Hyperhomocysteinemia induced by excessive methionine intake promotes rupture of cerebral aneurysms in ovariectomized rats.

BackgroundHyperhomocysteinemia (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.MethodsThirteen-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.ResultsDuring 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.ConclusionsWe 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

Impact of Right Ventricular Dilatation in Patients with Atrial Septal Defect

Objective. The aim of this study was to examine the relationship between right ventricular (RV) volume and exercise capacity in adult patients with atrial septal defect (ASD) and to determine the degree of RV dilatation for transcatheter ASD closure. Background. RV dilatation is an indication of transcatheter ASD closure; however, few studies have reported the clinical significance of RV dilatation. Methods. We enrolled 82 consecutive patients (mean age, 49 +/- 18 years; female, 68%) who underwent cardiac magnetic resonance imaging and symptom-limited cardiopulmonary exercise test before ASD closure. The relationship between RV volume and peak oxygen uptake (VO2) was evaluated. Results. The mean RV end-diastolic volume index was 108 +/- 27 ml/m(2) (range, 46 to 180 ml/m(2)). The mean peak VO2 was 24 +/- 7 ml/min/kg (range, 14 to 48 ml/min/kg), and the mean predicted peak VO2 was 90 +/- 23%. There were significant negative relationships of RV end-diastolic volume index with peak VO2 (r = -0.28, p= 120 ml/m(2) was related to the reduction in peak VO2. This criterion of RV dilatation may be valuable for the indication of transcatheter ASD closure

Treatment with the PPARγ Agonist Pioglitazone in the Early Post-ischemia Phase Inhibits Pro-inflammatory Responses and Promotes Neurogenesis Via the Activation of Innate- and Bone Marrow-Derived Stem Cells in Rats

Neurogenesis is essential for a good post-stroke outcome. Exogenous stem cells are currently being tested to promote neurogenesis after stroke. Elsewhere, we demonstrated that treatment with the PPARγ agonist pioglitazone (PGZ) before cerebral ischemia induction reduced brain damage and activated survival-related genes in ovariectomized (OVX) rats. Here, we tested our hypothesis that post-ischemia treatment with PGZ inhibits brain damage and contributes to neurogenesis via activated stem cells. Bone marrow (BM) cells of 7-week-old Wistar female rats were replaced with BM cells from green fluorescent protein-transgenic (GFP+BM) rats. Three weeks later, they were ovariectomized (OVX/GFP+BM rats). We subjected 7-week-old Wistar male and 13-week-old OVX/GFP+BM rats to 90-min cerebral ischemia. Male and OVX/GFP+BM rats were divided into two groups, one was treated with PGZ (2.5 mg/kg/day) and the other served as the vehicle control (VC). In both male and OVX/GFP+BM rats, post-ischemia treatment with PGZ reduced neurological deficits and the infarct volume. In male rats, PGZ decreased the mRNA level of IL-6 and M1-like macrophages after 24 h. In OVX/GFP+BM rats, PGZ augmented the proliferation of resident stem cells in the subventricular zone (SVZ) and the recruitment of GFP+BM stem cells on days 7–14. Both types of proliferated stem cells migrated from the SVZ into the peri-infarct area. There, they differentiated into mature neurons, glia, and blood vessels in association with activated Akt, MAP2, and VEGF. Post-ischemia treatment with PGZ may offer a new avenue for stroke treatment through contribution to neuroprotection and neurogenesis

MEDICAL TREATMENT OF UNRUPTURED CEREBRAL ANEURYSMS

Background: 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. Methods: 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. Results: 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%. Conclusion: 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

クモマクカ シュッケツ ニ ゾクハツ シタ ジュウショウ ノ Neurogenic stress cardiomyopathy ノ ケントウ

Neurogenic stress cardiomyopathy（NSC）is caused by catecholamine excess and／or sympathetic nerve activation, presented as a transient cardiac wall motion abnormality. It is reported to occur in ４‐１５％ of patients suffering from subarachnoid hemorrhage（SAH）. Of particular concern, severe NSC leading to cardiac dysfunction is especially important to consider when treating SAH patients in the acute stage because it could affect the prognosis of SAH and the timing of surgery. Currently, the incidence of severe NSC and risk factors are not well characterized. In the present study, we reviewed the medical records of８５patients（２０men,６５women）who were admitted and treated for ruptured cerebral aneurysms at Tokushima University Hospital during the period from January ２０１０ to May ２０１２. NSC occurred in five patients（５．９％）, and three of those patients（３．５％）showed severe NSC with cardiac dysfunction. NSC was observed only in patients with poor SAH-grade, and those resulting in severe cardiac dysfunction were all in women. Notably, the incidence of severe NSC was particularly high in female patients with poor SAH-grades （１７．６％）. We reported the morbidity of severe NSC in patients with SAH. It is important to pay special attention to severe NSC in female patients, particular those with poor SAH-grades

