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This study aimed to investigate the effects of focal brain cooling (FBC) on spreading depolarization (SD), which is associated with several neurological disorders. Although it has been studied from various aspects, no medication has been developed that can effectively control SD. As FBC can reduce neuronal damage and promote functional recovery in pathological conditions such as epilepsy, cerebral ischemia, and traumatic brain injury, it may also potentially suppress the onset and progression of SD. We created an experimental rat model of SD by administering 1 M potassium chloride (KCl) to the cortical surface. Changes in neuronal and vascular modalities were evaluated using multimodal recording, which simultaneously recorded brain temperature (BrT), wide range electrocorticogram, and two-dimensional cerebral blood flow. The rats were divided into two groups (cooling [CL] and non-cooling [NC]). Warm or cold saline was perfused on the surface of one hemisphere to maintain BrT at 37°C or 15°C in the NC and CL groups, respectively. Western blot analysis was performed to determine the effects of FBC on endothelial nitric oxide synthase (eNOS) expression. In the NC group, KCl administration triggered repetitive SDs (mean frequency = 11.57/h). In the CL group, FBC increased the duration of all KCl-induced events and gradually reduced their frequency. Additionally, eNOS expression decreased in the cooled brain regions compared to the non-cooled contralateral hemisphere. The results obtained by multimodal recording suggest that FBC suppresses SD and decreases eNOS expression. This study may contribute to developing new treatments for SD and related neurological disorders., Competing Interests: The authors declare that they have no conflicts of interest., (© 2024 The Authors.)

The tendency of global urban expansion to be slope climbing has partly become possible with scarce cropland resources in plains. However, the scientific understanding of the quantity, intensity, pattern, and effect of the slope climbing of urban expansion (SCE) is minimal globally. In this study, we have attempted to quantify and evaluate global SCE from Suomi National Polar-orbiting Partnership (SNPP)-Visible Infrared Imaging Radiometer Suite (VIIRS)-like data and other auxiliary data. Results revealed that global SCE areas unevenly increased from 22,760 km 2 to 90,720 km 2 from 2000 to 2020, with an annual growth rate of 21.72%, in which low-environment cost type areas increased from 21,550 km 2 to 84,010 km 2 while high-environment cost type (HEC) areas increased from 1210 km 2 to 6710 km 2 . One remarkable phenomenon is that China's SCE areas in 2020 were more than 11 times those in 2000. In addition, global SCE intensity increased by about 3.4-fold from 2000 to 2020 and the rapid growth of HEC intensity is concentrated in Asia and North America. SCE is mostly affected by urban population growth and terrain. Economic development also promotes its development to a certain extent. We also noted that global SCE potentially made a considerable contribution to saved cropland, saving about 46,747 km 2 with a theoretical increased grain yield of 25,020 × 10 3  t. Our study provides timely and transparent monitoring of global SCE and offers new insights into sustainable urban development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Land urbanization (LU) and population urbanization (PU) maintain the nature of spatiotemporal heterogeneity in China. As a municipality directly administered by the central government in the mode of "large cities and large rural areas", Chongqing's urbanization process is the epitome of China's urbanization process. This paper examines the spatiotemporal variability of LU and PU in Chongqing on the basis of nighttime light data, the elasticity coefficient of the coupling relationship, and GWR. The results show that (1) the urban land and urban population in Chongqing grew notably from 2008 to 2018, with average annual growth rates of 9.4% and 2.3%, respectively. (2) The coupling coordination coefficient of LU and PU in Chongqing was 0.24, and the total number of districts and counties with uncoordinated development increased, but the overall uncoordinated situation gradually improved over the period. (3) The influence of PU on LU in each district and county increased year by year, and it showed a decreasing trend from southwest to northeast in Chongqing, which indicates that LU was increasingly adapted to the construction needs of PU. The gap between LU and PU widened due to the household registration system, land fiscal policies and other policies. After the reform of the household registration system and the adjustment of new pilot policies targeting the construction of new-type urbanization, the coupling relationship between LU and PU was gradually improving to the coordinated mode. The findings indicate that Chinese urban areas should adhere to the principle of new-type urbanization construction and carry out scientific land planning strategies, strictly controlling land expansion to promote the reasonable development of population growth.

Objective: Traditionally, angiographic vasospasm (aVS) has been thought to cause delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, successful treatment of aVS alone does not result in improved neurological outcome. Therefore, there may be other potential causes of poor neurological outcome, including spreading depolarization (SD). A recent study showed beneficial effects of cilostazol on DCI and neurological outcome. The present prospective clinical trial and experimental study focused on effects of cilostazol on SDs., Methods: Fifty aSAH patients were treated with clip ligation and randomly assigned to a cilostazol (n = 23) or control group (n = 27). Effects of cilostazol on DCI, aVS, and SDs, measured with subdural electrodes, were examined. The effect of cilostazol on SD-induced perfusion deficits (spreading ischemia) was assessed in an aSAH-mimicking model., Results: There was a trend for less DCI in the cilostazol group, but it did not reach our threshold for statistical significance (13.0% vs 40.0%, odds ratio = 0.266, 95% confidence interval [CI] = 0.059-1.192, p = 0.084). However, the total SD-induced depression duration per recording day (22.2 vs 30.2 minutes, β = -251.905, 95% CI = -488.458 to -15.356, p = 0.043) and the occurrence of isoelectric SDs (0 vs 4 patients, β = -0.916, 95% CI = -1.746 to -0.085, p = 0.037) were significantly lower in the cilostazol group. In rats, cilostazol significantly shortened SD-induced spreading ischemia compared to vehicle (Student t test, difference = 30.2, 95% CI = 5.3-55.1, p = 0.020)., Interpretation: Repair of the neurovascular response to SDs by cilostazol, as demonstrated in the aSAH-mimicking model, may be a promising therapy to control DCI. Ann Neurol 2018;84:873-885., (© 2018 American Neurological Association.)

