Background/Aims: Heme oxygenase-1 (HO-1) plays a central role in cellular defense against inflammatory insults, and its induction in macrophages potentiates their efferocytic activity. In this study, we explored the potential role of macrophage HO-1 in the resolution of experimentally induced colitis. Methods: To induce colitis, male C57BL/6 mice were treated with 2% dextran sulfate sodium (DSS) in the drinking water for 7 days. To investigate efferocytosis, apoptotic colon epithelial CCD 841 CoN cells were coincubated with bone marrow-derived macrophages (BMDMs). Results: Administration of the HO-1 inhibitor zinc protoporphyrin IX (ZnPP) blunted the resolution of DSS-induced intestinal inflammation and expression of the proresolving M2 macrophage marker CD206. BMDMs treated with apoptotic colonic epithelial cells showed significantly elevated expression of HO-1 and its regulator Nrf2. Under the same experimental conditions, the proportion of CD206-expressing macrophages was also enhanced. ZnPP treatment abrogated the upregulation of CD206 expression in BMDMs engulfing apoptotic colonic epithelial cells. This result was verified with BMDMs isolated from HO-1-knockout mice. BMDMs, when stimulated with lipopolysaccharide, exhibited increased expression of CD86, a marker of M1 macrophages.Coculture of lipopolysaccharide-stimulated BMDMs with apoptotic colonic epithelial cell debris dampened the expression of CD86 as well as the pro-inflammatory cytokines in an HO-1-dependent manner. Genetic ablation as well as pharmacologic inhibition of HO-1 significantly reduced the proportion of efferocytic BMDMs expressing the scavenger receptor CD36. Conclusions HO-1 plays a key role in the resolution of experimentally induced colitis by modulating the polarization of macrophages.

Objective: : The etiology of angiographically occult spontaneous subarachnoid hemorrhage (AOsSAH) is unclear. Threedimensional (3D) high-resolution vessel wall magnetic resonance imaging (HVM) might be useful in detecting the hidden arterial wall angiopathy in patients with AOsSAH. We aimed to demonstrate the feasibility of HVM for detecting the arterial cause of AOsSAH. Methods: : Patients, who were diagnosed with AOsSAH in the first evaluations and underwent HVM, were enrolled. Their clinical and radiologic data were retrospectively reviewed. Especially, focal enhancement of arterial wall on HVM and repetitive catheterized angiograms were precisely compared. Results: : Among 251 patients with spontaneous SAH, 22 patients were diagnosed with AOsSAH in the first evaluations (8.76%). After excluding three patients who did not undergo 3D-HVM, 19 patients were enrolled and classified as convexal (n=2) or perimesencephalic (n=4), and diffuse (n=13) groups. In convexal and perimesencephalic groups, no focal enhancement on HVM and no positive findings on repetitive angiography were noted. In diffuse group, 10 patients showed focal enhancement of arterial wall on HVM (10/13, 76.9%). Repeated angiography with 3D reconstruction revealed four patients of angiographically positive causative arteriopathy and possible lesion in one case in the concordant location of intramural enhancement on 3D-HVM (5/10, 50%). Three of them were treated with endovascular stent insertion. All patients, except one, recovered with good clinical outcome (3-month modified Rankin score, 0 and 1). Conclusion : 3D-HVM was useful in detecting hidden true arteriopathy in AOsSAH. It may provide new insights into the etiologic investigation of AOsSAH by proving information about the arterial wall status.

