Search

The primary objective of this study was to investigate the potential facilitating effects of daily rehabilitation for chronic cerebral ischemia following the intravenous infusion of mesenchymal stem cells (MSC) in rats. The middle cerebral artery (MCA) was occluded by intraluminal occlusion using a microfilament (MCAO). Eight weeks after MCAO induction, the rats were used as a chronic cerebral ischemia model. Four experimental groups were studied: Vehicle group (medium only, no cells); Rehab group (vehicle + rehabilitation), MSC group (MSC only); and Combined group (MSC + rehabilitation). Rat MSCs were intravenously infused eight weeks after MCAO induction, and the rats received daily rehabilitation through treadmill exercise for 20 min. Behavioral testing, lesion volume assessment using magnetic resonance imaging (MRI), and histological analysis were performed during the observation period until 16 weeks after MCAO induction. All treated animals showed functional improvement compared with the Vehicle group; however, the therapeutic efficacy was greatest in the Combined group. The combination therapy is associated with enhanced neural plasticity shown with histological analysis and MRI diffusion tensor imaging. These findings provide behavioral evidence for enhanced recovery by combined therapy with rehabilitation and intravenous infusion of MSCs, and may form the basis for the development of clinical protocols in the future., 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 © 2023 Elsevier B.V. All rights reserved.)

Ciguatoxins (CTXs) stand as the primary toxins causing ciguatera fish poisoning (CFP) and are essential compounds distinguished by their characteristic polycyclic ether structure. In a previous report, we identified the structures of product ions generated via homolytic fragmentation by assuming three charge sites in the mass spectrometry (MS)/MS spectrum of ciguatoxin-3C (CTX3C) using LC-MS. This study aims to elucidate the homolytic fragmentation of a ciguatoxin-3C congener. We assigned detailed structures of the product ions in the MS/MS spectrum of a naturally occurring ciguatoxin-3C congener, 51-hydroxyciguatoxin-3C (51-hydoxyCTX3C), employing liquid chromatography/quadrupole time-of-flight mass spectrometry with an atmospheric pressure chemical ionization (APCI) source. The introduction of a hydroxy substituent on C51 induced different fragmentation pathways, including a novel cleavage mechanism of the M ring involving the elimination of 51-OH and the formation of enol ether. Consequently, new cleavage patterns generated product ions at m / z 979 (C 55 H 79 O 15 ), 439 (C 24 H 39 O 7 ), 149 (C 10 H 13 O), 135 (C 9 H 11 O), and 115 (C 6 H 11 O 2 ). Additionally, characteristic product ions were observed at m / z 509 (C 28 H 45 O 8 ), 491 (C 28 H 43 O 7 ), 481 (C 26 H 41 O 8 ), 463 (C 26 H 39 O 7 ), 439 (C 24 H 39 O 7 ), 421 (C 24 H 37 O 6 ), 171 (C 9 H 15 O 3 ), 153 (C 9 H 13 O 2 ), 141 (C 8 H 13 O 2 ), and 123 (C 8 H 11 O).

Background: Perinatal brain injury is multifactorial and primarily associated with brain prematurity, inflammation, and hypoxia-ischemia. Although recent advances in perinatal medicine　have improved the survival rates of preterm infants, neurodevelopmental disorders remain a significant complication. We tested whether the intravenous infusion of mesenchymal stem cells (MSCs) had therapeutic efficacy against perinatal brain injury in rats., Methods: Pregnant rats at embryonic day (E) 18 received lipopolysaccharide and the pups were born at E21. On postnatal day (PND) 7, the left common carotid artery of each pup was ligated, and they were exposed to 8% oxygen for 2 h. They were randomized on PND10, and MSCs or vehicle were intravenously infused. We performed behavioral assessments, measured brain volume using MRI, and performed histological analyses on PND49., Results: Infused MSCs showed functional improvements in our model. In vivo MRI revealed that MSC infusion increased non-ischemic brain volume compared to the vehicle group. Histological analyses showed that cortical thickness, the number of NeuN + and GAD67 + cells, and synaptophysin density in the non-ischemic hemisphere in the MSC group were greater than the vehicle group, but less than the control group., Conclusions: Infused MSCs improve sensorimotor and cognitive functions in perinatal brain injury and enhance neuronal growth., Impact: Intravenous infusion of MSCs improved neurological function in rats with perinatal brain injury, including motor, sensorimotor, cognitive, spatial, and learning memory. Infused MSCs increased residual (non-ischemic) tissue volume, number of neuronal cells, GABAergic cells, and cortical synapses in the contralesional (right) hemisphere. Intravenous administration of MSC might be suitable for the treatment of perinatal brain injury., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Rationale: Marine polycyclic ethers have drawn attention owing to their unique chemical structures and involvement in food poisoning and fish killing. To study structural diversity, we performed a structural assignment of product ions produced from a representative ladder-shaped polycyclic ether, ciguatoxin-3C, and elucidated the mechanism of generation., Methods: The product ions used for the structural assignment were produced from a precursor ion [M + H] + using liquid chromatography/quadrupole time-of-flight mass spectrometry, by employing an atmospheric pressure chemical ionization source., Results: Three charged sites were considered at both terminals of a molecule. Typical charge-remote fragmentation was produced at the respective charge sites, yielding a hybrid spectrum. C-C bonds bordering two ethers could cleave and trigger the fission of two other bonds. Prominent ions indicating the serial loss of water molecules resulted from the simultaneous deprivation of ethereal oxygen and hydrogen atoms. The resultant double bonds formed long chains of conjugated polyenes, which stabilized charge via resonance., Conclusions: Three alternative charge sites produce a hybrid spectrum. The simultaneous fission of three bonds was explained. For the first time, intense ions due to serial dehydration were explained by the elimination of ether oxygen atoms and the subsequent conjugation of double bonds. All product ions were considered by the structural features of polycyclic ether that facilitates the formation of conjugated polyenes., (© 2023 John Wiley & Sons Ltd.)