Background and Objective: Despite intensive therapy, vasospasm remains a major cause of delayed cerebral ischemia (DCI) in worsening patient outcome after aneurysmal subarachnoid hemorrhage (aSAH). Transcranial Doppler (TCD) and transcranial color-coded duplex sonography (TCCS) are noninvasive modalities that can be used to assess vasospasm. However, high flow velocity does not always reflect DCI. The purpose of this study was to investigate the utility of TCD/TCCS in decreasing permanent neurological deficits., Methods: We retrospectively enrolled patients with aSAH who were treated within 72 hours after onset. TCCS was performed every day from days 4 to 14. Peak systolic velocity (PSV), mean velocity (MV), and pulsatility index were recorded and compared between DCI and non-DCI patients. In patients with DCI, endovascular therapy was administered to improve vasospasm, which led to a documented change in velocity., Results: Of the 73 patients, 7 (9.6%) exhibited DCI. In 5 of the 7 patients, DCI was caused by vasospasm of M2 or the more peripheral middle cerebral artery (MCA), and the PSV and MV of the DCI group were lower than those of the non-DCI group after day 7. Intra-arterial vasodilator therapy (IAVT) was performed for all patients with DCI immediately to increase the flow volume by the next day., Conclusions: Increasing flow velocity cannot always reveal vasospasm excluding M1. In patients with vasospasm of M2 or more distal arteries, decreasing flow velocity might be suggestive of DCI. IAVT led to increases in the flow velocity through expansion of the peripheral MCA., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Delayed cerebral ischemia (DCI) is a prominent complication after aneurysmal subarachnoid hemorrhage (aSAH). Although vasospasm of proximal cerebral arteries has been regarded as the main cause of DCI, vasospasm of distal arteries, microthrombosis, impaired autoregulation, cortical spreading depolarization (CSD), and spreading ischemia are thought to be involved in DCI after aSAH. Here, we describe a patient with aSAH in whom CSD and cerebrovascular autoregulation were evaluated using simultaneous electrocorticography and monitoring of the pressure reactivity index (PRx) after surgical clipping of a ruptured posterior communicating artery aneurysm. In this patient, a prolonged duration of CSD and elevation of PRx preceded delayed neurological deficit. Based on this observation, we propose a relationship between these factors and DCI. Assessment of cerebrovascular autoregulation may permit detection of the inverse hemodynamic response to cortical depolarization. Detection of DCI may be achieved through simultaneous monitoring of CSD and PRx in patients with aSAH., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: The importance of acute-phase brain temperature management is widely accepted for prevention of exacerbation of brain damage by a high body temperature., Methods: In this study, we investigated the influence of body temperature in the early postoperative period on the outcomes of 62 patients with subarachnoid hemorrhage who were admitted to our department. Body temperature was measured from day 4 to day 14 after onset. The patients were divided into those treated with surgical clipping (clip group) and coil embolization (coil group), those graded I-III (mild) and IV-V (severe) based on the Hunt & Hess classification on admission, those with and without development of delayed cerebral ischemia (DCI), and those with favorable and poor outcomes. Body temperatures throughout the hospital stay were compared in each group., Results: There was no significant difference in body temperature between the clip and coil groups or between the mild and severe groups, but body temperature was significantly higher in patients with DCI compared to those without DCI, and in patients with a poor outcome compared to those with a favorable outcome., Conclusions: Fever in the early postoperative period of subarachnoid hemorrhage is associated with development of DCI and a poor outcome., (Copyright © 2016 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: The aims of this study were to reveal the strategies and pitfalls of motor-evoked potential (MEP) monitoring methods during supratentorial aneurysm surgery, and to discuss the drawbacks and advantages of each method by reviewing our experiences., Methods: Intraoperative MEP monitoring was performed in 250 patients. Results from 4 monitoring techniques using combinations of 2 stimulation sites and 2 recording sites were analyzed retrospectively., Results: MEP was recorded successfully in 243 patients (97.2%). Direct cortical stimulation (DCS)-spinal recorded MEP (sMEP) was used in 134 patients, DCS-muscle recorded MEP (mMEP) in 97, transcranial electrical stimulation (TES)-mMEP in 11 and TES-sMEP in 1. TES-mMEP during closure of the skull was used in 21 patients. DCS-mMEP was able to detect waveforms from upper and/or lower limb muscles. Alternatively, DCS-sMEP (direct [D]-wave) could accurately estimate amplitude changes. A novel "early warning sign" indicating ischemia was found in 21 patients, which started with a transiently increased amplitude of D-wave and then decreased after proximal interruption of major arteries. False-negative findings in MEP monitoring in 2 patients were caused by a blood insufficiency in the lenticulostriate artery and by a TES-sMEP recording, respectively., Conclusions: The results of this study suggest that to perform accurate MEP monitoring, DCS-mMEP or DCS-sMEP recording should be used as the situation demands, with combined use of TES-mMEP recording during closure of the skull. DCS-sMEP is recommended for accurate analysis of waveforms. We also propose a novel "early warning sign" of blood insufficiency in the D-wave., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Background: Transcranial color-coded duplex sonography (TCCS) is a noninvasive technique for monitoring of cerebral vasospasm after neurosurgery for aneurismal subarachnoid hemorrhage. In this surgery, surgical materials are used. The goal of the study was to identify materials that can be used with ultrasound and to propose methods for cranioplasty and duraplasty using materials that permit TCCS., Methods: The chosen neurosurgical materials were titanium mesh plate (TMP), Gore-tex, SEAMDURA, gelatinous sponge, and oxidized cellulose. B-mode imaging was recorded with the materials placed between urethane resin 10 mm in diameter and the urethane phantom model. TCCS was performed to detect middle cerebral artery flow through TMP and Gore-tex., Results: TMP and SEAMDURA permitted penetration of ultrasound in B-mode and Doppler imaging, but the other materials did not do so., Conclusions: A postcraniotomy window (PCW) on a line extending from the horizontal portion of M1 using only TMP permitted flow imaging with TCCS. In external decompression, TCCS was effective only without use of Gore-tex around the postcraniotomy window. This method allows the middle cerebral artery flow to be detected easily., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the efficacy and safety of 5 mg perindopril arginine salt and 4 mg perindopril tert-butylamine salt for patients with mild to moderate essential hypertension., Methods: The study was designed as multicenter, randomized, double-blind, active controlled trial with two parallel groups enrolling 524 participants with mild to moderate essential hypertension. After 2-week run-in period, 186 patients were enrolled and randomly treated with 5 mg perindopril arginine salt and 183 patients were enrolled and randomly treated with 4 mg perindopril tert-butylamine salt. The random sequence was generated by the I.R.I.S., and a balance was made in each center. After double-blind treatment for 8 weeks, the dose could be doubled for patients with uncontrolled BP ((SBP) ≥ 140 mmHg (1 mmHg = 0.133 kPa) or diastolic blood pressure (DBP) ≥ 90 mmHg) and patients were treated for another 4 weeks., Results: The sitting SBP was similarly decreased by (19.9 ± 17.2) mmHg in perindopril arginine group and (18.5 ± 14.7) mmHg (P = 0.000 5) in perindopril tert-butylamine group post 8 weeks treatment. Dose was doubled in 109 patients (59.9%) in perindopril arginine group and 116 patients (63.7%) in perindopril tert-butylamine group. At 12 weeks post therapy, the sitting SBP decreased by (19.8 ± 16.2) and (19.6 ± 16.3) mmHg respectively in the 2 groups. The decrease of sitting DBP was also similar in both groups (-12.0 ± 10.0) mmHg and (-11.0 ± 8.9) mmHg (P < 0.000 1), respectively. The control rate or response rate was also similar between the two groups (control rate over 8 weeks was 38.5% vs. 31.3%, 95% CI (-2.6-16.9), control rate over 12 weeks was 36.3% vs. 35.7%, 95% CI (-9.3-10.4), response rate over 8 weeks was 64.3% vs. 63.2%, 95% CI (-8.8-11.0), response rate over 12 weeks was 65.9% vs. 64.8%, 95% CI (-8.7-10.9)). Incidence of adverse events was low and similar in both therapy groups., Conclusions: The results show that perindopril arginine salt 5 mg is as efficient as perindopril tert-butylamine 4 mg on lowering BP for patients with mild to moderate essential hypertension. Both drugs have good safety profile and are well tolerated by patients in this cohort.

