Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Tetsuro Ago Last modified date:2021.10.27

Associate Professor / Department of Medicine and Clinical Science, Graduate School of Medical Sciences / Department of Clinical Medicine / Faculty of Medical Sciences


Papers
1. Kiyohara T, Matsuo R, Hata J, Nakamura K, Wakisaka Y, Kamouchi M, Kitazono T, Ago T, beta-Cell Function and Clinical Outcome in Nondiabetic Patients With Acute Ischemic Stroke, STROKE, 10.1161/STROKEAHA.120.031392, 52, 8, 2621-2628, 2021.08.
2. Fukuda K, Matsuo R, Kamouchi M, Kiyuna F, Sato N, Hata J, Ago T, Imaizumi T, Kai H, Kitazono T., Day-by-day blood pressure variability in the subacute stage of ischemic stroke and long-term recurrence, STROKE, 2021.10.
3. Irie F, Matsuo R, Nakamura K, Wakisaka Y, Ago T, Kamouchi M, Kitazono T, Sex differences in the risk of 30-day death after acute ischemic stroke, Neurol Clin Pract , 2021.10.
4. Wakisaka Y, Matsuo R, Nakamura K, Ago T, Kamouchi M, Kitazono T, Pre-stroke cholinesterase inhibitor treatment is beneficially associated with functional outcome in patients with acute ischemic stroke and pre-stroke dementia: the Fukuoka Stroke Registry. , Cerebrovasc Dis, 50, 4, 390-396, 2021.04.
5. Maeda M, Fukuda H, Matsuo R, Kiyuna F, Ago T, Kitazono T, Kamouchi M, Nationwide temporal trend analysis of reperfusion therapy utilization and mortality in acute ischemic stroke patients in Japan, MEDICINE, 10.1097/MD.0000000000024145, 100, 1, 2021.01.
6. Shibahara T, Ago T, et al., Pericyte-Mediated Tissue Repair through PDGFRbeta Promotes Peri-Infarct Astrogliosis, Oligodendrogenesis, and Functional Recovery after Acute Ischemic Stroke, eNeuro, 10.1523/ENEURO.0474-19.2020, 2020.03.
7. Okahara A, Koga J, Matoba T, Fujiwara M, Tokutome M, Ikeda G, Nakano K, Tachibana M, Ago T, Kitazono T, Tsutsui H, Egashira K, Simultaneous targeting of mitochondria and monocytes enhances neuroprotection against ischemia-reperfusion injury, SCIENTIFIC REPORTS, 10.1038/s41598-020-71326-x, 10, 1, 2020.09.
8. Kana Ueki, Kuniyuki Nakamura, Yoshinobu Wakisaka, Shinichi Wada, Yoji Yoshikawa, Shinya Matsumoto, Taeko Hotta, Dongchong Kang, Takanari Kitazono, Tetsuro Ago, An Embolic Stroke in a Patient With PROC p.Lys193del, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2019.104597, 29, 5, 2020.05, We report a 58-year-old woman who suddenly developed brain infarction with weakness of the left lower extremity and left perioral dysesthesia during postoperative tamoxifen therapy for breast cancer and prednisolone therapy for rheumatoid arthritis. Diffusion-weighted images detected multiple areas of hyperintensity in the posterior circulation system of the brain. Despite extensive examinations, we could not identify any embolic sources except hypoplasia of the right vertebral artery. We found decreased activity of protein C against its antigen level (activity: 59% versus antigen: 122%) with enhanced activity of coagulation factor VIII (178%) and von Willebrand factor (285%). DNA sequencing identified trinucleotide deletion of the PROC gene leading to 1 amino acid deletion at Lys-193 (p.Lys193del). We speculate that the PROC gene polymorphism may have participated in tamoxifen- and prednisolone- associated hypercoagulable state, leading to development of an embolic stroke in this patient..
9. Sato N, Matsuo R, Kiyuna F, Nakamura K, Hata J, Wakisaka Y, Ago T, Kamouchi M, Kitazono T, Association between anticoagulation therapy and risk of stroke recurrence in ESUS patients without potential embolic source identified, Cerebrovasc Dis, 49, 6, 601-608, 2020.06.
10. Kana Ueki, Yoshinobu Wakisaka, Kuniyuki Nakamura, Yuji Shono, Shinichi Wada, Yoji Yoshikawa, Yuta Matsukuma, Takeshi Uchiumi, Dongchong Kang, Takanari Kitazono, Tetsuro Ago, Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes due to m.3243A > G mutation in a 76-year-old woman, Journal of the Neurological Sciences, 10.1016/j.jns.2020.116791, 412, 2020.05.
11. Yukihiko Aoyagi, Tadashi Furuyama, Kentaro Inoue, Daisuke Matsuda, Yutaka Matsubara, Arihide Okahara, Tetsuro Ago, Yutaka Nakashima, Masaki Mori, Takuya Matsumoto, Attenuation of Angiotensin II–Induced Hypertension in BubR1 Low-Expression Mice Via Repression of Angiotensin II Receptor 1 Overexpression, Journal of the American Heart Association, 10.1161/JAHA.118.011911, 8, 23, 2019.12, Background: Angiotensin II (Ang II) can cause hypertension and tissue impairment via AGTR1 (Ang II receptor type 1), particularly in renal proximal tubule cells, and can cause DNA damage in renal cells via nicotinamide adenine dinucleotide phosphate oxidase. BubR1 (budding uninhibited by benzimidazole-related 1) is a multifaceted kinase that functions as a mitotic checkpoint. BubR1 expression can be induced by Ang II in smooth muscle cells in vitro, but the relationship between systemic BubR1 expression and the Ang II response is unclear. Methods and Results: Twenty 24-week-old male BubR1 low-expression mice (BubR1L/L mice) and age-matched BubR1+/+ mice were used in this study. We investigated how Ang II stimulation affects BubR1L/L mice. The elevated systolic blood pressure caused by Ang II stimulation in BubR1+/+ mice was significantly attenuated in BubR1L/L mice. Additionally, an attenuated level of Ang II–induced perivascular fibrosis was observed in the kidneys of BubR1L/L mice. Immunohistochemistry revealed that the overexpression of AGTR1 induced by Ang II stimulation was repressed in BubR1L/L mice. We evaluated AGTR1 and Nox-4 (nicotinamide adenine dinucleotide phosphate oxidase-4) levels to determine the role of BubR1 in the Ang II response. Results from in vitro assays of renal proximal tubule cells suggest that treatment with small interfering RNA targeting BubR1 suppressed Ang II-induced overexpression of AGTR1. Similarly, the upregulation in Nox4 and Jun N-terminal kinase induced by Ang II administration was repressed by treatment with small interfering RNA targeting BubR1. Conclusions: Ang II–induced hypertension is caused by AGTR1 overexpression in the kidneys via the upregulation of BubR1 and Nox4..
