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ABSTRACT: BACKGROUND AND PURPOSE: Fluid-attenuated inversion recovery vascular hyperintensity (FVH) is often identified in patients with acute ischemic stroke. The purpose of this study was to determine the clinical significance of FVH in patients with transient ischemic attack (TIA). METHODS: Consecutive inpatients with TIA who underwent MRI within 24 hours of symptom onset were studied. The frequency, relative factors, and time course of FVH were determined. RESULTS: Of the 202 patients who were enrolled (76 women, mean age, 69.0±13.2 years), FVH was identified in 41 patients (20%). Multivariate analysis showed that atrial fibrillation (odds ratio, 7.14; 95% confidence interval [CI], 2.69-18.1), arterial occlusive lesion (odds ratio, 4.89; 95% CI, 3.03-12.2), and hemiparesis (odds ratio, 2.81; 95% CI, 1.17-7.48) was independently associated with FVH. Of 23 recurrence-free patients with FVH positive undergoing follow-up MRI at a median of 7 days after the onset, FVH was no longer positive in 15 patients (65%). Atrial fibrillation was more common (P=0.027) and arterial occlusive lesion was less common (P<0.001) in patients with transient FVH compared with those with persistent FVH. Within 90 days after the onset, 13 patients developed recurrent TIA or ischemic stroke. After Cox proportional hazard analysis, FVH (hazard ratio, 3.65; 95% CI, 1.09-12.7), arterial occlusive lesion (hazard ratio, 4.15; 95% CI, 1.18-17.1), and coexistence of FVH and arterial occlusive lesion (hazard ratio, 13.9; 95% CI, 3.36-71.0) were significantly associated with recurrent TIA or ischemic stroke. CONCLUSIONS: The presence of FVH early after symptom onset may help to diagnosis TIA, to identify the potential mechanisms of TIA and to predict recurrence risk after a TIA.
Stroke 05/2013; · 5.73 Impact Factor
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ABSTRACT: Background: Various mechanisms can be considered in ischemic stroke with internal carotid artery (ICA) occlusive diseases. We clarified the etiologic mechanisms from lesion patterns on diffusion-weighted imaging (DWI). Methods: One hundred and twenty consecutive ischemic stroke patients with ipsilateral ICA occlusive diseases were enrolled and classified into 3 groups according to the size of DWI lesions: group A, massive; group B, moderate-to-large; and group C, small. Group C was divided into 3 subgroups according to the number of lesions: C1, 1-3; C2, 4-9; and C3, 10 or more. The relationship between the DWI findings and stroke subtypes according to the TOAST classification was investigated. Results: Cardioembolism was significantly more common in groups A and B than in group C, while large-artery atherosclerosis (LAA) was more frequent in group C than in groups A and B. In group A, cardioembolism accounted for 32%, while LAA was not observed. Statistical analyses showed trends toward a higher frequency of LAA in groups C2 and C3 than in group C1. Conclusions: Mechanisms of acute stroke in ICA diseases can be simply assessed from the lesion size and number, which may be useful in considering acute therapeutic strategies.