Background: To predict possible enlargement of cerebral aneurysms with aging, we retrospectively analyzed aneurysm size in relation to patient age and aneurysm site., Methods: We included 1332 unruptured and 2362 ruptured aneurysms detected in patients from the Yamaguchi Prefecture, Japan, from 1995 to 2005., Results: Age-specific site distribution was not found in the unruptured aneurysms. In the ruptured aneurysms, the incidence of anterior communicating artery (AComA) aneurysms was higher than that of internal carotid posterior communicating (ICPC) artery aneurysms among the patients aged 40-49 years (32.6% versus 14.4%), whereas the difference was small among the elderly patients aged 70-79 years (25.8% versus 24.9%). In the AComA aneurysms, either in the unruptured or ruptured cases, no age-related change in size was found. In the ICPC aneurysms, either in the unruptured or in the ruptured cases, the size of the aneurysms 7 mm or larger increased with age., Conclusions: The sizes of AComA aneurysms may remain stable with aging. Therefore, the risk of rupture may be similar in young and elderly patients. Meanwhile, ICPC artery aneurysms may continue to grow throughout the patient's life, with an increasing risk of rupture., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Hyperlipidemia is a risk factor for abnormal cerebrovascular events. Rafts are cholesterol-enriched membrane microdomains that influence signal transduction. We previously showed that Rho-kinase-mediated Ca(2+) sensitization of vascular smooth muscle (VSM) induced by sphingosylphosphorylcholine (SPC) has a pivotal role in cerebral vasospasm. The goals of the study were to show SPC-Rho-kinase-mediated VSM contraction in vivo and to link this effect to cholesterol and rafts. The SPC-induced VSM contraction measured using a cranial window model was reversed by Y-27632, a Rho-kinase inhibitor, in rats fed a control diet. The extent of SPC-induced contraction correlated with serum total cholesterol. Total cholesterol levels in the internal carotid artery (ICA) were significantly higher in rats fed a cholesterol diet compared with a control diet or a β-cyclodextrin diet, which depletes VSM cholesterol. Western blotting and real-time PCR revealed increases in flotillin-1, a raft marker, and flotillin-1 mRNA in the ICA in rats fed a cholesterol diet, but not in rats fed the β-cyclodextrin diet. Depletion of cholesterol decreased rafts in VSM cells, and prevention of an increase in cholesterol by β-cyclodextrin inhibited SPC-induced contraction in a cranial window model. These results indicate that cholesterol potentiates SPC-Rho-kinase-mediated contractions of importance in cerebral vasospasm and are compatible with a role for rafts in this process.

Background: Indications of clipping (Clip) or coil embolization (Coil) for unruptured cerebral aneurysms (uAN) was not elaborated because prediction of rupture and risk of treatment are difficult. This study aims to determine the risk-benefit analysis of treating uAN by a comprehensive and retrospective investigation of the adverse events and sequelae in patients treated by our Clip/Coil combined units., Methods: Clip and Coil were performed in 141 and 80 patients, respectively; Clip for middle cerebral artery AN and Coil for paraclinoid or basilar apex AN. Worsening of modified Rankin scale or mini-mental state examination was defined as major morbidity. Minor morbidity or transient morbidity was defined as other neurologic deficits. Mortality and these morbidities were considered as serious adverse events. Convulsion or events outside the brain were defined as mild adverse events., Results: Total mortality and major morbidity were low. Incidence of serious adverse events was not significantly different between the Clip and Coil (17 patients [12.1%] and 6 patients [7.5%]), but the number of total adverse events was significantly different (32 patients [22.7%] in Clip vs. 8 patients [10.0%] in Coil). Because mild morbidities were significantly more frequent in the Clip (20 patients [14.2%]) compared with the Coil (2 patients [2.5%]). Convulsion occurred in 11 (7.8%) patients in the Clip but none in the Coil., Conclusions: Our combined unit decreased the occurrence of mortality/major morbidity; however, minor adverse effects were common, especially in the Clip group because of many intrinsic problems of Clip itself. This result suggests further consideration for the treatment modality for uAN., (Copyright © 2015 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Intracranial meningiomas are the most common types of neoplasms that cause mental disorders. Although higher brain function can be restored and even improved in some patients after tumor resection, the mechanisms remain unclear. We investigated changes in the brains of patients after resection of an intracranial meningioma using (123)I-Iomazenil (IMZ)-single photon emission computed tomography (SPECT). Ten patients underwent IMZ-SPECT within 4 weeks before and 3 months after intracranial meningioma resection. Changes in IMZ accumulation in brain parenchyma were assessed as ratios of counts in the lesion-to-contralateral hemisphere (L/C ratios). Mean Mini-Mental State Examination scores before and after resection of 19.9±11.4 vs. 26.5±3.8, respectively (p=0.03) indicated that the cognitive function of these patients was significantly improved after tumor resection. The average L/C ratios calculated from image counts of IMZ were 0.92±0.05 and 0.98±0.02 before and after surgery, respectively. The L/C ratio of IMZ accumulation was significantly decreased after tumor resection (p=0.0003). In contrast, regional cerebral blood flow calculated from (123)I-Iodoamphetamine-SPECT images did not significantly differ after tumor resection. The recovered binding potential of IMZ in brain parenchyma surrounding the tumor bulk after resection indicates that the viability of central benzodiazepine receptors was reversibly depressed and recoverable after release from compression by the tumor. The recovered neuronal viability revealed by IMZ-SPECT might be responsible for the improved cognitive function after intracranial meningioma resection., (Copyright © 2014. Published by Elsevier B.V.)

We report the case of a 37-year-old male with Cowden disease that caused a gradual neurological deficit because of rupture of a brain stem cavernous hemangioma. Removal of the hemangioma and hematoma was performed with an infrafacial triangle approach. Nine months after the operation, magnetic resonance imaging showed abnormal vessels on the cerebellar surface. Digital subtraction angiography showed a dural arteriovenous fistula (dAVF) from part of the meningeal artery to the ectatic inferior vermian vein with cortical reflux. After embolization, surgical obliteration of the dAVF was performed. Surgical findings showed neovascularization in the thickened dura, in which dural vessels shunted to cerebellar vessels through adhesion between the dura mater and cerebellar surface. Therefore, the thickened dura was removed with the cerebellar surface. This case suggests that postoperative angiogenesis may cause arteriovenous fistula in patients with Cowden disease., (Published by Elsevier Inc.)

