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Objective. Treatment of super‐refractory status epilepticus (SRSE) is associated with various complications of anaesthetic coma therapy. This study aimed to describe the factors affecting the prognosis, especially in‐hospital mortality, of patients receiving pentobarbital coma therapy for the treatment of SRSE. Methods. This was a retrospective cohort study conducted in a single tertiary referral centre with patients who received pentobarbital coma therapy for the treatment of SRSE from 2006 to 2018. Exploratory analyses were performed for clinical, laboratory, electrographic, and radiological factors for the entire cohort and were compared between the mortality and survivor groups. Results. In total, 19 patients were enrolled, and five (26.3%) patients died in the hospital. The maximal pentobarbital infusion dose was higher in the mortality group than in the survivor group (4.4±1.0 mg/kg/h vs. 2.9±1.4 mg/kg/h, respectively; p=0.025). The high‐dose pentobarbital infusion group (>3.75 mg/kg/h) underwent longer mechanical ventilation (24 [20–36.75] vs. 41 [28–70], p=0.025) and blood culture results were more frequently positive, suggestive of septicaemia (8.3% vs. 57.1%, p=0.038). Significance. The group of SRSE patients treated with pentobarbital coma therapy who died in the hospital received a higher pentobarbital infusion dose compared to survivors; a complication of high‐dose pentobarbital infusion was septicaemia. Considering the high rate of septicaemia observed, systematic treatment strategies focusing on infectious complications should be established and implemented. The association between maximal pentobarbital infusion dose and in‐hospital mortality needs to be further validated.

Although ex vivo culture expansion is necessary to use autologous mesenchymal stem cells (MSCs) in treating stroke patients, and several researchers have utilized culture-expanded cells in their studies, the effects of culture expansion on neurogenesis and trophic support are unknown. Thus, we evaluated the impact of the passage of MSCs on their effects in a rat stroke model. The IV application of ex vivo-cultured human MSCs, earlier (passage 2) or later passage (passage 6), was performed in a rat stroke model. Behavioral tests, immunohistochemical studies, and quantitative analysis using the CAST-grid system were performed to evaluate the degree of neurogenesis. We also evaluated the levels of trophic factors in both control and MSC-treated rat brain extract. Compared to rats that received later-passage human MSCs, behavioral recovery and neurogenesis as revealed by bromodeoxyuridine staining were more pronounced in rats that received earlier-passage human MSCs (p < 0.01 in both cases). Double staining showed that most of the endogenous neuronal progenitor cells, but few human MSCs, expressed neuronal and glial phenotypes. Tissue levels of trophic factors, including glial cell line-derived neurotrophic factor, nerve growth factor, vascular endothelial growth factor, and hepatocyte growth factor, were higher in earlier-passage MSC-treated brains than in control or later-passage MSC-treated brains (p < 0.01 in all cases). Our results indicate that ischemia-induced neurogenesis was enhanced by the IV administration of human MSCs. The effects were more pronounced with earlier-passage than with later-passage human MSCs, which may be related to the differential capacity in trophic support, depending on their passage.