Background: Magnetic resonance angiography (MRA) is an important tool in rat models of cerebrovascular disease. Although MRA has long been used in rodents, the image quality is typically not as high as that observed in clinical practice. Moreover, studies on MRA image quality in rats are limited. This study aimed to develop a practical high-spatial-resolution MRA protocol for imaging cerebral arteries in rats., New Method: We used the "half position method" regarding coil placement and modified the imaging parameters and image reconstruction method. We applied this new imaging method to measure maturation-related signal changes on rat MRAs., Results: The new practical high-spatial-resolution MRA imaging protocol obtained a signal intensity up to 3.5 times that obtained using a basic coil system, simply by modifying the coil placement method. This method allowed the detection of a gradual decrease in the signal in cerebral vessels with maturation., Comparison With Existing Methods: A high-spatial-resolution MRA for rats was obtained with an imaging time of approximately 100 min. Comparable resolution and image quality were obtained using the new protocol with an imaging time of 30 min CONCLUSIONS: The new practical high-spatial-resolution MRA protocol can be implemented simply and successfully to achieve high image quality with an imaging time of approximately 30 min. This protocol will benefit researchers performing MRA imaging in cerebral artery studies in rats., Competing Interests: Declaration of Competing Interest None of the author has any conflict of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Although limited spontaneous recovery occurs after spinal cord injury (SCI), current knowledge reveals that multiple forms of axon growth in spared axons can lead to circuit reorganization and a detour or relay pathways. This hypothesis has been derived mainly from studies of the corticospinal tract (CST), which is the primary descending motor pathway in mammals. The major CST is the dorsal CST (dCST), being the major projection from cortex to spinal cord. Two other components often called "minor" pathways are the ventral and the dorsal lateral CSTs, which may play an important role in spontaneous recovery. Intravenous infusion of mesenchymal stem cells (MSCs) provides functional improvement after SCI with an enhancement of axonal sprouting of CSTs. Detailed morphological changes of CST pathways, however, have not been fully elucidated. The primary objective was to evaluate detailed changes in descending CST projections in SCI after MSC infusion. The MSCs were infused intravenously one day after SCI. A combination of adeno-associated viral vector (AAV), which is an anterograde and non-transsynaptic axonal tracer, was injected 14 days after SCI induction. The AAV with advanced tissue clearing techniques were used to visualize the distribution pattern and high-resolution features of the individual axons coursing from above to below the lesion. The results demonstrated increased observable axonal connections between the dCST and axons in the lateral funiculus, both rostral and caudal to the lesion core, and an increase in observable axons in the dCST below the lesion. This increased axonal network could contribute to functional recovery by providing greater input to the spinal cord below the lesion.

Background: Brain injuries resulting from motor vehicle accidents and falls, as well as hypoxic insults and other conditions, are one of the leading causes of disability and death in the world. Current treatments are limited but include continuous rehabilitation, especially for chronic brain injury. Recent studies have demonstrated that the intravenous infusion of mesenchymal stem cells (MSCs) has therapeutic efficacy for several neurological diseases, including stroke and spinal cord injury., Objective: The objective of our investigator-initiated clinical trial is to assess the safety and potential efficacy of the intravenous infusion of autoserum-expanded autologous MSCs for patients with chronic brain injury., Methods: The (phase 2) trial will be a single-arm, open-label trial with the primary objective of confirming the safety and efficacy of autoserum-expanded autologous MSCs (STR-01; produced under good manufacturing practices) when administered to patients with chronic brain injury. The estimated number of enrolled participants is 6 to 20 patients with a modified Rankin Scale grade of 3 to 5. The assessment of safety and the proportion of cases in which the modified Rankin Scale grade improves by 1 point or more at 180 days after the injection of STR-01 will be performed after MSC infusion., Results: We received approval for our clinical trial from the Japanese Pharmaceuticals and Medical Devices Agency on December 12, 2017. The trial will be completed on June 11, 2023. The registration term is 5 years. The recruitment of the patients for this trial started on April 20, 2018, at Sapporo Medical University Hospital in Japan., Conclusions: Our phase 2 study will aim to address the safety and efficacy of the intravenous infusion of MSCs for patients with chronic brain injury. The use of STR-01 has been performed for patients with cerebral infarction and spinal cord injury, providing encouraging results. The potential therapeutic efficacy of the systemic administration of autoserum-expanded autologous MSCs for chronic brain injury should be evaluated, given its safety and promising results for stroke and spinal cord injury., Trial Registration: Japan Medical Association Center for Clinical Trials JMA-IIA00333; https://tinyurl.com/nzkdfnbc., International Registered Report Identifier (irrid): DERR1-10.2196/37898., (©Shinichi Oka, Tomohiro Yamaki, Masanori Sasaki, Ryo Ukai, Mitsuhiro Takemura, Takahiro Yokoyama, Yuko Kataoka-Sasaki, Rie Onodera, Yoichi M Ito, Shigeki Kobayashi, Jeffery D Kocsis, Yasuo Iwadate, Osamu Honmou. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 06.07.2022.)

Background Selecting the appropriate direct oral anticoagulants (DOACs) for embolic ischemic stroke patients, especially on concurrent antiplatelet therapy, is important. However, a limited number of studies have reported on the pharmacological differences in platelet aggregation of each DOAC. We aimed to evaluate the antiplatelet effects of selected DOACs, by comparing dabigatran (a direct oral thrombin inhibitor) and factor Xa (FXa) inhibitors (apixaban and rivaroxaban) in patients who had suffered a cardioembolic stroke. Methods We retrospectively evaluated 12 patients diagnosed with a cardioembolic stroke who took any DOAC without an antiplatelet drug and underwent platelet aggregation tests within 60 days from the onset of symptoms. The platelet aggregation tests were analyzed by both light transmission aggregometry and VerifyNow®. Results Six patients (50%) took dabigatran, while the other six (50%) took an FXa inhibitor (n = 4 for apixaban and n = 2 for rivaroxaban). From the light transmission aggregometry analysis, it was found that the maximal extent of aggregation for adenosine diphosphate (ADP) was significantly higher with dabigatran than with FXa inhibitors, and the ED 50 value of ADP on platelet aggregation was significantly lower with dabigatran than with FXa inhibitors. Moreover, the VerifyNow® analyses revealed that P2Y 12 reaction units were significantly higher with dabigatran than with FXa inhibitors. Conclusions Dabigatran had little impact on platelet aggregation compared to FXa inhibitors in patients who had suffered a cardioembolic stroke with atrial fibrillation, and who took DOACs for secondary prevention within 60 days from the onset., Competing Interests: Declarations of Competing Interest MN, MS, and HO received honoraria from Boehringer Ingelheim Japan, Inc for lectures. SO, HM, RK, RO, RU, and YKS report no competing interests., (Copyright © 2022 Elsevier Inc. All rights reserved.)