Objective: The sphingosylphosphorylcholine-Rho-kinase pathway plays an important role in Ca(2+) sensitization of vascular smooth muscle contraction. Eicosapentaenoic acid (EPA) inhibits sphingosylphosphorylcholine -Rho-kinase-activated Ca(2+)-sensitization in vitro and in subarachnoid hemorrhage (SAH) models in vivo and has also been shown to inhibit the occurrence of cerebral vasospasm (CIV) after the onset of SAH in a prospective, nonrandomized study. The current prospective, multicenter, randomized study was performed to confirm the preventive effects of EPA on CIV in patients with SAH., Methods: The trial population comprised 162 patients who underwent surgical clipping within 72 hours of the onset of SAH. Of these patients, 81 received 2700 mg/day EPA from the day after surgery until day 30 (EPA group), and 81 did not receive EPA (control group). The primary end point was the occurrence of symptomatic vasospasm (SV) or cerebral infarction caused by CIV., Results: The occurrences of SV (15% vs. 30%; P = 0.022) and CIV (7% vs. 21%; P = 0.012) were lower in the EPA group. Multivariate analysis revealed an adjusted odds ratio of 0.39 (95% confidence interval, 0.17-0.89; P = 0.028) for SV inhibition by EPA and 0.27 (95% confidence interval, 0.09-0.72; P = 0.012) for CIV inhibition., Conclusions: These results indicate that oral EPA reduces the frequency of SV and CIV after the onset of aneurysmal SAH., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: After cardioembolic stroke (CES), left atrial thrombus (LAT) is detected by transesophageal echocardiography (TEE) in some cases but not in others. We propose that there are 2 types of embolization in CES: fragmental and massive embolization., Methods: Consecutive patients with nonvalvular atrial fibrillation (AF) of acute CES or transient ischemic attack (TIA) were prospectively enrolled in the study between May 2009 and July 2011. TEE was performed within 7 days of admission. The patients were classified into 2 groups: those with occlusion of the main trunk (internal carotid artery, M1, and basilar artery; group M) and those with occlusion of other distal arteries (group D). Clinical features were compared between patients who did and did not have a thrombus on TEE., Results: Of the 41 patients in the study, 21 were in group M and 20 were in group D. Age, sex, and treatment with tissue plasminogen activator did not differ significantly between the 2 groups. The rate of detection of LAT was significantly higher in group D (14% v 65%; P < .001)., Conclusions: Patients with distal artery occlusion had a significantly higher rate of LAT compared to those with main trunk occlusion. Distal artery occlusion in CES therefore tends to result from fragmental embolization and is associated with a remnant LAT, with which there may be a concern of a risk of early recurrence., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

We report the case of a 67-year-old man with repeating cerebral embolism caused by a dolichoectatic right common carotid artery. The patient had a history of hypertension, hypercholesterolemia, cigarette smoking, and a postoperative abdominal aortic aneurysm. He presented with a sudden onset of weakness of the left arm and leg. Magnetic resonance imaging revealed old and fresh infarction in the right cerebral hemisphere. Carotid duplex ultrasonography showed a dolichoectatic right common carotid artery with a maximum diameter of 39 mm with thick plaque and strong spontaneous echo contrast. The flow velocity was considerably reduced, which caused thrombus formation, and strong antithrombotic therapy was required. This case provides a rare example of ischemic stroke caused by extracranial carotid artery dolichoectasia., (Copyright © 2011 by the American Society of Neuroimaging.)

Background and Purpose: Systemic circulation management has not been established for patients with poor grade aneurysmal subarachnoid hemorrhage (SAH) or delayed cerebral ischemia (DCI) after SAH. The aims of the study were to examine hemodynamic variables in these patients and to establish treatment strategies., Methods: A multicenter prospective cohort study of hemodynamic variables from days 1 to 14 was performed using a transpulmonary thermodilution system (PiCCO Plus). Parameters were analyzed by Mann-Whitney test. Multivariate analysis was performed to identify parameters involved in onset of DCI., Results: The subjects were 204 patients, including 138 with poor grade SAH (World Federation of Neurological Surgeons grades IV and V) and 52 who developed DCI. The extravascular lung water index, pulmonary vascular permeability index, and systemic vascular resistance index were significantly greater in patients with poor grade SAH compared with those with good grade SAH (World Federation of Neurological Surgeons I-III) on day 2 (P=0.049, P=0.039, and P=0.038). Cardiac index was significantly lower in patients with poor grade SAH on days 1 and 2 (P=0.027 and P=0.011). In patients with DCI, the global end-diastolic volume index was significantly lower than in those without DCI on days 3 to 5 (P=0.0053; P=0.048; and P=0.048). In multivariate analysis, median global end-diastolic volume index, cardiac index, and systemic vascular resistance index at an early stage of SAH (days 3-6) were independently related to onset of DCI (P=0.023, P=0.013, and P=0.003)., Conclusions: Patients with poor grade SAH developed heart failure-like afterload mismatch at an early stage, and those with DCI had decreased global end-diastolic volume index (hypovolemia) in the early stage of SAH., Clinical Trial Registration Url: http://www.clinicaltrials.gov. Unique identifier: UMIN000003794.

The blood-brain-barrier (BBB) is formed by different cell types, of which brain microvascular endothelial cells are major structural constituents. The goal of this study was to examine the effects of cooling on the permeability of the BBB with reference to tight junction formation of brain microendothelial cells. The sensorimotor cortex above the dura mater in adult male Wistar rats was focally cooled to a temperature of 5 °C for 1 h, then immunostaining for immunoglobulin G (IgG) was performed to evaluate the permeability of the BBB. Permeability produced by cooling was also evaluated in cultured murine brain endothelial cells (bEnd3) based on measurement of trans-epithelial electric resistance (TEER). Immunocytochemistry and Western blotting of proteins associated with tight junctions in bEnd3 were performed to determine protein distribution before and after cooling. After focal cooling of the rat brain cortex, diffuse immunostaining for IgG was observed primarily around the small vasculature and in the extracellular spaces of parenchyma of the cortex. In cultured bEnd3, TEER significantly decreased during cooling (15 °C) and recovered to normal levels after rewarming to 37 °C. Immunocytochemistry and Western blotting showed that claudin-5, a critical regulatory protein for tight junctions, was translocated from the membrane to the cytoplasm after cooling in cultured bEnd3 cells. These results suggest that focal brain cooling may open the BBB transiently through an effect on tight junctions of brain microendothelial cells, and that therapeutically this approach may allow control of BBB function and drug delivery through the BBB.

