miR-142 induces accumulation of reactive oxygen species (ROS) by inhibiting pexophagy in aged bone marrow mesenchymal stem cells.

Elevation of the levels of reactive oxygen species (ROS) is a major tissue-degenerative phenomenon involved in aging and aging-related diseases. The detailed mechanisms underlying aging-related ROS generation remain unclear. Presently, the expression of microRNA (miR)-142-5p was significantly upregulated in bone marrow mesenchymal stem cells (BMMSCs) of aged mice. Overexpression of miR-142 and subsequent observation revealed that miR-142 involved ROS accumulation through the disruption of selective autophagy for peroxisomes (pexophagy). Mechanistically, attenuation of acetyltransferase Ep300 triggered the upregulation of miR-142 in aged BMMSCs, and miR-142 targeted endothelial PAS domain protein 1 (Epas1) was identified as a regulatory protein of pexophagy. These findings support a novel molecular mechanism relating aging-associated ROS generation and organelle degradation in BMMSCs, and suggest a potential therapeutic target for aging-associated disorders that are accompanied by stem cell degeneration.

miR-155 inhibits mitophagy through suppression of BAG5, a partner protein of PINK1.

Removal of dysfunctional mitochondria is essential step to maintain normal cell physiology, and selective autophagy in mitochondria, called mitophagy, plays a critical role in quality control of mitochondria. While in several diseases and aging, disturbed mitophagy has been observed. In stem cells, accumulation of damaged mitochondria can lead to deterioration of stem cell properties. Here, we focused on miR-155-5p (miR-155), one of the most prominent miRNAs in inflammatory and aged tissues, and found that miR-155 disturbed mitophagy in mesenchymal stem cells (MSCs). As a molecular mechanism of miR-155-mediated mitophagy suppression, we found that BCL2 associated athanogene 5 (BAG5) is a direct target of miR-155. Reduction of BAG5 resulted in destabilization of PTEN-induced kinase (PINK1) and consequently disrupted mitophagy. Our study suggests a novel mechanism connecting aging and aging-associated inflammation with mitochondrial dysfunction in stem cells through a miRNA-mediated mechanism.

Ephedrine-Induced Increases in Blood Pressure and Heart Rate Due to Suspected Cardiac Sympathetic Denervation Supersensitivity in a Patient with Parkinson's Disease Under Spinal Anesthesia.

BACKGROUND Denervation supersensitivity to sympathomimetic drugs has been noted in patients with Parkinson's disease (PD) whose cardiac sympathetic nerves are denervated. This phenomenon is not as well recognized as other complications of PD patients, but anesthesiologists should be aware of it because sympathomimetic drugs can sometimes be dangerous to these patients. CASE REPORT A 60-year-old woman was scheduled for total hip joint replacement under combined spinal-epidural anesthesia and sedation. She had been diagnosed as PD (stage 4 on the Hoehn and Yahr scale) with a history of orthostatic hypotension. Her ¹²³I-metaiodobenzylguanidine (MIBG) scintigraphy revealed marked reduction of ¹²³I-MIBG accumulation in the heart. In the operating room, we placed an epidural catheter through the Th12-L1 space, and spinal anesthesia (2.6 mL of 0.5% normobaric bupivacaine) was administered. During the surgery, we infused propofol at 100 mg·hr⁻¹ for sedation. When 4 mg of ephedrine was administered intravenously because of marked decrease in patient's blood pressure, we observed unexpectedly large increases in the systolic blood pressure, from 78 mmHg to 168 mmHg, and the heart rate increased from 52 to 84 beats per minute (bpm). This phenomenon recurred each time 4 mg of ephedrine was administered. CONCLUSIONS We report a case in which ephedrine induced unexpectedly large increases in blood pressure and heart rate in a patient who suffered from PD with severe cardiac sympathetic nerve denervation. We speculate that this phenomenon was caused by denervation supersensitivity of the patient's heart.

A spinal cord infarction that occurred after laparoscopic gastrectomy performed under general anesthesia and epidural analgesia.