The purple-flesh potato ( Solanum tuberosum L.) cultivar "Shadow Queen" (SQ) naturally contains anthocyanins. This randomized, double-blind, placebo-controlled study determines whether ingesting purple potatoes increases the number of mesenchymal stem cells (MSC) and improves stress response, a minor health complaint in healthy adults (registration number: UMIN000038876). A total of 15 healthy subjects (ages: 50-70 years) with minor health complaints were randomly assigned to one of two groups. For 8 weeks, the placebo group received placebo potatoes cv. "Haruka" and the test group received test potato cv. SQ containing 45 mg anthocyanin. The MSC count and several stress responses were analyzed at weeks 0 and 8 of the intake periods. The ingestion of a SQ potato did not affect the MSC count but markedly improved psychological stress response, irritability, and depression as minor health complaints compared with "Haruka". No adverse effects were noted. Hence, an 8-week intake of SQ could improve stress responses.

Objective: Stroke is a major cause of long-term disability, and there are few effective treatments that improve function in patients during the chronic phase of stroke. Previous research has shown that single systemic infusion of mesenchymal stem cells (MSCs) improves motor function in acute and chronic cerebral ischemia models in rats. A possible mechanism that could explain such an event includes the enhanced neural connections between cerebral hemispheres that contribute to therapeutic effects. In the present study, repeated infusions (3 times at weekly intervals) of MSCs were administered in a rat model of chronic stroke to determine if multiple dosing facilitated plasticity in neural connections., Methods: The authors induced middle cerebral artery occlusion (MCAO) in rats and, 8 weeks thereafter, used them as a chronic stroke model. The rats with MCAO were randomized and intravenously infused with vehicle only (vehicle group); with MSCs at week 8 (single administration: MSC-1 group); or with MSCs at weeks 8, 9, and 10 (3 times, repeated administration: MSC-3 group) via femoral veins. Ischemic lesion volume and behavioral performance were examined. Fifteen weeks after induction of MCAO, the thickness of the corpus callosum (CC) was determined using Nissl staining. Immunohistochemical analysis of the CC was performed using anti-neurofilament antibody. Interhemispheric connections through the CC were assessed ex vivo by diffusion tensor imaging., Results: Motor recovery was better in the MSC-3 group than in the MSC-1 group. In each group, there was no change in the ischemic volume before and after infusion. However, both thickness and optical density of neurofilament staining in the CC were greater in the MSC-3 group, followed by the MSC-1 group, and then the vehicle group. The increased thickness and optical density of neurofilament in the CC correlated with motor function at 15 weeks following induction of MCAO. Preserved neural tracts that ran through interhemispheric connections via the CC were also more extensive in the MSC-3 group, followed by the MSC-1 group and then the vehicle group, as observed ex vivo using diffusion tensor imaging., Conclusions: These results indicate that repeated systemic administration of MSCs over 3 weeks resulted in greater functional improvement as compared to single administration and/or vehicle infusion. In addition, administration of MSCs is associated with promotion of interhemispheric connectivity through the CC in the chronic phase of cerebral infarction.

Objectives: Ischaemic spinal cord injury (SCI) is one of the most serious complications of aortic surgery. Ischaemic SCIs occur due to various aetiologies, and prediction of the risk is difficult. Magnetic resonance imaging (MRI) is useful to detect the details of spinal cord infarction. There are few studies about MRI for evaluating ischaemic SCI after cardiovascular surgery and aortic events. We report 9 cases of postoperative ischaemic SCI and analyse their MRI features., Methods: T2-weighted MRI scans of 9 patients who developed ischaemic SCI due to cardiovascular surgery and aortic events between 2012 and 2017 were evaluated., Results: In all patients, high-intensity areas were observed on T2-weighted magnetic resonance images. The site of infarction was the thoracic spinal cord level (9 cases) and additionally at the lumbar spinal cord level (5 cases). The area of infarction area was categorized based on the arterial territory: anterior spinal artery territory (3 cases), posterior spinal artery territory (2 cases), spinal sulcal artery territory (1 case) and artery of Adamkiewicz territory (3 cases)., Conclusions: MRI revealed the infarction sites in all cases and the differences in the infarction patterns in each case. MRI could thus be useful for investigating the aetiology of ischaemic SCI following aortic surgeries and events., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative fatal disorder in which motor neurons within the brain and spinal cord degenerate. A single infusion of mesenchymal stem cells (MSCs) delays disease progression by protecting motor neurons and restoring the blood-spinal cord barrier in the SOD1G93A transgenic ALS rat model. However, the therapeutic effect of a single infusion of MSCs is transient and does not block disease progression. In this study, we demonstrated that repeated administration of MSCs (weekly, four times) increased the survival period, protected motor functions, and reduced deterioration of locomotor activity compared to a single infusion and vehicle infusion, after which rats displayed progressive deterioration of hind limb function. We also compared the days until gait ability was lost in rats and found that the repeated-infused group maintained gait ability compared to the single-infusion and vehicle-infusion groups. These results suggest that repeated administration of MSCs may prevent the deterioration of motor function and extend the lifespan in ALS.