The nature of the association between ischemic stroke and Alzheimer’s disease (AD) at the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insults on the regulation of amyloid precursor protein (APP) processing. We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation) to evaluate the effect of ischemic neuronal insults on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line and primary cultured cells of transgenic mice which expressed human APP (Tg2576). Ischemic neuronal insults increased the production of Aβ in Tg2576 primary culture cells compared to controls. A disintegrin and metalloprotease 10 (ADAM 10) was markedly increased in early stage of ischemic insults, which was followed by decreased level of ADAM 10 expression in later stage. The protein and mRNA expression of β-site cleavage enzyme (BACE) and BACE activity was not significantly different between the group of ischemic insults and control. By contrast, the activity of γ-secretase was significantly increased after 4 h of ischemic insults, as compared to controls. The present study showed that the ischemic neuronal insults increased the production of Aβ by influencing APP metabolism, which may link the role of ischemic insults to the pathogenesis of AD.The nature of the association between ischemic stroke and Alzheimer’s disease (AD) at the cellular and molecular level is still unknown. We evaluated the effect of ischemic neuronal insults on the regulation of amyloid precursor protein (APP) processing. We used an in vitro model of cerebral ischemia (oxygen-glucose deprivation) to evaluate the effect of ischemic neuronal insults on the amyloidogenic and non-amyloidogenic pathways using human neuroblastoma cell line and primary cultured cells of transgenic mice which expressed human APP (Tg2576). Ischemic neuronal insults increased the production of Aβ in Tg2576 primary culture cells compared to controls. A disintegrin and metalloprotease 10 (ADAM 10) was markedly increased in early stage of ischemic insults, which was followed by decreased level of ADAM 10 expression in later stage. The protein and mRNA expression of β-site cleavage enzyme (BACE) and BACE activity was not significantly different between the group of ischemic insults and control. By contrast, the activity of γ-secretase was significantly increased after 4 h of ischemic insults, as compared to controls. The present study showed that the ischemic neuronal insults increased the production of Aβ by influencing APP metabolism, which may link the role of ischemic insults to the pathogenesis of AD.

The purpose of this study was to better understand the frequency and mechanisms of stroke recurrence after the stroke with no determined cause (NC). We prospectively studied consecutive patients with acute cerebral infarcts. We divided the patients into five groups (large artery disease [LAD], cardioembolism [CE], small artery disease [SAD], two or more causes [TMC], and NC) and registered recurrent strokes and prognosis for 1 year. Those in the NC group were compared with other subtypes. A total of 204 patients were included; 56 LAD, 22 CE, 62 SAD, 27 TMC, and 37 NC. During follow-up, there were 7 deaths and 31 first recurrent strokes. Patients of the NC group showed a significantly higher rate (30%) of recurrent stroke than those of other subtypes (LAD 16%; CE 14%; SAD 2%), and it was associated with the existence of mild stenosis (≤50%) on relevant artery or the stenosis of greater than 50% on nonrelevant artery. Occlusive lesions other than significant stenosis of relevant artery may play an important role in the development of stroke recurrence in patients of the NC group. Therefore, from the therapeutic and prognostic point of view, the detection of such occlusive lesions in patients with cryptogenic stroke may be needed.Ann Neurol 2003

The purpose of this study was to better understand the frequency and mechanisms of stroke recurrence after the stroke with no determined cause (NC). We prospectively studied consecutive patients with acute cerebral infarcts. We divided the patients into five groups (large artery disease [LAD], cardioembolism [CE], small artery disease [SAD], two or more causes [TMC], and NC) and registered recurrent strokes and prognosis for 1 year. Those in the NC group were compared with other subtypes. A total of 204 patients were included; 56 LAD, 22 CE, 62 SAD, 27 TMC, and 37 NC. During follow‐up, there were 7 deaths and 31 first recurrent strokes. Patients of the NC group showed a significantly higher rate (30%) of recurrent stroke than those of other subtypes (LAD 16%; CE 14%; SAD 2%), and it was associated with the existence of mild stenosis (≤50%) on relevant artery or the stenosis of greater than 50% on nonrelevant artery. Occlusive lesions other than significant stenosis of relevant artery may play an important role in the development of stroke recurrence in patients of the NC group. Therefore, from the therapeutic and prognostic point of view, the detection of such occlusive lesions in patients with cryptogenic stroke may be needed.Ann Neurol 2003

