Search

Background: The relationship between focal brain atrophy and delusions in patients with Dementia of the Alzheimer's Type (DAT) is not well understood. Few studies have been reported on the association between medial temporal atrophy (MTA) and persecutory delusions in patients with DAT. We investigated the relationship between MTA and persecutory delusions in patients with DAT using voxel-based specific regional analysis system for Alzheimer's disease (VSRAD) advance software, which allows us to quantify the laterality and the degree of MTA on magnetic resonance imaging (MRI) scans., Methods: Thirty-one patients diagnosed with DAT were recruited and scanned with a 1.5 tesla MRI scanner. All MRI data were analyzed using VSRAD advance. The target volume of interest (VOI) included the entire region of the entorhinal cortex, hippocampus, and amygdala. The degree of MTA was obtained from the averaged positive z score (Z-score) on the target VOI, with higher scores indicating more severe. These DAT patients were divided into a group with (D group: n = 13) and without (ND group: n = 18) persecutory delusions., Results: In the D group, the mean the bilateral, right, and left Z-scores were 2.45, 2.69, and 2.19, respectively. These mean Z-scores of the ND group were 2.00, 2.00, and 1.95, respectively. The right Z-scores for the D group were significantly higher than those for the ND group (p < 0.05)., Conclusions: These findings suggest that right MTA could contribute to the development of persecutory delusions in patients with DAT.

We describe three cases of J-wave syndrome in which ventricular fibrillation (VF) was probably induced by corticosteroid therapy. The patients involved were being treated with prednisolone for concomitant bronchial asthma. One of the three patients had only one episode of VF during her long follow-up period (14 years). Two patients had hypokalemia during their VF episodes. Corticosteroids have been shown to induce various types of arrhythmia and to modify cardiac potassium channels. We discuss the possible association between corticosteroid therapy and VF in J-wave syndrome based on the cases we have encountered.

Background: Angiotensin II (AII) plays a central role in vascular remodeling via oxidative stress. However, the interaction between AII and reduced glutathione (GSH) redox status in cardiovascular remodeling remains unknown., Methods: In vivo: The cuff-induced vascular injury model was applied to Sprague Dawley rats. Then we administered saline or a GSH inhibitor, buthionine sulfoximine (BSO, 30 mmol/L in drinking water) for a week, subsequently administered 4 more weeks by osmotic pump with saline or AII (200 ng/kg/minute) to the rats. In vitro: Incorporation of bromodeoxyuridine (BrdU) was measured to determine DNA synthesis in cultured rat vascular smooth muscle cells (VSMCs)., Results: BSO reduced whole blood GSH levels. Systolic blood pressure was increased up to 215 ± 4 mmHg by AII at 4 weeks (p<0.01), which was not affected by BSO. Superoxide production in vascular wall was increased by AII and BSO alone, and was markedly enhanced by AII+BSO. The left ventricular weight to body weight ratio was significantly increased in AII and AII+BSO as compared to controls (2.52 ± 0.08, 2.50 ± 0.09 and 2.10 ± 0.07 mg/g respectively, p<0.05). Surprisingly, the co-treatment of BSO totally abolished these morphological changes. Although the vascular circumferential wall stress was well compensated in AII, significantly increased in AII+BSO. The anti-single-stranded DNA staining revealed increasing apoptotic cells in the neointima of injured arteries in BSO groups. BrdU incorporation in cultured VSMCs with AII was increased dose-dependently. Furthermore it was totally abolished by BSO and was reversed by GSH monoethyl ester., Conclusions: We demonstrated that a vast oxidative stress in impaired GSH redox system totally abolished AII-induced vascular, not cardiac remodeling via enhancement of apoptosis in the neointima and suppression of cell growth in the media. The drastic suppression of remodeling may result in fragile vasculature intolerable to mechanical stress by AII.

We report a 47-year-old man in whom Tc human serum albumin diethylene-triamine-pentaacetic acid protein-losing scintigraphy, performed with SPECT/CT, was useful for diagnosing Ménétrier disease. Planar images taken 1 and 3 hours after radioactive isotope injection yielded a suspicion that the stomach was the site of protein loss in this case. However, the protein loss from the stomach was precisely diagnosed after SPECT/CT was performed; this helped to diagnose Ménétrier disease.

