Shu Sogabe, HABOSHI Tatsuya, Izumi Yamaguchi, Masaaki Korai, Nobuaki Yamamoto, Kenji Shimada, Yasuhisa Kanematsu and Yasushi Takagi : Experience of using coronary perfusion balloon catheter for acute middle cerebral artery occlusion, Surgical Neurology International, Vol.14, No.365, 365, 2023.
(要約)
We present the case of an individual with acute occlusion of the middle cerebral artery caused by atherosclerosis. The patient underwent angioplasty using a coronary perfusion balloon, which resulted in a favorable clinical outcome. A 66-year-old male patient presented with an acute onset of right hemiplegia and dysarthria. Magnetic resonance imaging revealed an occlusion of the left middle cerebral artery, and alteplase was administered, followed by a mechanical thrombectomy and intracranial balloon catheter angioplasty. Due to restenosis, a coronary perfusion balloon catheter was used for a 15-minute angioplasty procedure while maintaining the perfusion. This treatment approach led to the recanalization of the artery and favorable clinical outcomes. The coronary perfusion balloon may represent a viable therapeutic alternative for the management of refractory intracranial atherosclerotic large vessel occlusion.
Yuki Yamamoto, Nobuaki Yamamoto, Tomohiro Matsuda, Kazutaka Kuroda, Izumi Yamaguchi, Shu Sogabe, Masaaki Korai, Kenji Shimada, Yasuhisa Kanematsu, Yasushi Takagi and Yuishin Izumi : Stent retrieval for free-floating thrombus attached to carotid artery stenosis: A report of two cases., Surgical Neurology International, Vol.14, 274, 2023.
(要約)
In cases of carotid artery stenosis with FFT, it is technically possible to retrieve a thrombus with a stent retriever. Although thrombus removal may help reduce the risk of ischemic complications in a series of urgent CAS procedures, there are concerns such as mechanical irritation to the carotid artery plaque, and its indications and alternative treatments should be carefully considered.
Nobuaki Yamamoto, Kazutaka Kuroda, Yuki Yamamoto, Izumi Yamaguchi, Shu Sogabe, Kenji Shimada, Ryoma Morigaki, Yasuhisa Kanematsu, Yuishin Izumi and Yasushi Takagi : Long-sheath Introducer-assisted Revascularization (L-SHARE) Technique for Treating Large-vessel Occlusion by a Giant Clot, Internal Medicine, Vol.62, No.6, 909-913, 2023.
(要約)
Revascularization for common carotid artery (CCA) occlusion might be difficult. We reported our strategy for revascularizing CCA occlusion by giant clots. A 94-year-old woman was transferred to our hospital because of right hemiparesis and aphasia. CCA occlusion and giant clots were detected on ultrasonography. We performed mechanical thrombectomy using a 9-Fr balloon-guiding catheter, stent retriever, and aspiration catheter through a 9-Fr long-sheath introducer [long-sheath introducer-assisted revascularization (L-SHARE) technique]. We successfully recanalized CCA occlusion using this method. The L-SHARE technique might be useful for recanalization of CCA occlusion.
Yuki Kanazawa, Tosiaki Miyati, Masafumi Harada, Mitsuharu Miyoshi, Yuki Matsumoto, Hiroaki Hayashi, Yasuhisa Kanematsu and Yasushi Takagi : Evaluation of Biological Metabolic Activity within an Atherosclerotic Plaque using Chemical Exchange Saturation Transfer Imaging, Proceedings of ISMRM, Vol.32, No.2982, 2023.
Cerebrovascular and cardiovascular disease are the main causes of death in Japan. The leading causes of the need for long-term care in Japan are also cerebrovascular and cardiovascular disease, which together account for more than one-fourth of the total. The Cerebrovascular and Cardiovascular Disease Control Act, of Japanese national law, was promulgated by a legislative act in 2018. On the basis of the Cerebrovascular and Cardiovascular Disease Control Act, the Ministry of Health, Labour and Welfare, Japan, published the Japanese National Plan for Promotion of Measures Against Cerebrovascular and Cardiovascular Disease (Japanese National Plan) in 2020. By the example of the Japanese National Plan, Tokushima prefecture established a cerebrovascular and cardiovascular disease countermeasure promotion plan to progress cerebrovascular and cardiovascular disease measures according to their own circumstances. One of the important measures of the plan is improving emergency transportation systems. Patients with intracranial large vessel occlusion strokes should be served by direct transfer to endovascular capable centers avoiding delays by misguided transfer to primary stroke centers. Considering the limited availability of endovascular capable centers, accurate identification of patients with high probability of having large vessel occlusion strokes in the prehospital setting is importance. To address this problem, we introduced prehospital scale called Field Assessment Stroke Triage for Emergency Destination (FAST-ED) on emergency transportation systems in Tokushima city.
(キーワード)
Cerebrovascular and cardiovascular disease / emergency transportation systems / prehospital scale
Takayoshi Shinya, Tomoki MATSUSHITA, Yuka HIROSHIMA, Youichi Otomi, Yasuhisa Kanematsu, Yoshimi Bando, Hisanori Uehara, Yoshiaki Kitamura and Masafumi Harada : Imaging features of a myoepithelial carcinoma of the nasal cavity: A case report and literature review, Radiology Case Reports, Vol.18, No.1, 386-391, 2022.
(要約)
Myoepithelial carcinoma of the nasal cavity is extremely rare. We report the case of a 66-year-old man with myoepithelial carcinoma of the nasal cavity. Computed tomography (CT) and magnetic resonance imaging revealed a lobulated soft tissue mass with central necrosis and hemorrhage, as well as an invasion of the skull base and left orbit. The patient presented with continuous nasal congestion and heavy head and had no elevated level of squamous cell carcinoma-related antigen. CT, magnetic resonance imaging, or F-fluorodeoxyglucose (FDG) positron emission tomography/CT revealed no evidence of a metastatic lesion. F-FDG accumulation in the tumor was inhomogeneous and moderate. Histopathological examination of the resected specimen confirmed a well-circumscribed solid tumor with septa, a small area of hemorrhage, and necrosis. The subsequent diagnosis was a myoepithelial carcinoma of the left nasal cavity. This case shows that nasal myoepithelial carcinoma might appear as a well-defined lobulated mass with hemorrhagic necrosis and intense contrast enhancement in the solid component. We conjecture that hemorrhagic necrosis and intense enhancement values may be potential markers of nasal myoepithelial carcinoma.
Kenji Shimada, Kazuhisa Miyake, Izumi Yamaguchi, Shu Sogabe, Masaaki Korai, Yasuhisa Kanematsu and Yasushi Takagi : Efficacy of Utilizing Both 3-Dimensional Multimodal Fusion Image and Intra-Arterial Indocyanine Green Videoangiography in Cerebral Arteriovenous Malformation Surgery, World Neurosurgery, Vol.169, e260-e269, 2022.
(要約)
An understanding of the complex morphology of an arteriovenous malformation (AVM) is important for successful resection. We have previously reported the utility of intra-arterial indocyanine green (ICG) videoangiography for this purpose, but that method cannot detect the angioarchitecture covered by brain tissue. 3-dimensional (3D) multimodal fusion imaging is reportedly useful for this same purpose, but cannot always visualize the exact angioarchitecture due to poor source images and processing techniques. This study examined the results of utilizing both techniques in patients with AVMs. Both techniques were applied in 12 patients with AVMs. Both images were compared with surgical views and evaluated by surgeons. Although evaluations for identifying superficial feeders by ICG videoangiography were high in all cases, the more complicated the AVM, the lower the evaluation by 3D multimodal fusion imaging. Conversely, evaluation of the estimated range of the nidus was high in all cases by 3D multimodal fusion imaging, but low in all but one case by ICG videoangiography. Nidus flow reduction was recognized by Flow 800 analysis obtained after ICG videoangiography. These results showed that utilizing both techniques together was more useful than each modality alone in AVM surgery. This was particularly effective in identifying superficial feeders and estimating the range of the nidus. This technique is expected to offer an optimal tool for AVM surgery.
Eiji Shikata, Takeshi Miyamoto, Tadashi Yamaguchi, Izumi Yamaguchi, Hiroshi Kagusa, Daiki Gotoh, Kenji Shimada, Yoshiteru Tada, Kenji Yagi, 北里 慶子, Yasuhisa Kanematsu and Yasushi Takagi : An imbalance between RAGE/MR/HMGB1 and ATP1α3 is associated with infammatory changes in rat brain harboring cerebral aneurysms prone to rupture, Journal of Neuroinflammation, Vol.19, No.161, 161, 2022.
(要約)
An aneurysmal subarachnoid hemorrhage is a devastating event. To establish an effective therapeutic strategy, its pathogenesis must be clarified, particularly the pathophysiology of brain harboring intracranial aneurysms (IAs). To elucidate the pathology in brain harboring IAs, we examined the significance of the receptor for advanced glycation end-products (RAGE)/mineralocorticoid receptor (MR) pathway and Na/K-ATPase (ATP1α3). Ten-week-old female rats were subjected to oophorectomy as well as hypertension and hemodynamic changes to induce IAs, and were fed a high-salt diet. Brain damage in these rats was assessed by inflammatory changes in comparison to sham-operated rats fed a standard diet. Six weeks after IA induction (n = 30), irregular morphological changes, i.e., an enlarged vessel diameter and vascular wall, were observed in all of the left posterior cerebral arteries (Lt PCAs) prone to rupture. Approximately 20% of rats had ruptured IAs within 6 weeks. In brain harboring unruptured IAs at the PCA, the mRNA levels of RAGE and MR were higher, and that of ATP1α3 was lower than those in the sham-operated rats (p < 0.05, each). Immunohistochemically, elevated expression of RAGE and MR, and decreased expression of ATP1α3 were observed in the brain parenchyma adjacent to the Lt PCA, resulting in increased Iba-1 and S100B expression that reflected the inflammatory changes. There was no difference between the unruptured and ruptured aneurysm rat groups. Treatment with the MR antagonist esaxerenone abrogated these changes, and led to cerebral and vascular normalization and prolonged subarachnoid hemorrhage-free survival (p < 0.05). Regulation of the imbalance between the RAGE/MR pathway and ATP1α3 may help attenuate the damage in brain harboring IAs, and further studies are warranted to clarify the significance of the down-regulation of the MR/RAGE pathway and the up-regulation of ATP1α3 for attenuating the pathological changes in brain harboring IAs.
Kenji Shimada, Izumi Yamaguchi, Takeshi Miyamoto, Shu Sogabe, Kazuhisa Miyake, Yasuhisa Kanematsu and Yasushi Takagi : Efficacy of intraarterial indocyanine green videoangiography in surgery for arteriovenous fistula at the craniocervical junction in a hybrid operating room: illustrative cases, Journal of Neurosurgery. Case Lessons, Vol.3, No.23, 1-6, 2022.
(要約)
Sufficient understanding of the angioarchitecture of an arteriovenous fistula (AVF) at the craniocervical junction (CCJ) is crucial to surgical treatment but is often difficult because of the complex vascular anatomy. Intraarterial indocyanine green (ICG) videoangiography has emerged as a more useful option for understanding the vascular anatomy than intravenous ICG videoangiography. This report describes two cases of CCJ AVFs successfully treated by surgery using intraarterial ICG videoangiography and describes the efficacy of this technique. Case 1 involved a 71-year-old man presenting with tetraparesis after sudden onset of severe headache due to subarachnoid hemorrhage (SAH). Digital subtraction angiography (DSA) demonstrated CCJ epidural AVF. Intraarterial ICG videoangiography revealed the drainer, which had been difficult to identify. The AVF disappeared after disconnection of the drainer. Case 2 involved a 68-year-old man presenting with severe headache due to SAH. DSA showed multiple AVFs at the CCJ and cerebellar tentorium. Intraarterial ICG videoangiography demonstrated concomitant perimedullary AVF and dural AVF at the CCJ. All AVFs disappeared postoperatively. Intraarterial ICG videoangiography was useful for definitive diagnosis of CCJ AVF, facilitating identification of feeders and drainers with bright and high phase contrast and allowing repeated testing to confirm flow direction.
Izumi Yamaguchi, Yasuhisa Kanematsu, Kenji Shimada, Nobuaki Yamamoto, Kazuhisa Miyake, Takeshi Miyamoto, Shu Sogabe, Eiji Shikata, Manabu Ishihara, 山本 陽子, Kazutaka Kuroda and Yasushi Takagi : Single-session hematoma removal and transcortical venous approach for coil embolization of an isolated transverse-sigmoid sinus dural arteriovenous fistula in a hybrid operating room: illustrative case, Journal of Neurosurgery. Case Lessons, Vol.3, No.21, CASE2267, 2022.
(要約)
Dural arteriovenous fistula (DAVF) can present with massive hematoma, which sometimes requires emergent removal. Therefore, a surgical strategy for single-session hematoma removal and shunt occlusion in the same surgical field is important. A 73-year-old man was transferred to the authors' hospital with a headache. Brain computed tomography (CT) revealed an intracerebral hematoma in the right temporoparietal lobe (hematoma volume 12 ml). A cerebral angiogram revealed a right isolated transverse-sigmoid sinus (TSS)-DAVF fed by the occipital artery and middle meningeal artery. There was cortical venous reflux into the Labbé vein and posterior parietal vein. Percutaneous transarterial and transvenous embolization were unsuccessful. The following day, his consciousness level acutely declined with a headache, and brain CT showed hematoma expansion (hematoma volume 41 ml) with a midline shift. Therefore, the authors performed single-session hematoma removal and a transcortical venous approach for coil embolization of an isolated TSS-DAVF in a hybrid operating room. His postoperative course was uneventful. No recurrence was observed 3 months postoperatively on cerebral angiography. Single-session hematoma removal and a transcortical venous approach for coil embolization of an isolated TSS-DAVF is considered in cases with massive hematoma. This strategy is useful, considering recent developments in hybrid operating rooms.
Tadashi Yamaguchi, Takeshi Miyamoto, Eiji Shikata, Izumi Yamaguchi, Kenji Shimada, Kenji Yagi, Yoshiteru Tada, Masaaki Korai, Keiko T. Kitazato, Yasuhisa Kanematsu and Yasushi Takagi : Activation of the NLRP3/IL-1β/MMP-9 pathway and intracranial aneurysm rupture associated with the depletion of ERα and Sirt1 in oophorectomized rats, Journal of Neurosurgery, 1-8, 2022.
(要約)
Subarachnoid hemorrhage (SAH) due to intracranial aneurysm (IA) rupture is often a devastating event. Since the incidence of SAH increases especially in menopause, it is crucial to clarify the detailed pathogenesis of these events. The activation of vascular nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes has been studied in ischemic stroke and cardiovascular disease. However, the role of NLRP3 in IA rupture still needs to be explained. The authors sought to test their hypothesis that, under estrogen-deficient conditions, activation of NLRP3 inflammasomes via downregulation of the estrogen receptor (ER) facilitates IA rupture. Ten-week-old female Sprague Dawley rats with and without oophorectomy were subjected to hemodynamic changes and hypertension (OVX+/HT and OVX-/HT, respectively) and fed a high-salt diet. Separately, using human brain endothelial cells (HBECs) and human brain smooth muscle cells (HBSMCs), the authors tested the effect of NLRP3 under estrogen-free conditions and in the presence of estradiol or of ER agonists. In OVX+/HT rats, the frequency of IA rupture was significantly higher than in OVX-/HT rats (p = 0.03). In the left posterior cerebral artery prone to rupture in OVX+/HT rats, the levels of the mRNAs encoding ERα and Sirt1, but not of that encoding ERβ, were decreased, and the levels of the mRNAs encoding NLRP3, interleukin-1β (IL-1β), and matrix metalloproteinase 9 (MMP-9) were elevated. Immunohistochemical analysis demonstrated that the expression profiles of these proteins correlated with their mRNA levels. Treatment with an ER modulator, bazedoxifene, normalized the expression profiles of these proteins and improved SAH-free survival. In HBECs and HBSMCs under estrogen-free conditions, the depletion of ERα and Sirt1 and the accumulation of NLRP3 were counteracted by exposure to estradiol or to an ERα agonist but not to an ERβ agonist. To the authors' knowledge, this work represents the first demonstration that, in an aneurysm model under estrogen-deficient conditions, the depletion of ERα and Sirt1 may contribute to activation of the NLRP3/IL-1β/MMP-9 pathway, facilitating the rupture of IAs in the estrogen-deficient rat IA rupture model.
Yoshiteru Tada, Toshitaka Fujihara, Kenji Shimada, Nobuaki Yamamoto, Hiroki Yamazaki, Yuishin Izumi, Masafumi Harada, Yasuhisa Kanematsu and Yasushi Takagi : Seizure types associated with negative arterial spin labeling and positive diffusion-weighted imaging on peri-ictal magnetic resonance imaging, Journal of the Neurological Sciences, Vol.436, 1-8, 2022.
(要約)
Arterial spin labeling (ASL) and diffusion-weighted imaging (DWI) are useful for assessing hyperperfusion and cytotoxic edema, respectively, caused by acute seizures. This study investigated the clinical characteristics associated with normal ASL findings and DWI abnormalities in patients with acute seizures. Overall, 41 patients with ASL and DWI images that were obtained within 48 h of focal onset seizure diagnosis, due to epilepsy or acute symptomatic seizures, were divided into groups based on initial ASL findings (ASL-negative vs. ASL-positive), and DWI abnormalities (DWI-negative vs. DWI-positive). The diagnosis was made based on seizure semiology, electroencephalography, and conventional imaging modalities. ASL and DWI abnormalities were based on visual assessment. Of the 41 patients, eight (19.5%) displayed normal ASL findings. The proportion of patients with focal aware seizures (FAS) was significantly higher among ASL-negative patients (62.5%) than that in ASL-positive patients (15.2%); the proportion of patients with focal impaired awareness seizures (FIAS) was significantly lower among ASL-negative patients (12.5%) than that among ASL-positive patients (57.6%). Hyperintensity findings on DWI were observed in 12 patients (29.3%, DWI-positive). The proportion of patients with FIAS was significantly higher among DWI-positive patients (75.0%) than that among DWI-negative patients (37.9%). Multivariate analysis revealed that FAS and FIAS were associated with normal ASL findings (odds ratio [OR]: 21.37, P = 0.010) and DWI abnormalities (OR = 6.11, P = 0.028). A diagnosis of seizures should not be excluded based on normal ASL findings, especially in patients with FAS. FIAS may be a risk factor for neuronal damage caused by seizure activity.