We evaluated the accuracy of transcranial Doppler (TCD) criteria in detecting middle cerebral artery (MCA) stenoses other than solitary severe stenoses. Three TCD criteria were evaluated in patients with acute MCA territory infarction who also underwent angiography: abnormalities in mean velocity (MV), focal areas of spectral waveform abnormalities, and compensatory increase in MV in collateral vessels. Among 102 patients studied, angiography revealed MCA lesions in 48: 16 had uncomplicated lesions (single stenosis of moderate to severe degree), 19 had mildly complicated lesions (single MCA stenosis of other than moderate to severe degree, or moderate to severe MCA stenosis with a concomitant lesion outside the MCA), and 13 had severely complicated lesions (MCA stenosis of other than moderate to severe degree with a concomitant lesion outside the MCA). The sensitivity of abnormalities in MV in uncomplicated MCA lesions was 81%, whereas it was 53% in mildly complicated MCA lesions and 38% in severely complicated MCA lesions. However, a compensatory increase in MV in collaterals was more frequently found in complicated MCA lesions, and focal areas of spectral waveform abnormalities were observed fairly consistently in all groups. TCD findings of focal areas of spectral waveform abnormalities and compensatory collateral flow were common in complicated MCA lesions and may improve the specificity of TCD in the diagnosis of MCA stenosis. © 2003 Wiley Periodicals, Inc. J Clin Ultrasound 31:142–151, 2003

Background and Purpose. The transcranial Doppler (TCD) findings in symptomatic small deep infarction are not well known. The aim of this study was to evaluate the role of TCD in striatocapsular small deep infarctions (SSDIs). Methods. The cerebral angiography and TCD findings were analyzed on 100 patients with symptomatic cerebral infarcts on the middle cerebral artery (MCA) territory. The sensitivity, specificity, and accuracy of TCD in detecting the MCA lesions were compared between lacunar group (the patients with lacunar syndrome and SSDIs on magnetic resonance image) and nonlacunar group. Results. Thirty‐eight patients were classified as the lacunar group, whereas 62 patients as the nonlacunar group. On angiography, occlusive lesion of MCA was found in 18 of the lacunar group and 24 patients of the nonlacunar group. The degree of MCA stenosis was higher in the nonlacunar group (80.8%± 21.2%) than the lacunar group (60.4%± 21.6%). The accuracy of TCD for the detection of MCA stenosis was not different between the groups. However, the sensitivity of TCD in the lacunar group was lower (72%) than in the nonlacunar group (88%), and it might have been due to the difference in the degree of MCA stenosis among the groups. Conclusions. Occlusive lesions of the MCA should be considered as a potential cause of SSDIs. In this respect, TCD may be used for screening candidates for conventional angiography in those patients. High rate of mild‐degree stenosis of MCA in patients with SSDIs, however, caused a risk for missing such stenosis on TCD.

The role of PKCε in amyloid precursor protein (APP) processing was investigated using APP-overexpressing B103 cells. As reported previously, a PKC activator, phorbol-12,13-dibutyrate (PDBu), enhanced secretion of APPα, and this effect was blocked by a PKC inhibitor, GF109203X in this system. Selective inhibition of PKCε by overexpressing the PKCε V1 region, which binds specifically to the receptor for activated C-kinase (RACK), blocked PDBu-induced enhancement of APPα secretion as well as PDBu-induced decrease in β-secretase-derived APP C-terminal fragment production. On the other hand, the level of PKCε, but not that of PKCα or PKCγ, was substantially lower in the brains of Alzheimer's disease patients compared to age-matched controls. These results add to a growing body of evidence that PKCε plays an important role in modulating APP processing, and suggest that reduced PKCε activity may contribute to the development of Alzheimer's disease.

