Total synthesis of (-)-domoic acid, a potent ionotropic glutamate receptor agonist and the key compound in oceanic harmful algal blooms.

The stereo-controlled total synthesis of (-)-domoic acid is described. The critical construction of the C1'-C2' Z-configuration was accomplished by taking advantage of an unsaturated lactam structure. The side chain fragment was introduced in the final stages of synthesis through a modified Julia-Kocienski reaction, aiming for its efficient derivatization.

Clinical outcomes of cerebral infarction in nonagenarians compared among four age groups.

BACKGROUND: Average female life expectancy in Japan is approximately 90 years. Occasionally, we encounter stroke patients older than 90 years. AIMS: To determine the clinical features and outcomes associated with cerebral infarction in patients aged ≥ 90 years. METHODS: We examined 289 consecutive patients (163 males, 129 females; mean age 77.5 years) diagnosed with cerebral infarction. We divided them into four groups according to age in years: middle (< 65), pre-old (65-74), old (75-89), and super old (≥ 90). We divided the super old group into mild symptoms (NIHSS ≤ 5) and severe symptoms (NIHSS > 5) and examined outcomes. RESULTS: Statistically significant associations were observed between female sex, cardiogenic infarction, and high complication rates and super old age. NIHSS and mRS scores at 30-day post-stroke were higher in the super old group. In some cases, complications led to poor prognoses. Eighty-seven percent of patients with mild symptoms (NIHSS ≤ 5) recovered to mRS 0-2 similar to the younger age group. None of the patients with severe symptoms (NIHSS > 5) recovered to mRS 0-2. DISCUSSION: We investigated the clinical outcomes following cerebral infarction in patients aged 90 years or older and found that mild symptoms were consistently associated with good prognoses, regardless of patients' age. CONCLUSIONS: Patients in the super old group had more severe symptoms and poorer outcomes than younger age groups. However, patients with mild symptoms tended to have better prognoses and returned to daily life similar to the younger age group.

Removal of Double Cavernous Angioma of the Frontal Lobe using a Three-Dimensional Printed Model: A Case Report.

Cerebral cavernous angiomas are vascular anomalies with dilated spaces. We report the case of rare double cavernous angiomas causing higher brain dysfunction. A 74-year-old man exhibited cognitive dysfunction. Magnetic resonance imaging showed two tumors with hemorrhage in the left frontal lobe. Preoperative diagnosis was hemorrhage caused by cavernous angiomas. A 3D model of the double cavernous angioma was made to confirm their association with cortical veins and tumors. Tumors were removed using a single small corticotomy. This is the first report of a rare double cavernous angioma and the 3D printed model facilitated removal of the tumors.

Importance of Finding Embolic Sources for Patients with Embolic Stroke of Undetermined Source.

OBJECTIVE: The concept of embolic stroke of undetermined source refers to cryptogenic strokes caused by either major or minor risks. Although antiplatelet treatments are most often used for secondary prevention of embolic stroke of undetermined source, optimal strategies remain unclear. To determine the ideal treatment strategy for secondary prevention, we investigated embolic sources among patients with embolic stroke of undetermined source. METHODS: The study included 292 consecutive patients (135 men, 157 women; mean age: 74.3 ± 11.6 years) diagnosed with cerebral infarction, 27 of whom were diagnosed with embolic stroke of undetermined source (9.2%; 14 men, 13 women; mean age: 70.7 ± 11.5 years). These 27 patients were examined using contrast-enhanced whole-body computed tomography, transesophageal echocardiography, and Holter electrocardiography. We evaluated whether antiplatelet or anticoagulant treatment was preferred based on the embolic source. RESULTS: Embolic sources among patients with embolic stroke of undetermined source included valve calcification (11.1%), left ventricle diastolic dysfunction (18.5%), cancer-associated stroke (25.9%), covert atrial fibrillation (7.4%), aortic arch atherosclerotic plaques (11.1%), paradoxical embolism (3.7%), and sick sinus syndrome (3.7%). Embolic sources remained unidentified in 5 patients (18.5%). Our analysis revealed that 21 of the 27 patients (77.8%) with embolic stroke of undetermined source required anticoagulant therapy for secondary prevention. CONCLUSION: Although aspirin is the most commonly used antithrombotic drug for embolic stroke of undetermined source, our results suggest that some patients require anticoagulant therapy. Determining embolic sources is important for selecting the appropriate treatment options for this patient population.