Background and Aim: (18) F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) may detect primary lesions (PLs) and extrahepatic metastases (EHMs) only in advanced hepatocellular carcinoma (HCC) patients. We investigated the requirement of PET and the optimal timing of PET scanning for accurate staging and treatment planning., Methods: We conducted a retrospective investigation of 64 HCC patients who underwent PET (median age, 74 years; male/female, 41/23; etiology, 46 hepatitis C virus/4 hepatitis B virus/4 alcoholic/10 others). To determine the best timing for PET examinations, we analyzed PET result-based recommended treatment changes and characteristics of patients with FDG-avid PLs or EHMs., Results: FDG-avid PLs were detected by PET in 22 patients (34%): 18 with hypervascular PL, 11 with serum α-fetoprotein levels ≥ 200 ng/mL, and 11 beyond Milan criteria. EHMs were detected in 21 patients (33%: lymph nodes, 8; lung, 5; abdominal wall, 4; bone, 3; other organs, 4 [including overlapping]). Recommended treatments changed for 16 patients (25%) because of Barcelona Clinic Liver Cancer stage increases based on PET scanning. In multivariate analyses, serum α-fetoprotein levels ≥ 200 ng/mL and beyond Milan criteria were independent factors for FDG-avid PLs and a maximum standardized uptake value (SUVmax) of PLs of ≥ 4.0 was an independent factor for FDG-avid EHMs (P = 0.002, 0.008, and 0.045, respectively)., Conclusions: PET allows detection of HCC spread in patients with elevated serum α-fetoprotein levels or those beyond Milan criteria and detects EHMs in patients with PLs with high SUVmax values. Optimally timed PET scans can complement conventional imaging for accurate staging and treatment strategy determination., (© 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd.)

Purpose: Gastrointestinal (GI) bleeding scintigraphy in combination with single-photon emission computed tomography/computed tomography (SPECT/CT) remains to be studied in detail. This study aimed to examine the diagnostic ability of this tool., Methods: GI bleeding scintigraphy using (99m)Tc-human serum albumin-diethylenetriaminepentaacetic acid was performed for 38 patients with suspected GI bleeding. Twenty-four patients were diagnosed using planar images alone (planar group) and 14 patients were diagnosed using planar images and additional SPECT/CT images (planar + SPECT/CT group). The diagnostic ability of each method was analyzed., Results: GI bleeding was observed in 20 of the 38 patients. For the existence of GI bleeding, planar images alone showed a sensitivity of 70%, specificity of 93%, positive predictive value (PPV) of 88%, negative predictive value (NPV) of 81%, and an overall accuracy of 83%, whereas planar images + SPECT/CT showed a sensitivity of 100%, specificity of 75%, PPV of 91%, NPV of 100%, and an overall accuracy of 93%. The source of bleeding was accurately diagnosed in 50% in the planar group and 78% in the planar + SPECT/CT group. In the planar + SPECT/CT group, 44% of the evaluable patients showed correct localization of the source of GI bleeding by additional SPECT/CT images, although planar images only showed incorrect localization., Conclusion: GI bleeding scintigraphy in combination with SPECT/CT is a noninvasive and useful tool for the examination of GI bleeding.

A database is an important factor in the statistical analysis of myocardial scintigraphy. Our aim in this study was to verify the validity of the threshold method using phantoms and to create a clinical database using this method. Since this method involves artificially excluding a low count area on a polar map, we created a myocardial phantom with defects. Then, we applied this method to the construction of a control database (CDB) for which we used stress-rest scans of 152 male and 52 female Japanese patients. The clinical relevance of this database was investigated by comparison of the values between the CDB and a Japanese normal database. In the study evaluation, we mainly used the summed extent score (SES) and a severity map (severity). Data from the phantom with defects demonstrated that the threshold method could compensate for defective areas, enabling the use of data for the creation of the CDB. Comparison of the CDB with the Japanese normal database showed a good relationship with respect to the SES and severity (Initial post-stress: SES: r = 0.978; severity: r = 0.997, Redistribution: SES: r = 0.944; severity: r = 0.993). The threshold method facilitates the effective creation of a database by use of clinical data. This enables individual institutions to build their own databases, taking into account differences in collection and processing conditions between institutions as well as the characteristics of individual equipment.