12. Kuniyuki Nakamura, Tomoko Ikeuchi, Kazuki Nara, Craig S. Rhodes, Peipei Zhang, Yuta Chiba, Saiko Kazuno, Yoshiki Miura, Tetsuro Ago, Eri Arikawa-Hirasawa, Yoh Suke Mukouyama, Yoshihiko Yamada, Perlecan regulates pericyte dynamics in the maintenance and repair of the blood-brain barrier, The Journal of cell biology, 10.1083/jcb.201807178, 218, 10, 3506-3525, 2019.10, Ischemic stroke causes blood-brain barrier (BBB) breakdown due to significant damage to the integrity of BBB components. Recent studies have highlighted the importance of pericytes in the repair process of BBB functions triggered by PDGFRβ up-regulation. Here, we show that perlecan, a major heparan sulfate proteoglycan of basement membranes, aids in BBB maintenance and repair through pericyte interactions. Using a transient middle cerebral artery occlusion model, we found larger infarct volumes and more BBB leakage in conditional perlecan (Hspg2)-deficient (Hspg2-/--TG) mice than in control mice. Control mice showed increased numbers of pericytes in the ischemic lesion, whereas Hspg2-/--TG mice did not. At the mechanistic level, pericytes attached to recombinant perlecan C-terminal domain V (perlecan DV, endorepellin). Perlecan DV enhanced the PDGF-BB-induced phosphorylation of PDGFRβ, SHP-2, and FAK partially through integrin α5β1 and promoted pericyte migration. Perlecan therefore appears to regulate pericyte recruitment through the cooperative functioning of PDGFRβ and integrin α5β1 to support BBB maintenance and repair following ischemic stroke..
13. Yoji Yoshikawa, Tetsuro Ago, Junya Kuroda, Yoshinobu Wakisaka, Masaki Tachibana, Motohiro Komori, Tomoya Shibahara, Hideyuki Nakashima, Kinichi Nakashima, Takanari Kitazono, Nox4 Promotes Neural Stem/Precursor Cell Proliferation and Neurogenesis in the Hippocampus and Restores Memory Function Following Trimethyltin-Induced Injury, Neuroscience, 10.1016/j.neuroscience.2018.11.046, 398, 193-205, 2019.02, Reactive oxygen species (ROS) modulate the growth of neural stem/precursor cells (NS/PCs) and participate in hippocampus-associated learning and memory. However, the origin of these regulatory ROS in NS/PCs is not fully understood. In the present study, we found that Nox4, a ROS-producing NADPH oxidase family protein, is expressed in primary cultured NS/PCs and in those of the adult mouse brain. Nox inhibitors VAS 2870 and GKT137831 or Nox4 deletion attenuated bFGF-induced proliferation of cultured NS/PCs, while lentivirus-mediated Nox4 overexpression increased the production of H 2 O 2 , the phosphorylation of Akt, and the proliferation of cultured NS/PCs. Nox4 did not significantly affect the potential of cultured NS/PCs to differentiate into neurons or astrocytes. The histological and functional development of the hippocampus appeared normal in Nox4 / mice. Although pathological and functional damages in the hippocampus induced by the neurotoxin trimethyltin were not significantly different between wild-type and Nox4 / mice, the post-injury reactive proliferation of NS/PCs and neurogenesis in the subgranular zone (SGZ) of the dentate gyrus were significantly impaired in Nox4 / animals. Restoration from the trimethyltin-induced impairment in recognition and spatial working memory was also significantly attenuated in Nox4 / mice. Collectively, our findings suggest that Nox4 participates in NS/PC proliferation and neurogenesis in the hippocampus following injury, thereby helping to restore memory function..
14. Motohiro Komori, Tetsuro Ago, Yoshinobu Wakisaka, Kuniyuki Nakamura, Masaki Tachibana, Yoji Yoshikawa, Tomoya Shibahara, Kei Yamanaka, Junya Kuroda, Takanari Kitazono, Early initiation of a factor Xa inhibitor can attenuate tissue repair and neurorestoration after middle cerebral artery occlusion, Brain Research, 10.1016/j.brainres.2019.05.020, 1718, 201-211, 2019.09, The timing of anti-coagulation therapy initiation after acute cardioembolic stroke remains controversial. We investigated the effects of post-stroke administration of a factor Xa inhibitor in mice, focusing on tissue repair and functional restoration outcomes. We initiated administration of rivaroxaban, a Xa inhibitor, immediately after permanent distal middle cerebral artery occlusion (pMCAO)in CB-17 mice harboring few leptomeningeal anastomoses at baseline. Rivaroxaban initiated immediately after pMCAO hindered the recovery of blood flow in ischemic areas by inhibiting leptomeningeal anastomosis development, and led to impaired restoration of neurologic functions with less extensive peri-infarct astrogliosis. Within infarct areas, angiogenesis and fibrotic responses were attenuated in rivaroxaban-fed mice. Furthermore, inflammatory responses, including the accumulation of neutrophils and monocytes/macrophages, local secretion of pro-inflammatory cytokines, and breakdown of the blood–brain barrier, were enhanced in infarct areas in mice treated immediately with rivaroxaban following pMCAO. The detrimental effects were not found when rivaroxaban was initiated after transient MCAO or on day 7 after pMCAO. Collectively, early post-stroke initiation of a factor Xa inhibitor may suppress leptomeningeal anastomosis development and blood flow recovery in ischemic areas, thereby resulting in attenuated tissue repair and functional restoration unless occluded large arteries are successfully recanalized..