[Takotsubo Cardiomyopathy and Neurogenic Pulmonary Edema Following Fibrinolytic Therapy for Embolic Stroke:A Case Report].

A 79-year-old man presented with left hemiparesis and disturbance of consciousness. Brain magnetic resonance(MR)imaging revealed an infarction in the right insular cortex. MR angiography showed a defect in the inferior trunk of the right middle cerebral artery. The patient was treated with alteplase about 2.5 h after onset. Immediately after the intravenous alteplase administration, the hemiparesis improved. However, his respiratory condition unexpectedly worsened 10 h after onset. Chest radiography demonstrated an infiltrative shadow in both lung fields. Transthoracic echocardiogram showed a dysfunction in the left ventricle and no contraction at the apex of the heart, consistent with a type of cardiomyopathy, known as takotsubo cardiomyopathy(TCM). Gradually, the patient's respiratory and cardiac function improved. Here, we describe a very rare case of TCM and neurogenic pulmonary edema(NPE)following an acute cerebral infarction, which was treated with alteplase intravenous administration. TCM and NPE have a poor prognosis, therefore diagnosis, management, and treatment in the acute phase is required.

A Case of Acromegaly in which a Pituitary Gland Tumor was Reduced Significantly by Administering Octreotide Long Acting Release (LAR) and Could Be Removed Surgically.

A 54-year-old woman was admitted to our hospital for detailed examination of acromegaly because she noticed bilateral hand and finger swelling at the age of 43 and plantar thickening, facial changes and unclear articulation at the age of 49. She had prominent brow ridges, mandibular protrusion, and enlargement of the hands, feet, nasal wings, lips and tongue. Her growth hormone (GH) level was 39.8 ng/ml, insulin-like growth factor-1 (IGF-1) level was 717 ng/ml, GH level was not suppressed (22.9 ng/ml) during a 75-g oral glucose tolerance test (OGTT). Radiography showed cauliflower-like enlargement of the distal phalanx of the fingers, thickening/enlargement of the plantar soft tissues, and increased antero-posterior diameter of the sella turcica. Magnetic resonance imaging showed a mass (21×17 mm) growing towards the right suprasellar region and invading the cavernous sinus. She was diagnosed with acromegaly based on the characteristic physical findings, GH excess, high IGF-1, lack of GH suppression during the 75-g OGTT, and the presence of a pituitary tumor. She was started on octreotide long acting release (Oct-LAR) 20 mg/4w for tumor shrinkage. After three doses, her GH and IGF-1 levels decreased to 2.19 ng/ml (1.69 during the 75-g OGTT) and 205 ng/ml, respectively, meeting cure criteria for acromegaly. In this case, a decrease in GH and IGF-1 levels, tumor shrinkage, and resolution of cavernous sinus invasion allowed the patient to undergo surgery with curative intent (the first-line treatment for acromegaly) without postoperative complications. Thus, preoperative Oct-LAR administration has the potential to improve treatment outcomes of acromegaly.

Prediction of hard meningiomas: quantitative evaluation based on the magnetic resonance signal intensity.