European Neurology 12/2012; 69(3):142-148. · 1.81 Impact Factor
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ABSTRACT: BACKGROUND AND PURPOSE: For optimal acute stroke management and secondary prevention, discrimination of stroke etiology is crucial. We hypothesized that a low Alberta Stroke Program Early CT Score (ASPECTS) on diffusion-weighted imaging (DWI) immediately after stroke onset was associated with the presence of atrial fibrillation (AF). METHODS: Consecutive patients admitted within 24h from stroke onset with an occlusion at the horizontal segment of the middle cerebral artery (M1) on initial MRA were retrospectively enrolled. AF was diagnosed based on continuous electrocardiogram monitoring during acute hospitalization or its confirmed history. RESULTS: Of the 206 patients (95 women, median age 77 [IQR 69-85] years, NIHSS score 18 [13-23]) enrolled, AF was identified in 138 patients (AF group): chronic AF in 89, known paroxysmal AF (pAF) in 13, and masked pAF on admission in 36. The ASPECTS score on the initial DWI, performed a median of 2.5h after onset, was lower in the AF group than in the others (4 [2-6] vs. 7 [4-8], p<0.001). With the optimal cut-off value of ≤6 (sensitivity, 78%; specificity, 57%; area under the ROC curve, 0.682), DWI-ASPECTS was independently associated with the presence of any AF (OR 5.05, 95%CI 2.36 to 10.8), as well as the presence of any pAF (OR 8.64, 95%CI 3.00 to 24.9) and that of masked pAF on admission (OR 10.0, 95%CI 3.06 to 32.9). CONCLUSION: Extensive early ischemic change assessed by DWI-ASPECTS predicts the presence of AF, even initially masked pAF, in acute stroke patients with M1 occlusion.
Journal of the neurological sciences 09/2012; · 2.32 Impact Factor
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Masatoshi Koga,
Kazunori Toyoda,
Hiroshi Yamagami,
Satoshi Okuda,
Yasushi Okada,
Kazumi Kimura,
Yoshiaki Shiokawa,
Jyoji Nakagawara,
Eisuke Furui,
Yasuhiro Hasegawa,
Kazuomi Kario,
Masato Osaki,
Tetsuya Miyagi,
Kaoru Endo, Kazuyuki Nagatsuka,
Kazuo Minematsu
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ABSTRACT: OBJECTIVE:: Optimal blood pressure (BP) control in acute intracerebral hemorrhage (ICH) remains controversial. We determined the effects of SBP lowering to 160 mmHg or more using intravenous nicardipine for acute ICH patients. METHODS:: This is a prospective, multicenter, observational study conducted in Japan, with the lack of control groups. Patients with supratentorial ICH within 3 h of onset, admission SBP 180 mmHg or more, Glasgow Coma Scale (GCS) 5 or more, and hematoma volume less than 60 ml were initially treated with intravenous nicardipine to maintain SBP between 120 and 160 mmHg with 24-h frequent BP monitoring. The primary endpoints were neurological deterioration within 72 h [GCS decrement ≥2 points or National Institutes of Health Stroke Scale (NIHSS) increment ≥4 points; estimated 90% confidence interval (CI) on the basis of previous studies: 15.2-25.9%] and serious adverse effects (SAE) to stopping intravenous nicardipine within 24 h (1.8-8.9%). The secondary endpoints included hematoma expansion more than 33% at 24 h (17.1-28.3%), modified Rankin Scale (mRS) 4 or more (54.5-67.9%) and death at 3 months (6.0-13.5%). RESULTS:: We enrolled 211 Japanese patients (81 women, 65.6 ± 12.0 years old). At baseline, BP was 201.8 ± 15.7/107.9 ± 15.0 mmHg. Median hematoma volume was 10.2 ml (interquartile range 5.6-19.2), and NIHSS score was 13 (8-17). Neurological deterioration was identified in 17 patients (8.1%), SAE in two (0.9%), hematoma expansion in 36 (17.1%), mRS 4 or more in 87 (41.2%), and death in four (1.9%). All the results were equal to or below the estimated lower 90% CI. CONCLUSION:: SBP lowering to 160 mmHg or less using nicardipine appears to be well tolerated and feasible for acute ICH.
Journal of hypertension 09/2012; · 4.02 Impact Factor
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Shoichiro Sato,
Masatoshi Koga,
Hiroshi Yamagami,
Satoshi Okuda,
Yasushi Okada,
Kazumi Kimura,
Yoshiaki Shiokawa,
Jyoji Nakagawara,
Eisuke Furui,
Yasuhiro Hasegawa,
Kazuomi Kario,
Shoji Arihiro, Kazuyuki Nagatsuka,
Kazuo Minematsu,
Kazunori Toyoda
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ABSTRACT: Conjugate eye deviation (CED) occurs frequently in patients with acute stroke. The purpose of this study was to elucidate the factors that correlate with CED as well as the relationship between CED and outcomes in patients with acute intracerebral hemorrhage.
