Shinji Nagahiro

Oxidized LDL in Carotid Plaques and Plasma Associates With Plaque Instability

Objective—Oxidation of LDL plays a significant pathogenic role in atherosclerosis. In this study, we attempted to clarify the correlation between the morphology of human atherosclerotic plaques and the oxidized LDL (OxLDL) levels in plasma and carotid plaques. Methods and Results—OxLDL levels (ng/&mgr;g apolipoprotein B) in plasma and carotid plaques from 44 patients undergoing carotid endarterectomy and OxLDL levels in 17 control plasma and 9 normal intima samples were determined by a sandwich ELISA by using specific antibodies against OxLDL (DLH3) and apolipoprotein B. The plaques were immunohistochemically classified as macrophage (M&phgr;)-rich and M&phgr;-poor. In paired samples from individual patients, plaque OxLDL was nearly 70 times higher than plasma OxLDL (mean±SEM, 11.9±1.7 vs 0.18±0.01 ng/&mgr;g apoB, P <0.0001). The OxLDL level was significantly higher in M&phgr;-rich- than M&phgr;-poor plaques (19.6±2.8 vs 5.50±0.77ng/&mgr;g apoB, P <0.0001) and corresponded with DLH3 antigen positivity of the plaques. In patients with M&phgr;-rich plaques, plasma OxLDL was significantly higher than in the controls (0.20±0.02 vs 0.13±0.01ng/&mgr;g apoB, P =0.02). Conclusions—Our results suggest that LDL undergoes further oxidation in plaques, and that high plasma and plaque levels of OxLDL are correlated with the vulnerability to rupture of atherosclerotic lesions.

Consensus statement on concussion in sport-the 5th international conference on concussion in sport held in Berlin, October 2016

The 2017 Concussion in Sport Group (CISG) consensus statement is designed to build on the principles outlined in the previous statements1–4 and to develop further conceptual understanding of sport-related concussion (SRC) using an expert consensus-based approach. This document is developed for physicians and healthcare providers who are involved in athlete care, whether at a recreational, elite or professional level. While agreement exists on the principal messages conveyed by this document, the authors acknowledge that the science of SRC is evolving and therefore individual management and return-to-play decisions remain in the realm of clinical judgement. This consensus document reflects the current state of knowledge and will need to be modified as new knowledge develops. It provides an overview of issues that may be of importance to healthcare providers involved in the management of SRC. This paper should be read in conjunction with the systematic reviews and methodology paper that accompany it. First and foremost, this document is intended to guide clinical practice; however, the authors feel that it can also help form the agenda for future research relevant to SRC by identifying knowledge gaps. A series of specific clinical questions were developed as part of the consensus process for the Berlin 2016 meeting. Each consensus question was the subject of a specific formal systematic review, which is published concurrently with this summary statement. Readers are directed to these background papers in conjunction with this summary statement as they provide the context for the issues and include the scope of published research, search strategy and citations reviewed for each question. This 2017 consensus statement also summarises each topic and recommendations in the context of all five CISG meetings (that is, 2001, 2004, 2008, 2012 as well as 2016). Approximately 60 000 published articles were screened by the expert panels for the Berlin …

Edaravone, a Free Radical Scavenger, Inhibits MMP-9–Related Brain Hemorrhage in Rats Treated With Tissue Plasminogen Activator

Background and Purpose— Intracerebral hemorrhage, induced by recombinant tissue plasminogen activator (rtPA) in ischemic stroke, is attributable to the increased activity of matrix metalloproteinase-9 (MMP-9). Patients with acute infarct benefit from the neuroprotective drug edaravone, a free radical scavenger. We examined the mechanisms by which edaravone may help to suppress rtPA-induced brain hemorrhage. Methods— Male Wistar rats weighing 250 to 280 g were subjected to 3-hour transient middle cerebral artery occlusion (MCAO) and divided randomly into 3 groups. Immediately after reperfusion, 1 group was intravenously injected with 10 mg/kg rtPA, another with rtPA plus 3 mg/kg edaravone, and the 3rd group received no treatment. We assessed the hemorrhage volume and the activity of MMP-9 in the brain 24 hours postischemia. We also studied the activity of MMP-9, its mRNA expression, and nuclear factor-kappa B (NF-&kgr;B) activity in rtPA-stimulated human microvascular endothelial cells (HBECs). Results— The degree of hemorrhage and the level of endothelial cell–derived MMP-9 were elevated in rats treated with rtPA alone and attenuated in rats treated with rtPA plus edaravone. In rtPA-stimulated HBECs, edaravone suppressed the activity and mRNA expression of MMP-9 in a dose-dependent manner. Edaravone also inhibited NF-&kgr;B activation. Conclusions— We demonstrate that edaravone inhibits rtPA-induced cerebral hemorrhage in the ischemic brain of rats via the inhibition of MMP-9 expression in vivo, which is substantiated by inhibition of MMP-9 expression and NF-&kgr;B activation in HBECs. Edaravone may render thrombolytic therapy safer for the administration of rtPA in patients with ischemic stroke.