Unlabelled: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disease characterized by chronic, profound, disabling, and unexplained fatigue. Although it is hypothesized that brain inflammation is involved in the pathophysiology of CFS/ME, there is no direct evidence of neuroinflammation in patients with CFS/ME. Activation of microglia or astrocytes is related to neuroinflammation. (11)C-(R)-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline-carboxamide ((11)C-(R)-PK11195) is a ligand of PET for a translocator protein that is expressed by activated microglia or astrocytes. We used (11)C-(R)-PK11195 and PET to investigate the existence of neuroinflammation in CFS/ME patients., Methods: Nine CFS/ME patients and 10 healthy controls underwent (11)C-(R)-PK11195 PET and completed questionnaires about fatigue, fatigue sensation, cognitive impairments, pain, and depression. To measure the density of translocator protein, nondisplaceable binding potential (BP(ND)) values were determined using linear graphical analysis with the cerebellum as a reference region., Results: The BP(ND) values of (11)C-(R)-PK11195 in the cingulate cortex, hippocampus, amygdala, thalamus, midbrain, and pons were 45%-199% higher in CFS/ME patients than in healthy controls. In CFS/ME patients, the BP(ND) values of (11)C-(R)-PK11195 in the amygdala, thalamus, and midbrain positively correlated with cognitive impairment score, the BP(ND) values in the cingulate cortex and thalamus positively correlated with pain score, and the BP(ND) value in the hippocampus positively correlated with depression score., Conclusion: Neuroinflammation is present in widespread brain areas in CFS/ME patients and was associated with the severity of neuropsychologic symptoms. Evaluation of neuroinflammation in CFS/ME patients may be essential for understanding the core pathophysiology and for developing objective diagnostic criteria and effective medical treatments., (© 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Congenital portosystemic shunt (CPSS) has the potential to cause hepatic encephalopathy and thus needs long-term follow-up, but an effective follow-up method has not yet been established. We aimed to evaluate the importance of per-rectal portal scintigraphy (PRPS) for long-term follow-up of CPSS., Methods: We retrospectively examined shunt severity time course in patients (median: 9.6 y, range: 5.2-16.6 y) with intrahepatic (n = 3) or extrahepatic (n = 3) CPSS by using blood tests, ultrasonography or computed tomography, and PRPS. Per-rectal portal shunt index (cutoff: 10%) was calculated by PRPS., Results: PRPS demonstrated that the initial shunt index was reduced in all intrahepatic cases (from 39.7 ± 9.8% (mean ± SD) to 14.6 ± 4.7%) and all extrahepatic cases (from 46.2 ± 10.9 to 27.5 ± 12.6%) during the follow-up period. However, ultrasonography and computed tomography disclosed different shunt diameter time courses between intrahepatic and extrahepatic CPSSs. Initial shunt diameter (5.8 ± 3.5 mm) reduced to 2.0 ± 0.3 mm in intrahepatic cases, but the initial diameter (6.3 ± 0.7 mm) increased to 10.6 ± 1.0 mm in extrahepatic cases. All patients had elevated serum total bile acid or ammonia levels at initial screening, but these blood parameters were insufficient to assess shunt severity because the values fluctuate., Conclusion: PRPS can track changes in the shunt severity of CPSS and is more reliable than ultrasonography and computed tomography in patients with extrahepatic CPSS.