Objective: Reperfusion therapy is a standard therapeutic strategy for acute stroke. Non-favorable outcomes are thought to partially result from impaired microcirculatory flow in ischemic tissue. Intravenous infusion of mesenchymal stem cells (MSCs) reduces stroke volume and improves behavioral function in stroke. One suggested therapeutic mechanism is the restoration of the microvasculature. The goal of this study was to determine whether infused MSCs enhance the therapeutic efficacy of reperfusion therapy following stroke in rats., Methods: First, to establish a transient middle cerebral artery occlusion (MCAO) model displaying approximately identical neurologic function and lesion volume as seen in permanent MCAO (pMCAO) at day 7 after stroke induction, we transiently occluded the MCA for 90, 110, and 120 minutes. We found that the 110-minute occlusion met these criteria and was used as the transient MCAO (tMCAO) model. Next, 4 MCAO groups were used to compare the therapeutic efficacy of infused MSCs: (1) pMCAO+vehicle, (2) tMCAO+vehicle, (3) pMCAO+MSC, and (4) tMCAO+MSC. Our ischemic model was a unique ischemic model system in which both pMCAO and tMCAO provided similar outcomes during the study period in the groups without MSC infusion groups. Behavioral performance, ischemic volume, and regional cerebral blood flow (rCBF) using arterial spin labeling-magnetic resonance imaging and histologic evaluation of microvasculature was performed., Results: The behavioral function, rCBF, and restoration of microvasculature were greater in group 4 than in group 3. Thus, infused MSCs facilitated the therapeutic efficacy of MCA reperfusion in this rat model system., Conclusions: Intravenous infusion of MSCs may enhance therapeutic efficacy of reperfusion therapy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

ALS is a devastating neurodegenerative disease with few curative strategies. Both sporadic and familial ALS display common clinical features that show progressive paralysis. The pathogenesis remains unclear, but disruption of the blood-spinal cord barrier (BSCB) may contribute to the degeneration of motor neurons. Thus, restoration of the disrupted BSCB and neuroprotection for degenerating motor neurons could be therapeutic targets. We tested the hypothesis that an intravenous infusion of MSCs would delay disease progression through the preservation of BSCB function and increased expression of a neurotrophic factor, neurturin, in SOD1 G93A ALS rats. When the open-field locomotor function was under 16 on the Basso, Beattie, and Bresnahan (BBB) scoring scale, the rats were randomized into two groups; one received an intravenous infusion of MSCs, while the other received vehicle alone. Locomotor function was recorded using BBB scoring and rotarod testing. Histological analyses, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), were performed. The MSC group exhibited reduced deterioration of locomotor activity compared to the vehicle group, which displayed progressive deterioration of hind limb function. We observed the protection of motor neuron loss and preservation of microvasculature using Evans blue leakage and immunohistochemical analyses in the MSC group. Confocal microscopy revealed infused green fluorescent protein + (GFP + ) MSCs in the spinal cord, and the GFP gene was detected by nested PCR. Neurturin expression levels were significantly higher in the MSC group. Thus, restoration of the BSCB and the protection of motor neurons might be contributing mechanisms to delay disease progression in SOD1 G93A ALS rats., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Advances in the understanding of the pathogenesis of arteriosclerosis, abdominal aorta aneurysms and dissections, and carotid artery plaques have focused on chronic inflammation. In this study, we report that inflammatory changes of thrombi contribute to the enlargement and growth of giant intracranial thrombotic aneurysms. Surgical and postmortem samples were collected from 12 cases of large or giant intracranial thrombotic aneurysms diagnosed via pathological investigations. Degeneration of the aneurysmal wall and the infiltration of inflammatory cells in the thrombi were assessed. The number of blood cells and immunohistochemical stain-positive cells was enumerated, and the inflammation and neovascularization in the thrombi were assessed. In all cases, the appearance of inflammatory cells (CD68 + cells, CD206 + cells, lymphocytes, and neutrophils) was apparent in the thrombi. The number of CD34 + cells was moderately correlated with the number of CD68 + cells, and CD34 + cells significantly and strongly correlated with the number of CD206 + cells. Based on the number of neutrophils per CD68 + cells, we classified the cases into 2 groups: a macrophage inflammation-dominant group and a neutrophilic inflammation-dominant group. The neutrophilic inflammation-dominant group had significantly more cases with previous treatments and neurological symptoms due to mass effect than the macrophage inflammation-dominant group. Chronic inflammation due to macrophages in thrombi is a fundamental mechanism in the enlargement of an intracranial thrombotic aneurysm, and neutrophilic inflammation can accelerate this process. Microvascularization in thrombi is linked to inflammation and might promote thickening of the intima and repeated intimal microbleeds.

Objective: Grade 2 meningioma is more likely to recur than grade 1 meningioma. Recurrence decreases overall survival in patients with grade 2 meningioma. However, the clinical course of grade 2 meningioma with several repeated recurrences is poorly understood. The purpose of this study was to clarify the clinical characteristics of grade 2 meningioma with repeated recurrences., Methods: This study included 28 patients with grade 2 meningioma treated at our institution from January 1994 to December 2017. The relationship between survival and factors including age, sex, number of recurrences, malignant transformation, radiation therapy, tumor location, MIB-1 labeling index, Simpson grade, Karnofsky Performance Status, and surgical interval were analyzed., Results: The average age at the initial operation was 53.4 years. The number of recurrences was 3.7 times on average during the follow-up of 113.9 months after the initial operation. An increasing number of recurrences resulted in shortening of the surgical interval, increase in the MIB-1 labeling index, and decrease in Karnofsky Performance Status. In fatal cases, the average surgical interval before death was approximately 1 year. Three factors were related to poor prognosis: number of recurrences (odds ratio, 1.620; P = 0.030), malignant transformation (odds ratio, 10.625; P = 0.019), and high MIB-1 labeling index (odds ratio, 1.089; P = 0.044)., Conclusions: Shortening of the surgical interval within 1 year because of multiple recurrences led to death in patients with grade 2 meningioma. Malignant transformation was the most potent among the poor prognostic factors., (Copyright © 2020. Published by Elsevier Inc.)

Competing Interests: The authors declare no conflict of interest.

