dies deutet möglicherweise auf eine Beziehung zwischen BBB-Störung und abnormalen hämodynamischen Antworten auf SDs und IEEs hin

Thrombocytopenia Associated with Levodopa Treatment

There were few cases of thrombocytopenia associated with levodopa. Herein, we report a patient with Parkinson’s disease, who suffered thrombocytopenia related to long-term use of levodopa