A total of 211 patients with acute supratentorial intracerebral hemorrhage were recruited in a multicenter, prospective study. CED was assessed with a National Institutes of Health Stroke Scale "best gaze" subscore of ≥1. Hematoma location and volume were assessed on CT.
Forty-five percent of the patients had CED. On multivariable analysis, right-sided lesion (OR, 2.36; 95% CI, 1.18-4.93), hematoma volume (OR, 1.07; 95% CI, 1.04-1.10 per 1 mL), and baseline Glasgow Coma Scale score (OR, 0.66; 95% CI, 0.53-0.80 per 1 point) were independently associated with CED. After adjusting for sex, age, intraventricular extension of the hematoma, baseline Glasgow Coma Scale score, and hematoma volume, the presence of CED both on admission and 72 hours later was an independent predictor of death or dependency at 3 months poststroke (OR, 5.77; 95% CI, 2.27-16.94). The optimal cutoff volume of hematoma related to CED was ≥13.5 mL for patients with putaminal hemorrhage (sensitivity, 76%; specificity, 72%) and ≥7.7 mL for patients with thalamic hemorrhage (sensitivity, 82%; specificity, 83%).
The persistence of CED was a significant predictor of death or dependency after acute supratentorial intracerebral hemorrhage even after adjusting for initial severity and hematoma volume. CED can be evoked by a relatively smaller thalamic hematoma than a putaminal hematoma.
Stroke 09/2012; 43(11):2898-903. · 5.73 Impact Factor
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ABSTRACT: Cell-based therapies are a novel approach for regeneration of microvasculature. We have shown that administration of CD34-positive cells, the rich cell fraction of endothelial progenitor cells, after stroke induces angiogenesis that results in enhanced endogenous neurogenesis and functional recovery in a murine model. Moreover, injury-induced neurogenesis occurs in the human brain following a stroke during the acute to sub-acute period. Based on these observations, clinical trials of cell therapies that aim to regenerate micro-circulation in the brain following a stroke are ongoing worldwide. This review summarizes the current basic research findings about the link between angiogenesis and neurogenesis in the post-stroke brain and introduces the ongoing clinical trials of cell-based therapies for patients that have suffered a stroke.
Current Vascular Pharmacology 01/2012; 10(3):285-8. · 2.90 Impact Factor
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ABSTRACT: Neuronal stem cells are mobilized after cerebral infarction. We had shown that appropriate support of these stem cells, achieved by therapeutic angiogenesis, enhances neurological recovery in experimental stroke model. Based on these observations, we started cell based therapy using autologous bone marrow mononuclear cells for patients after cerebral embolism as phase 1/2a clinical trial. We have treated 6 patients in low dose group (harvest 25 ml of bone marrow cells) and none of them showed treatment-related adverse effects. We are now recruiting another 6 patients in high dose group (harvest 50 ml of bone marrow cells) and are planning to evaluate the effectiveness and safety of the therapy after obtaining the results of all 12 patients.
Rinshō shinkeigaku = Clinical neurology. 11/2011; 51(11):1081-2.
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ABSTRACT: The present study clarifies associations between stroke outcomes after intravenous tissue plasminogen activator (tPA) and blood pressure (BP) as well as heart rate (HR) profiles.
We assessed 125 patients with stroke who received tPA within 3 h of onset. We obtained baseline, mean, maximum, minimum, and coefficient of variation values for BP and HR during the initial 24 h. The primary outcome was independence at 3 months corresponding to a modified Rankin Scale score of 2 or less. The secondary outcomes were early neurological improvement at 24 h and intracerebral hemorrhage (ICH) within 36 h.