Objectives: Arterial spin labeling (ASL) is a magnetic resonance imaging (MRI) technique used to assess cerebral perfusion. When tissue perfusion is impaired, such as in Moyamoya disease, a hyperintense band called the arterial transit artifact (ATA) may occur, which interferes with accurate measurements on ASL-MRI. In this study, we evaluated the correlation of ATAs with magnetic resonance angiography (MRA) and single-photon emission computed tomography (SPECT) imaging results in Moyamoya disease. The aim of our study was to elucidate the pathophysiology of ATAs and risk factors for high ATA scores., Materials and Methods: This retrospective study included 28 patients (56 hemispheres) with Moyamoya disease treated at our institution. MRI, MRA, ASL perfusion, and N-isopropyl-[ 123 I] b-iodoamphetamine ( 123 I-IMP) SPECT were performed. In order to semi-quantitatively evaluate the degree of ATA, the ATA scores were measured according to the number of hyperintense signal bands in the cerebral cortex. The relationship between the ATA scores and clinical and radiological factors were analyzed., Results: Regional cerebral blood flow (rCBF) determined with ASL weakly correlated with that determined by 123 I-IMP SPECT (ρ=0.31, p=0.027). There was no significant association between the ATA scores and rCBF values determined with 123 I-IMP SPECT (p=0.872, 0.745, 0.743 at PLD1000 (post-labeling delay), 1500, and 2000, respectively). However, there was a significant correlation between ATA scores and MRA scores (ρ=0.427 p=0.001; ρ=0.612 p=0.001; ρ=0.563 p=0.001 at PLD1000, 1500, and 2000, respectively). An analysis of patient background characteristics revealed a significantly higher incidence of high ATA scores in female patients, patients with high MRA scores, and patients with a distinguishable ivy sign. A multivariate analysis confirmed that female sex, high MRA score, and presence of an ivy sign were risk factors for high ATA scores., Conclusion: ATA scores were moderately correlated with MRA scores, and presence of an ivy sign was the most predictive factor for high ATA scores. A high ATA score determined using ASL in a patient with Moyamoya disease might suggest an advanced disease stage and a reduction in cerebrovascular reserve capacity., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Extracranial-to-intracranial (EC-IC) bypass surgery is an effective treatment for patients with moyamoya disease and other conditions. Some patients with moyamoya disease have a risk of acute thrombogenesis at the anastomotic site just after bypass surgery. The purpose of this study was to study risk factors of acute thrombogenesis and determine effective countermeasures. This study included 48 patients (66 EC-IC bypass procedures) with moyamoya disease and 52 controls (54 procedures) without moyamoya disease. The development of acute thrombogenesis was compared between the moyamoya disease and control groups. In the moyamoya disease group, clinical and radiological characteristics were assessed with respect to acute thrombogenesis. In the patients with acute thrombogenesis, causes of technical problems were retrospectively examined. The incidence of acute thrombogenesis was significantly higher in the moyamoya disease group than those in the control group. In the moyamoya disease group, acute thrombogenesis was observed in seven patients. In the moyamoya disease group, the magnetic resonance angiography (MRA) scores were significantly higher in patients with acute thrombogenesis than those in the patients without acute thrombogenesis. In the multivariate analysis, the predictive factor of acute thrombogenesis in moyamoya disease was a high MRA score (odds ratio, 2.336; p = 0.009). During EC-IC bypass surgery for moyamoya disease, acute thrombogenesis should be considered to obtain a high patency rate, particularly in patients with high MRA scores. Acute thrombogenesis will not influence morbidity if proper countermeasures are followed; therefore, the prediction and recognition of white thrombus are important for a successful bypass surgery.

Epileptic nystagmus is a quick, repetitive, jerky movement of the eyeball caused by seizure activity, which is unaccompanied by other ictal phenomena. We report a case of moyamoya disease with epileptic nystagmus. A 23-year-old woman presented with a headache and transient hemiparesis on her left side. Magnetic resonance imaging showed no ischemic or hemorrhagic stroke lesions. Digital subtraction angiography confirmed stenosis of the terminal portion of the right internal carotid artery and the formation of moyamoya vessels on the right side. 123 I-N-isopropyl-iodoamphetamine ( 123 I-IMP) single photon emission computed tomography (SPECT) showed decreased uptake in the right basal ganglia, frontal, and parietal regions. After electroencephalography (EEG) and a hyperventilation test were performed, nystagmus appeared and was accompanied with a declining level of consciousness. Ictal EEG during an attack showed no epileptiform discharge. Moreover, the patient sometimes experienced simultaneous upper limb-shaking and gelastic attacks. After superficial temporal artery to middle cerebral artery bypass surgery was performed on the right side, symptom frequency and duration gradually decreased. Decreased 123 I-IMP SPECT blood flow in the right frontal region is considered a mechanism that causes the onset of epileptic nystagmus. It is presumed that the attack was caused by an ischemic abnormality in the saccade region of the frontal eye field. Moreover, revascularization can effectively treat the symptoms of moyamoya disease., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Bone metastasis of prostate cancer is associated with pain and reduced overall survival (OS). Radium-223, which is expected to reduce bone pain and prolong OS, was recently approved in Japan., Aim: The aim of this study was to investigate the usefulness of the bone scan index by comparing the outcomes and factors according to response in Japanese patients treated with radium-223., Methods and Results: Twenty patients receiving radium-223 were divided into two groups according to whether they did or did not achieve a bone scan index decrease of at least one point (beneficial and non-beneficial groups, respectively). The clinical characteristics at baseline and after three and six treatment cycles were compared using χ 2 tests and Student's t-tests or Mann-Whitney U tests, and survival was estimated and compared using the Kaplan-Meier method and log-rank test, respectively. Fourteen (70%) and six patients (30%) were categorized into the beneficial and non-beneficial groups, respectively. Patients in the former group were significantly more likely to have a higher Eastern Cooperative Oncology Group performance status score and receive a greater number of radium-223 injections (P < 0.05). Furthermore, patients in the beneficial group had a significantly longer OS (P < 0.05). Regarding safety, one and three patients in the beneficial and non-beneficial groups, respectively, prematurely discontinued radium-223 because of an increased prostate-specific antigen level, decreased hemoglobin level, or femoral fracture., Conclusion: Radium-223 appears generally safe in this population. Patients with good bone scan index response have better performance status, receive more injections of radium-223, and achieve OS prolongation. Bone scan index is a useful biomarker of survival outcomes and can be a valuable assessment tool in patients with metastatic castration-resistant prostate cancer who are treated with radium-223., (© 2019 Wiley Periodicals, Inc.)