Objective: Subarachnoid clots play an important role in development of delayed vasospasm after subarachnoid hemorrhage (SAH). The purpose of this study was to compare clearance of subarachnoid clots using external ventricular drainage (EVD) or lumbar drainage (LD) after Guglielmi detachable coil (GDC) embolization for aneurysmal SAH., Methods: The subjects were 51 treated with GDC coil embolization for aneurysmal Fisher group 3 SAH within 72 h of ictus. Software-based volumetric quantification of the subarachnoid clots was performed on CT scans and the hemoglobin (Hb) level was measured in CSF drained from each catheter., Results: Clearance of subarachnoid clots was more rapid in patients treated with LD (n=34) compared to those treated with EVD (n=17). The Hb level in CSF was significantly higher in the LD group on Days 4-5 after onset of SAH (P<0.05), but was higher in the EVD group on Days 8-9. The incidence of symptomatic vasospasm did not differ between the two groups. The rate of occurrence of a new low density area on CT scans was higher in patients treated with EVD, but not significantly higher than the rate in the LD group., Conclusion: GDC embolization followed by lumbar drainage accelerates the reduction of subarachnoid clots, but EVD may contribute to stasis of hemorrhage within subarachnoid spaces., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Although systemic hypothermia provides favorable outcomes in stroke patients, it has only been adopted in a limited number of patients because of fatal complications. To resolve these issues, focal brain cooling (FBC) has recently drawn attention as a less-invasive treatment for brain injuries. Therefore, we investigated whether FBC has a favorable effect on focal cerebral ischemia (FCI). Male-adult-Wistar rats were used. Under general anesthesia, a small burr hole was made and FCI was induced in the primary sensorimotor area (SI-MI) using photothrombosis. An additional craniotomy was made over the SI-MI and FBC was performed at a temperature of 15°C for 5h. Electrocorticograms (ECoG) were recorded on the border cortex of the ischemic focus. Thereafter, rats were sacrificed and the infarct area was measured. In another experiment, rats were allowed to recover for 5 days after cooling and neurobehavioral function was evaluated. FBC suppressed all ECoG frequency bands during and after cooling (p<0.05), except for the delta frequency band in the precooling versus rewarming periods. The injured areas in the cooling and non-cooling groups were 0.99±0.30 and 1.71±0.54 mm(2), respectively (p<0.03). The grip strength at 2 days after surgery was preserved in the cooling group (p<0.05). We report the novel finding that epileptiform discharges were suppressed in the ischemic border, the infarct area was reduced and neurobehaviour was preserved by FBC. These results indicate that FBC is neuroprotective in the ischemic brain and has demonstrated therapeutic potential for cerebral infarction., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Objective: The right and left sides of the brain play different roles in cognition. Therefore, the side of treatment should be taken into consideration when evaluating cognitive outcome following revascularization. Thus, we designed a study to evaluate changes in right hemisphere cognitive function in patients undergoing right carotid artery stentings (CAS) and left hemispheric cognitive function in patients undergoing left CAS. In addition, we studied CAS-related changes in regional cerebral blood flow to determine potential correlations with changes in cognitive function., Methods: We performed a prospective assessment of 39 CAS patients, all of whom were right-handed. Patients with contralateral stenotic lesions were excluded. Twenty-one patients underwent CAS of the right internal carotid artery (Right CAS group) and 18 underwent CAS of the left internal carotid artery (Left CAS group). Neuropsychological testing was performed preoperatively and 6 months after endovascular treatment. Cerebral blood flow was determined by 123I-labeled N-isopropyl-p-iodoamphetamine single-photon emission computed tomography before and 6 months after CAS., Results: In the Right CAS group, postoperative performance intelligence quotient score (91.1±18.2) was significantly improved compared with the preoperative score (84.9±16.7; P<.001). In the Left CAS group, postoperative verbal intelligence quotient score (104.0±18.8) was significantly higher than that before endovascular treatment (97.9±15.8; P<.005). Postoperative regional cerebral blood flow was not significantly different from that before endovascular treatment in either group. However, regional cerebrovascular reactivity of the treated side showed significant improvement after treatment., Conclusions: Amelioration of cognitive function may be dependent on the side of revascularization. Performance intelligence quotient improved after CAS in patients with severe carotid artery stenosis on the right side. Verbal intelligence quotient also improved on the left side after endovascular treatment. These effects seemed to involve improvement in regional cerebrovascular reactivity by CAS., (Copyright © 2013 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Background: This study was a cerebral aneurysm registry study conducted in a region with few climatic differences. Based on data collected for over 20 years, seasonal variations and characteristics of subarachnoid hemorrhage (SAH) due to ruptured aneurysms were analyzed., Methods: This study included 5,007 patients in the Yamaguchi Prefecture with aneurysmal SAH between 1986 and 2005. Incidence rates by month, sex, age, severity, and aneurysm site were analyzed., Results: In women, seasonal variation was observed, in particular among those aged ≥50 years. Among those aged 50-69 years, the highest incidence was in October, and the nadir was in June (peak-to-trough ratio = 1.72). At age ≥70 years, this was slightly different, with the highest incidence in December and the nadir in July (peak-to-trough ratio = 1.48). However, there was no seasonal variation in men overall; it was limited to elderly men at age ≥70 years, with the highest incidence in January and the nadir in July (peak-to-trough ratio = 2.9). Aneurysm site and severity showed no relationship with seasonal variation., Conclusion: The present study shows seasonal variations in the onset of SAH. Seasonal variations in SAH differed depending on age and sex., (Copyright © 2013 S. Karger AG, Basel.)

Single photon emission computed tomography (SPECT) is used widely in clinical studies. However, the technique requires image reconstruction and the methods for correcting scattered radiation and absorption are not standardized among SPECT procedures. Therefore, quantitation of cerebral blood flow (CBF) may not be constant across SPECT models. The quantitative SPECT (QSPECT) software package has been developed for standardization of CBF. Using the QSPECT/dual-table autoradiographic (DTARG) method, CBF and cerebral vascular reactivity (CVR) at rest and after acetazolamide challenge can be evaluated using (123)I-iodoamphetamine in a single SPECT session. In this study, we examined the reproducibility of quantitative regional CBF and CVR in QSPECT/DTARG using different SPECT models at two facilities. The subjects were nine patients with chronic cerebral ischemic disease who underwent QSPECT/DTARG at both facilities with use of different γ-cameras and collimators. There were significant correlations for CBF at rest and after acetazolamide challenge measured at the two facilities. The consistency of the CBFs of the patients measured at the two facilities were good in all cases. Our results show that CBF measured by QSPECT/DTARG in the same patients is reproducible in different SPECT models. This indicates that standardized evaluation of CBF can be performed in large multicenter studies.