破裂脳動脈瘤の発症12日目に別の未破裂脳動脈瘤が破裂した1例

　67歳女性．以前より左中大脳動脈・脳底動脈本幹・左海綿静脈洞部内頚動脈に未破裂脳動脈瘤を指摘されていた．突然に激しい頭痛・嘔気が出現し，その5日後に他院でsubarachnoid hemorrhage（SAH）を指摘されたため，当院紹介となった．CT で左シルビウス裂・左大脳半球脳溝を中心にSAH を認めるも，脳幹周囲には認めなかった．緊急DSA では，左中大脳動脈瘤は4.9mm でbleb を伴っていたが，脳底動脈瘤は6.5mm，左内頚動脈瘤は2.9mm で，いずれもblebはなかった．左中大脳動脈瘤の破裂と考え，緊急で同部位にコイル塞栓術を施行し，ほぼ完全閉塞された．しかし，第12病日に突然昏睡状態となり，CT で橋腹側を中心に新たなSAH を認めた．脳底動脈瘤の破裂と診断し，緊急コイル塞栓術を行った．術後意識状態は改善し，NPH に対しVP シャントを追加し，mRS1で自宅退院となった．短期間で2個の動脈瘤が破裂した比較的稀な症例と考えられ，報告する．　We report a rare case of recurrent bleeding caused by another cerebral aneurysm during the subacute phase of aneurymal subarachnoid hemorrhage (SAH). A 67-yearold woman developed severe headache and visited our hospital on the 5th day from the onset. Her computed tomography (CT) confirmed SAH, and her angiography revealed three intracranial aneurysms: a 4.9-mm left middle cerebral artery aneurysm (MCA An) with bleb formation, a 6.5-mm basilar trunk aneurysm (BA trunk An) without bleb, and a 2.9-mm internal carotid cavernous sinus aneurysm without bleb. As the SAH was present mostly in the left cerebral hemisphere and left Sylvian fissure without the involvement of the basal cistern. MCA An was thought to bleed. Subsequently, she underwent coil embolization and recovered well. However, she suddenly became comatose on the 12th day from the onset. Her CT showed diffuse SAH localized around the prepontine cistern. Second angiography demonstrated the expanded BA trunk An. Coil embolization was then successfully performed. VP shunt insertion was added for hydrocephalus secondary to SAH, and left our hospital with favorable outcome

Stretching Actin Filaments within Cells Enhances their Affinity for the Myosin II Motor Domain

To test the hypothesis that the myosin II motor domain (S1) preferentially binds to specific subsets of actin filaments in vivo, we expressed GFP-fused S1 with mutations that enhanced its affinity for actin in Dictyostelium cells. Consistent with the hypothesis, the GFP-S1 mutants were localized along specific portions of the cell cortex. Comparison with rhodamine-phalloidin staining in fixed cells demonstrated that the GFP-S1 probes preferentially bound to actin filaments in the rear cortex and cleavage furrows, where actin filaments are stretched by interaction with endogenous myosin II filaments. The GFP-S1 probes were similarly enriched in the cortex stretched passively by traction forces in the absence of myosin II or by external forces using a microcapillary. The preferential binding of GFP-S1 mutants to stretched actin filaments did not depend on cortexillin I or PTEN, two proteins previously implicated in the recruitment of myosin II filaments to stretched cortex. These results suggested that it is the stretching of the actin filaments itself that increases their affinity for the myosin II motor domain. In contrast, the GFP-fused myosin I motor domain did not localize to stretched actin filaments, which suggests different preferences of the motor domains for different structures of actin filaments play a role in distinct intracellular localizations of myosin I and II. We propose a scheme in which the stretching of actin filaments, the preferential binding of myosin II filaments to stretched actin filaments, and myosin II-dependent contraction form a positive feedback loop that contributes to the stabilization of cell polarity and to the responsiveness of the cells to external mechanical stimuli

Post-ischemic hyperperfusion after clipping of a ruptured internal carotid-posterior communicating artery aneurysm under suction decompression

A 64-year-old woman presenting with subarachnoid hemorrhage (World Federation of Neurosurgeons grade IV) from the rupture of a right large internal carotid-posterior communicating artery aneurysm suffered neuronal damage associated with post-ischemic hyperperfusion after neck clipping of the aneurysm under suction decompression. She did not completely recover consciousness after the operation. Diffusion-weighted imaging (DWI) performed on the first postoperative day showed subtle cortical hyperintensity in the parietal lobe. Arterial spin-labeling (ASL) and 123I-iodoamphetamine (123I-IMP) single photon emission computed tomography (SPECT) demonstrated hyperperfusion in the right temporo-parietal lobes. Delayed 123I-iomazenil (123I-IMZ) SPECT images showed a reduced IMZ uptake in the right temporo-parietal lobe corresponding to the hyperperfusion area on ASL images. DWI repeated on postoperative day 3 revealed progression of a hyperintensity lesion in the right parietal lobe. Blood pressure control and the use of a free radical scavenger relieved her symptoms. One month later, the area of reduced IMZ uptake was further expanded. Our findings suggest that post-ischemic hyperperfusion after suction decompression may result in neuronal damage demonstrated on 123I-IMZ SPECT images