Yuki Yamamoto, Nobuaki Yamamoto, Yasuhisa Kanematsu, Izumi Yamaguchi, Manabu Ishihara, Takeshi Miyamoto, Shu Sogabe, Kenji Shimada, Yasushi Takagi and Yuishin Izumi : The claw sign predicts first-pass effect in mechanical thrombectomy for cerebral large vessel occlusion in the anterior circulation, Surgical Neurology International, Vol.13, No.72, 1-7, 2022.
(要約)
Mechanical thrombectomy (MT) is an effective treatment for acute cerebral large vessel occlusion (LVO). Complete recanalization of vessels in a single procedure is defined as the first-pass effect (FPE) and is associated with good prognosis. In this study, angiographic clot protruding sign termed the "claw sign," was examined as candidate preoperative imaging factor for predicting the FPE. We retrospectively analyzed data from 91 consecutive patients treated for acute LVO in the anterior circulation by MT between January 2014 and December 2019. The claw sign was defined as a thrombus that protruded proximally by more than half of the diameter of the parent artery. Radiological findings such as claw sign, clinical and etiological features, and outcomes were compared between groups with and without successful FPE. Multivariate analysis was conducted to evaluate perioperative factors associated with FPE. FPE was achieved in 26 of 91 (28.6%) patients and the claw sign was observed in 34 of 91 (37.4%) patients. The claw sign was significantly more frequent in the successful FPE group than in the failed FPE group (53.8% vs. 30.8%; = 0.040). After the multivariate analysis, the claw sign was the only pretreatment parameter that could predict FPE (odds ratio, 2.67; 95% confidence interval, 1.01-7.06; = 0.047). The claw sign is an angiographic imaging factor that might predict FPE after MT for anterior circulation acute ischemic stroke.
Kenya Kusunose, Hironori Takahashi, Susumu Nishio, Yukina Hirata, Robert Zheng, Takayuki Ise, Koji Yamaguchi, Shusuke Yagi, Daiju Fukuda, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Kenji Shimada, Yasuhisa Kanematsu, Yasushi Takagi and Masataka Sata : Predictive value of left atrial function for latent paroxysmal atrial fibrillation as the cause of embolic stroke of undetermined source, Journal of Cardiology, Vol.78, No.5, 355-361, 2021.
(要約)
In patients with embolic stroke of undetermined source (ESUS), paroxysmal atrial fibrillation (AF) is often diagnosed, however, the risk of paroxysmal AF in ESUS has not been well described. Several studies have suggested a linkage between left atrial (LA) functional parameters and risk of AF in stroke patients. The aim of this study was to assess the role of LA functional parameters as predictors of latent paroxysmal AF in ESUS on admission. Between January 2015 and December 2019, consecutive stroke patients with suspected ESUS at admission were prospectively included in this study. They were under hospital electrocardiographic monitoring for detection of new-onset AF. Various echocardiographic parameters including left atrial strain were assessed for association with new-onset AF. We gathered 1082 consecutive patients with ischemic stroke. After exclusions, 121 patients with suspected ESUS at admission formed the study cohort. New-onset AF was detected in 46 (38%) patients during hospital electrocardiographic monitoring (median follow-up: 18 days). LA pump and reservoir strains were significantly and independently associated with new-onset AF. Receiver operating characteristic analysis for the association with new-onset AF showed that the areas under the curve (AUCs) of clinical parameters plus one of each strain (LA pump strain: AUC: 0.86±0.04 and LA reservoir strain: AUC: 0.76±0.05) models were significantly better than plus LA volume index (AUC: 0.68±0.04, compared p-values <0.05). LA strain was significantly associated with new development of AF. Patients with impaired LA function at admission should be carefully monitored to find AF.
Kenji Shimada, Izumi Yamaguchi, Manabu Ishihara, Takeshi Miyamoto, Shu Sogabe, Kazuhisa Miyake, Yoshiteru Tada, 北里 慶子, Yasuhisa Kanematsu and Yasushi Takagi : Involvement of Neutrophil Extracellular Traps in Cerebral Arteriovenous Malformations, World Neurosurgery, E1-E7, 2021.
(要約)
Cerebral arteriovenous malformations (cAVMs) represent tangles of abnormal vasculature without intervening capillaries. High-pressure vascular channels due to abnormal arterial and venous shunts can lead to rupture. Multiple pathways are involved in the pathobiology of cAVMs including inflammation and genetic factors such as KRAS mutations. Neutrophil release of nuclear chromatin, known as neutrophil extracellular traps (NETs), plays a multifunctional role in infection, inflammation, thrombosis, intracranial aneurysms, and tumor progression. However, the relationship between NETs and the pathobiology of cAVMs remains unknown. We tested whether NETs play a role in the pathobiology of cAVMs. We analyzed samples from patients who had undergone surgery for cAVM and immunohistochemically investigated expression of citrullinated histone H3 (CitH3) as a marker of NETs. CitH3 expression was compared among samples from cAVM patients, epilepsy patients, and normal human brain tissue. Expressions of thrombotic and inflammatory markers were also examined immunohistochemically in samples from cAVM patients. Expression of CitH3 derived from neutrophils was observed intravascularly in all cAVM samples but not other samples. Nidi of AVMs showed migration of many Iba-I-positive cells adjacent to the endothelium and endothelial COX2 expression, accompanied by expression of IL-6 and IL-8 in the endothelium and intravascular neutrophils. Unexpectedly, expression of CitH3 was not necessarily localized to the vascular wall and thrombus. Our results offer the first evidence of intravascular expression of NETs, which might be associated with vascular inflammation in cAVMs.
Masaaki Korai, Yasuhisa Kanematsu, Izumi Yamaguchi, Tadashi Yamaguchi, Yuki Yamamoto, Nobuaki Yamamoto, Takeshi Miyamoto, Kenji Shimada, Junichiro Satomi, Mami Hanaoka, Kazuhito Matsuzaki, Koichi Satoh and Yasushi Takagi : Subarachnoid Hemorrhage Due to Rupture of Vertebral Artery Dissecting Aneurysms: Treatments, Outcomes, and Prognostic Factors, World Neurosurgery, Vol.152, e86-e93, 2021.
(要約)
Mortality rate after subarachnoid hemorrhage due to rupture of vertebral artery dissecting aneurysms (VADAs) is high; endovascular coil trapping is the first-line therapy to prevent rerupture. To select optimal treatments, the positional relationship between the VADA and posterior inferior cerebellar artery (PICA) and the morphology of the contralateral vertebral artery must be considered, and outcome predictors of different treatment methods and their possible complications must be identified. We retrospectively studied 44 patients with ruptured VADAs who had undergone endovascular or surgical treatment. VADA morphology was assessed on conventional preoperative angiograms, and VADAs were categorized based on their site in relation to the PICA. VADA site, treatment method, and complications were used to identify prognostic factors. The sites of the 44 VADAs were PICA-proximal (n = 3), PICA-distal (n = 22), PICA-absent (n = 7), and PICA-involved (n = 12). Treatments included internal coil trapping (n = 30), proximal coil occlusion (n = 5), and stent placement (n = 3); surgical flow alteration via an occipital artery-PICA bypass and ligation at the proximal vertebral artery and the PICA origin was performed in 6 patients. Periprocedural rebleeding was associated with a poor outcome. Internal coil trapping prevented the rerupture of PICA-proximal and PICA-absent VADAs, and flow alteration prevented rerupture of PICA-involved VADAs; there were no complications directly attributable to these procedures. Periprocedural rebleeding was a poor prognostic factor. Internal trapping of PICA-proximal and PICA-absent VADAs and flow alteration in PICA-involved VADAs prevented rerupture.
Yasuhisa Kanematsu, Kenji Shimada, Yoshiteru Tada, Masaaki Korai, Takeshi Miyamoto, Shu Sogabe, Izumi Yamaguchi, Yoko Ymamoto, Nobuaki Yamamoto, Yuki Yamamoto, Koichi Satoh and Yasushi Takagi : Coil embolization with overlapping horizontal low-profile stents to treat a giant thrombosed fetal posterior cerebral aneurysm using contralateral approach through anterior communicating artery: Case report., Surgical Neurology International, Vol.12, No.347, 2021.
(要約)
The treatment of internal carotid artery (ICA) - posterior communicating artery aneurysms (ICPC aneurysms) is challenging when a fetal posterior cerebral artery (PCA) arises from the saccular neck. This complex angioarchitecture renders endovascular approaches difficult. Giant thrombosed IC-PC aneurysms are also hard to treat by endovascular coiling because its flow-diversion effect is insufficient. We report the first case of a ruptured giant thrombosed IC-PC aneurysm associated with a fetal PCA that was successfully treated by coil embolization with retrograde overlap horizontal stenting using low-profile stents introduced through the contralateral ICA. The aneurysm was completely occluded and follow-up MRI scans demonstrated the reduction of the aneurysmal size. Our technique is advantageous because low-profile stents can be used to treat lesions not accessible with flow-diverter stents due their presence in complex angioarchitectures, and overlap stenting may have flow-diversion effects that can result in the complete occlusion of giant thrombosed aneurysms.
Pham Tran Phuong, Daiju Fukuda, Sachiko Nishimoto, JR Kim-Kaneyama, XF Lei, Yutaka Takahashi, Tomohito Sato, Kimie Tanaka, Kumiko Suto, Yutaka Kawabata, Koji Yamaguchi, Shusuke Yagi, Kenya Kusunose, Hirotsugu Yamada, Takeshi Soeki, Tetsuzo Wakatsuki, Kenji Shimada, Yasuhisa Kanematsu, Yasushi Takagi, Michio Shimabukuro, Mitsutoshi Setou, Glen N Barber and Masataka Sata : STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases, European Heart Journal, Vol.42, No.42, 4336-4348, 2021.
(要約)
Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-β) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.
Kenji Shimada, Yoko Yamamoto, Takeshi Miyamoto, Shu Sogabe, Toshitaka Fujihara, Kohhei Nakajima, Yoshifumi Mizobuchi, Yasuhisa Kanematsu and Yasushi Takagi : Efficacy of Intra-arterial Indocyanine Green Videoangiography in Hemangioblastoma Surgery: A Case Report., NMC Case Report Journal, Vol.8, No.1, 295-300, 2021.
(要約)
Intravenous indocyanine green (ICG) videoangiography is reportedly useful for vascular neurosurgery, and for treating hemangioblastoma due to its high vascularity. Videoangiography obtained after intra-arterial ICG injection has emerged as a more useful option than that after intravenous injection. This report offers the first description of a case of hemangioblastoma successfully treated using intra-arterial ICG videoangiography, and describes the efficacy of this technique. A 20-year-old man presented with progressive cerebellar ataxia and dysphagia. Magnetic resonance imaging (MRI) revealed an enhanced solid tumor in the medulla oblongata. Digital subtraction angiography (DSA) showed a highly vascularized tumor. Surgery was performed to remove the tumor in a hybrid operating room. A catheter was introduced into the vertebral artery (VA) for intra-arterial ICG videoangiography. Superficial feeders and drainers were identified and flow dynamic changes in the tumor were assessed by intra-arterial ICG videoangiography. The tumor was removed after confirming lack of flow in the drainer. Intra-arterial ICG videoangiography was more useful than intravenous ICG videoangiography in hemangioblastoma surgery for identifying feeders and drainers and assessing flow dynamics in the tumor. Use of Flow 800 made these findings simpler and easier to evaluate.
Nobuaki Yamamoto, Yuki Yamamoto, Izumi Yamaguchi, Shu Sogabe, Takeshi Miyamoto, Kenji Shimada, Yasuhisa Kanematsu, Ryoma Morigaki, Yuishin Izumi and Yasushi Takagi : Percutaneous Transluminal Angioplasty and Stenting Using an Aspiration Catheter, Journal of Neuroendovascular Therapy, Vol.16, No.5, 277-282, 2021.
(要約)
<p><b>Objective</b>: During percutaneous transluminal angioplasty (PTA) for the vertebral artery, occlusion of the subclavian artery using a balloon guiding catheter may be useful to prevent embolism of clots and/or debris distal to an atherosclerotic lesion. However, when placing a balloon guiding catheter at the intended vessels is difficult, it may be useful to use an aspiration catheter (AC) for mechanical thrombectomy as an intermediate catheter to suction way clots and/or debris. We report two cases in which PTA was performed for an atherosclerotic lesion at the intracranial vertebral artery using an AC, which ended without complications.</p><p><b>Case Presentations</b>: Case 1: A 74-year-old man presented with dysarthria and was admitted to our hospital. MRI revealed severe left vertebral artery stenosis and diffuse cerebral infarct areas at the territory of the posterior circulation. The patient had an abdominal aortic aneurysm and abnormally shaped left tortuous subclavian artery. Therefore, we performed PTA and stenting via the left brachial artery. We guided a 6-Fr long sheath to the left subclavian artery, and a 6-Fr AC for thrombectomy was guided through the long sheath to the V4 portion of the left vertebral artery. Thereafter, PTA was carried out under manual aspiration from the AC. As restenosis at the atherosclerotic lesion occurred after PTA, we performed stenting using a coronary stent system for this lesion under manual aspiration from the AC. No new infarct areas were observed on post-procedural MRI. Case 2: A 74-year-old woman presented with dysarthria and was admitted to our hospital. MRI demonstrated basilar artery occlusion and diffuse cerebral infarct areas at the territory of the posterior circulation. As her symptom worsened after admission, we performed urgent mechanical thrombectomy. We first performed thrombectomy using a stent retriever and then performed PTA and stenting (PTAS) for residual basilar artery stenosis via the AC under manual aspiration.</p><p><b>Conclusion</b>: When it is difficult to place a guiding catheter at the intended vessels during PTA, an AC may be useful to prevent distal embolization.</p>
Manabu Ishihara, Nobuto Nakanishi, Rie Tsutsumi, Kanako Hara, Kyoka Machida, Nobuaki Yamamoto, Yasuhisa Kanematsu, Hiroshi Sakaue, Jun Oto and Yasushi Takagi : Elevated Urinary Titin and its Associated Clinical Outcomes after Acute Stroke., Journal of Stroke & Cerebrovascular Diseases, Vol.30, No.3, 2021.
(要約)
Forty-one patients were included (29 male; age, 68 ± 15 years), 29 had ischemic stroke, 8 had intracerebral hemorrhage, and 4 had subarachnoid hemorrhage. The levels of urinary titin on days 1, 3, 5, and 7 were 9.9 (4.7-21.1), 16.2 (8.6-22.0), 8.9 (4.8-15.2), and 8.7 (3.6-16.2) pmol/mg Cr, respectively. The peak urinary titin level was associated with the mRS score (r = 0.55, p < 0.01), the NIHSS score (r = 0.72, p < 0.01), and the BI (r = -0.59, p < 0.01) upon hospital discharge. In multivariate analysis, the peak urinary titin was associated with poor outcome (p = 0.03).
(キーワード)
Aged / Aged, 80 and over / Biomarkers / Connectin / Disability Evaluation / Female / Functional Status / Humans / Male / Middle Aged / Patient Discharge / Predictive Value of Tests / Prospective Studies / Recovery of Function / Stroke / Time Factors / Treatment Outcome / Up-Regulation / Urinalysis
Nobuaki Yamamoto, Yuishin Izumi, Yuki Yamamoto, K Kuroda, Izumi Yamaguchi, Shu Sogabe, Takeshi Miyamoto, Kenji Shimada, Yasuhisa Kanematsu, Ryoma Morigaki and Yasushi Takagi : Factors associated with DWI-ASPECTS score in patients with acute ischemic stroke due to cerebral large vessel occlusion, Clinical Neurology and Neurosurgery, Vol.199, 106316, 2020.
(要約)
The Alberta Stroke Program Early CT score (ASPECTS) of patients with acute ischemic stroke at the time of admission varies. It is crucial to select appropriate methods of treatment, such as recombinant tissue-plasminogen activator, and/or endovascular thrombectomy. According to the recent guidelines, endovascular thrombectomy for patients with large vessel occlusion (LVO) and lesion of ischemic tissue that was not yet infarcted is effective. This result demonstrates the importance of patient selection based on neuroradiological imaging. However, there are many patients who are judged as ineligibility for recanalization therapy because of presence of large ischemic core, indicating unfavorable ASPECTS, at the time of admission. We investigated the factors associated with favorable diffusion-weighted image (DWI)-ASPECTS score at the time of admission. We studies patients with LVO within 24 h from onset who were admitted into our hospital. We divided them into two groups, with favorable DWI-ASPECTS (≥6), and unfavorable DWI-ASPECTS (<6) at the time of admission. We investigated factors associated with favorable DWI-ASPECTS by evaluation of our patients' severity of clinical symptom, etiology, and radiological findings. This study showed that mild white matter lesion (Fazekas scale ≤1), absence of internal carotid artery (ICA) occlusion and cardioembolic stroke were independent factor of favorable DWI-ASPECTS at the time of admission. (odds ratio 12.92, p < 0.001, odds ratio 0.31, p = 0.001, odds ratio 0.16, p = 0.001, respectively) CONCLUSIONS: Absence of severe white matter lesion, cardioembolic stroke, and ICA occlusion might be associated with favorable DWI-ASPECTS at the time of admission.
(キーワード)
Aged / Aged, 80 and over / Brain Ischemia / Cerebrovascular Disorders / Diffusion Magnetic Resonance Imaging / Female / Humans / Ischemic Stroke / Male / Middle Aged / Patient Admission / Prospective Studies / Retrospective Studies / Severity of Illness Index
Nobuhito Naito, Hiroshi Kawano, Yuya Yamashita, Mayo Kondou, Shotaro Haji, Ryosuke Miyamoto, Yuko Toyoda, Yasuhisa Kanematsu, Yuishin Izumi, Yoshimi Bando and Yasuhiko Nishioka : Neuropsychiatric systemic lupus erythematosus with cerebellar vasculitis and obstructive hydrocephalus requiring decompressive craniectomy., Modern Rheumatology Case Reports, Vol.5, No.1, 52-57, 2020.
(要約)
A 36-year-old woman who had been diagnosed with systemic lupus erythematosus (SLE) was admitted to our hospital due to increasing disease SLE activity. Despite the intensification of immunosuppressive treatment, headache newly developed and worsened. Magnetic resonance imaging (MRI) revealed spreading of a high-intensity area along the sulci of the bilateral cerebellar hemispheres. She was diagnosed with neuropsychiatric SLE and methylprednisolone (mPSL) pulse therapy was started. However, consciousness disorder due to cerebellar oedema with obstructive hydrocephalus appeared and required decompressive craniectomy. The histological findings of the biopsy specimens from cerebellar vermis were compatible with features of vasculitis. She was successfully treated adding intravenous cyclophosphamide therapy.