Bilateral deep brain stimulation of the globus pallidus internus in tardive dystonia

Tardive dystonia is a disabling movement disorder as a consequence of exposure to neuroleptic drugs. We followed 6 patients with medically refractory tardive dystonia treated by bilateral globus pallidus internus (GPi) deep brain stimulation (DBS) for 21 ± 18 months. At last follow‐up, the Burke‐Fahn‐Marsden Dystonia Rating Scale (BFMDRS) motor score improved by 86% ± 14%, and the BFMDRS disability score improved by 80% ± 12%. Bilateral GPi‐DBS is a beneficial therapeutic option for the long‐term relief of tardive dystonia.

Raised plasma oxidised LDL in acute cerebral infarction.

Background: The association between oxidised low density lipoprotein (OxLDL) and cerebral infarction is suspected but not established. Objectives: To determine whether plasma OxLDL is a useful marker for monitoring oxidative stress in stroke patients. Methods: Plasma OxLDL concentrations were determined in 56 stroke patients with cerebral infarction (n = 45) or cerebral haemorrhage (n = 11), and in 19 age matched controls, using a novel sandwich enzyme linked immunosorbent assay. Results: Compared with the controls (0.130 (0.007) ng/μg LDL, mean (SEM)), OxLDL was significantly raised in patients with cerebral infarction (0.245 (0.022); p < 0.0001) but not in those with haemorrhage (0.179 (0.023)). Patients with cortical ischaemic infarcts (n = 22) had higher OxLDL levels than either the controls (p < 0.0001) or the patients with non-cortical ischaemic infarcts (n = 23) (p < 0.001). Increased OxLDL concentrations in patients with cortical infarcts persisted until the third day after stroke onset. The National Institutes of Health stroke scales in patients with cortical infarction were higher than in those with non-cortical infarction (p < 0.01). Conclusions: There is a significant association between raised plasma OxLDL and acute cerebral infarction, especially cortical infarction. Plasma OxLDL may reflect oxidative stress in stroke patients.

Differential involvement of striosome and matrix dopamine systems in a transgenic model of dopa-responsive dystonia

Dopa-responsive dystonia (DRD) is a hereditary dystonia characterized by a childhood onset of fixed dystonic posture with a dramatic and sustained response to relatively low doses of levodopa. DRD is thought to result from striatal dopamine deficiency due to a reduced synthesis and activity of tyrosine hydroxylase (TH), the synthetic enzyme for dopamine. The mechanisms underlying the genesis of dystonia in DRD present a challenge to models of basal ganglia movement control, given that striatal dopamine deficiency is the hallmark of Parkinsons disease. We report here behavioral and anatomical observations on a transgenic mouse model for DRD in which the gene for 6-pyruvoyl-tetrahydropterin synthase is targeted to render selective dysfunction of TH synthesis in the striatum. Mutant mice exhibited motor deficits phenotypically resembling symptoms of human DRD and manifested a major depletion of TH labeling in the striatum, with a marked posterior-to-anterior gradient resulting in near total loss caudally. Strikingly, within the regions of remaining TH staining in the striatum, there was a greater loss of TH labeling in striosomes than in the surrounding matrix. The predominant loss of TH expression in striosomes occurred during the early postnatal period, when motor symptoms first appeared. We suggest that the differential striosome-matrix pattern of dopamine loss could be a key to identifying the mechanisms underlying the genesis of dystonia in DRD.

Endothelial injury and inflammatory response induced by hemodynamic changes preceding intracranial aneurysm formation: experimental study in rats

OBJECT Intracranial aneurysms are the leading cause of subarachnoid hemorrhage, which is associated with high morbidity and mortality rates. Despite advances in the microsurgical and endovascular treatment of intracranial aneurysms, little is known about the mechanisms by which they originate, grow, and rupture. To clarify the series of early events leading to formation of intracranial aneurysms, the authors compared aneurysmal morphological changes on vascular corrosion casts with parallel pathological changes in the cerebral arteries of rats. METHODS The authors induced cerebral aneurysms by renal hypertension and right common carotid artery ligation in 40 male Sprague-Dawley rats; 10 intact rats served as the controls. The anterior cerebral artery-olfactory artery bifurcation was assessed morphologically by using vascular corrosion casts of Batson plastic reagent and immunohistochemically by using antibodies against endothelial nitric oxide synthase, alpha-smooth muscle actin, macrophages, and matrix metalloproteinase-9. RESULTS Surgically treated rats manifested different degrees of aneurysmal changes. Based on these staged changes, the authors propose that the formation of intracranial aneurysms starts with endothelial injury at the apical intimal pad (Stage I); this leads to the formation of an inflammatory zone (Stage II), followed by a partial tear or defect in the inflammatory zone. Expansion of this defect forms the nidus of the intracranial aneurysm (Stage III). CONCLUSIONS This is the first study to demonstrate the in vivo mechanisms of intracranial aneurysm formation. The inflammatory response that follows endothelial injury is the basic step in the pathogenesis of these lesions. In this study the investigators have expanded the understanding of the origin of intracranial aneurysms and have contributed to the further development of measures to prevent and treat aneurysms.