Aim: Delayed gastric emptying, including gastroparesis, is a common complication in diabetes mellitus. The association between delayed gastric emptying and overall diabetic complications remains to be studied in detail. We analysed this association., Methods: We performed gastric emptying scintigraphy of (99m) Tc-diethylenetriaminepentaacetic acid in 34 patients with diabetes to measure the gastric emptying half-times (T1/2) of the whole stomach (WS), proximal stomach (PS) and distal stomach (DS). We assessed T1/2, diabetic-related factors and complications., Results: The prevalence of autonomic neuropathy was higher in the group with delayed T1/2 of the WS than in the normal group. Analysis of intima-media thickness (IMT) and ankle brachial pressure index (ABI), which are risk indicators for vascular disorder, showed that IMT of the carotid bulb was greater in the group with delayed T1/2 of the WS than in the normal group (2·41 mm [1·50-2·81] versus 1·40 mm [0·81-2·08], P = 0·015). T1/2 of the WS correlated positively with IMT of the carotid bulb (r = 0·391, P = 0·027) and negatively with ABI (r = -0·389, P = 0·028). These correlations were mainly attributed to PS and were the same in patients without autonomic neuropathy. In seven of nine patients who received scintigraphy again after diabetic treatment, glycosylated haemoglobin (HbA1c) levels decreased and T1/2 of the WS shortened compared with before treatment., Conclusion: Vascular disorder, among other cofactors such as autonomic neuropathy, could be involved in the pathophysiology of delayed gastric emptying. Medium- to long-term glycaemic control was associated with gastric emptying., (© 2013 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Purpose: Surgical removal of a mediastinal ectopic parathyroid is always challenging. We attempted to apply intraoperative radio-guided navigation for the minimally invasive focused removal of ectopic hyperparathyroid lesions in the mediastinum, and evaluated its significance., Methods: Five cases with ectopic mediastinal hyperfunctioning parathyroid were treated by intraoperative radio-guided navigation surgery. MIBI (methoxyisobutylisonitrile)-SPECT (single-photon emission computed tomography) was used to plan the surgical approach. (99m)Tc-MIBI (11.1 MBq/kg) was administered 2 h before surgery, and a handheld gamma probe was used intraoperatively to detect radioactivity in the lesion., Results: Two lesions found on the aortic arch were excised by left thoracoscopic resection. Two other lesions on the tracheal bifurcation were approached by right thoracotomy. We could remove two hidden adenomas by en bloc resection with the adjacent lymph nodes under radio-guidance. Another lesion, located at the ligamentum arteriosum, was excised with sternal division. Accumulations of radioactivity were identified in all lesions removed, with decreased radioactivity in the surgical field., Conclusions: Intraoperative radio-guided navigation is a useful tool for the focused removal of an ectopic mediastinal parathyroid by providing instant feedback to help guide the surgeon, while also providing precise localization of lesions.

Study Design: An open-labeled multicenter prospective nonrandomized controlled clinical trial., Objective: To confirm the feasibility of using granulocyte colony-stimulating factor (G-CSF) for treatment of acute spinal cord injury (SCI)., Summary of Background Data: We previously reported that G-CSF promotes functional recovery after compression-induced SCI in mice. On the basis of these findings, we conducted a multicenter prospective controlled clinical trial to assess the feasibility of G-CSF therapy for patients with acute SCI., Methods: The trial ran from August 2009 to March 2011, and included 41 patients with SCI treated within 48 hours of onset. Informed consent was obtained from all patients. After providing consent, patients were divided into 2 groups. In the G-CSF group (17 patients), G-CSF (10 μg/kg/d) was intravenously administered for 5 consecutive days, and in the control group (24 patients), patients were similarly treated except for the G-CSF administration. We evaluated motor and sensory functions using the American Spinal Cord Injury Association score and American Spinal Cord Injury Association impairment scale at 1 week, 3 months, 6 months, and 1 year after onset., Results: Only 2 patients did not experience American Spinal Cord Injury Association impairment scale improvement in the G-CSF group. In contrast, 15 patients in the control group did not experience American Spinal Cord Injury Association impairment scale improvement. In the analysis of increased American Spinal Cord Injury Association motor score, a significant increase in G-CSF group was detected from 1 week after the administration compared with the control group. After that, some spontaneous increase of motor score was detected in control group, but the significant increase in G-CSF group was maintained until 1 year of follow-up., Conclusion: Despite the limitation that patient selection was not randomized, the present results suggest the possibility that G-CSF administration has beneficial effects on neurological recovery in patients with acute SCI., Level of Evidence: 3.