BACKGROUND: From a surgical perspective, presurgical prediction of meningioma consistency is beneficial. PURPOSE: To quantitatively analyze the correlation between the magnetic resonance (MR) signal intensity (SI) or apparent diffusion coefficient (ADC) and meningioma consistency and to determine which MR sequence could help predicting hard meningiomas. MATERIAL AND METHODS: This study included 43 patients with meningiomas who underwent preoperative MR imaging (MRI), including T1-weighted (T1W) imaging, T2-weighted (T2W) imaging, fluid-attenuated inversion recovery (FLAIR), diffusion-weighted imaging (DWI), contrast-enhanced (CE)-T1W imaging, and CE-fast imaging employing steady-state acquisition (FIESTA). A neurosurgeon evaluated the tumor consistency using a visual analog scale (VAS) with the anchors "soft" (score = 0) and "hard" (score = 10). The SI ratio (tumor to cerebral cortex SI) and ADC value were compared with the tumor consistency. The sensitivity, specificity, and accuracy for predicting hard meningiomas (VAS score ≥8; 9 of 43 patients) were calculated using cutoff values for the SI ratio that were obtained in a receiver operating characteristic curve analysis. RESULTS: A significant negative correlation was observed between the tumor consistency and the SI ratio on T2W imaging, FLAIR, and CE-FIESTA (P < 0.05) but not on T1W imaging, CE-T1W imaging, and the ADC value. The sensitivity, specificity, and accuracy for predicting hard meningiomas were 89%, 79%, and 81% with T2W imaging; 89%, 76%, and 79% with FLAIR; and 100%, 74%, and 79% with CE-FIESTA, respectively. CONCLUSION: Our results suggest that a quantitative assessment using conventional T2W imaging or FLAIR may be a simple and useful method for predicting hard meningiomas.

Urinary Retention Associated with Stroke.

Patients often exhibit urinary retention following a stroke. Various neuropathological and animal studies have implicated the medulla oblongata, pons, limbic system, frontal lobe as areas responsible for micturition control, although the exact area responsible for urinary retention after stroke is not clear. The purpose of this study was to identify the stroke area responsible for urinary retention by localizing the areas where strokes occur. We assessed 110 patients with cerebral infarction and 27 patients with cerebral hemorrhage (78 men, 59 women; mean age, 73.0 years) who had been admitted to our hospital between October, 2012 and September, 2013. We used computed tomography (CT) and magnetic resonance imaging (MRI) to investigate the stroke location, and evaluated whether post-stroke urinary retention occurred. Twelve (8.8%) of the 137 patients (7 men, 5 women; mean age, 78.8 years) exhibited urinary retention after a stroke. Stroke occurred in the right/left dominant hemisphere in 7 patients; nondominant hemisphere in 1; cerebellum in 3; and brainstem in 1. Strokes in the dominant hemisphere were associated with urinary retention (P = 0.0314), particularly in the area of the insula (P < 0.01). We concluded that stroke affecting the insula of the dominant hemisphere tends to cause urinary retention.

Pilocytic astrocytoma presenting with atypical features on magnetic resonance imaging.

Pilocytic astrocytoma, which is classified as a grade I astrocytic tumor by the World Health Organization, is the most common type of glioma in children and young adults. Pilocytic astrocytoma generally appears as a well-circumscribed, contrast-enhancing lesion, frequently with cystic components on magnetic resonance imaging (MRI). However, it has been reported that the MRI appearance of pilocytic astrocytoma may be similar to that of high-grade gliomas in some cases. We here report on 6 cases of pilocytic astrocytoma with atypical MRI findings, including small cyst formation, heterogeneously enhancing tumor nodules, irregularly enhancing tumor nodules, and enhancing tumor nodules with internal hemorrhage. All tumors were successfully resected, and the histological diagnoses were pilocytic astrocytoma. When the tumor is located near a cerebral cistern or ventricle, the risk of leptomeningeal dissemination is increased. Furthermore, partial resection has also been associated with a higher risk of recurrence and leptomeningeal dissemination. To date, all but one patient are alive and recurrence-free. Because the preoperative diagnosis influences the decision on the extent of resection and because of the high risk of leptomeningeal dissemination associated with these tumors, careful and correct diagnosis by MRI is important.

[Pitfall in conservative therapy for working patients with brain ischemia].

A 59-year-old employed man was recommended to have surgical treatment for symptomatic left middle cerebral arterial stenosis. He refused surgical treatment for social reasons but was given conservative therapy for the prevention of the recurrence of cerebral infarction. Immediately after he retired, he had severe recurrent cerebral infarction with severe anemia and low blood pressure due to gastroduodenal ulcer bleeding. It was inferred from MRI findings that this recurrent cerebral infarction was related to a hemodynamic mechanism and mental stress due to the gastroduodenal ulcer. The influence of occupational mental stress has been reported to be a risk factor of gastroduodenal ulcer. The occupational situation of a patient should be an important factor in consideration of the prevention of cerebral apoplexy.

Limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies as a cause of adult-onset mesial temporal lobe epilepsy.

Recently, some reports have indicated that limbic encephalitis associated with anti-voltage-gated potassium channel complex antibodies (VGKC-Ab) is a cause of adult-onset mesial temporal lobe epilepsy (MTLE). We report a 53-year-old woman who had her first epileptic seizure at the age of 50 years old. Examination by 3-Tesla brain MRI revealed left hippocampal high signal intensity and swelling on fluid-attenuated inversion recovery (FLAIR) and T2-weighted imaging at 2 months after her first seizure. The patient received intravenous methylprednisolone and carbamazepine 300 mg/day. One month later, MRI revealed improvement of her left hippocampal abnormalities. Thereafter, she had no seizures, however, three years after her first seizure, EEG revealed a seizure pattern in the left temporal region. Brain MRI revealed left hippocampal high signal intensity and brain fluorodeoxyglucose positron emission tomography revealed hypermetabolism. Her serum VGKC-Ab levels were 118 pM(normal < 100 pM). Intravenous methylprednisolone therapy was reinitiated. Two months later, her hippocampal abnormalities had improved and 3 months later her VGKC-Ab levels decreased to 4.4 pM. Remission of the epileptic seizures was also observed. This MTLE in the middle age was considered as limbic encephalitis associated with anti- VGKC-Ab. In cases of unexplained adult-onset MTLE, limbic encephalitis associated with anti-VGKC-Ab, which responds well to immunotherapy, should be considered in the differential diagnosis.

[Case of spontaneous cervical internal carotid artery dissection with embolic stroke after a job-change].

A 51 year old male was admitted to our hospital with sudden consciousness disturbance, global aphagia and right hemiparesis. Magnetic resonance imaging (MRI) revealed fresh infarctions in the territory of the left middle cerebral artery, and MR angiography (MRA) showed occlusion of the left carotid artery and the left middle cerebral artery. We started conservative therapy, including antiplatelet drug and blood pressure control. Three days later, cervical MRA revealed hematoma in the intracranial carotid wall of the petrous portion, leading to a diagnosis of spontaneous intracranial carotid artery dissection of the petrous portion. Two weeks after admission, MRA and angiography showed recanalization and pearl and string sign in the left petrous internal carotid artery. After that, the patient's neurological deficit improved, and the dissection also improved. Four months later, MR-angiography revealed an almost normalized condition.

The roles of early brain injury in cerebral vasospasm following subarachnoid hemorrhage: from clinical and scientific aspects.

Cerebral vasospasm research has been focused on investigating the mechanisms of prolonged delayed vasoconstriction of cerebral arteries following subarachnoid hemorrhage (SAH). However, it has been clarified that induction of significant vasodilation of such arteries does not lead to better overall outcomes in SAH patients. On the other hand, early brain injury, such as cortical spreading depression, early cortical depolarization waves, and impairment of neurovascular coupling, is seen acutely after SAH and may play a significant role in early impairment of brain function following SAH. These results clearly indicate that it is time to reconsider what causes this early brain damage and dictates patient outcome following SAH; classical delayed cerebral vasospasm following SAH might be an epiphenomenon. It is of utmost importance to investigate whether early brain injury and delayed cerebral vasospasm correlate with each other following SAH or are independent. Recent results of cerebral vasospasm research indicates future directions, and such investigations would lead to better outcome for SAH patients.

Severe subarachnoid hemorrhage associated with cerebral venous thrombosis in early pregnancy: a case report.