Yamamoto Yuki, Nobuaki Yamamoto, Koji Fujita, Fukumoto Tatsuya, Murakami Nagahisa, Hideo Mure, Yasuhisa Kanematsu, Yasushi Takagi and Yuishin Izumi : Cerebral Venous Thrombosis: An Unexpected Complication with Cerebrospinal Fluid Leaks after a Fall in a Patient with Spinocerebellar Ataxia Type 6., Internal Medicine, Vol.59, No.14, 1749-1753, 2020.
Nobuaki Yamamoto, Yuki Yamamoto, Izumi Yamaguchi, Manabu Ishihara, Takeshi Miyamoto, Masaaki Korai, Kenji Shimada, Yasuhisa Kanematsu, Yuishin Izumi and Yasushi Takagi : Cone beam-computed tomography angiography by intravenous contrast injection is reliable to evaluate patients with large vessel occlusion, Journal of Clinical Neuroscience, Vol.70, 67-71, 2019.
(要約)
Mechanical thrombectomy (MT) for acute ischemic stroke (AIS) patients due to emergent large vessel occlusion (ELVO) is standard treatment, the benefits, however, are highly time-sensitive. After patient eligibility for reperfusion therapy is determined by conventional radiological examinations, the time to be transferred from the department of radiological examination to angiography-suites is critical. We speculated that the time required for the diagnosis of AIS might be reduced if we could determine MT eligibility in patients with ELVO at angiography-suites. Modern angiography-suites with flat panel detectors can perform cone beam (CB)-CT. We performed CB-CTA using intravenous injection of contrast agent to evaluate occlusion sites, collateral score, and construction of vessels distal to occlusion sites and determined if CB-CTA could be useful to evaluate patients with ELVO. We included 15 patients with ELVO diagnosed by conventional MRI or CT/CTA, and investigated whether CB-CTA was reliable to diagnose occlusion sites. We also studied if collateral score on CB-CTA was associated with prognosis after successful reperfusion by MT by comparison between favorable (modified Rankin scale (mRS) 0-2), and unfavorable outcome group (mRS 3-6). There was strong agreement of occlusion sites between CB-CTA and conventional radiological examination (κ = 0.80). Collateral score determined by CB-CTA was significantly different between favorable outcome and unfavorable outcome group (median collateral score 2.3 v.s. 1.3, p = 0.040). Although prospective study of AIS patients at a radiography department is indispensable, CB-CTA performed in an angiography-suite might be useful to evaluate patients with ELVO.
Izumi Yamaguchi, Yasuhisa Kanematsu, Kenji Shimada, Masaaki Korai, Takeshi Miyamoto, Eiji Shikata, Tadashi Yamaguchi, Nobuaki Yamamoto, Yuki Yamamoto, Keiko Kitazato, Yoshihiro Okayama and Yasushi Takagi : Active Cancer and Elevated D-Dimer Are Risk Factors for In-Hospital Ischemic Stroke, Cerebrovascular Diseases Extra, Vol.9, No.3, 129-138, 2019.
(要約)
Little attention has been paid to the pathogenesis of in-hospital stroke, despite poor outcomes and a longer time from stroke onset to treatment. We studied the pathophysiology and biomarkers for detecting patients who progress to in-hospital ischemic stroke (IHS). Seventy-nine patients with IHS were sequentially recruited in the period 2011-2017. Their characteristics, care, and outcomes were compared with 933 patients who had an out-of-hospital ischemic stroke (OHS) using a prospectively collected database of the Tokushima University Stroke Registry. Active cancer and coronary artery disease were more prevalent in patients with IHS than in those with OHS (53.2 and 27.8% vs. 2.0 and 10.9%, respectively; p < 0.001), the median onset-to-evaluation time was longer (300 vs. 240 min; p = 0.015), and the undetermined etiology was significantly higher (36.7 vs. 2.4%; p < 0.001). Although there was no significant difference in stroke severity at onset between the groups, patients with IHS had higher modified Rankin Scale (mRS) scores (3-6) at discharge (67.1 vs. 50.3%; p = 0.004) and rates of death during hospitalization (16.5 vs. 2.9%; p < 0.001). D-dimer (5.8 vs. 0.8 µg/mL; p < 0.001) and fibrinogen (532 vs. 430 mg/dL; p = 0.014) plasma levels at the time of onset were significantly higher in patients with IHS after propensity score matching. Multivariate logistic regression analysis revealed that active cancer (odds ratio [OR] 2.30; 95% confidence interval [CI] 1.26-4.20), prestroke mRS scores 3-5 (OR 6.78; 95% CI 3.96-11.61), female sex (OR 1.57; 95% CI 1.19-2.08), and age ≥75 years (OR 2.36; 95% CI 1.80-3.08) were associated with poor outcomes. Patients with IHS had poorer outcomes than those with OHS because of a higher prevalence of active cancer and functional dependence before stroke onset. Elevated plasma levels of D-dimer and fibrinogen, especially with active cancer, can help identify patients who are at a higher risk of progression to IHS.
Tadashi Yamaguchi, Takeshi Miyamoto, keiko Kitazato, Eiji Shikata, Izumi Yamaguchi, Masaaki Korai, Kenji Shimada, Kenji Yagi, Yoshiteru Tada, Yoshihito Matsuzaki, Yasuhisa Kanematsu and Yasushi Takagi : Time-dependent and site-dependent morphological changes in rupture-prone arteries: ovariectomized rat intracranial aneurysm model, Journal of Neurosurgery, 2019.
(要約)
The pathogenesis of intracranial aneurysm rupture remains unclear. Because it is difficult to study the time course of human aneurysms and most unruptured aneurysms are stable, animal models are used to investigate the characteristics of intracranial aneurysms. The authors have newly established a rat intracranial aneurysm rupture model that features site-specific ruptured and unruptured aneurysms. In the present study the authors examined the time course of changes in the vascular morphology to clarify the mechanisms leading to rupture. Ten-week-old female Sprague-Dawley rats were subjected to hemodynamic changes, hypertension, and ovariectomy. Morphological changes in rupture-prone intracranial arteries were examined under a scanning electron microscope and the association with vascular degradation molecules was investigated. At 2-6 weeks after aneurysm induction, morphological changes and rupture were mainly observed at the posterior cerebral artery; at 7-12 weeks they were seen at the anterior Willis circle including the anterior communicating artery. No aneurysms at the anterior cerebral artery-olfactory artery bifurcation ruptured, suggesting that the inception of morphological changes is site dependent. On week 6, the messenger RNA level of matrix metalloproteinase-9, interleukin-1β, and the ratio of matrix metalloproteinase-9 to the tissue inhibitor of metalloproteinase-2 was significantly higher at the posterior cerebral artery, but not at the anterior communicating artery, of rats with aneurysms than in sham-operated rats. These findings suggest that aneurysm rupture is attributable to significant morphological changes and an increase in degradation molecules. Time-dependent and site-dependent morphological changes and the level of degradation molecules may be indicative of the vulnerability of aneurysms to rupture.
Eiji Shikata, Tetsuya Tamura, Kiyohito Shinno, Yoshihiro Okayama, Naoki Shinohara, Kenji Shimada, Yasuhisa Kanematsu, Keiko T Kitazato, Shinji Nagahiro and Yasushi Takagi : Importance of Managing the Water-Electrolyte Balance by Delivering the Optimal Minimum Amount of Water and Sodium After Subarachnoid Hemorrhage., World Neurosurgery, Vol.129, e352-e360, 2019.
(要約)
After aneurysmal subarachnoid hemorrhage (aSAH), crystalloid fluids with a relatively high sodium concentration have been used to maintain the cerebral blood flow. However, the prophylactic delivery of water and sodium by intravenous (IV) infusion will not necessarily improve the prognosis of patients after aSAH, and the excessive supply of water and sodium can negatively affect the outcome. We hypothesized that the delivery of an optimal amount of water and sodium separately might improve the outcome after aSAH. We recruited 55 consecutive patients who had undergone clipping or endovascular coil embolization after aSAH. Group 1 (n = 33) received conventional therapy (i.e., prophylactic IV sodium and water [protocol 1]). Group 2 (n = 22) received the optimal amount of water and sodium separately (protocol 2). The median total of water and sodium chloride supplied in group 1 was significantly greater than that supplied in group 2 (P < 0.01). The modified Rankin scale score at discharge was 0-2 in 15 patients (95%) in group 2 and 23 patients (55%) in group 1 (P < 0.001). On multivariate logistic regression analysis, the odds ratio for a discharge modified Rankin scale score of 0-2 or 3-6 was significantly associated with the treatment protocol (P < 0.05) and the net fluid balance on days 4-8 (P < 0.05). The separate delivery of optimal amounts of water and sodium could be a promising therapeutic strategy to improve the prognosis after aSAH.
Toshiyuki Okazaki, Yasuhisa Kanematsu, Kenji Shimada, Masaaki Korai, Junichiro Satomi, Masaaki Uno, Shinji Nagahiro and Yasushi Takagi : A Single-center Retrospective Study with 5- and 10-year Follow-up of Carotid Endarterectomy with Patch Graft., Neurologia Medico-Chirurgica, Vol.59, No.6, 231-237, 2019.
(要約)
Carotid endarterectomy (CEA) is widely used for cervical artery stenosis. In Japan, primary closure after endarterectomy has been a standard technique. Recently, the patch closure has been shown to be superior to the primary suture for the prevention of restenosis and ipsilateral stroke. This study evaluated the 5- and 10-year outcomes following CEA with patch graft closure in our institution. Between January 2000 and March 2013, 134 patients, who underwent CEA with patch graft closure were investigated in the current retrospective study. Among these patients, 102 CEAs in 97 patients were followed up for 5 years and 66 CEAs in 61 patients were for 10 years after the procedure. Restenosis was defined as >50% recurrent luminal narrowing at the endarterectomy site. In 5 years, symptomatic restenosis exhibited minor stroke in one patient at 58 months after CEA (restenosis rate 1.0%). The ipsilateral minor stroke occurred in three patients including the above case (2.9%). In 10 years, asymptomatic restenosis occurred in three patients in addition to the above symptomatic case (restenosis rate 6.1%), and the ipsilateral minor stroke occurred in four patients (6.1%). Carotid endarterectomy with patch graft exerted a high protective effect from restenosis up to 5 and 10 years in our institution. The number of carotid artery stenting is increasing all over the world but we speculated that the established surgical procedure of patched CEA prevented restenosis and ipsilateral stroke.
Yamamoto Yuki, Nobuaki Yamamoto, Yasuhisa Kanematsu, Masaaki Korai, Kenji Shimada, Yuishin Izumi and Yasushi Takagi : The Claw Sign: An angiographic Predictor of Recanalization After Mechanical Thrombectomy for Cerebral Large Vessel Occlusion., Journal of Stroke & Cerebrovascular Diseases, Vol.28, No.6, 1555-1560, 2019.
(要約)
Mechanical thrombectomy undoubtedly improves functional outcomes for patients with acute ischemic stroke. Although we have observed occlusion sites that protrude proximally into the vessel on angiography, termed the "claw sign," we have been unable to state its clinical significance. In this study, we aimed to determine whether the presence of a claw sign was related to recanalization success after mechanical thrombectomy. We retrospectively included 73 consecutive patients treated for acute cerebral large vessel occlusion by mechanical thrombectomy between January 2014 and December 2017. The angiographic claw sign was defined as a thrombus that protruded proximally by more than half the diameter of the parent artery. Claw sign positivity, clinical and etiological features, and outcomes were compared between groups with and without recanalization. The claw sign was observed in 29 of 73 (40%) patients and was positive significantly more frequently in those with recanalization (50.0%) than in those without recanalization (5.9%) (P < .01). By multivariate analysis, the claw sign was the only pretreatment parameter to predict successful recanalization (odds ratio, 12.50; 95% confidence interval, 1.50-103.00; P = .019). The presence of the claw sign might predict successful recanalization in patients undergoing mechanical thrombectomy for large vessel occlusion.
(キーワード)
Aged / Aged, 80 and over / Angiography, Digital Subtraction / Cerebral Angiography / Cerebral Arteries / Cerebrovascular Circulation / Constriction, Pathologic / Female / Humans / Intracranial Thrombosis / Male / Middle Aged / Predictive Value of Tests / Retrospective Studies / Thrombectomy / Thrombolytic Therapy / Treatment Outcome / Vascular Patency
Akemi Hioka, Yoshiteru Tada, Keiko Kitazato, Yasuhisa Kanematsu, Yoshifumi Mizobuchi, Hideo Mure, Kenji Shimada, Toshiyuki Okazaki, Masaaki Korai, Noki Akazawa, Yuki Matsumoto, Yuki Matsumoto, Yasushi Takagi and Shinji Nagahiro : Activation of mirror neuron system during gait observation in sub-acute stroke patients and healthy persons., Journal of Clinical Neuroscience, Vol.60, 79-83, 2019.
(要約)
The observation of walking improves gait ability in chronic stroke survivors. It has also been suggested that activation of the mirror neuron system contributes to this effect. However, activation of the mirror neuron system during gait observation has not yet been assessed in sub-acute stroke patients. The objective of this study was to clarify the activation of mirror neuron system during gait observation in sub-acute stroke patients and healthy persons. In this study, we sequentially enrolled five sub-acute stroke patients who had undergone gait training and nine healthy persons. We used fMRI to detect neuronal activation during gait observation. During the observation period in the stroke group, neural activity in the left inferior parietal lobule, right and left inferior frontal gyrus was significantly higher than during the rest period. In the healthy group, neural activity in the left inferior parietal lobule, left inferior frontal gyrus, left middle frontal gyrus, left superior temporal lobule and right and left middle temporal gyrus was significantly higher than during the rest period. The results indicate that the mirror neuron system was activated during gait observation in sub-acute stroke patients who had undergone gait training and also in healthy persons. Our findings suggest that gait observation treatment may provide a promising therapeutic strategy in sub-acute stroke patients who have experienced gait training.
Shusuke Yagi, Yoshihito Saijo, Taku Matsuda, Yasuhisa Kanematsu and Masataka Sata : Spontaneous arteriovenous fistula of the superficial temporal artery, The Journal of Medical Investigation : JMI, Vol.66, No.1,2, 209-210, 2019.
(要約)
An arteriovenous fistula of the superficial temporal artery (STA) is a direct and abnormal communication between the STA, feeding artery, and superficial temporal vein, draining veins that bypass the capillary network. Several cases of trauma-induced or iatrogenic-induced arteriovenous fistula (AVF) of the STA have been reported ; however, spontaneous AVF of the STA not associated with trauma or medical treatment are extremely rare. Herein, we present a case of spontaneous AVF of the STA diagnosed in old age. J. Med. Invest. 66 : 209-210, February, 2019.
Shinji Nagahiro, Yoshiteru Tada, Junichiro Satomi, Tomoya Kinouchi, Kazuyuki Kuwayama, Kenji Yagi, Kohhei Nakajima, Nobuhisa Matsushita, Takeshi Miyamoto, Tadashi Yamaguchi, Kenji Shimada, Masaaki Korai, Hideo Mure, Y Okayama, Takashi Abe, Masafumi Harada, Keiko T. Kitazato and Yasuhisa Kanematsu : Treatment of Unruptured Cerebral Aneurysms with the Mineralocorticoid Receptor Blocker Eplerenone-Pilot Study., Journal of Stroke & Cerebrovascular Diseases, Vol.27, No.8, 2134-2140, 2018.
(要約)
Currently there are no pharmacological therapies for patients with unruptured cerebral aneurysms. Elsewhere we showed that the mineralocorticoid receptor antagonist eplerenone prevented the formation of cerebral aneurysms in our ovariectomized hypertensive aneurysm rat model. The current pilot study evaluated whether it can be used to prevent the growth and rupture of cerebral aneurysms in hypertensive patients. Between August 2011 and May 2014, we enrolled 82 patients with 90 aneurysms in an open-label uncontrolled clinical trial. All provided prior informed consent for inclusion in this study, and all were treated with eplerenone (25-100 mg/d). The primary end points of our study were the rupture and enlargement of the cerebral aneurysms. Of the 82 patients, 80 (88 unruptured aneurysms) were followed for a mean of 21.3 months (153.4 aneurysm-years); 12 patients (15.0%) permanently discontinued taking the drug. One month after the start of eplerenone administration and throughout the follow-up period, eplerenone kept the blood pressure within the normal range. Most notably, no aneurysms smaller than 9 mm ruptured or enlarged. However, of 2 large thrombosed aneurysms, 1 enlarged and the other ruptured. The overall annual rupture rate was .65%; it was 13.16% for aneurysms larger than 10 mm; the overall annual rate for reaching the primary end points was 1.30%. Our observations suggest that eplerenone may help to prevent the growth and rupture of unruptured cerebral aneurysms smaller than 9 mm. To assess its potential long-term clinical benefits, large clinical trials are needed.
Yasuhisa Kanematsu, Junichiro Satomi, Masaaki Korai, Toshiyuki Okazaki, Idumi Yamaguchi, Yoshiteru Tada, Masaaki Uno, Shinji Nagahiro and Yasushi Takagi : Flow Alteration Therapy for Ruptured Vertebral Artery Dissecting Aneurysms Involving the Posterior Inferior Cerebellar Artery, Neurologia Medico-Chirurgica, Vol.58, 341-349, 2018.
(要約)
Surgery for- and endovascular treatment of vertebral artery (VA) dissecting aneurysms involving the origin of the posterior inferior cerebellar artery (PICA) remain challenging. Their ideal treatment is complete isolation of the aneurysm by surgical or endovascular trapping plus PICA reconstruction. However, postoperative lower cranial nerve palsy and medullary infarction are potential complications. We report four patients with VA dissecting aneurysms involving the PICA origin who were treated by occipital artery (OA)-PICA bypass followed by proximal occlusion of the VA and clip ligation of the PICA origin instead of trapping. There were no procedural or ischemic complications. In all patients, angiography performed 2-3 weeks later showed good patency of the bypass graft and complete obliteration of the aneurysm. During the follow-up period ranging from 1 to 14 years, none experienced bleeding. Although retrograde blood flow to the dissecting aneurysm persisted in the absence of trapping, iatrogenic lower cranial nerve injury could be avoided. The decrease in aneurysmal flow might elicit spontaneous thrombosis and prevent aneurysmal rerupture. Our technique might be less invasive than aneurysmal trapping and help to prevent rebleeding.