We report the first case of pseudoaneurysm associated with polytetrafluoroethylene fiber used in microvascular decompression (MVD). A 62-year-old female who had undergone MVD for hemifacial spasm 30 years ago presented with a 4-month history of progressive facial palsy. Computed tomography angiography revealed a large thrombosed aneurysm originating from the right posterior inferior cerebellar artery and having a mass effect upon the pons. The aneurysm was treated by trapping and bypass procedure. Intraoperatively, the pseudoaneurysm adhered to the dura mater, and the thrombus contained a large amount of polytetrafluoroethylene fiber. The cause and management of pseudoaneurysm after MVD is discussed., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Scalp tissue shrinkage and volume contraction is a major problem in cranioplasty, and sometimes a tissue expander must be set before cranioplasty. The procedure for placing scalp expanders is cumbersome. In this study, we present a method for flattening the curvature of synthetic materials to relieve scalp skin tension and discuss the feasibility and limitations of the method., Methods: A total of 25 cranioplasty patients were included in this study. The optimal degree of curvature flattening for each piece of bone substitute material was determined based on cosmetic considerations and the extent of encephalomalacia or atrophy due to primary disease. In this series, the correlation between the degree of curvature flattening and the size or location of the bone flap was considered, and the amount of scalp surface area that could be obtained through curvature flattening was estimated., Results: The median degree of curvature flattening was 5.0 mm. The degree of curvature flattening showed moderate correlation with the rate of change in the area of synthetic material achieved through curvature flattening (p < 0.001). The 21 cases of fronto-temporal craniectomy were divided into two groups according to the distance from the midline. There was a statistically significant difference between these two groups in degree of flattening curvature., Conclusions: In the present cranioplasty series using synthetic materials, curvature flattening was a non-invasive and convenient method for skin closure. This method can be beneficial especially in patients requiring a larger craniotomy including convexity regions., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Microvascular anastomosis is an essential procedure in neurosurgery, but the opportunity to perform the surgery has gradually decreased for neurosurgeons. Therefore, training is necessary for obtaining and maintaining the skills required for the procedure. We describe the detailed anatomy of cervical and femoral regions in rats and discuss the advantages for practicing microvascular anastomosis., Methods: Cervical regions of Sprague-Dawley rats were dissected under intraperitoneal anesthesia. The step-by-step anatomic description was documented using a high-resolution charge-coupled device image sensor and recording systems. Using this model, temporal occlusion time and patency were measured, and these measures were compared between the trainee and trainer groups. The number of times the training needs to be completed to attain competency in the bypass procedure was estimated., Results: After exposing the carotid triangle, a half-ring was created by end-to-side anastomosis. Anastomosis was performed at the common carotid artery using the contralateral side of the carotid artery as a graft. The cutoff value for the temporal occlusion time was 79.3 minutes in the receiver operating characteristic curve based on a target temporal occlusion time for beginners determined during the training., Conclusions: Using a living animal model, a trainee has the opportunity to learn not only anastomotic techniques but also hemostatic control as well as overcoming mental strain during surgery. Living animal models are important in training because the fidelity of a living animal model is superior to nonliving models. Applying training using a half-ring model contributes to safe and efficient surgery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objectives: Enlarged perivascular spaces (EPVS) are often observed in small vessel disease on T2-weighted images. However, their role in ischemic conditions caused by cerebral large vessel disease remains unclear. We evaluated EPVS in patients with hemodynamic compromise associated with atherosclerotic large vessel disease and aimed to identify the pathophysiology of EPVS., Methods: We examined 28 adults with atherosclerotic large vessel disease. EPVS numbers in the basal ganglia and the centrum semiovale were assessed. For each affected hemisphere, the total numbers of EPVS were compared with those on the unaffected side. EPVS in the impaired hemodynamics group were compared with those in the unimpaired hemodynamics group. Moreover, EPVS were compared in the presence/absence of large stroke., Results: The number of EPVS was significantly increased on the affected side in the centrum semiovale (p = 0.023), particularly in the impaired hemodynamics group (p = 0.006). Moreover, in the small stroke subgroup of the impaired hemodynamics group, the number of EPVS was significantly increased on the affected side (p = 0.002), although this number was insignificant in the large ischemic stroke subgroup., Conclusions: The number of EPVS was increased in patients with atherosclerotic large vessel disease with hemodynamic compromise and decreased in the presence of a large stroke. EPVS might act as fluid absorbers in a hemodynamically compromised state until the occurrence of an ischemic stroke.

Extracranial-to-intracranial (EC-IC) bypass surgery may be necessary in patients with moyamoya disease and other ischemic conditions. However, there is a potential risk of wound-related complications in some cases. In this study, we report our approach to the prevention of wound-related complications in EC-IC bypass. Technical considerations and pitfalls of surgery are also discussed. This study included 89 patients with ischemic-onset moyamoya disease and atherosclerotic disease who underwent 108 superficial temporal artery (STA)-to-middle cerebral artery bypass procedures. Our study emphasized 3 major features. First, 3-dimensional simulation imaging was used to confirm STA anatomy. Second, the STA was meticulously dissected on the epigaleal layer to protect the galeal layer. Third, scalp skin ischemia was taken into consideration at each step until skin closure. There was no neurologic morbidity or mortality in this series. There were 2 cases of major wound-related complications requiring plastic surgical intervention, and 4 cases of minor complications that were treated conservatively. In major complication cases, the scalp defect was treated with pedicle flap reconstruction. In EC-IC bypass surgery, interdisciplinary management involving neurosurgery, plastic surgery, and radiology should reduce wound-related complications and achieve safe surgery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Lymphovascular invasion (LVI) in high-grade clinical T1 bladder cancer is usually considered a poor prognostic factor, but it is often difficult to achieve correct staging of T1 bladder cancer and diagnose the presence of LVI because of the inadequacy of conventional transurethral resection specimens. The aims of this study were to evaluate the prognostic value of LVI in patients with correctly staged high-grade pathological T1 (pT1) bladder cancer who initially underwent transurethral resection in one piece (TURBO)., Methods: Eighty-six high-grade pT1 bladder cancer patients who underwent TURBO were enrolled. Risk of tumor understaging was avoided by examining the vertical resection margin of the TURBO specimen. Immunohistochemical staining using D2-40 and CD31 was performed to confirm LVI. We examined the association of LVI with other clinicopathological factors and the impact of LVI on progression-free survival and cancer-specific survival., Results: The median follow-up period was 49 months (range, 6-142). In all patients, the tumors were accurately staged as pT1 at initial TURBO. LVI was detected in 15 patients (17%) and was significantly associated with tumor growth pattern (P = 0.001). Multivariate analysis identified LVI as the only independent predictor for reduced progression-free survival (HR, 4.48; 95% CI, 1.45-13.90; P = 0.009) and cancer-specific survival (HR, 4.35; 95% CI, 1.17-16.24; P = 0.029)., Conclusions: The presence of LVI in TURBO specimens independently predicts poor clinical outcomes in patients with high-grade pT1 bladder cancer. This information may help urologists to counsel their patients when deciding whether to choose a bladder-preserving strategy or radical cystectomy., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