An immature vasa vasorum in the adventitia of arteries has been implicated in induction of the formation of unstable atherosclerotic plaques. Normalization/maturation of the vasa vasorum may be an attractive therapeutic approach for arteriosclerotic diseases. Nerve growth factor (NGF) is a pleotropic molecule with angiogenic activity in addition to neural growth effects. However, whether NGF affects the formation of microvessels in addition to innervation during pathological angiogenesis is unclear. In the present study, we show a new role for NGF in neovessels around injured arterial walls using a novel in vivo angiogenesis assay. The vasa vasorum around arterial walls was induced to grow using wire-mediated mouse femoral arterial injury. When collagen-coated tube (CCT) was placed beside the injured artery for 7-14 days, microvessels grew two-dimensionally in a thin layer on the CCT (CCT-membrane) in accordance with the development of the vasa vasorum. The perivascular nerve was found at not only arterioles but also capillaries in the CCT-membrane. Biodegradable hydrogels containing VEGF and NGF were applied around the injured artery/CCT. VEGF significantly increased the total length and instability of microvessels within the CCT-membrane. In contrast, NGF induced regeneration of the peripheral nerve around the microvessels and induced the maturation and stabilization of microvessels. In an ex vivo nerve-free angiogenesis assay, although NGF potentially stimulated vascular sprouting from aorta tissues, no effects of NGF on vascular maturation were observed. These data demonstrated that NGF had potent angiogenic effects on the microvessels around the injured artery, and especially induced the maturation/stabilization of microvessels in accordance with the regeneration of perivascular nerves., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Atherosclerosis is considered an "inside-out" response, that begins with the dysfunction of intimal endothelial cells and leads to neointimal plaque formation. The adventitia of large blood vessels has been recognized as an active part of the vessel wall that is involved in the process of atherosclerosis. There are characteristic changes in the adventitial vasa vasorum that are associated with the development of atheromatous plaques. However, whether vasa vasorum plays a causative or merely reactive role in the atherosclerotic process is not completely clear. Recent studies report that the vascular wall contains a number of stem/progenitor cells that may contribute to vascular remodeling. Microvessels serve as the vascular niche that maintains the resident stem/progenitor cells of the tissue. Therefore, the vasa vasorum may contribute to vascular remodeling through not only its conventional function as a blood conducting tube, but also its new conceptual function as a stem cell reservoir. This brief review highlights the recent advances contributing to our understanding of the role of the adventitial vasa vasorum in the atherosclerosis and discusses new concept that involves vascular-resident factors, the vasa vasorum and its associated vascular-resident stem cells, in the atherosclerotic process.

We evaluated the efficacy of technetium-sestamibi ((99m) Tc-MIBI) SPECT/CT for planning parathyroidectomy in cases with primary hyperparathyroidism (pHPT), comparing with planar scintigraphy and ultrasound (US), in an aim to establish the proper surgical strategy according to the preoperative imaging studies. A retrospective review of consecutive 75 pHPT patients who had been operated on was conducted. The results of preoperative imaging modalities and the operative finding were analyzed. Seven cases were found to have multiple hyperplastic glands, and no responsible gland was found in three cases. Four cases underwent only US scan for preoperative imaging. Remaining 61 cases were found to have single adenoma, and were included in the evaluation of localization imaging. US scan, (99m) Tc-MIBI planar scan and (99m) Tc-MIBI SPECT/CT showed accurate localization in 77.0% (47/61), 75.4% (46/61) and 88.5% (46/52) of the evaluable cases, respectively. US and (99m) Tc-MIBI planar scan demonstrated consistent result in 42 cases (68.9%), and those cases showed accurate localization in 90.5% (38/42). When both US and (99m) Tc-MIBI SPECT/CT was consistent, all 37 lesions had been correctly indicated. No clinico-pathological features were suggested to influence in demonstrating the localization, other than only (99m) Tc-MIBI SPECT/CT exhibited 100% sensitivity in ectopic glands. Combination of US and (99m) Tc-MIBI SPECT/CT certainly contributes to the planning of minimally invasive operation in cases with pHPT by indicating correct localization of single adenoma.

The aim of this study is to improve the image quality using a post process rather than a correction process at acquisition time. We used a smoothing filter that is widely used on a compact digital camera. Especially for nuclear medicine, when we use a short acquisition time, we will get images that have a large increase in statistical noise. For those images, we validated the efficiency of the smoothing filter by assessing two characteristic parameters. In addition, we defined the best smoothing filter parameters to get stable images that reduced the influence of statistical noise.

Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifunctional protein that processes DNA-repair function and controls cellular response to oxidative stress. Endothelial progenitor cells (EPCs) are recruited to oxidative stress-rich injured vascular walls and positively contribute to vascular repair and endothelialization. We hypothesized that APE1 functions for EPCs-mediated inhibition of neointima formation in injured vasculature. EPCs isolated from bone marrow cells of C57BL6 mice (12-16 wk old) were able to survive in the presence of hydrogen peroxide (H2O2; up to 1,000 μM) due to the highly expressed reactive oxygen species (ROS) scavengers. However, adhesion capacity of EPCs was significantly inhibited by H2O2 (100 μM) even though an intracellular ROS was retained at small level. An APE1-selective inhibitor or RNA interference-mediated knockdown of endogenous APE1 in EPCs aggravated the H2O2-mediated inhibition of EPCs-adhesion. In contrast, when APE1 was overexpressed in EPCs using an adenovirus harboring the APE1 gene (APE-EPCs), adhesion was significantly improved during oxidative stress. To examine in vivo effects of APE1 in EPCs, APE-EPCs were transplanted via the tail vein after wire-mediated injury of the mouse femoral artery. The number of adherent EPCs at injured vascular walls and the vascular repair effect of EPCs were enhanced in APE-EPCs compared with control EPCs. Among the cellular functions of EPCs, adhesion is especially sensitive to oxidative stress. APE1 enhances in vivo vascular repair effects of EPCs in part through the maintenance of adhesion properties of EPCs. APE1 may be a novel and useful target gene for effective cellular transplantation therapy.

A male patient in his 20s presented at our clinic with pain caused by bone metastases of the primitive neuroectodermal tumor, and Sr-89 was administrated to palliate the pain. After receiving the injection, the patient complained of a slight burning pain at the catheterized area. Slight reddening and small circular swelling (diameter, 0.5 cm) were observed at the catheterized area. Sr-89 extravasation was suspected. To estimate the amount of subcutaneous Sr-89 leakage, bremsstrahlung imaging was immediately performed. We speculated that the skin-absorbed dose from subcutaneous infiltration of Sr-89 was 1.78 Gy. The mildest clinical sign of local radiation injury was erythema. The received dose was higher than 3 Gy, and the time of onset was from 2 to 3 weeks. In our patient, local radiation injuries (LRIs) did not occur. Though requiring further verification, subsequent bremsstrahlung imaging and estimation of the skin-absorbed dose from the subcutaneous infiltration of Sr-89 are useful in confirming Sr-89 extravasation and in the decision making for the choice of treatment strategies for LRIs caused by Sr-89 extravasation.

(99m)Tc-hydroxymethylene diphosphonate is not directly to Calcium of the bone matrix, but is binding to hydroxyapatite within the bone matrix. Strontium-89 is a member of family II A of the periodic table, same as Calcium, and is incorporated into bone matrix directly. It is very important that the the regions of the pain from bone metastases are present in the site of the abnormal uptake by bone metastases.

Background: Prostacyclin (PGI2) enhances angiogenesis, especially in cooperation with bone marrow (BM)-derived endothelial progenitor cells (EPCs). However, the mechanisms of PGI2 in EPC-mediated angiogenesis in vivo remain unclear. The purpose of this study was to clarify the role of PGI2 in EPC-mediated angiogenesis using BM-specific IP deletion mice., Methods and Results: Hind limb ischemia (HLI) was induced in wild-type (WT) mice transplanted with IP-deleted BM (WT/BM(IP(-/-)). Recovery of blood flow (RBF) in WT/BM(IP(-/-)) was impaired for 28 days after HLI, whereas RBF in IP(-/-)/BM(WT) was attenuated for up to 7 days compared with WT/BM(WT). The impaired RBF in WT/BM(IP(-/-)) was completely recovered by intramuscular injection of WT EPCs but not IP(-/-) EPCs. The impaired effects of IP(-/-) EPCs were in accordance with reduced formation of capillary and arterioles in ischemic muscle. An ex vivo aortic ring assay revealed that microvessel formation was enhanced by accumulation/adhesion of EPCs to perivascular sites as pericytes. IP(-/-)EPCs, in which expression of integrins was decreased, had impaired production of angiogenic cytokines, adhesion to neovessels and their angiogenic effects. The small-interfering RNA (siRNA)-mediated knockdown of integrin β1 in WT EPCs attenuated adhesion to microvessels and their in vivo and in vitro angiogenic effects., Conclusions: PGI2 may induce persistent angiogenic effects in HLI through adhesion of EPCs to perivascular sites of neovessels via integrins in addition to paracrine effects.