Yuki Yamamoto, Nobuaki Yamamoto, Junichiro Satomi, Idumi Yamaguchi, Masaaki Korai, Yasuhisa Kanematsu, Yasushi Takagi and Ryuji Kaji : Dural arteriovenous fistula in the superior orbital fissure, Surgical Neurology International, Vol.9, No.1, 95, 2018.
(要約)
Dural arteriovenous fistulas (dAVFs) are extremely rare in the superior orbital fissure, and they exhibit ocular symptoms similar to the dAVF in the cavernous sinus because of the intraorbital venous congestion. Hence, the distinction of these conditions is imperative because of some inherent differences in endovascular treatment techniques. A 58-year-old woman presented with a gradually worsening left eyeball protrusion and conjunctival congestion. The digital subtraction angiography revealed a dAVF with a shunting point in the left superior orbital fissure. Moreover, the inferolateral trunk of the left internal carotid artery and the left middle meningeal artery were involved as feeding arteries. Shunting blood flow drained into the facial vein through the superior ophthalmic vein (SOV) but not into the cavernous sinus, which was located just posterior to the superior orbital fissure. We performed transvenous coil embolization in the SOV through the facial vein, and the symptoms disappeared completely. We experienced a case of a dAVF in the superior orbital fissure. This case presented a possibility of the presence of one subtype of the dAVF in the part of the cavernous sinus separated at the superior orbital fissure in front. Transvenous coil embolization in the SOV through the facial vein efficiently occluded the fistula.
Nobuaki Yamamoto, Junichiro Satomi, Yuki Yamamoto, Kenji Shono, Yasuhisa Kanematsu, Yuishin Izumi, Shinji Nagahiro and Ryuji Kaji : Risk Factors of Neurological Deterioration in Patients with Cerebral Infarction due to Large Artery Atherosclerosis, Journal of Stroke & Cerebrovascular Diseases, Vol.26, No.8, 1801-1806, 2017.
(要約)
In some patients with acute ischemic stroke, neurological deterioration (ND) is observed, and it is difficult to predict at the time of admission. Especially in some patients with large-artery atherosclerosis (LAA), aggressive medical treatments and surgical interventions might be helpful to prevent ND. Therefore, we investigated factors associated with ND in patients with LAA. We studied patients with LAA who were admitted to our hospital. We divided them into 2 groups with (group 1) and without deterioration (group 2), and evaluated their medical records, risk factors, and radiological findings, such as number of diffusion-positive lesion and degree of stenosis. Our study population consisted of 171 patients; 71 (41.5%) did and 100 (58.5%) did not suffer deterioration. By univariate analysis, blood pressure (BP), heart rate, National Institutes of Health Stroke Scale (NIHSS) score, number of diffusion-positive lesion, count of red blood cell, high-density lipoprotein, and degree of stenosis differed significantly between the 2 groups. By multivariate analysis, systolic BP (170 mm Hg, odds ratio: 7.20, P <.001) was associated with ND. Furthermore, number of diffusion-weighted image (DWI)-positive lesion (8), degree of stenosis (>80.0%), and NIHSS score (4) were also independent factors associated with ND. High BP, severity of neurological deficit at the time of admission, and radiological findings, such as degree of stenosis and number of DWI-positive lesion, are independently associated with ND in patients with LAA.
Yasuhisa Kanematsu, Junichiro Satomi, Kazuyuki Kuwayama, Izumi Yamaguchi, Shotaroh Yoshioka, Tomoya Kinouchi, Yoshiteru Tada, Nobuaki Yamamoto, Shunji Matsubara, Kenji Shono and Shinji Nagahiro : Treatment Outcome of Carotid Artery Stenting Underwent within 14 Days of Stroke Onset - Consideration of Safety and Efficacy of Urgent Carotid Artery Stenting for Neurologically Progressing Patients, Neurologia Medico-Chirurgica, Vol.57, No.6, 278-283, 2017.
(要約)
As the safety and effectiveness of urgent carotid artery stenting (CAS) for neurologically progressing patients remain controversial, we retrospectively analyzed the outcome of urgent CAS based on the patients' pathophysiological condition and neuroimaging findings. We divided 71 patients who underwent CAS within 14 days of stroke onset into two groups. Group 1 (n = 35) was comprised of patients with progressing neurologic signs and a reversible ischemic penumbra on magnetic resonance images (MRI). They were treated by urgent CAS. Group 2 (n = 36) was neurologically stable and underwent prophylactic CAS. In all patients we recorded the National Institutes of Health Stroke Scale (NIHSS) score and the modified Rankin scale (mRS). Urgent CAS resulted in significant improvement in the NIHSS score, when compared before and after CAS in group 1 (5.3 ± 4.3, P < 0.01). The rate of good outcomes (mRS 0-2 at 3 months post-CAS) was 48.6% in group 1, and 75% in group 2. The cumulative incidence of ipsilateral stroke between 31 days and 1 year was 5.9% in group 1, and 0% in group 2. The procedural complication rate was similar in both groups (group 1: 5.7%, n = 2; group 2: 5.6%, n = 2). No patient suffered a symptomatic intracerebral hemorrhage. When the pathophysiological status and neuroimaging findings are used to determine patient eligibility for urgent CAS, this treatment improve neurologic outcome and can be performed as safely as prophylactic CAS in our cohort of patients with acute ischemic stroke.
Shu Sogabe, Junichiro Satomi, Yoshiteru Tada, Yasuhisa Kanematsu, Kazuyuki Kuwayama, Kenji Yagi, Shotaroh Yoshioka, Yoshifumi Mizobuchi, Hideo Mure, Izumi Yamaguchi, Takashi Abe, Nobuaki Yamamoto, Keiko Kitazato, Ryuji Kaji, Masafumi Harada and Shinji Nagahiro : Intra-arterial high signals on arterial spin labeling perfusion images predict the occluded internal carotid artery segment, Neuroradiology, Vol.59, No.6, 587-595, 2017.
(要約)
Arterial spin labeling (ASL) involves perfusion imaging using the inverted magnetization of arterial water. If the arterial arrival times are longer than the post-labeling delay, labeled spins are visible on ASL images as bright, high intra-arterial signals (IASs); such signals were found within occluded vessels of patients with acute ischemic stroke. The identification of the occluded segment in the internal carotid artery (ICA) is crucial for endovascular treatment. We tested our hypothesis that high IASs on ASL images can predict the occluded segment. Our study included 13 patients with acute ICA occlusion who had undergone angiographic and ASL studies within 48 h of onset. We retrospectively identified the high IAS on ASL images and angiograms and recorded the occluded segment and the number of high IAS-positive slices on ASL images. The ICA segments were classified as cervical (C1), petrous (C2), cavernous (C3), and supraclinoid (C4). Of seven patients with intracranial ICA occlusion, five demonstrated high IASs at C1-C2, suggesting that high IASs could identify stagnant flow proximal to the occluded segment. Among six patients with extracranial ICA occlusion, five presented with high IASs at C3-C4, suggesting that signals could identify the collateral flow via the ophthalmic artery. None had high IASs at C1-C2. The mean number of high IAS-positive slices was significantly higher in patients with intra- than extracranial ICA occlusion. High IASs on ASL images can identify slow stagnant and collateral flow through the ophthalmic artery in patients with acute ICA occlusion and help to predict the occlusion site.
Kenji Shono, Junichiro Satomi, Yoshiteru Tada, Yasuhisa Kanematsu, Nobuaki Yamamoto, Yuishin Izumi, Ryuji Kaji, Masafumi Harada and Shinji Nagahiro : Optimal Timing of Diffusion-Weighted Imaging to Avoid False-Negative Findings in Patients With Transient Ischemic Attack, Stroke, Vol.48, No.7, 1990-1992, 2017.
(要約)
We aimed to investigate the optimal timing of diffusion-weighted imaging (DWI) in patients with transient ischemic attack (TIA). Seventy-three consecutive patients with TIA underwent DWI on admission (initial DWI) and at 24 hours after admission (second DWI). Patients were divided into 2 groups based on initial DWI findings in relation to the second examination: false negative (group 1) and other (group 2). The probability of initial false-negative findings was determined for each hour from TIA onset to initial DWI. Multivariate analysis was used to evaluate the independent risk factors associated with false-negative findings on initial DWI. Of the 73 patients examined (56 men; mean age, 68 years), 9 (12%) were categorized into group 1. The latency from TIA onset to initial DWI was 1.7±0.6 hours for group 1 (range, 1-2.8 hours) and 3.3±2.6 hours for group 2 (range, 35 minutes to 12 hours). The probability of false-negative findings on initial DWI decreased in a time-dependent manner (25%, 21%, and 7% for 1, 2, and 3 hours, respectively), and no false-negative findings were observed on initial DWI performed at >3 hours from symptom onset. Short latency (2 hours) from TIA onset to initial DWI was an independent risk factor related to false-negative findings (odds ratio, 13.11; 95% confidence interval, 1.07-161.38; P=0.045). If the duration between TIA symptom onset and initial DWI is <2 hours, a repeat examination should be performed to minimize the risk of false-positive findings.
(キーワード)
Aged / Aged, 80 and over / Diffusion Magnetic Resonance Imaging / False Negative Reactions / Female / Humans / Ischemic Attack, Transient / Male / Middle Aged / Retrospective Studies / Risk Factors / Sensitivity and Specificity / Time Factors
Izumi Yamaguchi, Junichiro Satomi, Nobuaki Yamamoto, Shotaroh Yoshioka, Yoshiteru Tada, Kenji Yagi, Yasuhisa Kanematsu and Shinji Nagahiro : Coexistence of Quasi-moyamoya Disease and POEMS Syndrome in a Patient with Intracranial Hemorrhage: A Case Report and Literature Review, NMC Case Report Journal, Vol.4, 5-9, 2017.
(要約)
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare paraneoplastic syndrome elicited by plasma cell dyscrasia. Its clinical manifestations are multiple and stroke is not a recognized feature. A 44-year-old woman with a 3-month history of bilateral lower extremity sensorimotor disturbance was admitted to our hospital. Examinations revealed polyneuropathy, organomegaly, hypothyroidism, monoclonal gammopathy, pelvic plasmacytoma, and elevated serum vascular endothelial growth factor (VEGF) levels. A diagnosis of POEMS was made. Her condition was improved by radiation therapy of her pelvic plasmacytoma and she continued to be seen on an outpatient basis. Five years after her first admission she was re-admitted with sudden-onset right hemiparesis. A brain computed tomography (CT) scan revealed a left intracranial hemorrhage and magnetic resonance (MR) angiography and cerebral angiography showed occlusion of the proximal portion of the bilateral middle cerebral artery and narrowing of the bilateral internal carotid artery at the terminal portion; moyamoya vessels were seen. This is the first report of a patient whose intracranial hemorrhage was attributable to quasi-moyamoya disease associated with POEMS syndrome. We suggest that the POEMS syndrome be ruled out in the differential diagnosis of patients presenting with atypical stroke, multivessel stenotic lesions (moyamoya vessels), and polyneuropathy.
We assessed the current status of patients with acute in-hospital stroke. 63 patients with acute in-hospital stroke were enrolled. The most prevalent subtype of stroke was embolism(n＝24). The main cause of hospitalization were malignant neoplasms in15. Only 5 patients were treated with rt-PA, 8 patients received endovascular interventions. In-hospital stroke is a sever complication of in-patients and is associated with an unfavorable prognosis, but endovascular interventions offer safe and feasible therapeutic treatment options.
Recently,"Drip and Ship"treatment conducted in collaboration of a hospital in remote area and an institution capable of emergency stroke treatment under guidance by a stroke specialist has been reported to be effective. "Drip and Ship" treatment refers to initiating intravenous recombinant tissue-type plasminogen activator(rt-PA)infusion at a remote hospital(Drip)and then transporting patients to an institution capable of multimodality management and endovascular treatment of stroke(Ship). We report here a case analysis and examinations on treatment methods, prognosis, and some other parameters in 16 patients who were transported to the Stroke Care Unit(SCU)of the Tokushima University Hospital while undergoing"Drip and Ship"treatment between June 2013 and November 2015. Occluded vessels were recanalized by rt-PA administration in 5/12patients (42%). For 6 cases in which recanalization was not achieved with rt-PA, endovascular treatment was performed, and recanalization was obtained in 3 patients(50%). There was a marked improvement(8 4points on average)in NIHSS at the time of discharge compared to that before rt-PA administration. A representative case showed a 26-point improvement in NIHSS at the time of discharge compared to the pretreatment value. The advantage of"Drip and Ship"treatment is two-fold : It allows for rt-PA treatment of acute ischemic stroke patients at remote-area institutions incapable of multimodality stroke management, and also makes it possible to add endovascular treatment for rt-PA-irresponsive cases in which recanalization of occluded vessels could not be achieved with rt-PA therapy. The results suggest that the"Drip and Ship"treatment is a safe and effective means to eliminate regional disparities in intravenous rt-PA therapy and can make more contributions to the collaborative stroke care in the Tokushima prefecture in the future.
Masaaki Korai, 北里 慶子, Yoshiteru Tada, Takeshi Miyamoto, Kenji Shimada, Nobuhisa Matsushita, Yasuhisa Kanematsu, Junichiro Satomi, 橋本 友紀 and Shinji Nagahiro : Hyperhomocysteinemia induced by excessive methionine intake promotes rupture of cerebral aneurysms in ovariectomized rats, Journal of Neuroinflammation, Vol.13, No.1, 165, 2016.
(要約)
Hyperhomocysteinemia (HHcy) is associated with inflammation and a rise in the expression of matrix metalloproteinase-9 (MMP-9) in the vascular wall. However, the role of HHcy in the growth and rupture of cerebral aneurysms remains unclear. Thirteen-week-old female Sprague-Dawley rats were subject to bilateral ovariectomy and ligation of the right common carotid artery and fed an 8 % high-salt diet to induce cerebral aneurysms. Two weeks later, they underwent ligation of the bilateral posterior renal arteries. They were divided into two groups and methionine (MET) was or was not added to their drinking water. In another set of experiments, the role of folic acid (FA) against cerebral aneurysms was assessed. During a 12-week observation period, subarachnoid hemorrhage due to aneurysm rupture was observed at the anterior communicating artery (AcomA) or the posterior half of the circle of Willis. HHcy induced by excessive MET intake significantly increased the incidence of ruptured aneurysms at 6-8 weeks. At the AcomA of rats treated with MET, we observed the promotion of aneurysmal growth and infiltration by M1 macrophages. Furthermore, the mRNA level of MMP-9, the ratio of MMP-9 to the tissue inhibitor of metalloproteinase-2, and the level of interleukin-6 were higher in these rats. Treatment with FA abolished the effect of MET, suggesting that the inflammatory response and vascular degradation at the AcomA is attributable to HHcy due to excessive MET intake. We first demonstrate that in hypertensive ovariectomized rats, HHcy induced by excessive MET intake may be associated with the propensity of the aneurysm wall to rupture.
Teruyoshi Kageji, Fumiaki Obata, Hirofumi Oka, Yasuhisa Kanematsu, Ryo Tabata, Kenji Tani, Hiroyashu Bando and Shinji Nagahiro : Drip-and-ship thrombolytic therapy Supported by the telestroke system for acute ischemic stroke patients living in medically under-served Areas., Neurologia Medico-Chirurgica, Vol.56, No.12, 753-758, 2016.
(要約)
There are a few stroke specialists in medically under-served areas in Japan. Consequently, in remote area patients may not receive thrombolysis with intravenous recombinant tissue plasminogen activator (iv rt-PA), the standard treatment for acute ischemic stroke. Using a mobile telestroke support system (TSS) that accesses the internet via a smart phone, we implemented iv rt-PA infusion therapy under a drip-and-ship protocol to treat the stroke patients in medically under-served areas. The physicians at the Tokushima Prefectural Kaifu Hospital (TPKH), located in rural Japan, can relay CT or MRI scans and other patient data via their smart phone to off-site stroke specialists. In the course of 34 months, we used the TSS in 321 emergencies. A total of 9 of 188 (4.8%) with acute ischemic stroke, received iv rt-PA infusion therapy using a mobile TSS; in 5 among these (55.6%), we obtained partial or complete recanalization of occluded arteries. None suffered post-treatment hemorrhage and their average NIH stroke score fell from 14.6 at the time of admission to 6.8 at 24 h post-infusion. The drip-and-ship protocol contributed to the safe and effective treatment of the stroke patients living in medically under-served rural areas.
(キーワード)
Aged / Aged, 80 and over / Female / Fibrinolytic Agents / Humans / 日本 (Japan) / Male / Medically Underserved Area / Stroke / Telemedicine / Thrombolytic Therapy / Time-to-Treatment / Tissue Plasminogen Activator / Treatment Outcome
Takeshi Miyamoto, DK Kung, KT Kitazato, Kenji Yagi, Kenji Shimada, Yoshiteru Tada, Masaaki Korai, Yoshitaka Kurashiki, Tomoya Kinouchi, Yasuhisa Kanematsu, Junichiro Satomi, T Hashimoto and Shinji Nagahiro : Site-specific elevation of interleukin-1β and matrix metalloproteinase-9 in the Willis circle by hemodynamic changes is associated with rupture in a novel rat cerebral aneurysm model, Journal of Cerebral Blood Flow and Metabolism, Vol.37, No.8, 2795-2805, 2016.
(要約)
The pathogenesis of subarachnoid hemorrhage remains unclear. No models of cerebral aneurysms elicited solely by surgical procedures and diet have been established. Elsewhere we reported that only few rats in our original rat aneurysm model manifested rupture at the anterior and posterior Willis circle and that many harbored unruptured aneurysms at the anterior cerebral artery-olfactory artery bifurcation. This suggests that rupture was site-specific. To test our hypothesis that a site-specific response to hemodynamic changes is associated with aneurysmal rupture, we modified our original aneurysm model by altering the hemodynamics. During 90-day observation, the incidence of ruptured aneurysms at the anterior and posterior Willis circle was significantly increased and the high incidence of unruptured aneurysms at the anterior cerebral artery-olfactory artery persisted. This phenomenon was associated with an increase in the blood flow volume. Notably, the level of matrix metalloproteinase-9 associated with interleukin-1β was augmented by the increase in the blood flow volume, suggesting that these molecules exacerbated the vulnerability of the aneurysmal wall. The current study first demonstrates that a site-specific increase in interleukin-1β and matrix metalloproteinase-9 elicited by hemodynamic changes is associated with rupture. Our novel rat model of rupture may help to develop pharmaceutical approaches to prevent rupture.