BACKGROUND: Cerebral venous thrombosis (CVT) rarely induces subarachnoid hemorrhage (SAH). During late pregnancy and puerperium, CVT is an uncommon but important cause of stroke. However, severe SAH resulting from CVT is extremely rare during early pregnancy. OBJECTIVE: We report on a rare case of severe SAH due to CVT, and discuss the potential pitfalls of CVT diagnosis in early pregnancy. CASE REPORT: A 32-year-old pregnant woman (9th week of pregnancy) presented with slight head dullness. Initial magnetic resonance imaging (MRI) revealed focal, abnormal signal intensity in the left thalamus. Nine days later, the patient developed a generalized seizure and severe SAH was detected with computed tomography (CT) scan. MRI and cerebral angiography revealed a completely thrombosed superior sagittal sinus, vein of Galen, straight sinus, and right transverse sinus. Transvaginal sonography indicated a missed abortion. The day after admission, the patient presented again with a progressive loss of consciousness and signs of herniation. The patient underwent emergency decompressive craniotomy, followed by intrauterine curettage. Two months later, she made an excellent recovery except for a slight visual field defect. CONCLUSIONS: A rare case of severe SAH due to CVT is reported, with emphasis on the potential pitfalls of CVT diagnosis in early pregnancy.

Rate of return to work in patients with stroke under the health and employment support program of Rosai hospitals in Japan.

To facilitate return to work (RTW) in patients with stroke, a health and employment support (HES) program was started at Rosai hospitals in Japan. This study aimed to determine the rate of RTW in patients with stroke under this support program. We collected demographic and clinical data of patients with stroke from the implementation reports of the HES program. The program provided coordinated dual support, such as acute medical treatments, and stroke and vocational rehabilitation on the medical side, and management and support on the workplace side. The primary endpoint was RTW. Successful and unsuccessful RTW were examined using the χ2 test. The RTW rate curves were analyzed using the Kaplan-Meier method. We enrolled 483 patients; 355 (73%) and 128 (27%) patients had successful and unsuccessful RTW, respectively. Stroke types, neurological findings, and activities of daily living were significant factors for RTW. The Kaplan-Meier method revealed that left hemiplegia, right hemiplegia, and neuropsychological deficits, except for combined disability (hemiplegia with neuropsychological deficits), had similar RTW curves with an RTW rate of > 70%.

Delineation of optic nerves and chiasm in close proximity to large suprasellar tumors with contrast-enhanced FIESTA MR imaging.

PURPOSE: To evaluate whether contrast material-enhanced (CE) fast imaging employing steady-state acquisition (FIESTA) can depict the anterior optic pathways in patients with large suprasellar tumors. MATERIALS AND METHODS: Institutional review board approval was obtained. Twenty-eight patients with large suprasellar tumors undergoing surgical treatment (19 pituitary adenomas, six meningiomas, and three additional miscellaneous tumors) underwent preoperative magnetic resonance (MR) imaging, including CE FIESTA, at 3.0 T. Two radiologists assessed the visibility of five segments of the optic pathways (bilateral optic nerves and optic tracts, optic chiasm) with CE FIESTA and conventional MR imaging, including thin-section coronal T2-weighted imaging and CE T1-weighted imaging, by using a three-point scale. Moreover, the preoperative signal intensity of the optic pathways was correlated with pre- and postoperative visual impairment to determine whether high signal intensity at CE FIESTA is predictive of persistence of visual impairment after surgery. The χ(2) test was used to compare scores assigned to CE FIESTA and conventional MR images. RESULTS: The percentage of anterior optic pathways rated as visible was significantly higher with CE FIESTA than with conventional MR imaging (100% [140 of 140 segments] vs 78% [109 of 140 segments], P < .05). Thirty-one of the 140 segments (22%) were not depicted with conventional MR imaging; all of these 31 segments were visualized with CE FIESTA. For 12 patients who underwent transcranial surgery, the anatomic locations of the optic pathways at CE FIESTA were compatible with the surgical findings. CE FIESTA helped predict persistent visual impairment after surgical treatment with a sensitivity of 75% (three of four patients) and a specificity of 96% (23 of 24 patients). The accuracy of CT FIESTA in the prediction of visual loss was significantly higher than that of T2-weighted imaging (93% [26 of 28 patients] vs 50% [14 of 28 patients], P < .05). CONCLUSION: CE FIESTA is useful for the preoperative localization of the anterior optic pathways in patients with large suprasellar tumors and offers the potential to predict persistent visual impairment after decompression.

Monocarboxylate transporters 1 and 4 are involved in the invasion activity of human lung cancer cells.

