Toshiyuki Fujinaka

II. Cerebral Infarction/Transient Ischemic Attack (TIA)

Stroke is the third most common cause of death in Japan. Approximately 0.13 million people die of stroke each year, and in 60% of them it is attributable to cerebral infarction. The accurate incidence of cerebral infarction is unknown, but it is roughly estimated to be around 100-200 per 0.1 million population and 600 per 0.1 million population for people aged 40 years or older. In Japan where the super-aging of society is rapidly progressing, the incidence, the patient number and the mortality rates of cerebral infarction, and the people requiring care are anticipated to grow exponentially in the future. Cerebral infarctions are roughly classified into “lacunar infarction” associated with a small deep infarction attributable to a penetrating branch of a large artery; “atherothrombotic cerebral infarction” caused by large artery atherosclerosis; “cardioembolic stroke” attributable to car-

BDNF atelocollagen mini-pellet accelerates facial nerve regeneration

We investigated the effect of BDNF mini-pellet on the GAP-43 mRNA expression and functional status of facial nerve in a rat model of facial nerve transection and immediate repair. The facial function started to recover at 17 days in the placebo group and 14 days in the BDNF group. BDNF group had shorter period of increased GAP-43 mRNA expression than the placebo group. Topically applied BDNF may accelerate the facial nerve regeneration.

Endovascular Therapy for Asymptomatic Unruptured Intracranial Aneurysms JR-NET and JR-NET2 Findings

Background and Purpose— National registration studies (the Japanese Registry of Neuroendovascular Therapy [JR-NET] and JR-NET2) have determined the current status and outcomes of neuroendovascular therapy (neuro-EVT). We analyzed short-term outcomes of EVT for asymptomatic unruptured intracranial aneurysms (UIAs). Methods— We extracted periprocedural information about EVT for 4767 asymptomatic UIAs from 31 968 registered procedural records of all EVT in the JR-NET and JR-NET2 databases. We assessed the features of the aneurysms and procedures, immediate radiographic findings, procedure-related complications, and clinical outcomes at 30 days after the procedures. Results— We located 80.0% of UIAs in the anterior circulation, and the most frequent were paraclinoid. The diameter of 2.5%, 32.9%, 51.9%, 12.0%, and 0.7% of the UIAs was <3, 3 to 4, 5 to 9, 10 to 19, and >20 mm, respectively. EVT failed in only 2.1%. Adjunctive techniques were applied in 54.8% of procedures. Pre- and postprocedural antiplatelet agents were prescribed in 85.6% and 84.0%, respectively, of the procedures. The immediate radiographic outcomes of 57.7%, 31.9%, and 10.0% of the UIAs comprised complete occlusion, residual necks, and residual aneurysms, respectively. Complications that were associated with 9.1% of procedures comprised 2.0% hemorrhagic and 4.6% ischemic, and the 30-day morbidity and mortality rates were 2.12% and 0.31%, respectively. Conclusions— The radiographic results of EVT for asymptomatic UIAs in Japan were acceptable, with low mortality and morbidity rates.

Periprocedural Cilostazol Treatment and Restenosis after Carotid Artery Stenting: The Retrospective Study of In-Stent Restenosis after Carotid Artery Stenting (ReSISteR-CAS)

Restenosis after carotid artery stenting (CAS) is a critical issue. Cilostazol can reduce restenosis after interventions in coronary or femoropopliteal arteries. We investigated whether periprocedural cilostazol treatment was related to the incidence of in-stent restenosis (ISR) or target vessel revascularization (TVR) after CAS. The study group comprised 553 of 580 patients who underwent CAS between April 2003 and August 2006 and were followed for 30 months after the procedure. ISR was defined as stenosis of at least 50% detected on angiography or ultrasonography. TVR was defined as revascularization of the treated carotid artery. During CAS, 207 patients (37.4%) were treated with cilostazol. Over 30 months, ISR occurred in 23 patients (4.2%), TVR occurred in 16 patients (2.9%), and either ISR or TVR occurred in 25 patients (4.5%). The incidence of ISR or TVR was significantly lower in the cilostazol-treated group than in the untreated group (1.4% vs 6.4%; log-rank P = .006). In a multivariate analysis, cilostazol treatment (hazard ratio [HR], 0.28; 95% confidence interval [CI], 0.08-0.95; P = .041) and stent diameter (HR, 0.73/1-mm increase; 95% CI, 0.54-0.99; P = .044) were independent factors for the occurrence of ISR or TVR. The incidence of a composite of events, including thromboembolism, hemorrhage, death, and TVR, tended to be lower in the cilostazol-treated group than in the untreated group (15.0% vs 19.9%; log-rank P = .17). Periprocedural cilostazol treatment was associated with lower rates of ISR and retreatment after CAS. A prospective randomized controlled trial is needed to clarify the effect of cilostazol on ISR after CAS.