Objective: Motor-evoked potentials (MEPs) are commonly recorded from upper-extremity muscles, whereas lower-extremity MEP (LE-MEP) monitoring has not been adequately established. The goal of the study was to develop a MEP monitoring method using direct cortical stimulation (DCS) for predicting motor deficits of lower extremities., Methods: Intra-operative LE-MEP monitoring was performed in 22 patients. After craniotomy, a subdural electrode was placed on the cortex so that the optimal contact was positioned 2 cm lateral from the midline on the motor cortex. The electrodes for stimulation consisted of a cathode at Fpz and an anode at the optimal contact site on the motor cortex. After stimulation was performed with short trains of five stimuli, LE-MEPs were recorded from the lower-limb muscles., Results: LE-MEPs were consistently recorded in all patients. Disappearance or amplitude reduction of MEP waveforms was observed in five patients, but the MEP waveforms had recovered and remained at the control level by dural closure, and no permanent motor deficit was observed in any patient., Conclusions: We accomplished LE-MEP recording during supratentorial surgery using monopolar DCS with a subdural electrode placed on the convex side of the motor cortex., Significance: A useful method of intra-operative LE-MEP recording was described., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Our aim was to assess whether cardiac hypertrophy is associated with cognitive function independently of office, 24-h, or sleep blood pressure (BP) levels in older hypertensive patients treated with antihypertensive medications., Methods: In this cross-sectional study, we recruited 443 hypertensive patients aged over 60 years (mean age: 73.0 years; 41% men) who were ambulatory, lived independently, and were without clinically overt dementia. They underwent measurements of 24-h BP monitoring, echocardiographic left ventricular mass index (LVMI), and cognitive function (mini-mental state examination, MMSE)., Results: MMSE score was inversely associated with office, 24-h, awake, and sleep systolic BP (SBP) (each, P < 0.05). There was a close association between MMSE score and LVMI (ρ = -0.32; P < 0.001). Using multiple logistic regression analysis including numerous covariates (i.e., age, sex, obesity, current smoking, educational level, duration of antihypertensive medications, renal dysfunction, statin use, and previous history of cardiovascular disease), the odds ratio (OR) for the presence of cognitive dysfunction, defined as the lowest quartile of MMSE score (median MMSE score: 23 points; n = 115), was estimated; the presence of cardiac hypertrophy (LVMI ≥125 kg/m(2) in men and ≥110 kg/m(2) in women) as well as uncontrolled 24-h BP (mean 24-h SBP/diastolic BP (DBP) ≥130/80 mm Hg) or sleep BP (mean sleep SBP/DBP ≥120/70 mm Hg), but not uncontrolled office BP (mean office SBP/DBP ≥140/90 mm Hg), were independently associated with cognitive dysfunction (all P < 0.05)., Conclusions: Among older hypertensive patients with antihypertensive medications, those who had echocardiographically determined cardiac hypertrophy may be at high risk for cognitive dysfunction, irrespective of their office BP and 24-h BP levels.

Purpose: Focal brain cooling is effective for suppression of epileptic seizures, but it is unclear if seizures can be suppressed without a substantial influence on normal neurologic function. To address the issue, a thermoelectrically driven cooling system was developed and applied in free-moving rat models of focal seizure and epilepsy., Methods: Focal seizures limited to the unilateral forelimb were induced by local application of a penicillin G solution or cobalt powder to the unilateral sensorimotor cortex. A proportional integration and differentiation (PID)-controlled, thermoelectrically driven cooling device (weight of 11 g) and bipolar electrodes were chronically implanted on the eloquent area (on the epileptic focus) and the effects of cooling (20, 15, and 10°C) on electrocorticography, seizure frequency, and neurologic changes were investigated., Key Findings: Cooling was associated with a distinct reduction of the epileptic discharges. In both models, cooling of epileptic foci significantly improved both seizure frequency and neurologic functions from 20°C down to 15°C. Cooling to 10°C also suppressed seizures, but with no further improvement in neurologic function. Subsequent investigation of sensorimotor function revealed significant deterioration in foot-fault tests and the receptive field size at 15°C., Significance: Despite the beneficial effects in ictal rats, sensorimotor functions deteriorated at 15°C, thereby suggesting a lower limit for the therapeutic temperature. These results provide important evidence of a therapeutic effect of temperatures from 20 to 15°C using an implantable, hypothermal device for focal epilepsy., (Wiley Periodicals, Inc. © 2012 International League Against Epilepsy.)

Objective: Management of elderly patients with poor-grade subarachnoid hemorrhage (SAH) remains controversial. The objective of this study was to investigate whether there is an age-dependent difference in the outcome of poor-grade SAH after surgical obliteration of the aneurysm., Methods: Data were reviewed retrospectively for 156 patients with poor-grade aneurysmal SAH at multiple centers in Chugoku and Shikoku, Japan. Patients were divided into age groups of 65-74 and ≥75 years old. Factors influencing a favorable outcome at discharge (Glasgow Outcome Scale, good recovery or moderately disabled) were determined using multivariate logistic regression analyses., Results: A favorable outcome at discharge was achieved in 37 of the 156 patients (23.7%). Advanced age (≥75 years old, P < 0.01), improvement of World Federation of Neurosurgical Societies (WFNS) Grade after admission (P = 0.02), Fisher grade (P < 0.001), and a low density area (LDA) associated with vasospasm on computed tomography (CT) (P < 0.01) were significantly associated with outcome. Multivariate analysis identified advanced age (≥75 years old, P = 0.01), Fisher group 4 (P = 0.002), and a new LDA associated with vasospasm on CT (P = 0.007) as predictors of a poor outcome in elderly patients with poor-grade SAH after surgical obliteration of the aneurysm. WFNS Grade V at admission (P = 0.052) was weakly associated with a poor outcome., Conclusions: Advanced age (≥75 years old), Fisher group 4, and LDA associated with vasospasm on CT were independent predictors of clinical outcome in elderly patients with poor-grade SAH. A favorable outcome in these patients occurred more frequently after Guglielmi detachable coil embolization than after surgical clipping, but without a significant difference.

Background: Subarachnoid clot is important in the development of delayed vasospasm after subarachnoid hemorrhage (SAH)., Objective: To compare the clearance of subarachnoid clot and the incidence of symptomatic vasospasm in surgical clipping and embolization with Guglielmi detachable coils for aneurysmal SAH., Methods: The subjects were 115 patients with Fisher group 3 aneurysmal SAH on computed tomography scan at admission whose aneurysm was treated by surgical clipping (clip group; n = 86) or Guglielmi detachable coil embolization (coil group; n = 29) within 72 hours of ictus. Software-based volumetric quantification of the subarachnoid clot was performed, and the amount of hemoglobin in drained cerebrospinal fluid was measured., Results: Clearance of the subarachnoid clot on the computed tomography scan was rapid in the clip group until the day after the operation but slow in the coil group (58.9% removed vs 27.8% removed; P = .008). However, postoperative clearance of the clot occurred more rapidly in the coil group. Reduction of the clot until days 3 through 5 did not differ significantly between the 2 groups (72.9% removed vs 75.2% removed). The amount of hemoglobin in the clip group was > 0.8 g/d until day 3 and then gradually decreased (n = 15), but hemoglobin in the coil group remained at > 0.8 g/d until day 5 (n = 17). The incidence of symptomatic vasospasm did not differ between the groups., Conclusion: Subarachnoid clot can be removed directly during surgical clipping, which is not possible with endovascular treatment. However, the percentage reduction of the clot on days 3 through 5 did not differ between the 2 groups.