Among the patients, 64 (51%) achieved independence, 66 (53%) early improvement, and 26 (21%) developed ICH. The 24-h time courses of SBP (P = 0.033), pulse pressure (PP, P = 0.007), and HR (P < 0.001) were lower among patients who reached independence than among those who did not. After multivariate adjustment, 24-h mean levels of SBP (odds ratio 0.69, 95% confidence interval 0.48-0.97, per 10-mmHg increase), PP (0.63, 0.41-0.94), and HR (0.59, 0.42-0.80, per 10-bpm increase) were inversely associated with independence, as were their maximum and minimum values. In particular, mean SBP values were inversely associated with independence at 8-16 and 16-24 h (0.73, 0.54-0.97 and 0.66, 0.47-0.91, respectively), but not at 0-8 h (0.79, 0.57-1.07). Baseline and maximum SBP were inversely associated with early improvement. Maximum and coefficient of variation of SBP were associated with ICH.
Lower SBP, PP, and HR values during the initial 24 h after tPA, especially at 8 h thereafter, were associated with independence at 3 months.
Journal of hypertension 08/2011; 29(10):1980-7. · 4.02 Impact Factor
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Hiroyuki Kawano,
Haruko Yamamoto,
Shigeki Miyata,
Manabu Izumi,
Teruyuki Hirano,
Naomi Toratani,
Isami Kakutani,
Jo-Ann I Sheppard,
Theodore E Warkentin,
Akiko Kada,
Shoichiro Sato,
Sadahisa Okamoto, Kazuyuki Nagatsuka,
Hiroaki Naritomi,
Kazunori Toyoda,
Makoto Uchino,
Kazuo Minematsu
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ABSTRACT: Acute ischaemic stroke patients sometimes receive heparin for treatment and/or prophylaxis of thromboembolic complications. This study was designed to elucidate the incidence and clinical features of heparin-induced thrombocytopenia (HIT) in acute stroke patients treated with heparin. We conducted a prospective multicentre cohort study of 267 patients who were admitted to three stroke centres within 7 d after stroke onset. We examined clinical data until discharge and collected blood samples on days 1 and 14 of hospitalization to test anti-platelet factor 4/heparin antibodies (anti-PF4/H Abs) using an enzyme-linked immunosorbent assay (ELISA); platelet-activating antibodies were identified by serotonin-release assay (SRA). Patients with a 4Ts score ≥4 points, positive-ELISA, and positive-SRA were diagnosed as definite HIT. Heparin was administered to 172 patients (64·4%: heparin group). Anti-PF4/H Abs were detected by ELISA in 22 cases (12·8%) in the heparin group. Seven patients had 4Ts ≥ 4 points. Among them, three patients (1·7% overall) were also positive by both ELISA and SRA. National Institutes of Health Stroke Scale score on admission was high (range, 16-23) and in-hospital mortality was very high (66·7%) in definite HIT patients. In this study, the incidence of definite HIT in acute ischaemic stroke patients treated with heparin was 1·7% (95% confidence interval: 0·4-5·0). The clinical severity and outcome of definite HIT were unfavourable.
British Journal of Haematology 06/2011; 154(3):378-86. · 4.94 Impact Factor
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ABSTRACT: Stroke patients often develop deep-vein thrombosis (DVT), a potential cause of pulmonary thromboembolism. Little information is available on DVT in Asian patients with intracerebral hemorrhage (ICH).
We prospectively enrolled consecutive acute ICH patients. The main exclusion criteria were neurosurgical treatment, early death and coagulation disorders. DVT was evaluated using venous duplex ultrasonography on the day of admission, as well as 7 and 14 days later. Underlying characteristics, stroke features and laboratory data on admission were compared between patients who developed DVT by 14 days and those who did not.