Cancer cells show constitutive upregulation of glycolysis, and the concentration of lactate thus produced correlates with prognosis. Here, we examined whether lactate concentration and lactate transporter expression are related to migration and invasion activity. We found that the expression of the monocarboxylate transporters MCT1 and MCT4, but not MCT5, in human lung cancer cell lines was significantly correlated with invasiveness. To clarify the effects of MCT1 and MCT4 expression on invasion, we performed migration and invasion assays after transfection with siRNA specific for MCT1 or MCT4. Knockdown of MCT1 or MCT4 did not influence cell migration but reduced invasion; this was also observed for knockdown of the lactate transporter-associated protein basigin. We also demonstrated that both expression and activity of MMP9 and MMP2 were not correlated with invasion activity and not regulated by MCT1, MCT4 and basigin. Furthermore, the addition of lactate did not increase migration and invasion activity, but low concentration of 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS), a general anion channel blocker, as well as other MCT inhibitors quercetin and simvastatin, inhibited cell invasion without influencing migration activity and the cellular expression of MCT1 and MCT4. This is the first report suggesting that lactate transporters are involved in human cancer cell invasiveness. As such, these proteins may be promising targets for the prevention of cancer invasion and metastasis.

Dural attachment of intracranial meningiomas: evaluation with contrast-enhanced three-dimensional fast imaging with steady-state acquisition (FIESTA) at 3 T.

INTRODUCTION: The purpose of this study was to evaluate the role of contrast-enhanced fast imaging with steady-state acquisition (CE-FIESTA) for assessing whether dural attachment in intracranial meningiomas is adhesive or not by correlation with intraoperative findings. METHODS: Fourteen consecutive patients who were candidates for surgical treatment of meningiomas were prospectively analyzed with preoperative magnetic resonance imaging, including CE-FIESTA at 3 T. First, two neuroradiologists assessed several characteristics of the attachment of the meningioma to the dura mater or skull base on CE-FIESTA images. Second, the surgical findings of adhesion at the dural attachment of meningiomas were evaluated by two neurosurgeons. Finally, the CE-FIESTA findings were correlated with the surgical findings by one neurosurgeon and one neuroradiologist by consensus. RESULTS: CE-FIESTA clearly depicted a hypointense marginal line at the attachment site of the meningioma. When CE-FIESTA revealed smooth marginal lines or hyperintense zones along the marginal lines, tumors were detached easily from the dura mater. On the contrary, when CE-FIESTA showed an irregularity, such as partial disruption of the marginal lines, vessels, or bony hyperostosis, the tumors tended to adhere firmly to the dura mater, which was found to contain small vessels and fine fibrous tissues. CONCLUSIONS: There seems to be an excellent correlation between the characteristics of dural attachment of meningiomas on CE-FIESTA images and intraoperative findings. Therefore, for operative planning, CE-FIESTA may provide useful information regarding the adhesiveness of dural attachment.

Immunological response in early brain injury after SAH.

This study summarized the role of inflammation in the early brain injury after subarachnoid hemorrhage. Elevation of cytokines, activation of MMPs and phosphorylation of MAPK contributes to neuronal apoptosis and brain edema. Anti-inflammation may be potential strategy for the prevention and suppression of early brain injury after subarachnoid hemorrhage.

Preoperative radiological evaluation and surgical strategy for the preservation of visual acuity in patients with skull base meningiomas--two case reports.

Two women aged 48 and 73 years, respectively, presented with unilateral visual disturbance. On admission, magnetic resonance imaging (MRI) showed an extraaxial mass in the parasellar region. Contrast-enhanced fast imaging with steady-state acquisition (CE-FIESTA) showed that the optic nerves were compressed and encased by the tumors. At an early stage of surgery, we performed decompression of the optic nerves to avoid optic nerve injury. Both the patients were relieved of visual disturbances without any postoperative neurological deficit. In conclusion, CE-FIESTA is a useful diagnostic tool for preoperative evaluation of the optic nerves in patients with skull base meningiomas. Decompression of the optic nerves should be performed at an early stage of surgery in meningioma patients presenting with visual disturbance.