Background: There is a lack of unified information on diagnosis and treatment of cerebral vasospasm (CV) after subarachnoid hemorrhage (SAH) among the hospitals in Japan. Thus, the aim of the study was to define the current practice in this area based on a survey by Japanese neurosurgeons., Methods: A survey on diagnosis and treatment of CV was sent to 414 hospitals each of which performs >100 neurosurgeries annually., Results: Responses were received from 240 hospitals (58.0%). Because accurate criteria for diagnosis of symptomatic vasospasm (SVS) were used in only 33.8% of the hospitals, we proposed a clinical definition of SVS that was approved at the 25(th) Spasm Symposium (Consensus 2009). This definition is simplified as follows: (1) the presence of neurological worsening; (2) no other identifiable cause of neurological worsening; and (3) confirmation of vasospasm by medical examinations. The results also showed that the Fisher CT scale is used differently for patients with ICH or IVH, with 41.3% of cases with ICH/IVH based on SAH that met Fisher criteria classified into Fisher group 1, 2 or 3, and 46.3% classified into Fisher group 4. There were no major differences in prophylactic therapies of CV and therapy for cerebral ischemia among the hospitals. Endovascular treatment for vasospasm was performed in most hospitals (78.7%); however, the criteria differed among the hospitals: (1) angiographic vasospasm and SVS appeared (37.9%), (2) only when aggressive therapy was ineffective (41.4%)., Conclusion: We established a clinical definition of SVS based on the results of this survey (Consensus 2009).

Ebselen is a mimic of glutathione peroxidase that reacts with peroxynitrite and inhibits nitric oxide (NO) synthase. Ebselen has beneficial effects on the neurological outcome of patients with stroke. In this study, the mechanisms by which ebselen can elicit neuroprotective effects against ischemic brain injury were investigated in male Wistar rats. Experimental forebrain ischemia was induced by bilateral common carotid artery occlusion with hemorrhagic hypotension. Ebselen was administered to animals in the treatment group 2 hours prior to the induction of forebrain ischemia, and placebo was administered in the control group. Cerebral blood flow (CBF) was measured by the hydrogen clearance method. Cortical extracellular levels of excitatory amino acids (EAAs) and NO were evaluated using in vivo microdialysis. Neuronal damage in the CA1 subfield of the hippocampus was assessed in brains harvested after a 24-hour period of survival. CBF did not recover to normal physiological levels after ischemic insults in either the control or treatment groups. The differences in the sequential changes in extracellular EAA and NO levels between groups were not statistically significant. There was a significantly larger mean density of intact, undamaged neurons in the CA1 subfield in the treatment group than in the control group. The neuroprotective effects of ebselen were reflected in the histological findings, without significant inhibition of glutamate release or NO synthesis during the acute phase of experimentally induced cerebral ischemia.

Background: We report neuroendoscopic evacuation of an intraventricular hematoma (IVH) in 13 patients with thalamic hemorrhage. We discuss strategies to improve the outcome and to shorten the management period by using external ventricular drainage (EVD)., Methods: Patients were classified into fair (modified Rankin scale [mRS] grade 4 or less) and poor (mRS grade 5) outcome groups, and depending on the duration of EVD, into short (7 days or shorter) and long EVD (8 days or longer) groups., Results: The postoperative residual IVH, graded using the Graeb score, was better for the fair outcome group than for the poor outcome group (3.9 [1.2] vs. 5.7 [1.0], P < 0.05). The postoperative Graeb score was significantly better for the short EVD group than for the long EVD group (3.6 [0.8] vs. 6.0 [0.6], P < 0.01). The duration of EVD was not correlated with the IVH at the fourth ventricle, but it was correlated with the IVH at the foramen of Monro (P < 0.05) and the third ventricle (P < 0.01). Reduction in the volume of thalamic hemorrhage had no effect on the neurological outcome or duration of EVD., Conclusion: Neuroendoscopic evacuation of the IVH at the foramen of Monro and the third ventricle shortened the duration of EVD for hydrocephalus caused by thalamic hemorrhage with IVH involvement. Removal of the thalamic hemorrhage and IVH at the fourth ventricle was not necessary.

Background: The management of patients with poor-grade subarachnoid hemorrhage (SAH) continues to be controversial. The objective of this study was to examine predictors of outcome of poor-grade SAH after surgical obliteration of the aneurysm., Methods: The study was performed as a retrospective review of 283 patients with poor-grade SAH who underwent surgical obliteration of the aneurysm at multiple centers in Chugoku and Shikoku, Japan., Results: A favorable outcome at discharge was achieved in 97 of the 283 patients (34.3%). Age (p < 0.001), World Federation of Neurosurgical Societies (WFNS) grade V at admission (p = 0.002), improvement in WFNS grade after admission (p = 0.002), Fisher grade (p = 0.039) and a low-density area (LDA) associated with vasospasm on computed tomography (CT; p < 0.001) showed a significant association with outcome. Further analysis of WFNS grades indicated that most patients who only improved to preoperative grade IV from grade V at admission did not have a favorable outcome. Multivariate analysis identified age (especially of > or =65 years; p < 0.001), WFNS grade V (p < 0.001) and LDA associated with vasospasm on CT (p < 0.001) as predictors of a poor outcome, and improvement in WFNS grade (p = 0.001) as a predictor of a favorable outcome after surgical obliteration of the aneurysm., Conclusions: Advanced age, WFNS grade V, improvement in WFNS grade, and LDA associated with vasospasm on CT were found to be independent predictors of clinical outcome, whereas rebleeding, early aneurysm surgery and treatment modality (surgical clipping or Guglielmi detachable coil embolization) were not independently associated with outcome in patients with poor-grade aneurysm., (Copyright (c) 2010 S. Karger AG, Basel.)

A 64-year-old man presented with subarachnoid hemorrhage from a small brainstem arteriovenous malformation (AVM). Cerebral angiography showed a small AVM in the lateral midbrain, which was fed by a basilar perforating artery, and drained into the right transverse pontine vein and superior petrous vein. Endovascular embolization in the acute stage was selected to occlude the arteriovenous shunt and provide additional intensive treatment for cerebral spasm with lower risk of rebleeding. The AVM was occluded by embolization using n-butyl cyanoacrylate. Intraparenchymal hemorrhage in the ipsilateral pons was detected 1 month after treatment. The causes of the hemorrhage remain unclear.

This study investigates the role of sphingosylphosphorylcholine (SPC) in the mechanisms underlying cerebral vasospasm after subarachnoid hemorrhage (SAH). The levels of SPC were measured in cerebrospinal fluid (CSF) of patients with SAH and also in an experimental canine model. CSF samples were collected from 11 patients with SAH, and from dogs that had received an injection of SPC into the cisterna magna to examine SPC kinetics in the CSF. SPC was assayed using solid-phase extraction and triple quadrupole mass spectrometry. The SPC concentrations in SAH patients on days 3, 8, and 14 after the onset of SAH were significantly higher than those in normal CSF. In the canine model, rapid dilution of SPC in CSF was observed. In combination with data from previous studies, these results suggest that SPC is involved in the development of cerebral vasospasm. Rapid dilution of SPC in CSF suggests that SPC is released into CSF at higher concentrations than those measured in the present study.