Yoshiteru Tada, Kenji Yagi, Masaaki Uno, Nobuhisa Matsushita, Yasuhisa Kanematsu, Kazuyuki Kuwayama, Kenji Shimada, Kyoko Nishi, Motohiro Hirasawa, Junichiro Satomi, KT Kitazato, Teruyoshi Kageji, E Matsumura and Shinji Nagahiro : Improvement of plasma biomarkers after switching stroke patients from other angiotensin II type I receptor blockers to olmesartan, Journal of Stroke & Cerebrovascular Diseases, Vol.24, 1487-1492, 2015.
(要約)
Managing hypertension is crucial for preventing stroke recurrence. Some stroke patients experience resistant hypertension. In our experimental stroke model, olmesartan increased the expression of angiotensin (Ang) II converting enzyme-2. We hypothesized that switching to olmesartan affects biomarkers and the blood pressure (BP) in stroke patients whose BP is insufficiently controlled by standard doses of Ang II type I receptor blockers (ARBs) other than olmesartan. We recruited 25 patients to study our hypothesis. All had a history of stroke or silent cerebral infarction. We switched them to olmesartan (10-40 mg per day) for 12 weeks and determined their plasma level of Ang-(1-7), peroxiredoxin, oxidized low-density lipoprotein (oxLDL)/β-2-glycoprotein I (β2GPI) complex, adiponectin, high mobility group box 1 (HMGB1), and tumor necrosis factor-α (TNFα) and recorded their BP before and after olmesartan treatment. After switching the patients to olmesartan, their plasma level of Ang-(1-7) as a vasoprotective indicator and adiponectin regulating metabolic syndrome was increased, and peroxiredoxin and the oxLDL/β2GPI complex indicating its antioxidative stress and its proatherogenicity were lower than their baseline. This suggests that olmesartan may be more effective than other ARBs to improve these conditions. Neither HMGB1 nor TNFα reflecting an inflammatory response was affected, suggesting that the anti-inflammatory effects of olmesartan are similar to those of other ARBs. The recommended BP (<140/90) was obtained in 10 of the 25 patients after switching to olmesartan. No adverse events occurred. Switching from other ARBs to olmesartan may be a promising therapeutic option in patients with resistant hypertension.
Kenji Shimada, Hajime Furukawa, Kosuke Wada, Yuan Wei, Yoshiteru Tada, Atsushi Kuwabara, Fumiaki Shikata, Yasuhisa Kanematsu, Michael T. Lawton, Keiko T. Kitazato, Shinji Nagahiro and Tomoki Hashimoto : Angiotensin-(1-7) protects against the development of aneurysmal subarachnoid hemorrhage in mice, Journal of Cerebral Blood Flow and Metabolism, Vol.35, No.7, 1163-1168, 2015.
(要約)
Angiotensin-(1-7) (Ang-(1-7)) can regulate vascular inflammation and remodeling, which are processes that have important roles in the pathophysiology of intracranial aneurysms. In this study, we assessed the effects of Ang-(1-7) in the development of intracranial aneurysm rupture using a mouse model of intracranial aneurysms in which aneurysmal rupture (i.e., aneurysmal subarachnoid hemorrhage) occurs spontaneously and causes neurologic symptoms. Treatment with Ang-(1-7) (0.5 mg/kg/day), Mas receptor antagonist (A779 0.5 mg/kg/day or 2.5 mg/kg/day), or angiotensin II type 2 receptor (AT2R) antagonist (PD 123319, 10 mg/kg/day) was started 6 days after aneurysm induction and continued for 2 weeks. Angiotensin-(1-7) significantly reduced the rupture rate of intracranial aneurysms without affecting the overall incidence of aneurysms. The protective effect of Ang-(1-7) was blocked by the AT2R antagonist, but not by the Mas receptor antagonist. In AT2R knockout mice, the protective effect of Ang-(1-7) was absent. While AT2R mRNA was abundantly expressed in the cerebral arteries and aneurysms, Mas receptor mRNA expression was very scarce in these tissues. Angiotensin-(1-7) reduced the expression of tumor necrosis factor-α and interleukin-1β in cerebral arteries. These findings indicate that Ang-(1-7) can protect against the development of aneurysmal rupture in an AT2R-dependent manner.
(キーワード)
Aneurysm, Ruptured / Angiotensin I / Angiotensin II / Angiotensin II Type 2 Receptor Blockers / Animals / 脳 (brain) / Cerebral Arteries / 細胞質分裂 (cytokinesis) / Imidazoles / Male / Mice / Mice, Inbred C57BL / ノックアウトマウス (knockout mice) / Peptide Fragments / Pyridines / RNA, Messenger / Receptor, Angiotensin, Type 2 / Subarachnoid Hemorrhage
Yoshiteru Tada, K Wada, Kenji Shimada, H Makino, EI Liang, S Murakami, M Kudo, F Shikata, RAP Silva, KT Kitazato, DM Hasan, Yasuhisa Kanematsu, Shinji Nagahiro and T Hashimoto : Estrogen protects against intracranial aneurysm rupture in ovariectomized mice, Hypertension, Vol.63, 1339-1344, 2014.
(要約)
Clinical observations suggest that postmenopausal women have a higher incidence of aneurysmal rupture than premenopausal women. We hypothesize that a relative deficiency in estrogen may increase the risks of aneurysmal growth and subarachnoid hemorrhage in postmenopausal women. We assessed the effects of estrogen and selective estrogen receptor subtype agonists on the development of aneurysmal rupture in ovariectomized female mice. We used an intracranial aneurysm mouse model that recapitulates the key features of human intracranial aneurysms, including spontaneous rupture. Ten- to 12-week-old ovariectomized female mice received treatment with estrogen, nonselective estrogen receptor antagonist, estrogen receptor-α agonist, or estrogen receptor-β agonist starting 6 days after aneurysm induction so that the treatments affected the development of aneurysmal rupture without affecting aneurysmal formation. Estrogen significantly reduced the incidence of ruptured aneurysms and rupture rates in ovariectomized mice. Nonselective estrogen receptor antagonist abolished the protective effect of estrogen. Although estrogen receptor-α agonist did not affect the incidence of ruptured aneurysms or rupture rates, estrogen receptor-β agonist prevented aneurysmal rupture without affecting the formation of aneurysms. The protective role of estrogen receptor-β agonist was abolished by the inhibition of nitric oxide synthase. We showed that estrogen prevented aneurysmal rupture in ovariectomized female mice. The protective effect of estrogen seemed to occur through the activation of estrogen receptor-β, a predominant subtype of estrogen receptor in human intracranial aneurysms and cerebral arteries.
While the number of elderly patients who presented with aneurysmal subarachnoid hemorrhage (SAH) has been increasing, its optimal management in that population remains controversial. Therefore, we retrospectively reviewed the treatment outcomes in 49 consecutive patients aged between 80 and 94 years who presented with SAH. The neurological World Federation of Neurological Surgeons (WFNS) grade at the time of admission was Grade I in 7, Grade II in 11, Grade III in 8, Grade IV in 13, and Grade V in 10 patients. Of the 49 patients, 28 underwent coil embolization, and 7 (25%) had a favorable outcome (mRS: 0-2) at discharge, while in 21 (75%) the outcome was poor (mRS: 3-6). Six patients underwent clipping; the outcome was favorable in one patient (17%) and poor in 5 (83%). Of 15 patients under conservative therapy none had a favorable outcome. A low WFNS grade (I-II) was significantly associated with a favorable outcome (p<0.05). Although the treatment outcome in elderly patients with SAH was poor, radical treatment of ruptured aneurysms should be considered if their WFNS grade is low.
A regular neurosurgeon was absent in the southern part II health demographic division of medical services where Kaifu-gun of South Tokushima was located after 2008 and was the present conditions that stroke treatment could not perform enough in comparison with prefecture central part. Furthermore, medical care collapse progressed with the obstetrics and gynecology department and pediatrics closedown at one sweep from the same period and, at the prefectural Kaifu Hospital which was this local nucleus hospital, became hard to maintain the emergency care, and increase of closedown of the emergency outpatient department on Saturday and the emergency transportation to the prefecture central part became remarkable, and it was with a big social problem for Tokushima. A medical difference might occur about stroke medical care in central part and the southern part in Tokushima. We performed the epidemiology survey by stroke patient in the southern II demographic division of medical services (popular name ``Kaifu project'') as a President of University of Tokushima discretion project for this fact-finding individually in the University of Tokushima neurosurgery classroom. In addition, I worked on the enlightenment for inhabitants in Kaifu-gun. ``Local neurosurgical medical treatment part'' was established as a college course financially maintained by private donations of Tokushima University Hospital from November 1，2011． Kaifu Hospital neurosurgery medical treatment was enabled daylong, and emergency correspondence came to be in this way possible. The Kaifu Hospital devises the maintenance policy about Tokushima, local inhabitants, a medical association, a local government and the figure which there should be of ``the new Kaifu Hospital'' for a tsunami now in the plan of the full-scale reconstruction move to the hill in 2015．
Nobuhisa Matsushita, Keiko T. Kitazato, Yoshiteru Tada, Manabu Sumiyoshi, Kenji Shimada, Kenji Yagi, Yasuhisa Kanematsu, Junichiro Satomi and Shinji Nagahiro : Increase in body Na+-to-water ratio is associated with cerebral aneurysm formation in oophorectomized rats, Hypertension, Vol.60, No.5, 1309-1315, 2012.
(要約)
The incidence of cerebral aneurysms is higher in women than in men, especially postmenopause. Although hypertension is thought to be associated with a high incidence of stroke, not all patients with unruptured cerebral aneurysms are hypertensive. The possibility of water-free Na(+) storage associated with hypertension has been raised. However, whether the increase in the body Na(+)/water ratio that characterizes water-free Na(+) accumulation is associated with the formation of cerebral aneurysms remains obscure. To examine this relationship, Sprague-Dawley female rats subjected to carotid artery ligation were divided into 3 groups: a high-salt diet group (HSD) without and another with bilateral oophorectomy (HSD/OVX) and a third group that underwent additional renal artery ligation (HSD/OVX/RL). Compared with rats receiving a normal diet (shams), water retention was increased in HSD rats but not in HSD/OVX rats. Interestingly, compared with HSD rats, the incidence of cerebral aneurysms and the body Na(+)/water ratio were significantly higher in HSD/OVX and HSD/OVX/RL rats, independent of hypertension. In their aneurysmal wall, ATP12, a subtype of Na(+)/K(+)-ATPase, was downregulated, whereas inflammatory-related molecules were upregulated. Treatment with low-dose olmesartan that did not affect the blood pressure in hypertensive HSD/OVX/RL rats reduced the rate of cerebral aneurysm formation, body Na(+) retention, and the Na(+)/water ratio and upregulated ATP12. These results suggest that the increase in the Na(+)/water ratio and a reduction in ATP12 may be associated with cerebral aneurysm formation. We provide the new insight that the management of water-free Na(+) is important to prevent their development.
Background : The carotid plaque vulnerability is related to myocardial and cerebral infarction.We intended to develop an imaging system which enables to visualize tissue characteristics in thecarotid plaques based on ultrasound integrated backscatter(IB). And to test its clinical efficacy,effect of the statin therapy on the plaques was evaluated with our software. Methods and Results :Carotid ultrasound examination was performed and ultrasonographic RAW data of the plaqueswere obtained from8patients undergoing carotid artery endarterectomy. Tissue characteristicsin the plaques of resected examples were compared with preoperative ultrasonic images and thetissue IB values corresponding to the specimens were determined for developing our imaging system.Using this system, Color-coded maps of plaques in the three patients were constructed beforeand after lipid lowing therapy. We could demonstrate that lipid fraction in each plaque decreasedand fibrous or calcification fraction increased in the follow-up study. Conclusions : Changes inhistology of carotid plaques by statin could visualized with our imaging system. This techniquemay become a useful tool for the management of atherosclerosis.
(キーワード)
IBS (integrated backscatter) / carotid plaque / CEA (carotid endarterectomy)
Yoshiteru Tada, Keiko T. Kitazato, Kenji Yagi, Kenji Shimada, Nobuhisa Matsushita, Tomoya Kinouchi, Yasuhisa Kanematsu, Junichiro Satomi, Teruyoshi Kageji and Shinji Nagahiro : Statins Promote the Growth of Experimentally Induced Cerebral Aneurysms in Estrogen-Deficient Rats, Stroke, Vol.42, No.8, 2286-2293, 2011.
(要約)
The pathogenesis of cerebral aneurysms is linked to inflammation, degradation of the extracellular matrix, and vascular wall apoptosis. Statins exert pleiotropic effects on the vasculature, independent of their cholesterol-lowering properties. To explore the detailed pathogenesis of cerebral aneurysms, we examined their progression in a rat model and studied whether statins prevent their initiation and growth. Cerebral aneurysms were induced in female rats subjected to hypertension, increased hemodynamic stress, and estrogen deficiency. The development of aneurysm was assessed morphologically on corrosion casts. The effects of pravastatin (5, 25, or 50 mg/kg per day) and of simvastatin (5 mg/kg per day) on their aneurysms were studied. Human brain endothelial cells were also used to determine the effects of pravastatin. Pravastatin (5 mg/kg per day) reduced endothelial damage and inhibited aneurysm formation; there was an association with increased endothelial nitric oxide synthase (eNOS) levels and a decrease in human brain endothelial cell adhesion molecules. Unexpectedly, 25 mg/kg per day and 50 mg/kg per day pravastatin and 5 mg/kg per day simvastatin promoted aneurysmal growth, and high-dose pravastatin induced aneurysmal rupture. The deleterious effects exerted by these statins were associated with an increase in apoptotic caspase-3 levels and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, suggesting that statins exert bidirectional effects. Our results provide the first evidence that cerebral aneurysm growth is partly associated with apoptosis and issue a warning that statins exert bidirectional effects on cerebral aneurysms. Additional intensive research is necessary to understand better their mechanisms and to identify patients in whom the administration of statins may elicit deleterious effects.
Hideki Ohnishi, Satoshi Iwanaga, Kazuyoshi Kawazoe, Keisuke Ishizawa, Sakiko Orino, Shuhei Tomita, Koichiro Tsuchiya, Yasuhisa Kanematsu, Nagakatsu Harada, Kazuhiro Mori, Tomoko Tsuchihashi, Yasuko Ishikawa and Toshiaki Tamaki : Effect of iron-quercetin complex on reduction of nitrite in in vitro and in vivo systems, Journal of Agricultural and Food Chemistry, Vol.56, No.21, 10092-10098, 2008.
(要約)
This study investigated whether reducing agents such as quercetin and iron(II) facilitate formation of nitric oxide (NO) gas from orally ingested nitrite in an vivo study. When 3 mg/kg Na (15)NO2 was orally administered to rats with or without iron(II) or quercetin, Hb (15)NO, which is indicative of systemic (15)NO, was detected in the blood, with the maximum blood concentration of Hb (15)NO at 15 min after nitrite or nitrite plus quercetin treatment, whereas after administration of nitrite plus iron(II) or nitrite plus iron(II) and quercetin, the time was shortened to 10 min. Interestingly, iron(II), quercetin, or iron(II) plus quercetin did not affect the total amount of Hb (15)NO generated from orally administered Na (15)NO2. However, the systemic nitrite concentration was significantly decreased in the presence of iron(II) or iron(II) plus quercetin. These results may indicate that iron(II) is critical to the generation of NO gas from nitrite, whereas quercetin contributed little under the in vivo experimental conditions.
Yasuhisa Kanematsu, Kunihisa Yamaguchi, Hideki Ohnishi, Yuki Motobayashi, Keisuke Ishizawa, Yuki Izawa, Kazuyoshi Kawazoe, Shuji Kondo, Shoji Kagami, Shuhei Tomita, Koichiro Tsuchiya and Toshiaki Tamaki : Dietary doses of nitrite restore circulating nitric oxide level and improve renal injury in L-NAME-induced hypertensive rats, American Journal of Physiology, Renal Physiology, Vol.295, No.5, F1457-F1462, 2008.
(要約)
We have reported that pharmacological doses of oral nitrite increase circulating nitric oxide (NO) and exert hypotensive effects in Nomega-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. In this study, we examined the effect of a chronic dietary dose of nitrite on the hypertension and renal damage induced by chronic L-NAME administration in rats. The animals were administered tap water containing L-NAME (1 g/l) or L-NAME + nitrite (low dose: 0.1 mg/l, medium dose: 1 mg/l, high dose: 10 mg/l) for 8 wk. We evaluated blood NO levels as hemoglobin-NO adducts (iron-nitrosyl-hemoglobin), using an electron paramagnetic resonance method. Chronic administration of L-NAME for 8 wk induced hypertension and renal injury and reduced the blood iron-nitrosyl-hemoglobin level (control 38.8 +/- 8.9 vs. L-NAME 6.0 +/- 3.1 arbitrary units). Coadministration of a low dose of nitrite with L-NAME did not change the reduced iron-nitrosyl-hemoglobin signal and did not improve the L-NAME-induced renal injury. The blood iron-nitrosyl-hemoglobin signals of the medium dose and high dose of nitrite were significantly higher than that of L-NAME alone. Chronic administration of a medium dose of nitrite attenuated L-NAME-induced renal histological changes and proteinuria. A high dose of nitrite also attenuated L-NAME-induced renal injury. These findings suggest that dietary doses of nitrite that protect the kidney are associated with significant increase in iron-nitrosyl-hemoglobin levels. We conclude that dietary nitrite-derived NO generation may serve as a backup system when the nitric oxide synthase/L-arginine-dependent NO generation system is compromised.
H Liu, KT Kitazato, Masaaki Uno, Kenji Yagi, Yasuhisa Kanematsu, Tetsuya Tamura, Yoshiteru Tada, Tomoya Kinouchi and Shinji Nagahiro : Protective mechanisms of the angiotensin II type 1 receptor blocker candesartan against cerebral ischemia: in-vivo and in-vitro studies, Journal of Hypertension, Vol.26, No.7, 1435-1445, 2008.