A total of 81 (50 men, mean age 65 years, median NIH Stroke Scale, NIHSS, score 12) of 117 Japanese ICH patients were enrolled. DVT was detected in 4 patients on admission and was newly detected in 9 at 7 days. By 14 days, 17 patients (21%) were diagnosed as having DVT without thromboembolic complications, although 1 patient developed pulmonary thromboembolism. DVT was detected in the soleal veins of all 17 patients, followed by the peroneal veins (7 patients). After adjustment for age and related confounders, female sex was the only independent predictor for DVT (odds ratio 6.89, 95% confidence interval, CI, 1.56-36.34, p = 0.014). Female patients with an initial NIHSS score > or =12 had 19 times the risk for DVT compared to men with an NIHSS score <12 (95% CI 2.61-213.77, p = 0.007).
DVT formation was not rare in Japanese ICH patients. Contrary to previous findings reported from western countries, female sex was strongly associated with DVT formation.
Cerebrovascular Diseases 02/2009; 27(4):313-9. · 2.72 Impact Factor
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ABSTRACT: Aspirin inhibits platelet activation through the permanent inactivation of the cyclooxygenase (COX) activity of prostaglandin H synthase-1 (referred to as COX-1), and consequently inhibits the biosynthesis of thromboxane A2 (TXA2), a platelet agonist. Recent meta-analysis has revealed that long-term aspirin administration has clear benefits for the secondary prevention of cardiovascular diseases with an odds reduction of 23% and an absolute risk reduction of 3.1% over 2 years. However, this indicates that not all individuals respond equally to aspirin therapy and cardiovascular events may occur during aspirin therapy, this is often denoted as "clinical aspirin resistance". Several reports have, indeed, suggested that the effect of aspirin administration varies considerably among the patients at high risk for cardiovascular events. Approximately one forth of the patients showed persistent platelet reactivity in vitro despite the use of aspirin (denoted "laboratory aspirin resistance"), this was determined by laboratory tests including the test for arachidonic acid-induced platelet aggregation and the assays using point-of-care devices. Recent clinical studies have proposed that resistance to aspirin (laboratory aspirin resistance) can relate to the cardiovascular outcomes in patients treated with aspirin (clinical aspirin resistance). A systematic review and meta-analysis on aspirin resistance have indicated that patients who are resistant to aspirin are at a greater risk (odds ratio: 3.85) of clinically important cardiovascular morbidity than patients who are sensitive to aspirin. However, many issues are yet to be resolved in order to apply the concept of "aspirin resistance" to actual clinical practice. The relevance of the various ex vivo functional indexes of platelet capacity to in vivo platelet activation and the precise mechanisms underlying aspirin resistance are still largely unknown. To assess what kind of laboratory assays is the best predictor for cardiovascular events and the risk factors of aspirin resistance, including non-compliance, concurrent intake of other drugs such as nonsteroid anti-inflammatory drugs, and polymorphism of COX-1, we have conducted a multicenter, prospective cohort study (ProGEAR study). We hope that these results will contribute to an individualized antiplatelet therapy through the identification of aspirin nonresponders as a high-risk group for cardiovascular events.
Brain and nerve = Shinkei kenkyū no shinpo 12/2008; 60(11):1357-64.
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ABSTRACT: Echogenicity of carotid plaque well reflects the risk of ischemic stroke and may be predictive of the histologic content of the plaque. However, objective evaluation of plaque echogenicity has been hampered by a lack of established quantitative measures. This study examined the relation between echogenicity assessed by integrated backscatter (IBS) analysis and (1) symptomatic history and (2) histologic features of carotid plaques.
We used acoustic densitometry to quantify by IBS analysis the echogenicity of 31 carotid plaques of 26 patients undergoing carotid endarterectomy or stenting. IBS was subsequently compared with histologic findings of the respective tissue in 10 patients who underwent endarterectomy. The IBS value was calibrated with 2 reference structures (vessel lumen and adventitia) as the IBS index.