Background: Recently, decrease of immunoglobulin concentrations or neutrophil counts were reported in some cases several months after administration of rituximab. We examined a number of episodes of late onset neutropenia or immunoglobulin decrease in patients with malignant lymphoma who were in complete remission following autologous transplantation with or without rituximab., Method: Patients with follicular lymphoma and diffuse large B cell lymphoma transplanted with or without rituximab in our institutes were analyzed. Immunoglobulin concentrations and neutrophil counts after transplantation, both with and without rituximab were measured serially., Results: Four weeks after transplantation, blood samples revealed lower concentrations of IgG and IgA in the rituximab group than in the non-rituximab group. Neutrophil numbers did not fall below 0.5x10(9) /L four weeks or more after transplantation in the non-rituximab group. Neutrophil numbers dropped below 0.5x10(9) /L in 6 of 14 cases in the rituximab group., Conclusion: Although the present study was retrospective and disease composition and pre-transplantation regimens differed between the two groups, the addition of rituximab to autologous transplantation might bring about a decrease of immunoglobulin levels and transient LON.

Background and Purpose: Rho-kinase (ROK)-mediated Ca2+ sensitization of vascular smooth muscle (VSM) contraction plays a pivotal role in cerebral vasospasm (CV). We previously demonstrated that sphingosylphosphorylcholine (SPC) induces Ca2+ sensitization through sequential activation of the Src family protein tyrosine kinases (Src-PTKs) and ROK in vitro, and that Ca2+ sensitization is inhibited by eicosapentaenoic acid (EPA) through the selective inactivation of Src-PTK. In this study, we examined whether SPC induced CV in vivo, and, if it did, whether EPA would inhibit CV, as induced by SPC or in an in vivo model of subarachnoid hemorrhage (SAH)., Methods: Changes in the diameter of the canine basilar artery were investigated by angiography after administering SPC into the cisterna magna. Then, Y27632, a specific Rho-kinase inhibitor, or EPA was injected intracisternally and the effects of both agents were investigated. In another experiment using a single-hemorrhage model, Y27632 or EPA was injected on day 7 after SAH and the changes in the diameter of the canine basilar artery were investigated., Results: At cerebrospinal fluid concentrations of 100 and 300 micromol/l, SPC induced severe vasoconstriction (maximum vasoconstriction by SPC (100 micromol/l): 61.8 +/- 8.2%), which was markedly reversed by Y27632 (96.3 +/- 4.4%) or EPA (92.6 +/- 12.8%). SAH caused severe vasospasm on day 7 (67.6 +/- 7.8%), which was significantly blocked by Y27632 (95.5 +/- 10.6%) or EPA (90.0 +/- 4.4%)., Conclusions: SPC is a novel mediator of ROK-induced CV in vivo. The inhibition of CV induced by SPC or after SAH by EPA suggests beneficial roles of EPA in the treatment of CV. Our findings are compatible with the notion that the SPC-ROK pathway may be involved in CV., ((c) 2008 S. Karger AG, Basel)

Hypercholesterolemia is a major risk factor involved in abnormal cardiovascular events. Rho-kinase-mediated Ca(2+) sensitization of vascular smooth muscle (VSM) plays a critical role in vasospasm and hypertension. We recently identified sphingosylphosphorylcholine (SPC) and Src family tyrosine kinase (Src-TK) as upstream mediators for the Rho-kinase-mediated Ca(2+) sensitization. Here we report the strong linkage between cholesterol and the Ca(2+) sensitization of VSM mediated by a novel SPC/Src-TK/Rho-kinase pathway in both humans and rabbits. The extent of the sensitization correlated well with the total cholesterol or low-density lipoprotein cholesterol levels in serum. However, an inverse correlation with the serum level of high-density lipoprotein cholesterol was observed, and a correlation with other cardiovascular risk factors was nil. When cholesterol-lowering therapy was given to patients and rabbits with hypercholesterolemia, the SPC-induced contractions diminished. Depletion of VSM cholesterol by beta-cyclodextrin resulted in a loss of membrane caveolin-1, a marker of cholesterol-enriched lipid raft, and inhibited the SPC-induced Ca(2+) sensitization and translocation of Rho-kinase from cytosol to the cell membrane. Vasocontractions induced by membrane depolarization and by an adrenergic agonist were cholesterol-independent. Our data support the previously unreported concept that cholesterol potentiates the Ca(2+) sensitization of VSM mediated by a SPC/Src-TK/Rho-kinase pathway, and are also compatible with a role for cholesterol-enriched membrane microdomain, a lipid raft. This process may play an important role in the development of abnormal vascular contractions in patients with hypercholesterolemia.

A 54-year-old woman was admitted due to high-grade fever, cervical lymphadenopathy and general malaise in May 2003. On examination, severe anemia was noted, direct Coombs and cold hemagglutinin tests were positive and the haptoglobin level was low in the peripheral blood. However, a bone marrow examination revealed marked erythroid hypoplasia. A diagnosis was made of co-existing combined type autoimmune hemolytic anemia (AIHA) and erythroid hypoplasia. A pathologic diagnosis of de novo CD5-positive diffuse large B-cell lymphoma (de novo CD5+ DLBCL) was made based on a cervical lymph node biopsy. The patient was treated with CHOP accompanied by rituximab (R-CHOP), resulting in complete remission after 3 courses of chemotherapy. The AIHA and erythroid hypoplasia subsided after 2 courses of R-CHOP. The sera obtained during erythroid hypoplasia significantly inhibited the growth of erythroid progenitor cells (erythroid colony-forming units, CFU-E) from her bone marrow collected after recovery. We report here a patient with de novo CD5+ DLBCL associated with both AIHA and erythroid hypoplasia, suggesting that the lymphoma triggered an abnormal immunity which generated some humoral inhibitors against erythropoiesis.

Primary adrenal lymphoma is a rare lymphoma with clinical features consisting of a high incidence of bilateral adrenal involvement, diffuse large B-cell histology and secondary adrenal insufficiency. We report a successful treatment of a patient with primary adrenal lymphoma using a combined modality therapy (CMT). A 62-year-old man was hospitalized with pain of the flank, and a computed tomography (CT) scan of the abdomen revealed very large, bilateral adrenal masses. A needle biopsy of the left adrenal mass revealed diffuse large B-cell lymphoma. After irradiation of both adrenal lymphomas and CHOP therapy accompanied by intrathecal treatment and rituximab, the patient underwent a left adrenalectomy and high-dose chemotherapy with autologous peripheral blood stem cell transplantation. The patient has been disease-free for 2 years after the diagnosis of primary adrenal lymphoma. In contrast to the previous reports of poor response to conventional-dose chemotherapy alone and short-term survival of patients with primary adrenal lymphoma, our patient has demonstrated that radiation therapy combined with chemotherapy and rituximab may be an effective modality as a first-line therapeutic regimen for localized primary adrenal lymphoma.

Administration of imatinib exacerbated psoriasis vulgaris in a case of chronic myelogenous leukemia (CML). After the cessation of imatinib therapy, the psoriasis was alleviated. Upon readministration of imatinib, the psoriasis worsened despite the improvement of hematological and cytogenetic findings in the CML. Psoriasis is known to be an autoimmune skin disease characterized by Th1 cell-mediated hyperproliferation of keratinocytes, and the type 1 helper T (Th1) cell subset increased with imatinib therapy. Thus, the exacerbation of psoriasis was likely due to the increase in Th1 cells associated with imatinib therapy.