(要約)
Angiotensin II type 1 (AT1) receptor blockers decrease ischemia by mechanisms dependent on and independent of arterial blood pressure in hypertensive rats and AT1-R knockout mice, respectively. However, the detailed mechanisms underlying the effects of AT1 receptor blockers remain unclear. To elucidate the systemic and focal effects of AT1 receptor blockers against cerebral ischemia in in-vivo and in-vitro studies. Normotensive Wistar rats were treated for 2 weeks with 0.5 or 1 mg/kg candesartan cilexetil and then subjected to 2-h middle cerebral artery occlusion-reperfusion. Human umbilical endothelial cells were stimulated with the active form of candesartan and angiotensin II in the absence and presence of an angiotensin II type 2 (AT2) receptor antagonist. In candesartan-pretreated hypotensive and nonhypotensive rats, blood pressure was moderately increased during middle cerebral artery occlusion and fell gradually to the baseline after the reperfusion; it remained elevated in the control even after the reperfusion occlusion. Candesartan treatment resulted in a decrease in the cortical infarct volume and oxidative damage, the hypoxic status was improved, and the expression of repair-associated and growth-associated proteins in the cortical penumbra was augmented. Candesartan also increased the eNOS mRNA level and the lumen size of the middle cerebral artery. In human umbilical endothelial cells, candesartan increased the eNOS protein level AT2-R dependently, inhibited the expression of nicotinamide adenine dinucleotide phosphate oxidase subunits and angiotensin II-induced intracellular reactive oxygen species and nitric oxide, and promoted the extracellular release of nitric oxide, suggesting that it augmented the bioavailability of nitric oxide. Among the mechanisms candesartan exerts in its protection against cerebral ischemia, restoration of endothelial function may represent an attractive therapeutic goal to address cerebral ischemia.
(キーワード)
Angiotensin II Type 1 Receptor Blockers / Animals / Benzimidazoles / Biphenyl Compounds / Brain Ischemia / Disease Models, Animal / Endothelium, Vascular / Ligation / Middle Cerebral Artery / Nitric Oxide / Nitric Oxide Synthase Type II / Nitric Oxide Synthase Type III / Oxidative Stress / Rats / Rats, Wistar / Reactive Oxygen Species / Reperfusion Injury / Tetrazoles / Vasodilation
Teruyoshi Kageji, Shinji Nagahiro, Kazuhito Matsuzaki, Yasuhisa Kanematsu, M Nakatani, Y Okamoto and Tsutomu Watanabe : Successful neoadjuvant synchronous chemo- and radiotherapy for disseminated primary intracranial chriocarcinoma: case report, Journal of Neuro-Oncology, Vol.83, No.2, 199-204, 2007.
(要約)
We report a 17-year-old male with disseminated intracranial choriocarcinoma at the basal ganglia whose consciousness level was very low at diagnosis. He received neoadjuvant therapy (NAT) consisting of combined chemo- and radiotherapy prior to radical excision of the tumor. Postoperatively he was treated with three courses of high-dose chemotherapy (carboplatin (CBDCA), methotrexate (MTX), and etoposide (VP-16)) and peripheral blood stem-cell transplantation. This combination of therapies resulted in tumor regression on MRI and remarkable improvement in his neurological condition. Ours is the first report of the effectiveness of NAT followed by radical surgery in a patient with disseminated primary intracranial choriocarcinoma.
Ali Nermin, Masanori Yoshizumi, Seiji Yano, Saburo Sone, Hideki Ohnishi, Keisuke Ishizawa, Yasuhisa Kanematsu, Koichiro Tsuchiya and Toshiaki Tamaki : The novel Src kinase inhibitor M475271 inhibits VEGF-induced vascular endothelial-cadherin and β-catenin phosphorylation but increases their association, Journal of Pharmacological Sciences, Vol.102, No.1, 112-120, 2006.
(要約)
M475271, 4-quinazolinamine, N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl) methoxy]-(9Cl), is a new anilinoquinazoline derivative that displays selective inhibition of Src kinase activity and tumor growth in vivo. Vascular endothelial growth factor (VEGF)-induced angiogenesis plays a pivotal role in tumor growth and metastasis. Vascular endothelial (VE)-cadherin is an endothelial cell-specific adhesion molecule that can interact with the cytoskeleton via several anchoring molecules such as beta-catenin. Here, we examined the effect of M475271 on VE-cadherin and beta-catenin phosphorylation and association. We also examined its effect on VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation, migration, and tube formation. The findings reveal pretreatment with M475271 significantly inhibits VEGF-induced VE-cadherin and beta-catenin phosphorylation. However, M475271 significantly increases VE-cadherin and beta-catenin association compared to the VEGF-treated group. Confocal laser microscopic examination confirmed the augmentation effect of M475271 on VE-cadherin and beta-catenin association. Finally, M475271 was shown to have inhibitory effects comparable to those of PP2 and Herbimycin A on VEGF-induced HUVEC proliferation, migration, and tube formation. These findings suggest that M475271 attenuates VEGF-induced angiogenesis by maintaining cell-cell junction stability. Although the involvement of other signaling molecules cannot be ruled out, M475271 has potential as a drug for the inhibition of the angiogenesis needed for tumor growth and metastasis.
Shinji Abe, Hideki Ohnishi, Koichiro Tsuchiya, Keisuke Ishizawa, Mayumi Torii, Yasuhisa Kanematsu, Kazuyoshi Kawazoe, Kazuo Minakuchi, Masanori Yoshizumi and Toshiaki Tamaki : Calcium and reactive oxygen species mediated Zn2+-induced apoptosis in PC12 cells, Journal of Pharmacological Sciences, Vol.102, No.1, 103-111, 2006.
(要約)
The release of excessive Zn(2+) from presynaptic boutons into extracellular regions contributes to neuronal apoptotic events, which result in neuronal cell death. However, the mechanisms of Zn(2+)-induced neuronal cell death are still unclear. Therefore, we investigated the dynamics of intracellular Zn(2+), calcium, and reactive oxygen species in PC12 cells. The addition of Zn(2+) produced cell death in a concentration- and time-dependent manner. (45)Ca(2+) influx occurred just after the treatment with Zn(2+), although subsequent hydroxyl radical ((*)OH) production did not begin until 3 h after Zn(2+) exposure. (*)OH production was significantly attenuated in Ca(2+)-free medium or by L-type Ca(2+) channel antagonist treatment, but it was independent of the intracellular Zn(2+) content. Dantrolene treatment had no protective effects against Zn(2+)-induced cell death. Treatment with N-acetyl-L-cysteine blocked (*)OH generation and subsequent cell death. These data indicate that Ca(2+) influx and subsequent (*)OH production are critical events in Zn(2+)-induced toxicity in PC12 cells.
Yasuhisa Kanematsu, Koichiro Tsuchiya, Hideki Onishi, Yuki Motobayashi, Yuki Izawa, Manabu Ishihara, Keisuke Ishizawa, Shinji Abe, Kazuyoshi Kawazoe and Toshiaki Tamaki : Effects of angiotensin II type 1 receptor blockade on the systemic blood nitric oxide dynamics in Nω-nitro-L-arginine methyl ester-treated rats, Hypertension Research, Vol.29, No.5, 369-374, 2006.
(要約)
We previously succeeded in measuring the nitrosylhemoglobin (HbNO) level as an index of blood nitric oxide (NO) by the electron paramagnetic resonance (EPR) HbNO signal subtraction method. In this study, we examined the effects of olmesartan, an angiotensin II type 1 receptor blocker (ARB), on NO dynamics in N(omega)-nitro-L-arginine methyl ester (L-NAME)-treated rats by the EPR-subtraction method. Oral administration of L-NAME for 2 weeks induced serious hypertension, and the HbNO concentration was reduced to 37.6% of the level in controls. Coadministration of olmesartan improved hypertension and increased the blood HbNO concentration of L-NAME-treated rats. In contrast, coadministration of hydralazine improved hypertension but did not affect the blood HbNO concentration. In conclusion, our findings suggested that chronic administration of olmesartan ameliorated the endothelial dysfunction in L-NAME-treated rats.
Lysophosphatidylcholine (LPC), a major lipid component of oxidized low-density lipoprotein, is a bioactive lipid molecule involved in numerous biological processes including the progression of atherosclerosis. Recently orphan G protein-coupled receptors were identified as high-affinity receptors for LPC. Although several G protein-coupled receptor ligands transactivate receptor tyrosine kinases, LPC-stimulated transactivation of receptor tyrosine kinase has not yet been reported. Here we observed for the first time that LPC treatment of human umbilical vein endothelial cells (HUVECs) induces tyrosyl phosphorylation of vascular endothelial growth factor receptor 2 [fetal liver kinase-1/kinase-insert domain-containing receptor, Flk-1/KDR)]. Flk-1/KDR transactivation by LPC was inhibited by vascular endothelial growth factor receptor tyrosine kinase inhibitors, SU1498 and 4-[(4'-chloro-2'-fluoro) phenylamino]6,7-dimethoxyquinazoline (VTKi) in immunoprecipitation. Furthermore, we examined the effects of the Src family kinases inhibitors, herbimycin A and 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d] pyrimidine (PP2), on LPC-induced Flk-1/KDR transactivation. Results from Western blots, c-Src is involved in LPC-induced Flk-1/KDR transactivation because herbimycin A and PP2 inhibited this transactivation. Kinase-inactive (KI) Src transfection also inhibited LPC-induced Flk-1/KDR transactivation. In addition, results from Western blots, ERK1/2 and Akt, which are downstream effectors of Flk-1/KDR, were also activated by LPC, and this was inhibited by SU1498, VTKi, herbimycin A, PP2, and KI Src transfection in HUVECs. LPC-induced stimulation of HUVEC proliferation was shown to be secondary to transactivation because it was suppressed by SU1498, VTKi, herbimycin A, PP2, and KI Src transfection in dimethylthiazoldiphenyltetra-zoliumbromide assay. These findings suggest that LPC-induced Flk-1/KDR transactivation via c-Src may have important implications for the progression of atherosclerosis.
The nongenomic effects of aldosterone have been implicated in the pathogenesis of various cardiovascular diseases. Aldosterone-induced nongenomic effects are attributable in part to the activation of extracellular signal-regulated kinase 1/2 (ERK1/2), a classical mitogen-activated protein (MAP) kinase. Big MAP kinase 1 (BMK1), a newly identified MAP kinase, has been shown to be involved in cell proliferation, differentiation, and survival. We examined whether aldosterone stimulates BMK1-mediated proliferation of cultured rat aortic smooth muscle cells (RASMCs). Mineralocorticoid receptor (MR) expression and localization were evaluated by Western blotting analysis and fluorolabeling methods. ERK1/2 and BMK1 activities were measured by Western blotting analysis with the respective phosphospecific antibodies. Cell proliferation was determined by Alamar Blue colorimetric assay. Aldosterone (0.1 to 100 nmol/L) dose-dependently activated BMK1 in RASMCs, with a peak at 30 minutes. To clarify whether aldosterone-induced BMK1 activation is an MR-mediated phenomenon, we examined the effect of eplerenone, a selective MR antagonist, on aldosterone-induced BMK1 activation. Eplerenone (0.1 to 10 micromol/L) dose-dependently inhibited aldosterone-induced BMK1 activation in RASMCs. Aldosterone also stimulated RASMC proliferation, which was inhibited by eplerenone. Aldosterone-mediated phenomena were concluded to be attributable to a nongenomic effect because cycloheximide failed to inhibit aldosterone-induced BMK1 activation. Transfection of dominant-negative MAP kinase/ERK kinase 5 (MEK5), which is an upstream regulator of BMK1, partially inhibited aldosterone-induced RASMC proliferation, which was almost completely inhibited by MEK inhibitor PD98059. In addition to the classical steroid activity, rapid nongenomic effects induced by aldosterone may represent an alternative etiology for vascular diseases such as hypertension.
Ali Nermin, Masanori Yoshizumi, Yoshiko Fujita, Yuki Izawa, Yasuhisa Kanematsu, Keisuke Ishizawa, Koichiro Tsuchiya, Seiji Yano, Saburo Sone and Toshiaki Tamaki : A Novel Src Kinase Inhibitor, M475271, Inhibits VEGF-Induced Human Umbilical Vein Endothelial Cell Proliferation and Migration, Journal of Pharmacological Sciences, Vol.98, No.2, 130-141, 2005.
(要約)
Vascular endothelial growth factor (VEGF) was reported to be a potent proangiogenic factor that plays a pivotal role in both physiological and pathological angiogenesis. M475271, 4-quinazolinamine, N-(2-chloro-5-methoxyphenyl)-6-methoxy-7-[(1-methyl-4-piperidinyl) methoxy]-(9Cl), is a new anilinoquinazoline derivative that showed selective inhibition of Src kinase activity and tumor growth in vivo. Here, we examined the effect of M475271 on VEGF-induced human umbilical vein endothelial cell (HUVEC) proliferation and migration and their intracellular mechanisms. Our findings showed that M475271 pretreatment resulted in a significant inhibition of VEGF-induced HUVEC proliferation, [(3)H]thymidine incorporation, and migration. M475271 inhibited VEGF-induced Flk-1 and Src phosphorylation and their association. Confocal laser microscopic examination confirmed the inhibitory effect of M475271 on VEGF-induced Flk-1/Src association. M475271 inhibited VEGF-induced extracellular signal-regulated kinase1/2 (ERK1/2) and p38 but not Akt activation in a concentration-dependent manner. M475271, PI3-K inhibitor, and p38 inhibitor inhibited VEGF-induced HUVEC proliferation and migration. However, a MEK1/2 inhibitor inhibited VEGF-induced proliferation but not migration. These findings suggest that M475271 attenuates VEGF-induced HUVEC proliferation and migration through the inhibition of signaling pathways involving Src, ERK1/2, and/or p38. Taken together, these data indicate that M475271 may be a useful candidate for inhibition of endothelial cell proliferation and migration relevant to angiogenesis.
(キーワード)
M475271 / vascular endothelial growth factor / human umbilical vein endothelial cell proliferation and migration / angiogenesis
Koichiro Tsuchiya, Yasuhisa Kanematsu, Masanori Yoshizumi, Hideki Ohnishi, Kazuyoshi Kirima, Yuki Izawa, Michiyo Shikishima, Tatsuhiro Ishida, Shuji Kondo, Shoji Kagami, Yoshiharu Takiguchi and Toshiaki Tamaki : Nitrite is an alternative source of NO in vivo, American Journal of Physiology, Heart and Circulatory Physiology, Vol.288, No.5, H2163-H2170, 2005.
(要約)
In this study, we investigated whether orally administered nitrite is changed to NO and whether nitrite attenuates hypertension in a dose-dependent manner. We utilized a stable isotope of [15N]nitrite (15NO2-) as a source of nitrite to distinguish between endogenous nitrite and that exogenously administered and measured hemoglobin (Hb)-NO as an index of circulating NO in whole blood using electron paramagnetic resonance (EPR) spectroscopy. When 1 mg/kg Na15NO2 was orally administered to rats, an apparent EPR signal derived from Hb15NO (A(Z) = 23.4 gauss) appeared in the blood. The peak blood HbNO concentration occurred at the first measurement after intake (5 min) for treatment with 1 and 3 mg/kg (HbNO: 4.93 +/- 0.52 and 10.58 +/- 0.40 microM, respectively) and at 15 min with 10 mg/kg (HbNO: 38.27 +/- 9.23 microM). In addition, coadministration of nitrite (100 mg/l drinking water) with N(omega)-nitro-L-arginine methyl ester (L-NAME; 1 g/l) for 3 wk significantly attenuated the L-NAME-induced hypertension (149 +/- 10 mmHg) compared with L-NAME alone (170 +/- 13 mmHg). Furthermore, this phenomenon was associated with an increase in circulating HbNO. Our findings clearly indicate that orally ingested nitrite can be an alternative to L-arginine as a source of NO in vivo and may explain, at least in part, the mechanism of the nitrite/nitrate-rich Dietary Approaches to Stop Hypertension diet-induced hypotensive effects.
Masumi Okamoto, Koichiro Tsuchiya, Yasuhisa Kanematsu, Yuki Izawa, Masanori Yoshizumi, Susumu Kagawa and Toshiaki Tamaki : Nitrite-derived nitric oxide formation following ischemia-reperfusion injyury in kidney., American Journal of Physiology, Renal Physiology, Vol.288, No.1, 182-187, 2005.
(要約)
Nitric oxide (NO) is synthesized from l-arginine by nitric oxide synthase (NOS), and nitrite and nitrate are believed to be waste forms of NO. We previously reported an enzyme-independent pathway of NO generation from nitrite in acidic conditions. In this study, we show nitrite-derived NO formation in renal ischemia-reperfusion injury using electron paramagnetic resonance (EPR) spectroscopy. In this experiment, we utilized a stable isotope of [(15)N]nitrite as a source of nitrite to distinguish l-arginine-derived NO from [(15)N]nitrite-derived (15)NO. Intravenous infusion of a stable isotope of [(15)N]nitrite ((15)NO(2)(-)) facilitated the formation of Hb(15)NO during renal ischemia, which demonstrated that the origin of NO was nitrite. The EPR signal of Hb(15)NO in kidney appeared after 40 min of renal ischemia, and renal reperfusion decreased the Hb(15)NO level in the kidney and increased it in blood by contrast. In addition, the amount of HbNO was nitrite concentration dependent, and this formation was NOS independent. Our findings suggest that nitrite can be an alternative source of NO in ischemic kidney and that it binds with hemoglobin and then is spread by the circulation after reperfusion.
Koichiro Tsuchiya, Yoshiharu Takiguchi, Masumi Okamoto, Yuki Izawa, Yasuhisa Kanematsu, Masanori Yoshizumi and Toshiaki Tamaki : Malfunction of vascular control in lifestyle-related diseases : formation of systemic hemoglobin-nitric oxide Complex(HbNO) From Dietary Nitrite, Journal of Pharmacological Sciences, Vol.96, No.4, 395-400, 2004.
(要約)
Nitric oxide (NO) has many physiological functions. It is believed to be produced from L-arginine by nitric oxide synthase (NOS), and nitrite and nitrate are waste forms of it. By the way, nitrate and nitrite are abundant in vegetables and fruits, especially leafy vegetables and pickled vegetables. Orally-ingested nitrate is changed to nitrite by micro-organelles living in the hypopharynx area, and nitrite is expected to change to NO in the stomach due to its low pH. Indeed, some researchers reported that NO is produced in the gastric cavity, although few reports mentioned the physiological meanings of this NO formation. Therefore, we investigated whether the nitrite-derived NO can shift to the circulation and acts like NOS-derived NO does in tissues. We adopted a stable isotope of nitrite (15NO2-) in order to distinguish between the endogenous nitrite and the exogenously administered one and measured nitrosyl hemoglobin (HbNO) as an index of circulating NO using electron paramagnetic resonance spectroscopy. It appeared that the oral administration of 15N-nitrite formed the Hb15NO in rat blood and decreased the blood pressure of chronic L-NAME treated rats. Our findings suggest that the intake of nitrite (or nitrate)-rich foods such as vegetables and fruits would alter the systemic HbNO dynamism, resulting in the improvement of cardiovascular diseases.