Src Family Kinase Inhibitor PP1 Reduces Secondary Damage after Spinal Cord Compression in Rats

The synthetic pyrazolopyrimidine, 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1) is a novel, potent, and selective inhibitor of Src family tyrosine kinases. Vascular permeability appears to be mediated by vascular endothelial growth factor (VEGF), which requires the activation of downstream Src family kinases to exert its function. This study investigates the effects of PP1 on vascular permeability and inflammatory response in a rat spinal cord compression model. Ten minutes after compression, PP1 (PP1 group) or the vehicle only (control group) was administered. On days 1, 3, and 7 after compression, the spinal cords were removed and examined histopathologically to determine the expression of VEGF and the extent of edema and inflammation. The dryweight method was used to measure the water content of the spinal cords. The mRNA levels of tumor necrosis factor a (TNFalpha) and interleukin 1beta (IL-1beta), which is related to inflammatory responses, were measured with a real-time polymerase chain reaction (RT-PCR) system 6 h after compression. Although VEGF expression was similar in both groups, the extent of contusional lesion in the PP1 group was reduced by approximately 35% on day 3. Moreover, the water content on days 1, 3, and 7 was significantly reduced and macrophage infiltration on days 3 and 7 was dramatically reduced in the PP1 group. TNF and IL-1beta mRNA expression in the PP1 group were also significantly reduced. These results indicate that PP1 reduces secondary damage after spinal cord injury.

Kainic acid-induced seizure upregulates Na+/myo-inositol cotransporter mRNA in rat brain

A major organic osmolyte, myo-inositol protects cells from perturbing effects of high intracellular concentrations of electrolytes. Myo-inositol is accumulated into cells through Na(+)/myo-inositol cotransporter (SMIT). In order to investigate the regulation of SMIT in generalized seizure, we employed Northern blot analysis and in situ hybridization to study the changes in SMIT mRNA expression in kainic acid-injected rats. Northern blot analysis demonstrated that SMIT mRNA began to increase in the brain 2 h after onset of seizure, and peaked at 12 h. In situ hybridization revealed rapid increase of SMIT mRNA (2 h of seizure) in the CA3 hippocampal pyramidal cells and in the dentate granular cells. Then, at 4-6 h SMIT mRNA expression was observed in the other limbic structure such as amygdala and piriform cortex. Finally, in neocortex and in CA1 pyramidal cells, SMIT mRNA was slowly increased and peaked at 12 h. Microautoradiogram demonstrated that cells expressed SMIT mRNA were mainly neurons. These results suggest that SMIT mRNA is upregulated by kainic acid-induced seizure primarily in structures involved in seizure activity.

Interleukin-6 release after carotid artery stenting and periprocedural new ischemic lesions

Carotid artery stenting (CAS) is currently a standard procedure to treat severe carotid artery stenosis. This procedure causes mechanical plaque rupture, potentially releasing soluble factors into the circulating blood. The purpose of this study is to clarify whether inflammation factors are released from an atherosclerotic plaque after CAS and whether local release of inflammation factors is associated with periprocedural new ischemic lesions. The study consisted of 35 patients with 40 severely stenotic carotid arteries who underwent CAS. Blood samples were obtained from the aorta before the procedure and from the carotid plaque site just after the procedure. Blood levels of interleukin-6 (IL-6), interleukin-18, matrix metalloproteinase (MMP)-2, and tissue inhibitor of MMP-1 were determined. Diffusion-weighted magnetic resonance imaging was performed before and after the procedure. Among inflammatory markers, IL-6 levels markedly increased at the plaque site in comparison to those at the aorta (P<0.001). The IL-6 levels in the local samples were significantly higher in symptomatic lesions than those in asymptomatic lesions. More importantly, higher local IL-6 levels were associated with the appearance of new ischemic lesions (P=0.003). The association remained significant (P=0.030) after controlling for potential risk factors for CAS. Association of local IL-6 levels and periprocedural new ischemic lesions suggests that massive release from the plaque and entry into the cerebral circulation of IL-6 might be one of important factors on periprocedural complications related to CAS.