Objective: Granulocyte colony-stimulating factor (G-CSF) is a cytokine that is clinically used to treat neutropenia. G-CSF also has non-hematopoietic functions and could potentially be used to treat neuronal injury. To confirm the safety and feasibility of G-CSF administration for acute spinal cord injury (SCI), we have initiated a phase I/IIa clinical trial of neuroprotective therapy using G-CSF., Methods: The trial included a total of 16 SCI patients within 48 h of onset. In the first step, G-CSF (5 μg/kg/day) was intravenously administered for 5 consecutive days to 5 patients. In the second step, G-CSF (10 μg/kg/day) was similarly administered to 11 patients. We evaluated motor and sensory functions of patients using the American Spinal Cord Injury Association (ASIA) score and ASIA impairment scale (AIS) grade., Results: In all 16 patients, neurological improvement was obtained after G-CSF administration. AIS grade increased by one step in 9 of 16 patients. A significant increase in ASIA motor scores was detected 1 day after injection (P < 0.01), and both light touch and pin prick scores improved 2 days after injection (P < 0.05) in the 10 μg group. No severe adverse effects were observed after G-CSF injection., Conclusion: These results indicate that intravenous administration of G-CSF (10 μg/kg/day) for 5 days is essentially safe, and suggest that some neurological recovery may occur in most patients. We suggest that G-CSF administration could be therapeutic for patients with acute SCI.

F-18 FDG PET/CT has been widely used to diagnose primary tumors and lymph node metastases and to evaluate the response of head and neck squamous cell carcinoma (HNSCC) to therapy. The advantage of using PET/CT is that this combination allows metabolic information to be precisely overlapped with anatomical information, thereby improving the identification of sites with an abnormal accumulation of F-18 FDG. The role of FDG PET/CT in the therapeutic evaluation (such as in treatment planning, the therapeutic response, and the surveillance and examination of HNSCC patients) is discussed in this manuscript. When evaluating the post-treatment outcome via FDG PET/CT, it is important to exclude the post-treatment inflammation-related increase in glucose metabolism in lymph nodes, salivary gland, muscles, and soft tissues. The influence of inflammation can be eliminated if PET/CT is performed after 12 weeks, by which time post-treatment inflammation subsides. Further, FDG PET/CT affords a high negative predictive value. Based on the results of an FDG PET/CT test, some invasive tests that are performed to detect recurrence can be omitted.

Objective: Based on the neuroprotective effects of granulocyte colony-stimulating factor (G-CSF) on experimental spinal cord injury, we initiated a clinical trial that evaluated the safety and efficacy of neuroprotective therapy using G-CSF for patients with worsening symptoms of compression myelopathy., Methods: We obtained informed consent from 15 patients, in whom the Japanese Orthopaedic Association (JOA) score for cervical myelopathy decreased two points or more during a recent 1-month period. G-CSF (5 or 10 μg/kg/day) was intravenously administered for five consecutive days. We evaluated motor and sensory functions of the patients and the presence of adverse events related to G-CSF therapy., Results: G-CSF administration suppressed the progression of myelopathy in all 15 patients. Neurological improvements in motor and sensory functions were obtained in all patients after the administration, although the degree of improvement differed among the patients. Nine patients in the 10-μg group (n=10) underwent surgical treatment at 1 month or later after G-CSF administration. In the 10-μg group, the mean JOA recovery rates 1 and 6 months after administration were 49.9±15.1 and 59.1±16.3%, respectively. On the day following the start of G-CSF therapy, the white blood cell count increased to more than 22,700 cells/mm3. It varied from 12,000 to 50,000 and returned to preadministration levels 3 days after completing G-CSF treatment. No serious adverse events occurred during or after treatment., Conclusion: The results indicate that G-CSF administration at 10 μg/kg/day is safe for patients with worsening symptoms of compression myelopathy and may be effective for their neurological improvement.