Objective: : Given the high risk of rebleeding and recurrence of blood blister-like aneurysms (BBAs), we treated ruptured BBAs of the internal carotid artery (ICA) with stent-assisted coil embolization (SAC). This study aimed to evaluate the efficacy and safety of SACs. Methods: : We retrospectively reviewed clinical and radiological data from eight patients with ruptured BBAs of the supraclinoid ICA. The modified Rankin Scale (mRS) was used to assess clinical outcomes, while radiological outcomes were evaluated on angiographs. For a pooled analysis, data from literature reporting the outcomes of ruptured BBAs treated with SAC were collected and analyzed in conjunction with our data. Results: : In our cohort, the mean Raymond classification score was 1.57±0.53 immediately after initial endovascular treatment. There were no perioperative complications or rebleeding events during the follow-up period. The mean mRS score at patient discharge was 1.00±0.81 and improved to 0.28±0.48 by the last follow-up day. The recurrence rate was 25% with an asymptomatic presentation and successful treatment with multiple stent insertion. Pooled analysis of 76 cases of SAC revealed a complete occlusion rate immediately after treatment of 54.8%, rebleeding rate 7.94%, and recurrence rate 24.2%. Good clinical outcomes with mRS score 0–2 were observed in 89.9% by the last clinical follow-up. Total mortality rate was 7.7%. Conclusion : This treatment appears to not only minimize the hemodynamic burden on the fragile dome specific to this type of aneurysm, but also provides an opportunity for safe and effective treatment in recurrent cases.

Purpose: This study aimed to evaluate the surgical outcomes of unilateral medial rectus recession and lateral rectus resection (R&R) for patients with large-angle deviations of acute acquired concomitant esotropia (AACE) without a neurological disease. Further, we have also suggested the surgical dosage of R&R for large-angle deviations of AACE.
Methods: This was a retrospective study of patients with AACE who underwent surgery and followed up after surgery for at least 6 months between September 2016 and March 2020. Among them, patients with ocular deviations of ≥30 prism diopters (PD) who underwent unilateral R&R were included.
Results: Seventeen patients with AACE were enrolled in this study (mean age, 23.5 years; four females). The mean amount of deviation was 40.00 PD at distance and near (range, 30–55 PD). Fifteen patients (88.2%) had myopia. The mean interval between the initial visit and surgery was 7.7 months (range, 4–20 months). All included patients had resolved diplopia after the surgery. Most patients with decreased stereoacuity displayed stereoacuity recovery after surgical treatment. At the final visit (mean follow-up period, 12.8 months), the mean angle of esodeviation was 0.82 PD (range, 6–0 PD) at distance and 0.47 PD (range, 4–0 PD) near. No patient displayed over-correction or adduction limitations in the operated eye.
Conclusions The unilateral R&R procedure presented favorable surgical outcomes for patients with large-angle deviations of AACE. These results and proposed surgical dosage guidelines may be useful for surgeons in planning the surgical treatment of large-angle deviations of AACE.

Purpose: This study aimed to evaluate the surgical outcomes of unilateral medial rectus recession and lateral rectus resection (R&R) for patients with large-angle deviations of acute acquired concomitant esotropia (AACE) without a neurological disease. Further, we have also suggested the surgical dosage of R&R for large-angle deviations of AACE.
Methods: This was a retrospective study of patients with AACE who underwent surgery and followed up after surgery for at least 6 months between September 2016 and March 2020. Among them, patients with ocular deviations of ≥30 prism diopters (PD) who underwent unilateral R&R were included.
Results: Seventeen patients with AACE were enrolled in this study (mean age, 23.5 years; four females). The mean amount of deviation was 40.00 PD at distance and near (range, 30–55 PD). Fifteen patients (88.2%) had myopia. The mean interval between the initial visit and surgery was 7.7 months (range, 4–20 months). All included patients had resolved diplopia after the surgery. Most patients with decreased stereoacuity displayed stereoacuity recovery after surgical treatment. At the final visit (mean follow-up period, 12.8 months), the mean angle of esodeviation was 0.82 PD (range, 6–0 PD) at distance and 0.47 PD (range, 4–0 PD) near. No patient displayed over-correction or adduction limitations in the operated eye.
Conclusions The unilateral R&R procedure presented favorable surgical outcomes for patients with large-angle deviations of AACE. These results and proposed surgical dosage guidelines may be useful for surgeons in planning the surgical treatment of large-angle deviations of AACE.