We experimentally demonstrate a controlled-phase gate for continuous variables using a cluster-state resource of four optical modes. The two independent input states of the gate are coupled with the cluster in a teleportation-based fashion. As a result, one of the entanglement links present in the initial cluster state appears in the two unmeasured output modes as the corresponding entangling gate acting on the input states. The genuine quantum character of this gate becomes manifest and is verified through the presence of entanglement at the output for a product two-mode coherent input state. By combining our gate with the recently reported module for single-mode Gaussian operations [R. Ukai et al., Phys. Rev. Lett. 106, 240504 (2011)], it is possible to implement any multimode Gaussian operation as a fully measurement-based one-way quantum computation., (© 2011 American Physical Society)

One-way quantum computation is a very promising candidate to fulfill the capabilities of quantum information processing. Here we demonstrate an important set of unitary operations for continuous variables using a linear cluster state of four entangled optical modes. These operations are performed in a fully measurement-controlled and completely unconditional fashion. We implement three different levels of squeezing operations and a Fourier transformation, all of which are accessible by selecting the correct quadrature measurement angles of the homodyne detections. Though not sufficient, these linear transformations are necessary for universal quantum computation.

Objectives: To demonstrate the usefulness of transurethral resection in one piece (TURBO) as an accurate pathological staging tool for bladder tumor., Methods: Ninety-seven patients with newly diagnosed bladder cancer underwent TURBO that was performed either in an en bloc or in a divisional manner. The histological quality of the resection specimens was evaluated and the pathological stage was assigned on the basis of the depth of invasion, which was histologically determined., Results: Specimens obtained by TURBO were well oriented and their 3-D architecture was maintained. This allowed a histological assessment of the entire specimen. Portions of muscularis propria were identified beneath the tumor base in the specimens of 80 (82%) patients. In only seven (7%) patients, the tumors had a deep resection margin positive for carcinoma and were ambiguously staged as "pT1 or higher" or "pT2 or higher". Thus, definite pathological staging of TURBO specimens was possible in 90 (93%) patients (pTa, 30; pT1, 58; pT2, 2)., Conclusions: An accurate pathological stage can be assigned to the TURBO specimen in most bladder cancer patients.

Intravenous delivery of mesenchymal stem cells (MSCs) prepared from bone marrow (BMSCs) reduces infarction volume and ameliorates functional deficits in a rat cerebral ischemia model. MSC-like multipotent precursor cells (PMSCs) have also been suggested to exist in peripheral blood. To test the hypothesis that treatment with PMSCs may have a therapeutic benefit in stroke, we compared the efficacy of systemic delivery of BMSCs and PMSCs. A permanent middle cerebral artery occlusion (MCAO) in rat was induced by intraluminal vascular occlusion with a microfilament. Rat BMSCs and PMSCs were prepared in culture and intravenously injected into the rats 6 h after MCAO. Lesion size was assessed at 6 h, and 1, 3, and 7 days using MR imaging and histology. The hemodynamic change of cerebral blood perfusion on stroke was assessed the same times using perfusion-weighted image (PWI). Functional outcome was assessed using the treadmill stress test. Both BMSCs and PMSCs treated groups had reduced lesion volume, improved regional cerebral blood flow, and functional improvement compared to the control group. The therapeutic benefits of both MSC-treated groups were similar. These data suggest that PMSCs derived from peripheral blood could be an important cell source of cell therapy for stroke.

Amphoterin, the major product of the high mobility group-1 gene, is a ligand associated with cancer invasion and metastasis through activation of the receptor for advanced glycation end products (RAGE). Expression of amphoterin and RAGE was examined in prostatectomy specimens from 40 patients with pT3 prostate cancer (18 non-metastatic and 22 metastatic) preoperatively treated with lutenizing hormone-releasing hormone (LH-RH) agonist. Amphoterin expression was detected in tumor cells of 6 (27%) metastatic and 0 non-metastatic cases (p<0.0001). Amphoterin was also detected in prostatic stromal cells of 14 (63%) metastatic cases and 2 (11%) non-metastatic cases (p=0.0010). RAGE production was detected in cancer cells of 16 (73%) metastatic and 6 (33%) non-metastatic cases (p=0.0244). A total of 2 (22%) non-metastatic and 16 (73%) metastatic cases showed co-expression of amphoterin and RAGE in tumor cells or in tumor cells and stromal cells (p=0.0001). The in vitro invasive capacity of PC-3, a prostatic cancer cell line that co-expressed amphoterin and RAGE, was suppressed by treatment with amphoterin antisense S-oligodeoxynucleotide (ODN). Primary cultured human prostatic stromal cells secreted no amphoterin; however, amphoterin secretion was induced by androgen deprivation. The conditioned medium of human prostatic stromal cells deprived of androgen recovered the in vitro invasive capacity of PC-3 cells suppressed by amphoterin antisense S-ODN. These results suggest that androgen deprivation provides a paracrine interaction between cancer and stromal cells through the RAGE-amphoterin system in advanced prostate cancer.