15. Why are pericytes important for brain functions?.
16. Masahiro Shijo, Hideomi Hamasaki, Hiroyuki Honda, Satoshi O. Suzuki, Masaki Tachibana, Tetsuro Ago, Takanari Kitazono, Koji Iihara, Toru Iwaki, Upregulation of annexin A1 in reactive astrocytes and its subtle induction in microglia at the boundaries of human brain infarcts, Journal of neuropathology and experimental neurology, 10.1093/jnen/nlz079, 78, 10, 961-970, 2019.10, Annexin A1 (ANXA1) has multiple functions, including anti-inflammatory effects, and is thought to be neuroprotective in various pathophysiologies of the central nervous system. The importance of ANXA1 in microglia and endothelial cells in ischemic environments in the brain has been recognized, but its detailed behavior in astrocytes in the ischemic brain remains unknown. Using immunohistochemistry, we therefore assessed the altered distribution of ANXA1 in human brain infarcts using 14 autopsied samples and 18 surgical samples. Elevated expression of ANXA1 was observed in reactive astrocytes in peri-infarct regions. ANXA1 accumulated at the cell periphery and in swollen cytoplasmic processes of reactive astrocytes, as well as at the rim of vacuoles at the boundary of necrosis, and colocalized with aberrantly distributed aquaporin 4 and excitatory amino acid transporter 1. Foamy macrophages in the necrotic core also expressed abundant ANXA1, whereas resident microglia at the boundary of necrosis rarely showed intrinsic expression of ANXA1. This characteristic distribution of ANXA1 in human brain infarcts may represent the good adaptability of reactive astrocytes to ischemic damage..
17. S. Miura, R. Miyata, S. Matsumoto, Takahiro Higashi, Yoshinobu Wakisaka, Tetsuro Ago, Takanari Kitazono, Koji Iihara, Megumi Shimodozono, Quality Management Program of Stroke Rehabilitation Using Adherence to Guidelines
A Nationwide Initiative in Japan, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2019.06.028, 28, 9, 2434-2441, 2019.09, Background and Aim: In recent years, interest in the quality of medical care has rapidly increased worldwide. However, quality indicators that contribute to establishing standard treatment in stroke medicine, especially rehabilitation, are not well-developed in Japan. Japan has established Kaifukuki (convalescent) rehabilitation wards, and the development of quality indicators for stroke rehabilitation in the convalescent phase is an urgent issue. Methods: We first reviewed the literature regarding quality indicators for stroke rehabilitation. Next, we extracted candidate indicators from identified reports and guidelines and surveyed educational hospitals certified by the Japanese Association of Rehabilitation Medicine. On the basis of the survey results, we reevaluated the suitability of the proposed indicators in discussions with an expert panel. Results: The questionnaire survey highlighted several important items that revealed there is room for improvement in adherence. For stroke rehabilitation in the convalescent phase, we adopted 15 indicators that were feasible as indicators to be used for comparisons between facilities, based on scoring by and opinions of the expert panel. These indicators measured structure (2 indicators), process (5 indicators), and outcome (8 indicators). Conclusion: This is the first study to establish quality indicators to standardize stroke rehabilitation in Japan. We developed this set of 15 indicators using an evidence-based approach. However, many tasks remain for continuous quality improvement..
18. Yuka Kanazawa, Shuji Arakawa, Takafumi Shimogawa, Noriko Hagiwara, Sei Haga, Takato Morioka, Hiroaki Ooboshi, Tetsuro Ago, Takanari Kitazono, Arterial Spin Labeling Magnetic Resonance Imaging for Differentiating Acute Ischemic Stroke from Epileptic Disorders, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2019.02.020, 28, 6, 1684-1690, 2019.06, Background: Differential diagnosis between acute ischemic stroke (AIS) and epilepsy-related stroke mimics is sometimes difficult in the emergency department. We investigated whether a combination of diffusion-weighted imaging (DWI) and arterial spin labeling imaging (ASL) is useful in distinguishing AIS from epileptic disorders. Methods: The study included suspected AIS patients who underwent emergency MRI including both DWI and ASL, and who exhibited DWI high-intensity lesions corresponding to neurological symptoms. We investigated the relationship between the ASL results from within and/or around DWI lesions and the final clinical diagnosis. Results: Eighty-five cases were included (mean age, 71 ± 13 years; 47 men). The time from onset to the MRI examination was 493 ± 536 minutes. ASL showed hyperintensity in 13 patients, isointensity in 43, and hypointensity in 29. All ASL hyperintensities were observed in the cortex, with 4 patients (31%) presenting with AIS and 9 (69%) with an epileptic disorder. All of the AIS patients with ASL hyperintensity were diagnosed with cardioembolic stroke (4/4, 100%), with magnetic resonance angiography demonstrating recanalization of the occluded artery in all cases (4/4, 100%). In the 9 patients with an epileptic disorder, the area of ASL hyperintensity typically extended beyond the vascular territory (7/9, 78%) and involved the ipsilateral thalamus (7/9, 78%). All patients with ASL isointensity and hypointensity were diagnosed with AIS; none had epileptic disorders. Conclusions: Although cortical ASL hyperintensity can indicate cardioembolic stroke with recanalization, hyperintensity beyond the vascular territory may alternatively suggest an epileptic disorder in suspected AIS patients with DWI lesions..
19. Junya Kuroda, Ryu Matsuo, Yuko Yamaguchi, Noriko Sato, Masahiro Kamouchi, Jun Hata, Yoshinobu Wakisaka, Tetsuro Ago, Takanari Kitazono, Poor glycemic control and posterior circulation ischemic stroke, Neurology: Clinical Practice, 10.1212/CPJ.0000000000000608, 9, 2, 129-139, 2019.04, Background This study aimed at determining whether diabetes or glucose metabolism is associated with ischemic stroke in the posterior circulation. MethodsWe included 10,245 patients with acute ischemic stroke (mean age 72.7 ± 12.5 years, men 59.5%) who were enrolled in a multicenter hospital-based stroke registry in Fukuoka, Japan, between June 2007 and August 2016. Posterior circulation ischemic stroke (PCIS) was defined as brain infarction in the territory of the posterior cerebral artery and vertebro-basilar arteries. We investigated the associations between diabetes or glycemic parameters, including plasma glucose concentrations, hemoglobin A1c, and the homeostatic model assessment of insulin resistance (HOMA-IR), and PCIS using logistic regression analysis. To improve covariate imbalance, we further evaluated associations after propensity score matching using 1:1 nearest neighbor matching and inverse probability weighting.ResultsDiabetes was significantly associated with PCIS even after adjusting for multiple confounding factors (odds ratio - OR [95% confidence interval], 1.37 [1.25-1.50]). Similarly, fasting (1.07 [1.02-1.12]/SD), casual plasma glucose (1.16 [1.11-1.20]/SD) concentrations, and hemoglobin A1c (1.12 [1.08-1.17]/SD), but not HOMA-IR (1.02 [0.97-1.07]/SD), were associated with PCIS. These associations were maintained in patients with ischemic stroke because of thrombotic etiology and were unchanged even after the propensity score matching methods. In patients with diabetes, the ORs of PCIS further increased with an increase in hemoglobin A1c and the presence of microvascular complications.ConclusionsPoor glycemic control may be associated with an increased risk of thrombotic infarction that occurs preferentially in the posterior circulation of the brain..