BACKGROUND: Spinal cord infarction (SCI) after epidural anesthesia is quite rare. Although most cases of perioperative SCI are associated with aortic, cardiac, or spinal surgery, and/or abnormal preoperative conditions, such as spinal stenosis or hypercoagulopathy, intraoperative events, such as severe hypotension or epidural puncture and catheterization, can be contributory factors. CASE PRESENTATION: A 52-year-old male was underwent laparoscopic gastrectomy. Before induction of general anesthesia, an epidural catheter was placed without any problems. The patient had no pain and no complaint just after the operation, but suddenly complained of back pain and anuria, and could not move either of his lower limbs 30 h after the operation. As we thought that the incident would be caused by the migration of the epidural catheter into the subarachnoid space, we removed the catheter, but there was no recovery of the symptoms even 20 h later. The magnetic resonance imaging (MRI) scan showed no hematoma in the epidural space but an abnormal signal within the spinal cord, extending from the Th3 to Th8 levels, which was consistent with the SCI. Unfortunately, the patient's recovery from the paraplegia and abnormal sensation was poor. CONCLUSIONS: When a patient complains of lower limb muscle weakness and/or abnormal sensations, it is important to perform an MRI examination and treatment as early as possible to avoid permanent paraplegia, especially after epidural puncture and catheterization.

Sevoflurane causes greater QTc interval prolongation in chronically hyperglycemic patients than in normoglycemic patients.

QTc interval prolongation is a serious diabetic complication and increases mortality rate. Hyperglycemia inhibits the rapid component of delayed rectifier potassium channel currents (Ikr) and prolongs the QTc interval on electrocardiograms. Sevoflurane also inhibits the Ikr and causes QTc interval prolongation. In fact, torsade de pointes occurred in a patient with poorly controlled diabetes mellitus during sevoflurane anesthesia. We enrolled 74 patients, including 37 normoglycemic patients (glycated hemoglobin [HbA1c]: <6.5%) (NG group) and 37 chronically hyperglycemic patients (HbA1c: ≥6.5%) (HG group). Anesthesia was induced with 2 mg/kg propofol and 0.3 µg/kg/min remifentanil, and maintained with 2% sevoflurane in 40% O2 and 0.2-0.3 µg/kg/min remifentanil. The QT interval and Tp-e interval (from the peak to the end of the T wave) were measured before and at 5, 10, 30, 60, 90, and 120 min after the administration of sevoflurane and adjusted for the patient's heart rate (QTc and Tp-ec, respectively). P-values of <0.05 were considered statistically significant. The QTc and the Tp-ec intervals of the two groups did not differ significantly before the administration of sevoflurane. The QTc interval gradually increased with time in both groups and was significantly longer than the baseline value at 10 min after the administration of sevoflurane in both groups. The QTc interval of the HG group was significantly longer than that of the NG group at 90 min and 120 min after the administration of sevoflurane. The Tp-ec interval was not affected by sevoflurane in either group.We have demonstrated that sevoflurane significantly prolongs the QTc interval, and that the extent of the prolongation is significantly greater in chronically hyperglycemic patients than in normoglycemic patients. Although Tp-ec is not affected by sevoflurane, it should be noted that the simultaneous blockade of potassium channels would increase the risk of arrhythmias.

Sevoflurane prolonged the QTc interval and increased transmural dispersion of repolarization in a patient with long QT syndrome 3: a case report.

We report that sevoflurane not only caused marked QTc interval prolongation but also increased transmural dispersion of repolarization in a patient with long QT syndrome 3 (LQT3). A 16-year-old male with LQT3 underwent a shoulder operation. He experienced no episode of syncope or cardiac arrest, but his preoperative electrocardiography (ECG) showed marked QTc interval prolongation (631 ms) and Tp-e interval prolongation (126 ms). Anesthesia was induced with propofol and maintained with 2% sevoflurane and remifentanil. Although no lethal arrhythmias occurred in the perioperative period, not only the QTc interval but also Tp-e interval was further prolonged by sevoflurane. While sevoflurane has been recognized as a safe anesthetic in terms of QT interval prolongation, even in patients with long QT syndromes, we believe that sevoflurane might be avoided for poorly controlled LQT3 patients.