The IBS index of symptomatic plaques was lower than that of asymptomatic plaques (23.1 +/- 12.5 vs. 36.5 +/- 18.2, p < 0.05). The IBS index in fatty/necrotic atheromatous sites (n = 20, 16.6 +/- 10.7) was lower than that in fibrous (n = 26, 42.4 +/- 13.6, p < 0.01) or calcified (n = 11, 87.7 +/- 17.4, p < 0.01) sites and the same as that in intraplaque hemorrhagic sites (n = 50, 23.6 +/- 16.9).
Carotid plaque echogenicity, as quantitatively assessed by IBS analysis, correlates well with the presence or absence of prior symptoms and histologic contents of the plaques. IBS analysis may aid in the assessment of carotid plaque-related risk of stroke.
Cerebrovascular Diseases 10/2008; 26(6):578-83. · 2.72 Impact Factor
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Tong Yin,
Keiko Maekawa,
Kei Kamide,
Yoshiro Saito,
Hironori Hanada,
Kotaro Miyashita,
Yoshihiro Kokubo,
Yasuhisa Akaiwa,
Ryoichi Otsubo, Kazuyuki Nagatsuka,
Toshiho Otsuki,
Takeshi Horio,
Shin Takiuchi,
Yuhei Kawano,
Kazuo Minematsu,
Hiroaki Naritomi,
Hitonobu Tomoike,
Jun-ichi Sawada,
Toshiyuki Miyata
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ABSTRACT: CYP2C9, a drug-metabolizing enzyme, converts the angiotensin II receptor blocker losartan to its active form, which is responsible for its antihypertensive effect. We resequenced CYP2C9 in 724 Japanese individuals, including 39 hypertensive patients under treatment with losartan. Of two novel missense mutations identified, the Arg132Gln variant showed a fivefold lower intrinsic clearance toward diclofenac when expressed in a baculovirus-insect cell system, while the Arg335Gln variant had no substantial effect. Several known missense variations were also found, and approximately 7% of the Japanese individuals (53 out of 724) carried one of the deleterious alleles (CYP2C9*3, *13, *14, *30, and Arg132Gln) as heterozygotes. After 3 months of losartan treatment, systolic blood pressure was not lowered in two patients with CYP2C9* 1/*30, suggesting that they exhibited impaired in vivo CYP2C9 activity. CYP2C9*30 might be associated with a diminished response to the antihypertensive effects of losartan.
Hypertension Research 09/2008; 31(8):1549-57. · 2.58 Impact Factor
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Tomoyuki Yoshihara,
Akihiko Taguchi,
Tomohiro Matsuyama,
Yoko Shimizu,
Akie Kikuchi-Taura,
Toshihiro Soma,
David M Stern,
Hiroo Yoshikawa,
Yukiko Kasahara,
Hiroshi Moriwaki, Kazuyuki Nagatsuka,
Hiroaki Naritomi
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ABSTRACT: Increasing evidence points to a role for circulating endothelial progenitor cells, including populations of CD34-positive (CD34(+)) cells, in maintenance of cerebral blood flow. In this study, we investigated the link between the level of circulating CD34(+) cells and neovascularization at ischemic brain. Compared with control subjects, a remarkable increase of circulating CD34(+) cells was observed in patients with angiographic moyamoya vessels, although no significant change was observed in patients with major cerebral artery occlusion (or severe stenosis) but without moyamoya vessels. Our results suggest that the increased level of CD34(+) cells associated with ischemic stress is correlated with neovascularization at human ischemic brain.