The contribution of NMDA receptors to the expression of long-term potentiation (LTP) is controversial. In entorhinal cortex (EC) previous studies reported either that LTP was exclusively expressed through NMDA receptors or that both NMDA and non-NMDA receptors were involved in LTP expression. To reexamine this issue, horizontal entorhinal cortical slices were prepared from adult rats and electrical stimulation was delivered in layer II/III, while field potential recordings were made in layer III. In the standard condition (2.5 mM Mg⁺⁺), LTP was reliably induced by theta burst stimulation, but was blocked by 100 μM D-AP5, an NMDA receptor antagonist. This corroborates previous reports that NMDA receptor activation is required for induction of EC LTP. The field potential response was not affected by D-AP5, but completely blocked by 10 μM CNQX, a non-NMDA receptor antagonist. This indicates that the expression of LTP is mediated by non-NMDA receptors in the standard condition. LTP of NMDA receptor-mediated responses was tested by comparing NMDA responses before and after applying theta burst stimulation in medium containing low magnesium (0.4–1 mM). Theta burst stimulation induced 43.2±9.7% increase of non-NMDA responses (i.e., AP5-insensitive fast component) but 5.6±9.0% decrease of the NMDA receptor component (AP5-sensitive slow component). These results indicate that activation of NMDA receptors is critical for induction of LTP, but LTP expression is mediated by non-NMDA receptors in EC under these experimental conditions. Synapse 34:1–7, 2000. © 2000 Wiley-Liss, Inc.

The contribution of NMDA receptors to the expression of long-term potentiation (LTP) is controversial. In entorhinal cortex (EC) previous studies reported either that LTP was exclusively expressed through NMDA receptors or that both NMDA and non-NMDA receptors were involved in LTP expression. To reexamine this issue, horizontal entorhinal cortical slices were prepared from adult rats and electrical stimulation was delivered in layer II/III, while field potential recordings were made in layer III. In the standard condition (2.5 mM Mg⁺⁺), LTP was reliably induced by theta burst stimulation, but was blocked by 100 μM D-AP5, an NMDA receptor antagonist. This corroborates previous reports that NMDA receptor activation is required for induction of EC LTP. The field potential response was not affected by D-AP5, but completely blocked by 10 μM CNQX, a non-NMDA receptor antagonist. This indicates that the expression of LTP is mediated by non-NMDA receptors in the standard condition. LTP of NMDA receptor-mediated responses was tested by comparing NMDA responses before and after applying theta burst stimulation in medium containing low magnesium (0.4–1 mM). Theta burst stimulation induced 43.2±9.7% increase of non-NMDA responses (i.e., AP5-insensitive fast component) but 5.6±9.0% decrease of the NMDA receptor component (AP5-sensitive slow component). These results indicate that activation of NMDA receptors is critical for induction of LTP, but LTP expression is mediated by non-NMDA receptors in EC under these experimental conditions. Synapse 34:1–7, 2000. © 2000 Wiley-Liss, Inc.

The contribution of NMDA receptors to the expression of long‐term potentiation (LTP) is controversial. In entorhinal cortex (EC) previous studies reported either that LTP was exclusively expressed through NMDA receptors or that both NMDA and non‐NMDA receptors were involved in LTP expression. To reexamine this issue, horizontal entorhinal cortical slices were prepared from adult rats and electrical stimulation was delivered in layer II/III, while field potential recordings were made in layer III. In the standard condition (2.5 mM Mg++), LTP was reliably induced by theta burst stimulation, but was blocked by 100 μM D‐AP5, an NMDA receptor antagonist. This corroborates previous reports that NMDA receptor activation is required for induction of EC LTP. The field potential response was not affected by D‐AP5, but completely blocked by 10 μM CNQX, a non‐NMDA receptor antagonist. This indicates that the expression of LTP is mediated by non‐NMDA receptors in the standard condition. LTP of NMDA receptor‐mediated responses was tested by comparing NMDA responses before and after applying theta burst stimulation in medium containing low magnesium (0.4–1 mM). Theta burst stimulation induced 43.2±9.7% increase of non‐NMDA responses (i.e., AP5‐insensitive fast component) but 5.6±9.0% decrease of the NMDA receptor component (AP5‐sensitive slow component). These results indicate that activation of NMDA receptors is critical for induction of LTP, but LTP expression is mediated by non‐NMDA receptors in EC under these experimental conditions. Synapse 34:1–7, 2000. © 2000 Wiley‐Liss, Inc.