I. Stroke in general.

Stroke is the third most common cause of death following cancer and cardiac diseases in Japanese people. This order has not changed since 1980. However, because stroke is the most common disease leading to a bedridden state and its incidence is 3to 10-fold higher than that of myocardial infarction, there is no doubt that the prevention and treatment of stroke are important in Japan. Compared with Western countries, stroke may be more frequent in Japan due to differences in dietary habit such as higher salt intake and lower fat intake. The daily salt intake for Japanese people is around 12 g and is obviously higher than that for American people. Excessive salt intake is related to hypertension which is the greatest risk factor for stroke. In particular, salt sensitive hypertension is profoundly related to nocturnal hypertension, and may have a high risk of stroke. Nonetheless, non–salt-sensitive hypertension is somewhat more frequent than salt sensitive hypertension

The morphological and neurochemical effects of diffuse brain injury on rat central noradrenergic system

Abstract The central noradrenergic system is widely distributed throughout the brain and is closely related to spontaneous motility and level of consciousness. The study presented here evaluated the morphological as well as neurochemical effects of diffuse brain injury on the central noradrenergic system in rat. Adult male Sprague–Dawley rats were subjected to impact–acceleration brain injury produced with a weight-drop device. Morphological changes in locus coeruleus (LC) neurons were examined by using immuno-histochemistry for dopamine-β-hydroxylase, and norepinephrine (NE) turnover in the cerebral cortex was measured by high performance liquid chromatography with electrochemical detection. The size of LC neurons increased by 11% 24 h after injury but had decreased by 27% seven days after injury. Axons of noradrenergic neurons were swollen 24 h and 48 h after injury but the swelling had dwindled in seven days. NE turnover was significantly reduced seven days after injury and remained at a low level until eight weeks after injury. These results suggest that focal impairment of axonal transport due to diffuse brain injury causes cellular changes in LC and that the neurochemical effect of injury on the central noradrenargic system lasts over an extended period of time. Chronic suppression of NE turnover may explain the sustained behavioral and psychological abnormalites observed in a clinical situation.

Recent trends in neuroendovascular therapy in Japan: analysis of a nationwide survey--Japanese Registry of Neuroendovascular Therapy (JR-NET) 1 and 2.

The present study retrospectively analyzed the database of the Japanese Registry of Neuroendovascular Therapy 1 and 2 (JR-NET1&2) to determine annual trends, including adverse events and clinical outcomes at 30 days after undergoing neuroendovascular therapy. JR-NET1&2 are surveys that targeted all patients in Japan who underwent neuroendovascular therapy delivered by physicians certified by the Japanese Society of Neuroendovascular Therapy (JSNET) between 2005 and 2009. Medical information about the patients was anonymized and retrospectively registered via a website. Data from 32,608 patients were analyzed. The number of treated patients constantly increased from 5,040 in 2005 to 7,406 in 2009 and the rate of octogenarians increased from 7.0% in 2005 to 10.4% in 2009. The proportion of procedures remained relatively constant, but ratios of angioplasty slightly increased from 32.8% in 2005 to 33.7% in 2009. Procedural complications were associated more frequently with acute stroke (9.6%), ruptured aneurysms (7.4%), intracranial artery disease (ICAD) (5.4%), and arteriovenous malformation (AVM, 5.2%). The number of patients requiring neuroendovascular treatment in Japan is increasing and the outcomes of such therapy are clinically acceptable. Details of each type of treatment will be investigated in sub-analyses of the database.