Moe Kyaw, Masanori Yoshizumi, Koichiro Tsuchiya, Yuki Izawa, Yasuhisa Kanematsu, Yoshiko Fujita, Nermin Ali, Keisuke Ishizawa, Aiko Yamauchi and Toshiaki Tamaki : Antioxidant effects of stereoisomers of N-acetylcysteine (NAC), L-NAC and D-NAC, on angiotensin II-stimulated MAP kinase activation and vascular smooth muscle cell proliferation, Journal of Pharmacological Sciences, Vol.95, No.4, 483-486, 2004.
(要約)
We examined the effects of the stereoisomers of N-acetylcysteine (NAC), L-NAC and D-NAC, on cellular glutathione (GSH) concentration and whether NAC-regulated cellular GSH levels are directly associated with angiotensin II (Ang II)-induced intracellular signaling events in vascular smooth muscle cells (VSMC). Both L-NAC and D-NAC similarly increased intracellular GSH concentration. We found that L-NAC and D-NAC both inhibited Ang II-induced c-Jun N-terminal kinase and p38 mitogen-activated protein kinase activation and [(3)H]-thymidine incorporation in VSMC. Our present study indicates the comparable effects of NAC stereoisomers in regulating intracellular GSH and the redox-dependent intracellular signaling mechanisms in VSMC.
(キーワード)
Acetylcysteine / Angiotensin II / Animals / Antioxidants / Aorta, Thoracic / Cell Proliferation / Enzyme Activation / Glutathione / JNK Mitogen-Activated Protein Kinases / Male / Mitogen-Activated Protein Kinases / Muscle, Smooth, Vascular / Myocytes, Smooth Muscle / Rats / Rats, Sprague-Dawley / Signal Transduction / Stereoisomerism / Thymidine / p38 Mitogen-Activated Protein Kinases
Moe Kyaw, Masanori Yoshizumi, Koichiro Tsuchiya, Yuki Izawa, Yasuhisa Kanematsu and Toshiaki Tamaki : Atheroprotective effects of antioxidants through inhibition of mitogen-activated protein kinases, Acta Pharmacologica Sinica, Vol.25, No.8, 977-985, 2004.
(要約)
Reactive oxygen species (ROS) have been known to play an important role in the pathogenesis of atherosclerosis and several other cardiovascular diseases. It is now apparent that ROS induce endothelial cell damage and vascular smooth muscle cell (VSMC) growth and cardiac remodeling, which are associated with hypertension, atherosclerosis, heart failure, and restenosis. Several lines of evidence have indicated that ROS and mitogen-activated protein (MAP) kinases were involved in vascular remodeling under various pathological conditions. Recently, it was also reported that MAP kinases were sensitive to oxidative stress. MAP kinases play an important role in cell differentiation, growth, apoptosis, and the regulation of a variety of transcription factors and gene expressions. Bioflavonoids and polyphenolic compounds are believed to be beneficial for the prevention and treatment of atherosclerosis and cardiovascular diseases. One of the most widely distributed bioflavonoids, 3,3',4',5,7-penta-hydroxyflavone (quercetin) and its metabolite quercetin 3-O-beta-D-glucuronide (Q3GA) inhibited Angiotensin II-stimulated JNK activation and resultant hypertrophy of VSMC. Several studies have suggested that various antioxidants including probucol, N-acetyl-L-cysteine, diphenylene iodonium, Trolox C (vitamin E analogue), and vitamin C inhibit VSMC growth, which is associated with pathogenesis of cardiovascular diseases. Therefore, inhibition of MAP kinases by antioxidant treatment may prove to be a therapeutic strategy for cardiovascular diseases. In contrast, some clinical studies have reported that antioxidant vitamins did not show beneficial effects in coronary artery disease or in a number of high-risk people. Thus, further studies are needed to clarify why antioxidants showed beneficial effects in vitro, whereas less satisfactory results were obtained in some clinical conditions.
Keisuke Ishizawa, Masanori Yoshizumi, Koichiro Tsuchiya, Hitoshi Houchi, Kazuo Minakuchi, Yuki Izawa, Yasuhisa Kanematsu, Shoji Kagami, Masao Hirose and Toshiaki Tamaki : Dual effects of endothelin-1 (1-31): induction of mesangial cell migration and facilitation of monocyte recruitment through monocyte chemoattractant protein-1 production by mesangial cells, Hypertension Research, Vol.27, No.6, 433-440, 2004.
(要約)
We previously found that human chymase selectively cleaves big endothelin-1 (ET-1) at the Tyr31-Gly32 bond and produces 31-amino acid endothelins, ET-1 (1-31), without any further degradation products. In this study, we investigated the effect of ET-1 (1-31) on the migration of cultured rat mesangial cells (RMCs) and on cells of the human monocytic cell line, THP-1. In addition, we examined the interaction between RMCs and THP-1 cells using conditioned media from ET-1 (1-31)-stimulated RMCs. ET-1 (1-31) caused an increase in RMC migration in a concentration-dependent manner, and the degree of increase was similar to those by ET-1 and angiotensin II (All). The ET-1 (1-31)-induced increase in RMC migration was inhibited by BQ123, an endothelin ETA receptor antagonist, but not by BQ788, an endothelin ETB receptor antagonist. ET-1 (1-31) alone did not cause significant migration of THP-1 cells. However, significant recruitment of THP-1 cells was observed with conditioned media taken from ET-1 (1-31)-stimulated RMCs. The conditioned media-induced migration of THP-1 cells was inhibited by BQ123, but not by BQ788. Western blotting analysis of the lysate of RMCs revealed that the expression of monocyte chemoattractant protein-1 (MCP-1) protein in RMCs was increased by treatment with ET-1 (1-31). The addition of neutralizing antibody for MCP-1 to the medium inhibited the migration of THP-1 cells induced by conditioned media from ET-1 (1-31)-stimulated RMCs. These findings suggest that ET-1 (1-31) play a role in glomerulonephritis (GN) via dual effects that directly cause the migration of mesangial cells (MCs) and may be responsible for the recruitment of mononuclear cells mediated through the activation of MCs. Since human chymase has been reported to be involved in glomerular disease, ET-1 (1-31) may be among the mediators.
Yuki Suzaki, Masanori Yoshizumi, Shoji Kagami, Akira Nishiyama, Yuichi Ozawa, Moe Kyaw, Yuki Izawa, Yasuhisa Kanematsu, Koichiro Tsuchiya and Toshiaki Tamaki : BMK1 is activated in glomeruli of diabetic rats and in mesangial cells by high glucose conditions, Kidney International, Vol.65, No.5, 1749-1760, 2004.
(要約)
High glucose causes renal cell injury through various signal transduction pathways, including mitogen-activated protein (MAP) kinases cascades. Big MAP kinase 1 (BMK1), also known as extracellular signal-regulated kinase 5 (ERK5), is a recently identified MAP kinase family member and was reported to be sensitive to osmotic and oxidative stress. However, the role of BMK1 in diabetic nephropathy has not been elucidated yet. We investigated whether BMK1 is activated in the glomeruli of Otsuka Long Evans Tokushima Fatty (OLETF) rats, a model of type 2 diabetes mellitus in comparison with the control Long Evans Tokushima Otsuka (LETO) rats. We also examined the effect of high glucose on BMK1 activity in cultured rat mesangial cells. BMK1 and ERK1/2 but not p38 were activated in the glomeruli of OLETF rats, which showed diabetic nephropathy at 52 weeks of age. High glucose, in addition to a high concentration of raffinose, caused rapid and significant activation of BMK1 in rat mesangial cells. MAP kinase/ERK kinase (MEK) inhibitors, U0126 and PD98059, both inhibited BMK1 activation by high glucose in a concentration-dependent manner. Protein kinase C (PKC) inhibition by GF109203X and PKC down-regulation with long-time phorbol myristate acetate (PMA) treatment both inhibited BMK1 and Src kinase activation. Src kinase inhibitors, herbimycin A and PP2, also inhibited high glucose-induced BMK1 activation. PKC inhibitors, Src inhibitors and MEK inhibitors, all inhibited cell proliferation by high glucose. Finally, transfection of dominant-negative MEK5, which is an upstream regulator of BMK1, abolished the BMK1-mediated rat mesangial cell proliferation stimulated by high glucose. In the present study, we demonstrated that high glucose activates BMK1 both in vivo and in vitro. It was suggested that high glucose induces PKC- and c-Src-dependent BMK1 activation. It could not be denied that BMK1 activation is induced through an osmotic stress-sensitive mechanism. BMK1-mediated mesangial cell growth may be involved in the pathogenesis of diabetic nephropathy.
Moe Kyaw, Masanori Yoshizumi, Koichiro Tsuchiya, Shoji Kagami, Yuki Izawa, Yoshiko Fujita, Nermin Ali, Yasuhisa Kanematsu, Kazunori Toida, Kazunori Ishimura and Toshiaki Tamaki : Src and Cas are essentially but differentially involved in angiotensin II-stimulated migration of vascular smooth muscle cell via extracellur signal-regulated kinase 1/2 and c-Jun NH2-terminal kinase activation, Molecular Pharmacology, Vol.65, No.4, 832-841, 2004.
(要約)
Angiotensin II (Ang II) plays an important role in several cardiovascular diseases associated with vascular smooth muscle cell (VSMC) growth and migration. Src activity is known to be required for the migration of a number of cell types. p130Cas was reported to be essential for cell migration and actin filament reorganization. Mitogen-activated protein (MAP) kinases were also reported to be critical regulatory factors for growth and migration of VSMC. However, precise intracellular mechanisms involving c-Src, p130Cas, and MAP kinases in Ang II-stimulated migration of VSMC have not been well elucidated. Here we demonstrated that Ang II rapidly and significantly stimulated tyrosine phosphorylation of Src and Cas and their association in rat aortic smooth muscle cells (RASMC). Ang II-stimulated tyrosine phosphorylation of Src and Cas and activation of ERK1/2 and JNK, but not p38, were potently inhibited by Src family tyrosine kinase inhibitors, herbimycin A (HA) and PP2. Ang II-stimulated Src and Cas association, tyrosine phosphorylation of Cas, and activation of ERK1/2 and JNK were suppressed in kinase-inactive Src (KI Src)-overexpressed RASMC. Ang II-stimulated JNK activation but not ERK1/2 activation was blocked in substrate domain-deleted Cas (DeltaSD Cas)-overexpressed RASMC. In addition, HA, PP2, ERK1/2 inhibitor, 2'-amino-3'-methoxyflavone (PD98059) and JNK inhibitor, and anthra[1,9-cd]pyrazol-6(2H)-one (SP600125) significantly inhibited Ang II-stimulated migration of RASMC. Ang II-induced colocalization of Src and Cas and migration were inhibited in both KI Src- and DeltaSD Cas-overexpressed RASMC. These findings suggest that Src and Cas are essentially but differentially involved in Ang II-stimulated migration of VSMC through the activation of ERK1/2 and JNK.
(キーワード)
Angiotensin II / Animals / Cell Adhesion / Cell Movement / Cells, Cultured / Cellular Apoptosis Susceptibility Protein / Enzyme Activation / Genes, src / JNK Mitogen-Activated Protein Kinases / Male / Mitogen-Activated Protein Kinase 3 / Mitogen-Activated Protein Kinases / Muscle, Smooth, Vascular / リン酸化 (phosphorylation) / Rats / Rats, Sprague-Dawley / Tyrosine / Vinculin / src-Family Kinases
Nermin Ali, Masanori Yoshizumi, Koichiro Tsuchiya, Moe Kyaw, Yoshiko Fujita, Yuki Izawa, Shinji Abe, Yasuhisa Kanematsu, Shoji Kagami and Toshiaki Tamaki : Ebsalen inhibits p38MAP kinase-mediated endothelial cell death by hydrogen peroxide., European Journal of Pharmacology, Vol.485, No.1-3, 127-135, 2004.
(要約)
Ebselen (2-phenyl-1, 2-benzisoselenazol-3[2H]-one) is a seleno-organic compound exhibiting both glutathione peroxidase and antioxidant activity. Although it has been reported that ebselen is effective against hydrogen peroxide (H(2)O(2))-induced cell death in several cell types, its effect on endothelial cell damage has not yet been elucidated. In the present study, we examined the effect of ebselen on H(2)O(2)-induced human umbilical vein endothelial cells (HUVECs) death, and its intracellular mechanism. Our findings showed that pretreatment of HUVECs with ebselen resulted in a significant recovery from H(2)O(2)-induced cell death in a concentration-dependent manner. In addition to the inhibition of lactate dehydrogenase (LDH) leakage, ebselen inhibited H(2)O(2)-induced cytochrome c release and caspase-3 activation and the resultant apoptosis in HUVECs. Moreover, it was observed that H(2)O(2) significantly stimulated activation of mitogen-activated protein (MAP) kinases, i.e., p38 MAP kinase, c-Jun N-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK1/2). Ebselen inhibited H(2)O(2)-induced p38 MAP kinase, but not JNK or ERK1/2 activation. Furthermore, SB203580 (4-[4-fluorophenyl]-2-[4-methylsulfinylphenyl]-5-[4-pyridyl]-1H-imidazole), a specific p38 MAP kinase inhibitor, inhibited H(2)O(2)-induced p38 MAP kinase phosphorylation, cytochrome c release, caspase-3 activation, as well as cell death in HUVECs. These findings suggest that ebselen attenuates H(2)O(2)-induced endothelial cell death through the inhibition of signaling pathways mediated by p38 MAP kinase, caspase-3, and cytochrome c release. Thus, inhibition of p38 MAP kinase by ebselen may imply its usefulness for prevention and/or treatment of endothelial cell dysfunction, which was suggested to be the first step in the development of atherosclerosis.
Izumi Yamaguchi, Yasuhisa Kanematsu, Kenji Shimada, Nobuaki Yamamoto, Masaaki Korai, Kazuhisa Miyake, Takeshi Miyamoto, Shu Sogabe, Eiji Shikata, Manabu Ishihara, Yuki Yamamoto, Kazutaka KURODA and Yasushi Takagi : Evaluation of Serial Intra-Arterial Indocyanine Green Videoangiography in the Surgical Treatment of Cranial and Craniocervical Junction Arteriovenous Fistulae: A Case Series, Operative Neurosurgery, Vol.25, No.3, 292-300, 2023.
(要約)
Intravenous indocyanine green (IV-ICG) videoangiography is commonly performed to detect blood flow in the microscopic view. However, intra-arterial ICG (IA-ICG) videoangiography provides high-contrast imaging, repeatability within a short period of time, and clear-cut separation of the arterial and venous phases compared with IV-ICG. These features are useful for detecting retrograde venous drainage (RVD) and shunt occlusion in arteriovenous fistulae (AVF) surgery. This study aimed to investigate whether IA-ICG videoangiography can be repeatable within a short period of time and be useful for detecting RVD and shunt occlusion in cranial- and craniocervical junction (CCJ)-AVF surgery. Between January 2012 and December 2022, 50 patients were treated with endovascular or surgical intervention for cranial- and CCJ-AVF at Tokushima University Hospital. Of these, 5 patients (6 lesions) underwent open surgery with IA-ICG videoangiography in a hybrid operating room. We analyzed the data of these 5 patients (6 lesions). There were 4/patient (median, range 2-12) and 3.5/lesion (median, range 2-10) intraoperative IA-ICG runs. IA-ICG videoangiography detected RVD in all patients. Clearance of IA-ICG-induced fluorescence was achieved within 30 seconds in all patients at each region of interest. After the disconnection of the fistulae, IA-ICG videoangiography and intraoperative digital subtraction angiography (DSA) confirmed the disappearance of RVD in all patients. There were no complications associated with IA-ICG videoangiography. This study showed that IA-ICG videoangiography is repeatable within a short period of time before and after obliteration and can be useful for detecting RVD and shunt occlusion in cranial- and CCJ-AVF surgery. IA-ICG videoangiography also allows intraoperative DSA studies in a hybrid operating room. Considering the recent advancements in hybrid operating rooms, combining IA-ICG videoangiography with intraoperative DSA is a useful strategy for cranial- and CCJ-AVF surgery.
One of the major lipid components of oxidized low density lipoprotein, lysophosphatidylcholine(LPC)is involved in numerous biological processes as a bioactive lipid molecule and has beenshown to be involved in the progression of atherosclerosis. As counter-ligands, G2A and GPR4wereidentified with high binding affinity for LPC that are belonging to orphan G-protein-coupledreceptors(GPCRs)at plasma membranes. Although several GPCR ligands transactivate receptortyrosine kinases (RTKs), such as epidermal growth factor receptor, transactivation of RTK byLPC has not yet been reported. Here we observed for the first time that LPC treatment inducestyrosyl phosphorylation of vascular endothelial growth factor(VEGF)receptor2(fetal liverkinase-1/kinase-insert domain-containing receptor, Flk-1/KDR)in human umbilical vein endothelialcells(HUVEC). VEGF receptor tyrosine kinase inhibitors, SU1498and VTKi inhibited Flk-1/KDRtransactivation by LPC. Furthermore, we examined the effect of the Src family kinases inhibitors,Herbimycin A and PP2 on LPC-induced Flk-1/KDR transactivation. Herbimycin A and PP2inhibited Flk-1/KDR transactivation in HUVEC, suggesting that c-Src is involved in LPC-inducedFlk-1/KDR transactivation. Kinase-inactive(KI)Src transfection also inhibited LPC-induced Flk-1/KDR transactivation. In addition, LPC activated extracellular signal-regulated kinase1/2and Akt,which are downstream effectors of Flk-1/KDR, and these were inhibited by SU1498，VTKi,Herbimycin A, PP2and KI Src transfection in HUVEC. LPC-mediated HUVEC proliferation wasshown to be secondary to transactivation because it was suppressed by SU1498，VTKi, HerbimycinA, PP2and KI Src transfection. It is concluded that c-Src-mediated Flk-1/KDR transactivation byLPC may have important implications for the progression of atherosclerosis.
Yuki Kanazawa, Tosiaki Miyati, Masafumi Harada, Mitsuharu Miyoshi, Yuki Matsumoto, Hiroaki Hayashi, Yasuhisa Kanematsu and Yasushi Takagi : Evaluation of Biological Metabolic Activity within an Atherosclerotic Plaque using Chemical Exchange Saturation Transfer Imaging, The 32st Annual Meeting of ISMRM, Toronto, Jun. 2023.
2.
Mayuka Seguchi, Yuki Kanazawa, Tosiaki Miyati, Masafumi Harada, Mitsuharu Miyoshi, Yuki Matsumoto, Hiroaki Hayashi, Yasuhisa Kanematsu and Yasushi Takagi : Diffusion weighted-viscosity imaging for atherosclerotic plaques, The 32st Annual Meeting of ISMRM, Toronto, Jun. 2023.