Journal of Cerebral Blood Flow & Metabolism 07/2008; 28(6):1086-9. · 5.01 Impact Factor
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Akihiko Taguchi,
Tomohiro Matsuyama,
Takayuki Nakagomi,
Yoko Shimizu,
Ryuzo Fukunaga,
Yoshiaki Tatsumi,
Hiroo Yoshikawa,
Akie Kikuchi-Taura,
Toshihiro Soma,
Hiroshi Moriwaki, Kazuyuki Nagatsuka,
David M Stern,
Hiroaki Naritomi
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ABSTRACT: Maintenance of uninterrupted cerebral circulation is critical for neural homeostasis. The level of circulating CD34-positive (CD34(+)) cells has been suggested as an index of cerebrovascular health, although its relationship with cognitive function has not yet been defined. In a group of individuals with cognitive impairment, the level of circulating CD34(+) cells was quantified and correlated with clinical diagnoses. Compared with normal subjects, a significant decrease in circulating CD34(+) cells was observed in patients with vascular-type cognitive impairment, although no significant change was observed in patients with Alzheimer's-type cognitive impairment who had no evidence of cerebral ischemia. The level of cognitive impairment was inversely correlated with numbers of circulating CD34(+) cells in patients with vascular-type cognitive impairment, but not Alzheimer's type. We propose that the level of circulating CD34(+) cells provides a marker of vascular risk associated with cognitive impairment, and that differences in the pathobiology of Alzheimer's- and vascular-type cognitive impairment may be mirrored in levels of circulating CD34(+) cells in these patient populations.
Journal of Cerebral Blood Flow & Metabolism 04/2008; 28(3):445-9. · 5.01 Impact Factor
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Tong Yin,
Hironori Hanada,
Kotaro Miyashita,
Yoshihiro Kokubo,
Yasuhisa Akaiwa,
Ryoichi Otsubo, Kazuyuki Nagatsuka,
Toshiho Otsuki,
Akira Okayama,
Kazuo Minematsu,
Hiroaki Naritomi,
Hitonobu Tomoike,
Toshiyuki Miyata
Thrombosis Research 02/2008; 122(2):179-84. · 2.44 Impact Factor
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ABSTRACT: To find neurological or neuroimaging signs to predict neurological deterioration in acute lacunar infarctions.
Sixty-one consecutive patients with a supratentorial lacunar infarct, who were admitted within 48 h, were studied retrospectively. Progressive-type stroke (PS) was defined as progressive motor deficits that arose within 7 days after onset, by using the motor ratings of the National Institutes of Health Stroke Scale.
Sixteen patients (26%) were classified into the PS group. In the PS group, fluctuating or progressing onset (81 vs. 42%, p = 0.009), leg-predominant motor deficits on admission (63 vs. 16%, p = 0.001) and corona radiata lesion on diffusion-weighted MRI (100 vs. 69%, p = 0.013) were all more frequent than in the non-PS group.
Bedside neurological assessment and MRI findings may allow us to predict PS and start early intensive treatment for preventing further neurological deterioration.
European Neurology 01/2008; 60(3):137-41. · 1.81 Impact Factor
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Rina Kimura,
Kotaro Miyashita,
Yoshihiro Kokubo,
Yasuhisa Akaiwa,
Ryoichi Otsubo, Kazuyuki Nagatsuka,
Toshiho Otsuki,
Akira Okayama,
Kazuo Minematsu,
Hiroaki Naritomi,
Shigenori Honda,
Hitonobu Tomoike,
Toshiyuki Miyata
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ABSTRACT: The dose required for the anticoagulant effect of warfarin exhibits large inter-individual variations. This study sought to determine the contribution of four genes, vitamin K epoxide reductase (VKORC1), gamma-glutamyl carboxylase (GGCX), calumenin (CALU), and cytochrome P450 2C9 (CYP2C9) to the warfarin maintenance dose required in Japanese patients following ischemic stroke. We recruited 93 patients on stable anticoagulation with a target International Normalized Ratio (INR) of 1.6-2.6. We genotyped eleven representative single nucleotide polymorphisms (SNPs) in the three genes involved in vitamin K cycle and the 42613A>C SNP in CYP2C9, known as CYP2C93, and then examined an association of these genotypes with warfarin maintenance doses (mean+/-SD=2.96+/-1.06 mg/day). We found an association of effective warfarin dose with the -1639G>A (p=0.004) and 3730G>A genotypes (p=0.006) in VKORC1, the 8016G>A genotype in GGCX (p=0.022), and the 42613A>C genotype in CYP2C9 (p=0.015). The model using the multiple regression analysis including age, sex, weight, and three genetic polymorphisms accounted for 33.3% of total variations in warfarin dose. The contribution to inter-individual variation in warfarin dose was 5.9% for VKORC1 -1639G>A, 5.2% for CYP2C9 42613A>C, and 4.6% for GGCX 8016G>A. In addition to polymorphisms in VKORC1 and CYP2C9, we identified GGCX 8016G>A, resulting in the missense mutation R325Q, as a genetic determinant of warfarin maintenance dose in Japanese patients.