20. Yuichiro Ohya, Masato Osaki, Shigeru Fujimoto, Juro Jinnouchi, Takayuki Matsuki, Satomi Mezuki, Masaya Kumamoto, Makoto Kanazawa, Naoki Tagawa, Tetsuro Ago, Takanari Kitazono, Shuji Arakawa, Usefulness of Transesophageal Echocardiography for Predicting Covert Paroxysmal Atrial Fibrillation in Patients with Embolic Stroke of Undetermined Source, Cerebrovascular diseases extra, 10.1159/000502713, 9, 3, 98-106, 2019.01, Background: Covert paroxysmal atrial fibrillation (CPAF) is a major cause of embolic stroke of undetermined source (ESUS). However, detecting PAF during hospitalization in these patients is difficult. Objectives: This study aimed to determine whether findings of transesophageal echocardiography (TEE) during hospitalization are associated with later detection of PAF in patients with ESUS. Method: We retrospectively studied 348 patients with ESUS who were admitted to our hospital within 1 week of onset. These patients met the criteria of ESUS, underwent TEE during hospitalization, and were followed up for at least 1 year. Results: We found PAF in 35 (10.0%) patients. In patients with PAF, spontaneous echo contrast (SEC) and low left atrial appendage flow (LAAF) by TEE and enlargement of the left atrial dimension (LAD) by transthoracic echocardiography were identified more frequently compared with those who did not have PAF. In multivariate analysis, SEC and an LAD ≥42 mm were independently associated with later detection of PAF (p < 0.05). An association of LAAF <46.9 cm/s and PAF was marginal (p = 0.09). The specificity of the combined finding of SEC and/or LAAF with that of LAD increased up to 90%, while that of LAD alone was 70%. Conclusions: The findings of TEE during hospitalization may be useful for identifying patients at increased risk of CPAF in patients with ESUS..
21. Shuhei Okazaki, Takaaki Morimoto, Yoichiro Kamatani, Teppei Kamimura, Hatasu Kobayashi, Kouji Harada, Tsutomu Tomita, Aya Higashiyama, Jun C. Takahashi, Jyoji Nakagawara, Masatoshi Koga, Kazunori Toyoda, Kazuo Washida, Satoshi Saito, Atsushi Takahashi, Makoto Hirata, Koichi Matsuda, Hideki Mochizuki, Michael Chong, Guillaume Paré, Martin O'Donnell, Tetsuro Ago, Jun Hata, Toshiharu Ninomiya, Martin Dichgans, Stéphanie Debette, Michiaki Kubo, Akio Koizumi, Masafumi Ihara, Moyamoya Disease Susceptibility Variant RNF213 p.R4810K Increases the Risk of Ischemic Stroke Attributable to Large-Artery Atherosclerosis, Circulation, 10.1161/CIRCULATIONAHA.118.038439, 139, 2, 295-298, 2019.01.
22. Kei Yamanaka, Takuya Okata, Yoshiki Sambongi, Ikumi Yamanaka, Kazuki Tanimoto, Tetsuro Ago, Takanari Kitazono, Jiro Kitayama, Subacute Methotrexate Encephalopathy Mimicking Ischemic Stroke With Dynamic Changes on Magnetic Resonance Imaging, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2018.06.007, 27, 11, e233-e235, 2018.11, We report a 35-year-old woman who suddenly developed left hemiparesis and dysarthria at 13 days after treatment with intrathecal and intravenous methotrexate for intravascular large B cell lymphoma with possible central nervous system infiltration. Seven hours after onset, she developed further right hemiparesis and aphasia. However, the majority of neurologic symptoms disappeared spontaneously and completely by 34 hours. We also recorded the dynamic progression and regression of abnormal signals in the bilateral corona radiata on diffusion-weighted imaging, in parallel with neurologic symptoms. The rapid reversal of MR abnormalities and neurologic symptoms allowed us to diagnose methotrexate encephalopathy, and exclude intravascular large B cell lymphoma recurrence and regular brain infarction. The case provides new data on the dynamic changes of abnormal signals on magnetic resonance imaging in methotrexate encephalopathy over a short recovery time..
23. Yuji Shono, Hiroshi Sugimori, Ryu Matsuo, Yoshihisa Fukushima, Yoshinobu Wakisaka, Junya Kuroda, Tetsuro Ago, Masahiro Kamouchi, Takanari Kitazono, Safety of antithrombotic therapy for patients with acute ischemic stroke harboring unruptured intracranial aneurysm, International Journal of Stroke, 10.1177/1747493018765263, 13, 7, 734-742, 2018.10, Background: The safety of antithrombotic therapy for patients with acute ischemic stroke harboring unruptured intracranial aneurysms remains unclear. Aims: This study was performed to determine whether treatment with antiplatelets, anticoagulants, or intravenous thrombolytic agents is safe for patients with acute ischemic stroke and unruptured intracranial aneurysms. Methods: Among 9149 patients with acute ischemic stroke enrolled in the Fukuoka Stroke Registry from June 2007 to December 2014, 8857 patients with data on cerebrovascular imaging and three-month outcomes were included in this study. The frequency of adverse events, including intracranial hemorrhage, symptomatic intracranial hemorrhage, and in-hospital mortality, was compared between patients with and without unruptured intracranial aneurysms. The risk of a poor functional outcome (modified Rankin scale score of ≥3) at three months after stroke onset was estimated after adjusting for confounding factors by logistic regression analysis. Results: Unruptured intracranial aneurysms were identified in 412 (4.7%) patients, and the mean diameter was 4.1 ± 3.2 mm. There was no significant difference in the frequency of any adverse events between patients with and without unruptured intracranial aneurysms among the overall patients or patients receiving antiplatelets, anticoagulants, or intravenous thrombolytic agents. The odds ratios of a poor functional outcome were not significantly higher in the presence of unruptured intracranial aneurysms, even in patients undergoing antiplatelet therapy, anticoagulation therapy, or intravenous thrombolysis. Conclusions: These findings suggest that unruptured intracranial aneurysms are not associated with increased risks of adverse events or poor functional outcomes even after antithrombotic therapy for acute ischemic stroke. However, accumulation of cases is required to verify these findings..