Akt2 and Akt3 play a pivotal role in malignant gliomas

Akt, one of the major downstream effectors of phosphatidylinositol 3-kinase, is hyper-expressed and activated in a variety of cancers including glioblastoma. However, the expression profiles of the Akt isoforms Akt1/PKBalpha, Akt2/PKBbeta, and Akt3/PKBgamma and their functional roles in malignant glioma are not well understood. Therefore, we examined the protein and mRNA expression patterns of Akt isoforms in tissues from human astrocytomas, glioblastomas, and non-neoplastic regions. We also explored the biological role of each Akt isoform in malignant glioma cells using RNA interference-mediated knock-down and the over-expression of plasmid DNA of each isoform. The expression of Akt1 protein and mRNA was similar in glioma and normal control tissues. Although the protein and mRNA level of Akt2 increased with the pathological grade of malignancy, the expression of Akt3 mRNA and protein decreased as the malignancy grade increased. In U87MG, T98G, and TGB cells, the down-regulation of Akt2 or Akt3 by RNA interference reduced the expression of the phosphorylated form of Bad, resulting in the induction of caspase-dependent apoptosis. Akt1 knock-down did not affect cell growth or survival. We first demonstrate that the over-expression of Akt2 or Akt3 down-regulated the expression of the other protein and that endogenous Akt3 protein showed high kinase activity in U87MG cells. Our data suggest that Akt2 and Akt3 play an important role in the viability of human malignant glioma cells. Targeting Akt2 and Akt3 may hold promise for the treatment of patients with gliomas.

Angiographic changes in venous drainage of cavernous sinus dural arteriovenous fistulae after palliative transarterial embolization or observational management: a proposed stage classification.

OBJECTIVE:We assessed whether angiographic changes in venous drainage patterns occur over time in cavernous sinus dural arteriovenous fistulae (dAVFs) without a complete cure. METHODS:We classified 65 cavernous sinus dAVFs into three types on the basis of initial angiographic findings. In Type 1, both anterior and posterior drainage routes were open; in Type 2, the posterior drainage route was closed, whereas the anterior drainage route was open; and in Type 3, both the posterior and anterior drainage routes were closed. RESULTS:Of the 65 dAVFs, 40 were of Type 1, 21 of Type 2, and 4 of Type 3. During the follow-up period, 17 of the dAVFs that were treated palliatively with transarterial embolization (n = 11) or monitored without therapy (n = 6) demonstrated angiographic changes. In these 11 patients, there was a change in the venous drainage pattern from Type 1 to Type 2 (n = 5), from Type 2 to Type 3 (n = 3), and from Type 1 to Type 3 (n = 3). One of 11 had a conversion into a lesion with cortical venous drainage. The remaining 6 dAVFs (4 with observational management, 2 with transarterial embolization) demonstrated closure of the fistula; in 5 of these, the affected cavernous sinus was not depicted on follow-up angiograms. CONCLUSION:In some cavernous sinus dAVFs with palliative transarterial embolization or observational management, there was a change in the venous drainage patterns, consisting of a decrease in the number of venous drainage routes. There was a trend for the posterior route to close before the anterior drainage or cortical drainage route. This suggests the occurrence of a staged progression in a regular direction in cavernous sinus dAVFs. Without treatment aiming at a complete cure, most cavernous sinus dAVFs can behave benignly, with a low possibility of development of cortical venous reflux during follow-up.

Regional and Temporal Alterations in Ca2+/Calmodulin-Dependent Protein Kinase II and Calcineurin in the Hippocampus of Rat Brain After Transient Forebrain Ischemia

Abstract: We have investigated regional and temporal alterations in Ca2+/calmodulin‐dependent protein kinase II (CaM kinase II) and calcineurin (Ca2+/calmodulin‐dependent protein phosphatase) after transient forebrain ischemia. Immunoreactivity and enzyme activity of CaM kinase II decreased in regions CA1 and CA3, and in the dentate gyrus, of the hippocampus early (6–12 h) after ischemia, but the decrease in immunoreactivity gradually recovered over time, except in the CA1 region. Furthermore, the increase in Ca2+/calmodulin‐independent activity was detected up to 3 days after ischemia in all regions tested, suggesting that the concentration of intracellular Ca2+ increased. In contrast to CaM kinase II, as immunohistochemistry and regional immunoblot analysis revealed, calcineurin was preserved in the CA1 region until 1.5 days and then lost with the increase in morphological degeneration of neurons. Immunoblot analysis confirmed the findings of the immunohistochemistry. These results suggest that there is a difference between CaM kinase II and calcineurin in regional and temporal loss after ischemia and that imbalance of Ca2+/calmodulin‐dependent protein phosphorylation‐dephosphorylation may occur.