Thrombosis Research 02/2007; 120(2):181-6. · 2.44 Impact Factor
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Rina Kimura,
Yoshihiro Kokubo,
Kotaro Miyashita,
Ryoichi Otsubo, Kazuyuki Nagatsuka,
Toshiho Otsuki,
Toshiyuki Sakata,
Junko Nagura,
Akira Okayama,
Kazuo Minematsu,
Hiroaki Naritomi,
Shigenori Honda,
Kiyoshi Sato,
Hitonobu Tomoike,
Toshiyuki Miyata
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ABSTRACT: gamma-Glutamyl carboxylation, a reaction essential for the activity of vitamin K-dependent proteins, requires the concerted actions of gamma-glutamyl carboxylase (GGCX), vitamin K 2, 3-epoxide reductase complex 1 (VKORC1), and the chaperone calumenin (CALU). We evaluated the contribution of genetic polymorphisms in VKORC1, GGCX, and CALU to interindividual variation in the activities of plasma protein C and protein S. We sequenced these 3 genes in 96 Japanese individuals and geno-typed 9 representative single-nucleotide polymorphisms in 3655 Japanese individuals representative of the general population. The mean activity of protein C in women bearing the GG genotype of GGCX 8016G>A (130.8% +/- 1.5%, n = 156) was significantly greater (P = .002) than that of individuals with either the AG (126.8% +/- 0.7%, n = 728) or the AA (125.4% +/- 0.6%, n = 881) genotype, after adjusting for confounding factors. The GGCX 8016G>A change leads to the substitution of Gin for Arg at amino acid residue 325 (Arg 325 Gln). This effect was comparable to that of a previously defined polymorphism in the protein C promoter. Mean protein S activity was influenced by the VKORC1 3730G>A and CALU 20943T>A genotypes, after adjusting for confounding factors. Thus, polymorphisms in genes involved in the vitamin K-dependent gamma-carboxylation reaction influence interindividual variation in the activities of protein C and protein S in the general population.
International Journal of Hematology 12/2006; 84(5):387-97. · 1.27 Impact Factor
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ABSTRACT: The onset of intracerebral hemorrhage (ICH) has a circadian variation, with a lower risk during the asleep period. It is unclear, however, whether ICH during the asleep period differs from that during the awake period in pathophysiologic nature. The purpose of this study is to elucidate the incidences and clinical features of ICH during the asleep period.
We studied 129 consecutive patients with primary ICH and classified them into two groups according to the circumstance of their stroke onset, either during the awake period (awake ICH group) or the asleep period (asleep ICH group). Demographic and clinical characteristics were then compared between the two groups.
Of the patients, 19 (14.7%) had ICH during the asleep period. The mortality rate at 1 month after the stroke was significantly higher in the asleep ICH group than in the awake ICH group (21.1% v 4.9%, P = .0325). The hemorrhage volume in the asleep ICH group was also significantly larger than that in the awake ICH group (mean volume, 32.6 mL v 16.7 mL, P = .0122).
Our findings indicate that ICH during the asleep period may be more detrimental compared with ICH during the awake period, causing larger hematoma and higher mortality rates.
American Journal of Hypertension 05/2006; 19(4):403-6. · 3.18 Impact Factor