24. Shota Sakai, Masato Osaki, Masaoki Hidaka, Shunsuke Kimura, Yuichiro Ohya, Tetsuro Ago, Takanari Kitazono, Shuji Arakawa, Association between stroke-like episodes and neuronal hyperexcitability in MELAS with m.3243A>G
A case report, eNeurologicalSci, 10.1016/j.ensci.2018.08.003, 12, 39-41, 2018.09.
25. Fumi Kiyuna, Noriko Sato, Ryu Matsuo, Masahiro Kamouchi, Jun Hata, Yoshinobu Wakisaka, Junya Kuroda, Tetsuro Ago, Takanari Kitazono, Association of Embolic Sources With Cause-Specific Functional Outcomes Among Adults With Cryptogenic Stroke, JAMA network open, 10.1001/jamanetworkopen.2018.2953, 1, 5, e182953, 2018.09, Importance: It is unknown whether poststroke outcome varies between different potential causes in patients with cryptogenic stroke. Objective: To investigate whether functional outcome differs according to potential embolic sources after cryptogenic stroke. Design, Setting, and Participants: This multicenter, hospital-based, prospective stroke registry cohort study investigated potential embolic sources on admission and assessed 3-month outcome in patients with ischemic stroke hospitalized at 7 stroke centers in the Fukuoka Stroke Registry. This registry enlisted 9866 consecutive patients with acute ischemic stroke who were enrolled from June 11, 2007, to May 31, 2016, in Fukuoka, Japan. Patients with small vessel occlusion (n = 3130), extracranial and intracranial atherosclerosis causing at least 50% luminal stenosis in arteries supplying the area of ischemia (n = 2011), and other specific uncommon causes of stroke identified (n = 301) were excluded. Potential embolic sources were diagnosed in patients with embolic stroke of undetermined source (ESUS) based on the following criteria proposed by the Cryptogenic Stroke/ESUS International Working Group: minor-risk potential cardioembolic sources (MCS) (n = 209), covert paroxysmal atrial fibrillation (CPAF) (n = 43), cancer associated (CA) (n = 79), arteriogenic emboli (AE) (n = 522), paradoxical embolism (PE) (n = 190), and undetermined embolism (unidentified or ≥2 potential embolic sources) (UE) (n = 1120). Main Outcomes and Measures: The association between potential causes and functional outcome was evaluated in reference to cardioembolic stroke (CE) caused by major-risk cardioembolic sources after adjusting for age, sex, National Institutes of Health Stroke Scale score on admission, and reperfusion therapy using logistic regression analysis. Functional dependency (modified Rankin Scale score, 3-5) was evaluated at 3 months after onset. Results: The study enrolled 2261 patients with CE (mean [SD] age, 78.4 [10.7] years, 51.8% male) and 2163 patients with ESUS (mean [SD] age, 72.4 [12.6] years, 57.1% male). Compared with CE (median National Institutes of Health Stroke Scale score, 8 [interquartile range {IQR}, 3-17]), baseline neurological deficits did not differ in MCS (median, 7 [IQR, 2-18]), CPAF (median, 6 [IQR, 2-18]), and CA (median, 5 [IQR, 2-13]) but were less severe in AE (median, 2 [IQR, 1-4]), PE (median, 2 [IQR, 1-4]), and UE (median, 3 [IQR, 1-7]). Multivariable-adjusted odds ratios of functional dependency significantly increased in CA (3.61; 95% CI, 1.52-8.54 vs CE) but decreased in PE (0.33; 95% CI, 0.16-0.71 vs CE). Conclusions and Relevance: Potential causes are associated with poststroke outcome in patients with cryptogenic stroke. Embolic sources potentially underlying cryptogenic stroke should be considered significant variables associated with outcome..
26. Taisuke Kitamura, Shuji Arakawa, Kei Murao, Takanari Kitazono, Tetsuro Ago, Paradoxical Brain Embolism in Elderly Subjects with Small Atrial Septal Defects, Journal of Stroke and Cerebrovascular Diseases, 10.1016/j.jstrokecerebrovasdis.2018.02.053, 27, 7, 1987-1991, 2018.07, Background: Atrial septal defects have a low prevalence in the general population, and are recognized as a rare cause of paradoxical brain embolism. Methods: We extensively examined stroke causes in patients with acute stroke admitted to a single stroke center within 1 year. Results: Among 186 consecutive patients, transesophageal or transthoracic echocardiography revealed 5 cases of paradoxical brain embolism: 3 (1.6%) were related to atrial septal defects, whereas 2 were patent foramen ovale patients. Although right-to-left shunt may have occurred after the development of acute pulmonary embolism in atrial septal defects case #1, the Valsalva maneuver elicited right-to-left shunt in atrial septal defects cases #2 and #3. The 3 cases were elderly (>60 years old), harbored small defects with normal systemic hemodynamics, and had not experienced any clinical symptoms related to atrial septal defects. Conclusions: Small atrial septal defect may cause paradoxical embolism as its initial related event, particularly in elderly subjects..