Purpose: To determine whether the expression ratio of matrix metalloproteinase (MMP) to E-cadherin mRNA (MMP:E-cadherin) in biopsy (BX) samples of prostate cancer correlate with that of radical prostatectomy (RP) specimens and assists in predicting pathologic stage., Experimental Design: The mRNA expression levels for MMP-2 and -9 and of E-cadherin were determined by a colorimetric in situ hybridization assay in 44 paired BX and RP specimens. Clinical stage, BX Gleason score (GS), total length of cancer in BX cores, and serum prostate-specific antigen levels were also assessed., Results: Clinical stage was confined in 39 of 44 (89%) patients. Subsequent to RP, however, only 17 of 44 (39%) patients had proven organ-confined disease (pT2). BX GSs agreed with the RP GS in 77% of RP specimens. We found a strong correlation between BX and RP MMP:E-cadherin ratios (correlation coefficient = 0.755). The ratio increased as the GS increased and pathologic stage advanced (pT2 versus >/= pT3). Increasing clinical stage, GS, and serum prostate-specific antigen were significantly associated with advanced cancer at RP (P = 0.004-0.0001). The BX MMP:E-cadherin ratio, however, exhibited the strongest association with pathologic stage and independently predicted the status of 89% of the RP cases based on a BX ratio of <6 (predicted stage pT2 cancer at RP) versus >/=6 (predicted stage >/= pT3 at RP)., Conclusion: The BX MMP:E-cadherin ratio represents a novel prognostic assay for predicting stage of cancer at RP. These data provide proof of principle for directly assessing the biological potential of prostate cancer using molecular strategies in patient's specimens.

Purpose: We developed a new transurethral resection technique that not only removes the entire tumor, but also the surrounding mucosa and underlying stroma with superficial proper muscle in 1 piece to determine accurately the depth of invasion and infiltration pattern of superficial bladder cancer., Materials and Methods: A short curved needle electrode is used to make a circular incision around and level incisions underneath the tumor, and for tumor retrieval., Results: Tissue sections of the cut surface crossing the tumor center revealed accurate histology regarding the growth pattern and depth of invasion. No perforation, uncontrollable bleeding or other serious complications occurred., Conclusions: More accurate histological diagnosis regarding the growth pattern and depth of lamina propria invasion was possible with removal of the tumor and surrounding material in 1 piece compared to conventional transurethral resection.

A 60-year-old Japanese male with a chromophobe cell carcinoma of his left kidney is reported. The tumor, 18 x 27 mm in size, was incidentally found by abdominal ultrasonography. Computed tomography and magnetic resonance imaging demonstrated a well-demarcated solid tumor arising from the lower pole of the left kidney. Histopathological examination of the surgically removed tumor revealed that it was composed of solid sheets of cancer cells having abundant and slightly eosinophilic reticular cytoplasm with accentuated cell membranes making up a plant cell-like appearance. Electron microscopic examination demonstrated numerous intracytoplasmic microvesicles. Although the tumor cells were positive for cytokeratin and epithelial membrane antigen, they did not show vimentin immunoreactivity. The unique histological finding of this tumor from other reported renal chromophobe carcinomas was that it had a peripheral fibrotic area with a focus of metaplastic ossification.

Rats received a footshock for 10 min in a chamber with a metallic grid floor, and then placed into the chamber for 30 min after 6 days. The motility of the shocked rats showed a significant decrease (conditioned suppression of motility). In addition, the extracellular dopamine (DA) levels in the striatum were also reduced significantly in in vivo microdialysis study. Thus, dysfunction in the striatal DAergic neuronal systems is responsible for mental stress responses such as conditioned fear stress.

In order to establish a rapid and accurate in vitro drug assay method, we have applied the avidin D-biotin complex enzyme-linked immunosorbent assay using 5-bromodeoxyuridine (BrdU-ELISA) in the microplate cultures. To study the rat gastric cell proliferation, BrdU was treated with the cultured cells, and then, the rate of the uptake of BrdU into the cells was measured using an anti-BrdU antibody. Prostaglandin E2 (PGE2) (0.01, 0.1 and 1 microM), cimetidine (1, 3 and 10 microM) and omeprazole (3 and 10 microM) were shown to induce the significant proliferation of rat gastric cultured cells. Indomethacin (IND) (0.1, 0.25 and 0.5 mM) caused a dose-dependent inhibition of the proliferation of the cultured cells proliferation. The result obtained by the BrdU-ELISA method was more reproducible than that by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay method. PGE2 (0.01, 0.1 and 1 microM), cimetidine (1, 3 and 10 microM), omeprazole (1, 3 and 10 microM), cetraxate (3, 10 and 30 microM) and famotidine (30 microM), but not sofalcone and NC-1300-O-3, have been shown to protect significantly rat gastric cultured cells against IND-induced damage in vitro. From these results, it might be suggested that this BrdU-ELISA method is useful for investigating the effect of drugs on the proliferation of rat gastric cultured cells.

Effects of endorphins on behavioral stress responses were investigated in mice. For this purpose, we used environment-induced conditioned suppression of motility and forced swimming-induced immobility. The cerebral ventricular administration of alpha-endorphin (2.5-10 nmol), beta-endorphin (0.38-1.5 nmol), or gamma-endorphin (2.5-10 nmol) failed to affect either the environment-induced conditioned suppression of motility or the forced swimming-induced immobility. We have indicated previously that enkephalins attenuate both stress responses and, in contrast, dynorphin potentiates them. These findings indicate that the endorphinergic systems are not responsible for behavioral stress responses and that the role played by endorphins in the present stressful situations may be different from that of enkephalin and dynorphin.

The patients with advanced testicular tumors and bladder carcinoma were treated by combination chemotherapies including cis-diamminedichloroplatinum. Four patients with advanced testicular tumors were treated with a combination chemotherapy, consisting of cis-diamminedichloroplatinum, vinblastine, and bleomycin or pepleomycin according to Einhorn's regimen. Three patients with advanced bladder carcinoma were treated with a combination chemotherapy consisting of cis-diamminedichloroplatinum, cyclophosphamide, and adriamycin according to Yagoda's regimen. These chemotherapy regimens produced 25% complete and 75% partial responses in testicular tumors and 100% of no change in bladder carcinoma. Although an overall response rate of three patients with bladder carcinoma was 0%, one patient was plateaustable for more than three months. We believe that the combination chemotherapy including cis-diamminedichloroplatinum is promising in the management of patients with advanced testicular tumors or bladder carcinoma.