Preceding infection or inflammation such as bacterial meningitis has been associated with poor outcomes after stroke. Previously, we reported that intracorpus callosum microinjection of lipopolysaccharides (LPS) strongly accelerated the ischemia/reperfusion-evoked brain tissue damage via recruiting inflammatory cells into the ischemic lesion. Simvastatin, 3-hydroxy-3-methylgultaryl (HMG)-CoA reductase inhibitor, has been shown to reduce inflammatory responses in vascular diseases. Thus, we investigated whether simvastatin could reduce the LPS-accelerated ischemic injury. Simvastatin (20 mg/kg) was orally administered to rats prior to cerebral ischemic insults (4 times at 72, 48, 25, and 1-h pre-ischemia). LPS was microinjected into rat corpus callosum 1 day before the ischemic injury. Treatment of simvastatin reduced the LPS-accelerated infarct size by 73%, and decreased the ischemia/reperfusion-induced expressions of pro-inflammatory mediators such as iNOS, COX-2 and IL-1beta in LPS-injected rat brains. However, simvastatin did not reduce the infiltration of microglial/macrophageal cells into the LPS-pretreated brain lesion. In vitro migration assay also showed that simvastatin did not inhibit the monocyte chemoattractant protein-1-evoked migration of microglial/macrophageal cells. Instead, simvastatin inhibited the nuclear translocation of NF-kappaB, a key signaling event in expressions of various proinflammatory mediators, by decreasing the degradation of IkappaB. The present results indicate that simvastatin may be beneficial particularly to the accelerated cerebral ischemic injury under inflammatory or infectious conditions.
Animals ; Brain ; Corpus Callosum ; Inflammation ; Lipopolysaccharides ; Macrophages ; Meningitis, Bacterial ; Microglia ; Microinjections ; Monocytes ; NF-kappa B ; Oxidoreductases ; Rats ; Simvastatin* ; Stroke ; Vascular Diseases

Recently, we reported that the A3 adenosine receptor (A3AR) agonist LJ529 (2-chloro-N6-(3-iodobnzyl)-5'-N-methylcarbamoyl-4'-thioadenosine) reduces cerebral ischemic injury via inhibition of recruitment of peripheral inflammatory cells into ischemic brain lesion. A3AR agonists, however, are known to possess anti-platelet activity, which may deter the combination therapy with tissue plasminogen activator for the therapy of cerebral ischemic stroke. Thus, the present study investigates the neuroprotective/anti-ischemic effect of a synthetic seco-nucleoside, LMT497 ((S)-2-((R)-1-(2-chloro-6-(3-iodobenzylamino)-9H-purin-9-yl)-2-hydroxyethoxy)-3-hydroxy-N-methylpropanamide) with little anti-platelet activity. LMT497 neither showed A3AR binding activity nor anti-platelet activity. In our present study LMT497 significantly attenuated the injury/death of cortical neurons exposed to oxygen-glucose deprivation (OGD) followed by re-oxygenation (R). LMT497 significantly reduced the ascending cellular level of reactive oxygen species under ischemic conditions by increasing the superoxide dismutase (SOD) levels. LMT497 also inhibited the migration of microglia which mediates inflammatory responses in ischemia. In rats subjected to middle cerebral artery occlusion (MCAO, 1.5 h) followed by reperfusion, LMT497 largely reduced brain infarction volume, and edema, and improved neurological score. Therapeutic efficacy of LMT497 was obtained by twice treatments even at 10 h and 18 h after the onset of ischemia. Collectively, LMT497 could be a therapeutic drug candidate with a wide therapeutic time window for the treatment of cerebral ischemic stroke.
Animals ; Brain ; Brain Infarction ; Brain Ischemia ; Edema ; Infarction, Middle Cerebral Artery ; Inflammation ; Ischemia ; Microglia ; Neurons ; Oxidative Stress ; Rats ; Reactive Oxygen Species ; Receptors, Purinergic P1 ; Reperfusion ; Stroke ; Superoxide Dismutase ; Tissue Plasminogen Activator