27. Tomohiro Yubi, Jun Hata, Tomoyuki Ohara, Naoko Mukai, Yoichiro Hirakawa, Daigo Yoshida, Seiji Gotoh, Naoki Hirabayashi, Yoshihiko Furuta, Tetsuro Ago, Takanari Kitazono, Yutaka Kiyohara, Toshiharu Ninomiya, Prevalence of and risk factors for cerebral microbleeds in a general Japanese elderly community, Neurology: Clinical Practice, 10.1212/CPJ.0000000000000464, 8, 3, 223-231, 2018.06, Background We investigated the prevalence of and risk factors for cerebral microbleeds (CMBs) in a cross-sectional study of a general population of Japanese elderly. Methods In 2012, brain MRI scanning at 1.5T and comprehensive health examination were conducted for 1281 residents aged 65 years or older. CMBs were defined as ovoid hypointensity lesions less than 10 mm in diameter on T2-weighted images and classified into deep/infratentorial or lobar CMBs. Age- and sex-specific and overall prevalence of CMBs were estimated, and the associations of traditional cardiovascular risk factors and APOE polymorphism with the presence of CMBs were examined using a logistic regression analysis. Results The crude prevalences of total, deep/infratentorial, and lobar CMBs were 18.7% (n = 240), 13.5% (n = 173), and 9.6% (n = 123), respectively. The prevalence of total CMBs was 23.0% in men and 15.5% in women and increased with aging in both sexes (both p for trend <0.01). Hypertension was significantly associated with the presence of both deep/infratentorial and lobar CMBs. Lower serum total cholesterol was a significant risk factor for deep/infratentorial CMBs, but not for lobar CMBs, while APOE ϵ4 carriers had a significantly higher likelihood only of lobar CMBs compared with noncarriers. Conclusions Our study suggests that approximately 1 of 5 Japanese elderly people have CMBs, and that risk factors for deep/infratentorial and lobar CMBs are different, indicating the distinct pathologic backgrounds of these lesions..
28. Ago T, Matsuo R, Hata J, Wakisaka Y, Kuroda J, Kitazono T, Kamouchi M. Insulin resistance and clinical outcomes after ischemic stroke., Insulin resistance and clinical outcomes after ischemic stroke., Neurology, 90, 17, 1470-1477, 2018.05, インスリン抵抗性と脳梗塞発症後機能転帰の関連について検討した.本検討では4,655名の急性期脳梗塞患者(平均年齢70.3歳,男性63,5%,入院前自立,発症7日以内,入院前-中にインスリン治療を受けていない患者)について解析している.
入院後,空腹時血糖およびインスリン値によって計算されたHOMA-IRをインスリン抵抗性の指標として用いた.入院後の神経増悪の有無,3ヶ月後の転帰不良(mRS 3以上),及び 3ヶ月後再発・死亡との関連について解析した.
HOMA-IRを値の低い方から5群(Q1-Q5)にわけ,Q1を基準とすると,Q5では入院中の神経症候改善率が低く(オッズ比 0.68 [95% confidence interval, 0.56–0.83],転帰不良となるオッズ比が高値であった(2.02 [1.52–2.68]).
3ヶ月後の再発や死亡との関連は認められなかった.非糖尿病・非肥満の患者群でもこの関連は維持された.年齢,性,脳梗塞病型・重症度別に層別解析を行ったが異質性は認められなかった..
29. Rainer Malik, Ganesh Chauhan, Matthew Traylor, Muralidharan Sargurupremraj, Yukinori Okada, Aniket Mishra, Loes Rutten-Jacobs, Anne Katrin Giese, Sander W. Van Der Laan, Solveig Gretarsdottir, Christopher D. Anderson, Michael Chong, Hieab H.H. Adams, Tetsuro Ago, Peter Almgren, Philippe Amouyel, Hakan Ay, Traci M. Bartz, Oscar R. Benavente, Steve Bevan, Giorgio B. Boncoraglio, Robert D. Brown, Adam S. Butterworth, Caty Carrera, Cara L. Carty, Daniel I. Chasman, Wei Min Chen, John W. Cole, Adolfo Correa, Ioana Cotlarciuc, Carlos Cruchaga, John Danesh, Paul I.W. De Bakker, Anita L. Destefano, Marcel Den Hoed, Qing Duan, Stefan T. Engelter, Guido J. Falcone, Rebecca F. Gottesman, Raji P. Grewal, Vilmundur Gudnason, Stefan Gustafsson, Jeffrey Haessler, Tamara B. Harris, Ahamad Hassan, Aki S. Havulinna, Susan R. Heckbert, Elizabeth G. Holliday, George Howard, Fang Chi Hsu, Multiancestry genome-wide association study of 520,000 subjects identifies 32 loci associated with stroke and stroke subtypes, Nature genetics, 10.1038/s41588-018-0058-3, 50, 4, 524-537, 2018.04, Stroke has multiple etiologies, but the underlying genes and pathways are largely unknown. We conducted a multiancestry genome-wide-association meta-analysis in 521,612 individuals (67,162 cases and 454,450 controls) and discovered 22 new stroke risk loci, bringing the total to 32. We further found shared genetic variation with related vascular traits, including blood pressure, cardiac traits, and venous thromboembolism, at individual loci (n = 18), and using genetic risk scores and linkage-disequilibrium-score regression. Several loci exhibited distinct association and pleiotropy patterns for etiological stroke subtypes. Eleven new susceptibility loci indicate mechanisms not previously implicated in stroke pathophysiology, with prioritization of risk variants and genes accomplished through bioinformatics analyses using extensive functional datasets. Stroke risk loci were significantly enriched in drug targets for antithrombotic therapy..
30. Sakai Y, Yamamori T, Yoshikawa Y, Bo T, Suzuki M, Yamamoto K, Ago T, Inanami O., NADPH oxidase 4 mediates ROS production in radiation-induced senescent cells and promotes migration of inflammatory cells, Free Radic Res , 52, 1, 92-102, 2018.01.
31. Tachibana M, Ago T, Wakisaka Y, Kuroda J, Kitazono T, Early reperfusion after brain ischemia has beneficial effects beyond rescuing neurons, Stroke, 2017.08.
32. Satomi Mezuki, Kenji Fukuda, Tomonaga Matsushita, Yoshihisa Fukushima, Ryu Matsuo, Yu ichi Goto, Takehiro Yasukawa, Takeshi Uchiumi, Dongchon Kang, Takanari Kitazono, Tetsuro Ago, Isolated and repeated stroke-like episodes in a middle-aged man with a mitochondrial ND3 T10158C mutation
A case report, BMC neurology, 10.1186/s12883-017-1001-4, 17, 1, 2017.12, Background: Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) syndrome, is the most common phenotype of mitochondrial disease. It often develops in childhood or adolescence, usually before the age of 40, in a maternally-inherited manner. Mutations in mitochondrial DNA (mtDNA) are frequently responsible for MELAS. Case presentation: A 55-year-old man, who had no family or past history of mitochondrial disorders, suddenly developed bilateral visual field constriction and repeated stroke-like episodes. He ultimately presented with cortical blindness, recurrent epilepsy and severe cognitive impairment approximately 6 months after the first episode. Genetic analysis of biopsied biceps brachii muscle, but not of peripheral white blood cells, revealed a T10158C mutation in the mtDNA-encoded gene of NADH dehydrogenase subunit 3 (ND3), which has previously been thought to be associated with severe or fatal mitochondrial disorders that develop during the neonatal period or in infancy. Conclusion: A T10158C mutation in the ND3 gene can cause atypical adult-onset stroke-like episodes in a sporadic manner..