3.
Yuki Matsumoto, Yuki Kanazawa, Yuki Kinjo, Masafumi Harada, Toshiaki Miyati, Hiroaki Hayashi, Mitsuharu Miyoshi, Naoki Maeda, Yasuhisa Kanematsu, Yasushi Takagi and Akihiro Haga : Evaluation of Blood Flow and Plaque Vulnerability in Carotid Artery Stenosis Focusing on Morphological and Component Characteristics, ISMRM 30th Annual Meeting, London, May 2022.
4.
Naoki Maeda, Yuki Kanazawa, Yuki Kinjo, Yuki Matsumoto, Masafumi Harada, Tosiaki Miyati, Hiroaki Hayashi, Mitsuharu Miyoshi, Yasuhisa Kanematsu, Yasushi Takagi and Akihiro Haga : Is it possible to evaluate morphological carotid artery stenosis information using NASCET criteria?, RSNA2021 (Radiological Society of North America), Chicago, Nov. 2021.
5.
Harumi Kadota, Shoma Fujisawa, Masaki Oono, Ryoma Morigaki, Nobuaki Yamamoto, Yasuhisa Kanematsu, Manabu Ishihara and Masami Shishibori : Development of a 3D visualization system for the cerebral aneurysm coil embolization, Proceedings Volume 11794, Fifteenth International Conference on Quality Control by Artificial Vision; 117940C (2021), Tokushima, Jul. 2021.
Yoshiteru Tada, Toshitaka Fujihara, Kenji Shimada, Nobuaki Yamamoto, Hiroki Yamazaki, Yuishin Izumi, Masafumi Harada, Yasuhisa Kanematsu and Yasushi Takagi : Peri-ictal normal arterial spin labeling imaging in patients with seizures, 13 回アジア・オセアニアてんかん学会(13th AOEC), Jun. 2021.
7.
Yuki Kanazawa, Masafumi Harada, Tosiaki Miyati, Takashi Abe, Mitsuharu Miyoshi, Yuki Matsumoto, Hiroaki Hayashi, Yasuhisa Kanematsu and Yasushi Takagi : Chemical Exchange Saturation Transfer Imaging for Atherosclerotic Plaques, ISMRM Virtual Conference, Aug. 2020.
8.
Tadashi Yamaguchi, Keiko T Kitazato, Eiji Shikata, Idumi Yamaguchi, Takeshi Miyamoto, Masaaki Korai, Kenji Shimada, Yoshiteru Tada, Yasuhisa Kanematsu and Yasushi Takagi : Pro-inflammatory response promoted by Porphyromonas gingivalis lipopolysaccharide enhances the rupture of experimental intracranial aneurysms., Brain and Brain PET2019, Yokohama, Jul. 2019.
9.
Yuki Yamamoto, Nobuaki Yamamoto, K Kuroda, Yasuhisa Kanematsu, Masaaki Korai, Kenji Shimada, Yuishin Izumi and Yasushi Takagi : High White Blood Cell Count is a Risk Factor for Contrast-Induced Nephropathy following Mechanical Thrombectomy, The 5th European Stroke Organization Conference, ESOC 2019, Milan, May 2019.
10.
Nobuaki Yamamoto, Yuki Yamamoto, Masaaki Korai, Kenji Shimada, Yasuhisa Kanematsu, Yuishin Izumi, Yasushi Takagi and Ryuji Kaji : Hyperintense Signals on Arterial Spin-Labeled Imaging as a predictor for favorable outcome after Late Time Window Thrombectomy, The 5th European Stroke Organization Conference, ESOC 2019, Milan, May 2019.
11.
Eiji Shikata, Tetsuya Tamura, Kiyohito Shinnno, N Shinohara, Y Okayama, Yasuhisa Kanematsu and Yasushi Takagi : Separate management of water-electrolyte balance using maintenance fluid and salt leads to a favorable prognosis after aneurysmal subarachnoid hemorrhage, 11th World Stroke Congress 2018, Oct. 2018.
12.
Kyoko Nishi, Yasushi Takagi, Yasuhisa Kanematsu, Ryuji Kaji, Y Hamada, T Takagi, S Katoh and Shinji Nagahiro : Development and future prospects of Tokushima University Hospital stroke care unit (SCU), 11th World Stroke Congress 2018, Montreal, Oct. 2018.
13.
山口 泉, 四方 英二, 高麗 雅章, 兼松 康久, 里見 淳一郎, 北里 慶子, 永廣 信治, 髙木 康志 : Retrospective study of patients with in-hospital stroke, 11th World Stroke Congress 2018, モントリオール, 2018年10月.
14.
Tadashi Yamaguchi, Takeshi Miyamoto, Masaaki Korai, Kenji Shimada, Yoshiteru Tada, Yasuhisa Kanematsu, Junichiro Satomi, Shinji Nagahiro and Yasushi Takagi : Estrogen deficiency activates inflammasome in a rat model of intracranial aneurysms, 11th World Stroke Congress 2018, Montreal, Oct. 2018.
15.
Masaaki Korai, Yasuhisa Kanematsu, Idumi Yamaguchi, Nobuaki Yamamoto, Yuki Yamamoto, Junichiro Satomi and Yasushi Takagi : Treatment strategy and outcom of ruptured vertebral artry dissecting aneurysms, World Live Neurovascular Conference 2018, 神戸市, Apr. 2018.
16.
Yuki Yamamoto, Nobuaki Yamamoto, Idumi Yamaguchi, Masaaki Korai, Yasuhisa Kanematsu, Junichiro Satomi, Shinji Nagahiro and Ryuji Kaji : Crab claw sign predicts successful recanalization in acute mechanical thrombectomy, 14TH CONGRESS OF THE WORLD FEDERATION OF INTERVENTIONAL AND THERAPEUTIC NEURORADIOLOGY, Budapest, Oct. 2017.
17.
Masaaki Korai, Yasuhisa Kanematsu, Yoshiteru Tada, Idumi Yamaguchi, Nobuaki Yamamoto, Yuki Yamamoto and Junichiro Satomi : Treatment strategy and outcome of ruptured vertebral artery dissecting aneurysms, 14TH CONGRESS OF THE WORLD FEDERATION OF INTERVENTIONAL AND THERAPEUTIC NEURORADIOLOGY, Budapest, Oct. 2017.
18.
Junichiro Satomi, Yasuhisa Kanematsu, Masaaki Korai, Yuki Yamamoto, Nobuaki Yamamoto, Yoshifumi Mizobuchi, Hideo Mure, Yoshiteru Tada, Kohhei Nakajima, Toshiyuki Okazaki and Toshitaka Fujihara : Acute stroke management using image sharing on smart phones and tablet devices, 14TH CONGRESS OF THE WORLD FEDERATION OF INTERVENTIONAL AND THERAPEUTIC NEURORADIOLOGY, Budapest, Oct. 2017.
19.
Takeshi Miyamoto, Yoshiteru Tada, Kenji Shimada, Kenji Yagi, Masaaki Korai, Hidetsugu Maekawa, Tadashi Yamaguchi, Syotaro Soshioka, Tomoya Kinouchi, Yasuhisa Kanematsu, Junichiro Satomi and Shinji Nagahiro : Pro-inflammatory Response Elicited by Porphyromonas Gingivalis Lipopolysaccharide Exacerbates the Rupture of Experimental Cerebral Aneurysms, International Stroke Conference 2017, Houston, Feb. 2017.
20.
Takeshi Miyamoto, Keiko Kitazato, Hidetsugu Maekawa, Tadashi Yamaguchi, Kenji Shimada, Kenji Yagi, Yoshiteru Tada, Yoshitaka Kurashiki, syotaro Yoshioka, Yasuhisa Kanematsu, Junichiro Satomi and Shinji Nagahiro : Porphyromonas gingivalis lipopolysaccharide enhances the rupture of intracranial aneurysms in rats, 25th European Stroke Conference, Apr. 2016.
21.
Syotaro Yoshioka, Yoshiteru Tada, Junichiro Satomi, Kenji Yagi, Koji Naruishi, Kazuyuki Kuwayama, Keiko Kitazato, Takeshi Miyamoto, Yasuhisa Kanematsu, Masafumi Harada, Toshihiko Nagata and Shinji Nagahiro : Impact of Periodontal Disease and Bacteria on Intracranial Aneurysms, International Stroke Conference 2016, Los Angeles, Feb. 2016.
22.
Junichiro Satomi, Yoshiteru Tada, Yasuhisa Kanematsu, Kazuyuki Kuwayama, Kenji Yagi, Tomoya Kinouchi, Kohhei Nakajima, Nobuhisa Matsushita, Takeshi Miyamoto, Tadashi Yamaguchi, Masaaki Korai, Hideo Mure, Keiko Kitazato and Shinji Nagahiro : A Pilot Study of the Mineralocorticoid Receptor Blocker Eplerenone in Hypertensive Patients with Unruptured Cerebral Aneurysms, International Stroke Conference 2016, Los Angeles, Feb. 2016.
23.
Masaaki Korai, David K Kung, K.T Kitazato, Nobuhisa Matsushita, Yoshiteru Tada, Kenji Yagi, Kenji Shimada, Yasuhisa Kanematsu, Junichiro Satomi and Shinji Nagahiro : Role of hyperhomocysteinemia in the development of intracranial aneurysms, Congress Of Neurological Surgeons 2013 Annual Meeting, San Francisco, Oct. 2013.
24.
T Fujihara, Junichiro Satomi, Yasuhisa Kanematsu, Yoshiteru Tada, Kenji Yagi, Yoshifumi Mizobuchi, Teruyoshi Kageji and Shinji Nagahiro : Delayed intra-arterial urokinase thrombolysis based on MRI criteria has similar outcome compared to intravenous t-PA within 3 hours, Congress Of Neurological Surgeons 2013 Annual Meeting, San Francisco, Oct. 2013.
25.
Masaaki Korai, DK Kung, KT Kitazato, Nobuhisa Matsushita, Yoshiteru Tada, Kenji Yagi, Yasuhisa Kanematsu, Junichiro Satomi and Shinji Nagahiro : Imbalance between activation of matrix metalloprotease and its inhibition may facilitate the growth of cerebral aneurysm in female rats, International Stroke Conference 2013, Honolulu, Feb. 2013.
26.
Yasuhisa Kanematsu, Masaaki Korai, N Yamamoto, Junichiro Satomi and Shinji Nagahiro : Vascular reconstruction for internal carotid artery stenosis with contralateral carotid occlusion or severe stenosis - single-center experience -, 10th Meeting of Asian Australasian Federation of Interventional and Therapeutic Neuroradiology, Nagoya, Jun. 2012.
27.
Masaaki Korai, Junichiro Satomi, N Yamamoto, Yasuhisa Kanematsu and Shinji Nagahiro : The significance of endovascular therapy in vertebral artery dissecting aneurysm, 10th Meeting of Asian Australasian Federation of International and Therapeutic Neuroradiology, Nagoya, Jun. 2012.
28.
Yasuhisa Kanematsu, Masaaki Korai, Nobuaki Yamamoto, Junichiro Satomi and Shinji Nagahiro : Vascular Reconstruction for Internal Carotid Artery Stenosis with Contralateral Carotid Occlusion or severe stenosis - Single-Center Experience -, 10th Meeting of Asian Australasian Federation of Interventional and Therapeutic Neuroradiology, Nagoya, Jun. 2012.
29.
Junichiro Satomi, Yasuhisa Kanematsu, Kyoko Nishi and Shinji Nagahiro : Carotid artery stenting for symptomatic carotid stenosis in acute phase: comparison with carotid endarterectomy, 10th Meeting of Asian Australasian Federation of International and Therapeutic Neuroradiology, Nagoya, Jun. 2012.
30.
Nobuhisa Matsushita, Keiko T. Kitazato, Kenji Shimada, Tomoya Kinouchi, Manabu Sumiyoshi, Yasuhisa Kanematsu, Junichiro Satomi and Shinji Nagahiro : Impact of high salt intake on the formation and growth of cerebral aneurysm, The 5th International Aldosterone Forum in Japan, Tokyo, May 2012.
31.
Masaaki Korai, Keiko T. Kitazato, Tomoya Kinouchi, Kenji Shimada, Nobuhisa Matsushita, Manabu Sumiyoshi, Yasuhisa Kanematsu, Junichiro Satomi, Teruyoshi Kageji and Shinji Nagahiro : Activation of Nuclear Receptors on Neuroprotection after Experimental Cerebral Ischemia in Female Rats, American Association of Neurologial Surgeons Annual Scientific Meeting, Miami, Apr. 2012.
32.
Nobuhisa Matsushita, Keiko T. Kitazato, Kenji Shimada, Tomoya Kinouchi, Yasuhisa Kanematsu, Junichiro Satomi and Shinji Nagahiro : Influence of sodium retention on the formation of cerebral aneurysm, American Association of Neurologial Surgeons Annual Scientific Meeting, Miami, Apr. 2012.
33.
Yasuhisa Kanematsu, Junichiro Satomi, Yoshifumi Mizobuchi, Teruyoshi Kageji and Shinji Nagahiro : Comparative Analysis of the Peri-procedural Outcomes of Carotid Stenting and Carotid Endarterectomy in Elderly Patients, American Association of Neurologial Surgeons Annual Scientific Meeting, Miami, Apr. 2012.
34.
Keiko T. Kitazato, Yoshiteru Tada, Tetsuya Tamura, Kenji Yagi, Kenji Shimada, Nobuhisa Matsushita, Tomoya Kinouchi, Yasuhisa Kanematsu, Junichiro Satomi, Teruyoshi Kageji and Shinji Nagahiro : Vascular Mineralcorticoid Receptor Antagonism Combined with A Decrease in Salt-intake By Eplerenone Inhibits Cerebral Aneurysm without Affecting Blood Pressure, International Stroke Conference 2011, LosAngels, Feb. 2012.
35.
KT Kitazato, Yoshiteru Tada, Tetsuya Tamura, Kenji Yagi, Kenji Shimada, Nobuhisa Matsushita, Tomoya Kinouchi, Yasuhisa Kanematsu, Junichiro Satomi, Teruyoshi Kageji and Shinji Nagahiro : Vascular mineralcorticoid receptor antagonism combined with a decrease in salt-intake by eplerenone inhibits cerebral aneurysm without affecting blood pressure, International Stroke Conference 2011, Los Angeles, Oct. 2011.
36.
KT Kitazato, Tomoya Kinouchi, Kenji Shimada, Yoshiteru Tada, Nobuhisa Matsushita, Manabu Sumiyoshi, Yasuhisa Kanematsu, Junichiro Satomi, Teruyoshi Kageji and Shinji Nagahiro : Role of Nuclear receptors on neuroprotection after experimental cerebral ischemia in female rats, 115th International Symposium on Cerebral Blood Flow Metabolism and Function, Barcelona, May 2011.
37.
Manabu Sumiyoshi, Tomoya Kinouchi, T Tsutsumi, Keiko T. Kitazato, Kenji Shimada, Nobuhisa Matsushita, Yasuhisa Kanematsu, Junichiro Satomi and Shinji Nagahiro : High salt intake under hypoestrogenecity deteriorates ischemic brain damage without affecting blood pressure, 115th International Symposium on Cerebral Blood Flow,Metabolism,and Function, Barcelona, May 2011.
38.
Koichiro Tsuchiya, Yuya Horinouchi, Yasuhisa Kanematsu, Shinji Abe, Hideki Ohnishi, Soichiro Tajima, Keisuke Ishizawa, Toshiaki Tamaki and Yoshiharu Takiguchi : Production of nitrosonifedipine radical from nifedipine and its antioxidative activity in cultured cells, 13th annual meeting of society of free radical and biology of medicine, Denver, Nov. 2006.
39.
Hideki Ohnishi, Koichiro Tsuchiya, Yasuhisa Kanematsu, Shinji Abe, Soichiro Tajima and Toshiaki Tamaki : Effects of quercetin on NO production from nitrite at physiological conditions, 20th Scientific Meeting of the International Soiciety of Hypertension, Fukuoka, Japan, Oct. 2006.
40.
Koichiro Tsuchiya, Yasuhisa Kanematsu, Keisuke Ishizawa, Shinji Abe, Hideki Ohnishi, Soichiro Tajima, Kazuyoshi Kawazoe, Yoshiharu Takiguchi and Toshiaki Tamaki : Dietary nitrite is an alternative source of NO in vivo, International Society for Radical Research 13th Biennial Congress, Davos, Switzerland, Aug. 2006.
41.
Toshiaki Tamaki, Yasuhisa Kanematsu, Yuki Izawa, Hideki Ohnishi, Yuki Motobayashi, Shoji Kagami and Koichiro Tsuchiya : Chronic oral administration of nitrite restores circulating NO level and improves renal injury in L-NAME treated rats, 38th ASN annual meeting, Philadelphia, Nov. 2005.
42.
Soichiro Tajima, Koichiro Tsuchiya, Hideki Ohnishi, Yasuhisa Kanematsu, Masanori Yoshizumi, Toshiaki Tamaki, Mason P. Ronald and Yoshiharu Takiguchi : Immunochemical Dection of Thioredoxin-Derived Radicals Formed by Reaction with Hydrogen Peroxide, EPR 2005, Columbus, OH, Sep. 2005.
43.
Toshiaki Tamaki, Masumi Okamoto, Yasuhisa Kanematsu, Yuki Izawa, Shoji Kagami, Shuji Kondo, Masanori Yoshizumi and Koichiro Tsuchiya : Dietary dose of nitrite attenuates L-NAME-induced renal injury in rats, 3rd World Congress of Nephrology, Singapore, Jun. 2005.
44.
Masanori Yoshizumi, Keisuke Ishizawa, Yuki Izawa, Chieko Miki, Yoshiko Fujita, Yasuhisa Kanematsu, Koichiro Tsuchiya and Toshiaki Tamaki : Aldosterone stimulates vascular smooth muscle cell proliferation through big mitogen-activated protein kinase1 activation, 16th scientific meeting of the interamerican society of hypertension, Cancun, Mexico, Apr. 2005.
45.
Toshiaki Tamaki, Masumi Okamoto, Yasuhisa Kanematsu, Yuki Izawa, Shoji Kagami, Shuji Kondo, Maki Shimizu, Masanori Yoshizumi and Koichiro Tsuchiya : Nitrite-derived nitric oxide formation following ischemia-reperfusion injury in rat kidney, 37th ASN annual meeting, St. Louis, MO, Oct. 2004.