We investigated the effect of propofol and fentanyl on microelectrode recording (MER) and its clinical applicability during subthalamic nucleus (STN) deep brain stimulation (DBS) surgery. We analyzed 8 patients with Parkinson's disease, underwent bilateral STN DBS with MER. Their left sides were done under awake and then their right sides were done with a continuous infusion of propofol and fentanyl under local anesthesia. The electrode position was evaluated by preoperative MRI and postoperative CT. The clinical outcomes were assessed at six months after surgery. We isolated single unit activities from the left and the right side MERs. There was no significant difference in the mean firing rate between the left side MERs (38.7+/-16.8 spikes/sec, n=78) and the right side MERs (35.5+/-17.2 spikes/sec, n=66). The bursting pattern of spikes was more frequently observed in the right STN than in the left STN. All the electrode positions were within the STNs on both sides and the off-time Unified Parkinson's Disease Rating Scale part III scores at six months after surgery decreased by 67% of the preoperative level. In this study, a continuous infusion of propofol and fentanyl did not significantly interfere with the MER signals from the STN. The results of this study suggest that propofol and fentanyl can be used for STN DBS in patients with advanced Parkinson's disease improving the overall experience of the patients.
Aged ; Anesthetics, Intravenous/*pharmacology ; *Deep Brain Stimulation ; Electrodes, Implanted ; Female ; Fentanyl/*pharmacology ; Humans ; Magnetic Resonance Imaging ; Male ; Microelectrodes ; Middle Aged ; Parkinson Disease/*prevention & control ; Propofol/*pharmacology ; Severity of Illness Index ; Subthalamic Nucleus/*drug effects/physiology ; Tomography, X-Ray Computed

Glioblastoma multiforme (GBM) is well known as the most common malignant primary brain tumor. It could easily spread into the adjacent or distant brain tissue by infiltration, direct extension and cerebro-spinal fluid dissemination. The extranueural metastatic spread of GBM is relatively rare but it could have more progressive disease course. We report a 39-year-old man who had multiple bone metastases and malignant pleural effusion of the GBM without primary site recurrence.
Adult ; Brain ; Brain Neoplasms ; Central Nervous System* ; Glioblastoma* ; Humans ; Neoplasm Metastasis* ; Pleural Effusion ; Pleural Effusion, Malignant ; Recurrence* ; Spinal Neoplasms

N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity is one of the major causes for neuronal cell death during cerebral ischemic insult. Previously, we reported that the final product of lipid membrane peroxidation 4-hydroxy-2E-nonenal (HNE) synergistically increased NMDA receptor-mediated excitotoxicity (J Neurochem., 2006). In this study, we investigated the mechanism involved in the synergistic neuronal cell death induced by co-treatment with HNE and NMDA. Although neither HNE (1 microM) nor NMDA (2 microM) alone induced the death of cortical neurons, simultaneous treatment of neuronal cells with HNE and NMDA synergistically evoked the death of the cells. However, the synergistic effect on neuronal death was observed only in the presence of calcium. HNE neither increased the cytosolic calcium level ([Ca2+]i) nor altered the NMDA-induced intracellular calcium influx. However, HNE together with NMDA elevated the mitochondrial calcium level and depolarized the mitochondrial transmembrane potential. Furthermore, HNE evoked damage of isolated mitochondria at the cytosolic calcium level (200 nM), which is maximally induced by 2 microM NMDA. Consistently, ATP was depleted in neurons when treated with both HNE and NMDA together. Ciclopirox, a potent inhibitor of mitochondrial permeability transition pore opening (Br. J. Pharmacol., 2005), largely prevented the synergistic damage of mitochondria and death of cortical neurons. Therefore, although low concentrations of HNE and NMDA cannot individually induce neuronal cell death, they can evoke the neuronal cell death by synergistically accelerating mitochondrial dysfunction.
Adenosine Triphosphate ; Calcium ; Cell Death ; Cytosol ; Membrane Potentials ; Membranes ; Mitochondria ; Mitochondrial Membrane Transport Proteins ; N-Methylaspartate ; Neurons ; Permeability ; Pyridones