33. Matsuo R, Yamaguchi Y, Matsushita T, Hata J, Kiyuna F, Fukuda K, Wakisaka Y, Kuroda J, Ago T, Kitazono T, Kamouchi M, Association Between Onset-to-Door Time and Clinical Outcomes After Ischemic Stroke, Stroke, 48, 11, 3049-3056, 2017.11.
34. Ogata T, Matsuo R, Kiyuna F, Hata J, Ago T, Tsuboi Y, Kitazono T, Kamouchi M; FSR Investigators., Left Atrial Size and Long-Term Risk of Recurrent Stroke After Acute Ischemic Stroke in Patients with Nonvalvular Atrial Fibrillation. , J Am Heart Assoc, 6, 8, e006402, 2017.08.
35. Wakisaka Y, Matsuo R, Kuroda J, Ago T, Kitazono T, Kamouchi M, Adverse Influence of Pre-Stroke Dementia on Short-Term Functional Outcomes in Patients with Acute Ischemic Stroke: The Fukuoka Stroke Registry, Cerebrovascular diseases, 43, 1-2, 82-89, 2017.06.
36. Matsuo R, Ago T, Kitazono T, Kamouchi M, Short-Term Exposure to Fine Particulate Matter and Risk of Ischemic Stroke, Stroke, 47, 12, 3032-3034, 2016.12.
37. Nishimura A, Ago T, Kuroda J, et al., Detrimental role of pericyte Nox4 in the acute phase of brain ischemia., J Cereb Blood Flow Metab, 36, 6, 1143-1154, 2016.06.
38. Nakamura K, Arimura K, Ago T, et al., Possible involvement of basic FGF in the upregulation of PDGFR beta in pericytes after ischemic stroke, BRAIN RESEARCH, 10.1016/j.brainres.2015.11.003, 1630, 98-108, 2016.01.
39. Ishikawa H, Wakisaka Y, Matsuo R, Ago T, Kitazono T, Influence of Statin Pretreatment on Initial Neurological Severity and Short-Term Functional Outcome in Acute Ischemic Stroke Patients: The Fukuoka Stroke Registry, Cerebrovasc diseases, 42, 5-6, 395-403, 2016.05.
40. Tong X, Khandelwal AR, Wu X, Xu Z, Yu W, Chen C, Zhao W, Yang J, Qin Z, Weisbrod RM, Seta F, Ago T, et al., Pro-atherogenic role of smooth muscle Nox4-based NADPH oxidase, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 10.1016/j.yjmcc.2016.01.020, 92, 30-40, 2016.03.
41. Tong X, Khandelwal AR, Qin Z, Wu X, Chen L, Ago T, et al., Role of smooth muscle Nox4-based NADPH oxidase in neointimal hyperplasia, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 10.1016/j.yjmcc.2015.11.013, 89, 185-194, 2015.12.
42. Ago T, Sadoshima J., From Contractile Enhancement to Pathological Hypertrophy Angiotensin II-Induced Nox2-Mediated Reactive Oxygen Species, JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, 10.1016/j.jacc.2015.05.058, 66, 3, 273-277, 2015.07.
43. Makihara N, Ago T, et al., Involvement of platelet-derived growth factor receptor β in fibrosis through extracellular matrix protein production after ischemic stroke, Exp Neurol, 2015.02.
44. Kuroda J, Ago T, Nox4 is a major source of superoxide production in human brain pericytes, J Vasc Res, 2014.12.
45. Chen L, Xiao J, Kuroda J, Ago T, Both hydrogen peroxide and transforming growth factor beta 1 contribute to endothelial Nox4 mediated angiogenesis in endothelial Nox4 transgenic mouse lines, Biochim Biophys Acta, 2014.12.
46. Kuwashiro T, Ago T, Significance of plasma adiponectin for diagnosis, neurological severity and functional outcome in ischemic stroke - Research for Biomarkers in Ischemic Stroke (REBIOS)., Metabolism, 2014.09.
47. Wakisaka Y, Ago T, Plasma S100A12 is associated with functional outcome after ischemic stroke: Research for Biomarkers in Ischemic Stroke., J Neurol Sci. , 2014.05.
48. Shao D, Oka S, Liu T, Zhai P, Ago T, A redox-dependent mechanism for regulation of AMPK activation by Thioredoxin1 during energy starvation., Cell Metab, 2014.02.
49. Matsuo R, Ago T, Impact of the 1425G/A Polymorphism of PRKCH on the Recurrence of Ischemic Stroke: Fukuoka Stroke Registry., J Stroke Cerebrovasc Dis, 2014.02.
50. Matsuo R, Kamouchi M, Ago T, Thrombolytic therapy with intravenous recombinant tissue plasminogen activator in Japanese older patients with acute ischemic stroke: Fukuoka Stroke Registry., Geriatr Gerontol Int., 2013.12.
51. Kuwashiro T, Sugimori H, Ago T, Predictive role of C reactive protein in stroke recurrence after cardioembolic stroke: the Fukuoka Stroke Registry., BMJ open, 2013.11.
52. Nakamura A, Ago T, Intensity of anticoagulation and clinical outcomes in acute cardioembolic stroke: the Fukuoka Stroke Registry., Stroke, 2013.11.
53. Kuwashiro T, Sugimori H, Ago T, The impact of predisposing factors on long-term outcome after stroke in diabetic patients: the Fukuoka Stroke Registry., Eur J Neurol. , 2013.06.
54. Tokami H, Ago T, RANTES has a potential to play a neuroprotective role in an autocrine/paracrine manner after ischemic stroke., Brain Research, 2013.06.
55. Matsuo R, Ago T, Clinical significance of plasma VEGF value in ischemic stroke - research for biomarkers in ischemic stroke (REBIOS) study., BMC Neurology, 2013.04.
56. Matsushima S, Kuroda J, Ago T, Broad Suppression of NADPH Oxidase Activity Exacerbates Ischemia/Reperfusion Injury Through Inadvertent Downregulation of Hypoxia-inducible Factor-1α and Upregulation of Peroxisome Proliferator-activated Receptor-α., Circulation Research, 2013.04.
57. Matsushima S, Kuroda J, Ago T, Increased oxidative stress in the nucleus caused by Nox4 mediates oxidation of HDAC4 and cardiac hypertrophy., Circulation Research, 2013.02.
58. Ishitsuka K, Ago T(Corresponding author), Arimura K, Nakamura K, Tokami H, Makihara N, Kuroda J, Kamouchi M, Kitazono T., Neurotrophin production in brain pericytes during hypoxia: a role of pericytes for neuroprotection, Microvascular Research, 83, 3, 352-9, 2012.05.
59. Arimura K, Ago T(Corresponding author), Kamouchi M, Nakamura K, Ishitsuka K, Kuroda J, Sugimori H, Ooboshi H, Sasaki T, Kitazono T., PDGF receptor β signaling in pericytes following ischemic brain injury, Current Neurovascular Research, 9, 1, 1-9, 2012.02.
60. Kuwashiro T, Sugimori H, Ago T, Kamouchi M, Kitazono T; FSR Investigators, Risk factors predisposing to stroke recurrence within one year of non-cardioembolic stroke onset: the Fukuoka Stroke Registry, Cerebrovasc Dis, 33, 2, 141-9, 2012.02.
61. Kuwashiro T, Kamouchi M, Ago T, Hata J, Sugimori H, Kitazono T, The factors associated with a functional outcome after ischemic stroke in diabetic patients: the Fukuoka Stroke Registry, J Neurol Sci, 313, 1-2, 110-4, 2012.02.
62. Kamouchi M, Matsuki T, Hata J, Kuwashiro T, Ago T, Sambongi Y, Fukushima Y, Sugimori H, Kitazono T; FSR Investigators, Prestroke glycemic control is associated with the functional outcome in acute ischemic stroke: the Fukuoka Stroke Registry, Stroke, 42, 10, 2788-94, 2011.10.
63. Kuroda J, Ago T, Matsushima S, Zhai P, Schneider MD, Sadoshima J, NADPH oxidase 4 (Nox4) is a major source of oxidative stress in the failing heart., PNAS, 107, 35, 15565-70, 2010.08.
64. Ago T, Kuroda J, Pain J, Fu C, Li H, Sadoshima J., Upregulation of Nox4 by Hypertrophic Stimuli Promotes Apoptosis and Mitochondrial Dysfunction in Cardiac Myocytes., Circulation Research, 2010.04.
65. Ishikawa E, Ooboshi H, Kumai Y, Takada J, Nakamura K, Ago T, Sugimori H, Kamouchi M, Kitazono T, Ibayashi S, Iida M., Midkine gene transfer protects against focal brain ischemia and augments neurogenesis., J Neurol Sci. , 285, 78, 2009.05.
66. Nakamura K, Kamouchi M, Kitazono T, Kuroda J, Shono Y, Hagiwara N, Ago T, Ooboshi H, Ibayashi S, Iida M., Amiloride inhibits hydrogen peroxide-induced Ca2+ responses in human CNS pericytes., Microvasc Res., 77, 327, 2009.05.
67. Fu C, Wu C, Liu T, Ago T, Zhai P, Sadoshima J, Li H., Elucidation of thioredoxin target protein networks in mouse., 8, 1647, 2009.05.
68. Ago T, Yeh I, Yamamoto M, Schinke-Braun M, Brown JA, Tian B, Sadoshima J. , Thioredoxin1 Upregulates Mitochondrial Proteins Related to Oxidative Phosphorylation and TCA Cycle in the Heart., Antioxid Redox Signal , 8(9-10), 1635-1650., 2006.09.
69. Ago T, Kitazono T, Kuroda J, Kumai Y, Kamouchi M, Ooboshi H, Wakisaka M, Kawahara T, Rokutan K, Ibayashi S, Iida M, NAD(P)H oxidases in rat basilar arterial endothelial cells, Stroke, 10.1161/01.STR.0000163111.05825.0b, 36, 5, 1040-1046, 36(5): 1040-1046 , 2005.05.
70. Ago T, Kitazono T, Ooboshi H, Iyama T, Han YH, Takada J, Wakisaka M, Ibayashi S, Utsumi H, Iida M. , Nox4 as the major catalytic component of an endothelial NAD(P)H oxidase., Circulation, 10.1161/01.CIR.0000105680.92873.70, 109, 2, 227-233, 109(2): 227-233., 2004.01.
71. Ago T, Kuribayashi F, Hiroaki H, Takeya R, Ito T, Kohda D, Sumimoto H. , Phosphorylation of p47phox directs PX domain from SH3 domain towards phosphoinositides, leading to phagocyte NADPH oxidase activation. , PNAS, 10.1073/pnas.0735712100, 100, 8, 4474-4479, 100(8): 4474-9., 2003.04.
72. Ago T, Takeya R, Hiroaki H, Kuribayashi F, Ito T, Kohda D, Sumimoto H., The PX domain as a novel phosphoinositide-binding module., Biochem Biophys Res Commun , 10.1006/bbrc.2001.5629, 287, 3, 733-738, 287, 733-8 , 2001.09.
73. Hiroaki H, Ago T, Ito T, Sumimoto H, Kohda D. , Solution structure of the PX domain, a target of the SH3 domain. , Nature Structural Biology, 10.1038/88591, 8, 6, 526-530, 8, 526-30 , 2001.08.
74. Ago T, Nunoi H, Ito T, Sumimoto H., Mechanism for phosphorylation-induced activation of the phagocyte NADPH oxidase protein p47phox. Triple replacement of serines 303, 304, and 328 with aspartates disrupts the SH3 domain-mediated intramolecular interaction in p47phox, thereby activating the oxidase. , J Biol Chem , 10.1074/jbc.274.47.33644, 274, 47, 33644-33653, 274(47): 33644-33653., 1999.11.