Background/aims: We previously found that some cases of clinically diagnosed Alzheimer's disease (AD) were rated as Pittsburgh compound B (PiB) negative by amyloid imaging (i.e. cases of PiB-negative dementia). The present study was designed to analyze the clinical features of PiB-negative dementia patients in detail., Methods: Of the 64 cases of clinically diagnosed AD, 14 were rated PiB negative. Eleven of these were further analyzed using CSF biomarker levels and findings from MRI, FDG-PET, (123)I-MIBG myocardial scintigraphy and voxel-based morphometry (VBM)., Results: When examined by (123)I-MIBG myocardial scintigraphy, the heart/mediastinum ratio was significantly higher in the PiB-negative dementia group than in the dementia with Lewy bodies (DLB) group. Analyses of CSF biomarkers and MRI and FDG-PET findings suggested argyrophilic grain disease (AGD) in 3 cases, frontotemporal lobar degeneration (FTLD) in 3 cases, neurofibrillary tangle-predominant dementia (NFTD) in 1 case, and AD in 2 cases. In the VBM data analysis, the PiB-positive AD group showed significant atrophy of both hippocampi compared with the healthy control group, while the PiB-negative dementia group presented with significant atrophy of the left precuneus., Conclusion: PiB-negative dementia is unlikely to include DLB, while it most likely includes diseases of tauopathy, such as FTLD, AGD and NFTD. A better understanding of PiB-negative dementia is expected to further improve the accuracy of the clinical AD diagnosis., (Copyright © 2012 S. Karger AG, Basel.)

Background: Granulocyte colony-stimulating factor (G-CSF) is a protein that stimulates differentiation, proliferation, and survival of cells in the granulocytic lineage. Recently, a neuroprotective effect of G-CSF was reported in a model of cerebral infarction and we previously reported the same effect in studies of murine spinal cord injury (SCI). The aim of the present study was to elucidate the potential therapeutic effect of G-CSF for SCI in rats., Methods: Adult female Sprague-Dawley rats were used in the present study. Contusive SCI was introduced using the Infinite Horizon Impactor (magnitude: 200 kilodyne). Recombinant human G-CSF (15.0 µg/kg) was administered by tail vein injection at 1 h after surgery and daily the next four days. The vehicle control rats received equal volumes of normal saline at the same time points., Results: Using a contusive SCI model to examine the neuroprotective potential of G-CSF, we found that G-CSF suppressed the expression of pro-inflammatory cytokine (IL-1 beta and TNF- alpha) in mRNA and protein levels. Histological assessment with luxol fast blue staining revealed that the area of white matter spared in the injured spinal cord was significantly larger in G-CSF-treated rats. Immunohistochemical analysis showed that G-CSF promoted up-regulation of anti-apoptotic protein Bcl-Xl on oligpodendrocytes and suppressed apoptosis of oligodendrocytes after SCI. Moreover, administration of G-CSF promoted better functional recovery of hind limbs., Conclusions: G-CSF protects oligodendrocyte from SCI-induced cell death via the suppression of inflammatory cytokines and up-regulation of anti-apoptotic protein. As a result, G-CSF attenuates white matter loss and promotes hindlimb functional recovery.

Object: Granulocyte colony-stimulating factor (G-CSF) has neuroprotective effects on the CNS. The authors have previously demonstrated that G-CSF also exerts neuroprotective effects in experimental spinal cord injury (SCI) by enhancing migration of bone marrow-derived cells into the damaged spinal cord, increasing glial differentiation of bone marrow-derived cells, enhancing antiapoptotic effects on both neurons and oligodendrocytes, and by reducing demyelination and expression of inflammatory cytokines. Because the degree of angiogenesis in the subacute phase after SCI correlates with regenerative responses, it is possible that G-CSF's neuroprotective effects after SCI are due to enhancement of angiogenesis. The aim of this study was to assess the effects of G-CSF on the vascular system after SCI., Methods: A contusive SCI rat model was used and the animals were randomly allocated to either a G-CSF-treated group or a control group. Integrity of the blood-spinal cord barrier was evaluated by measuring the degree of edema in the cord and the volume of extravasation. For histological evaluation, cryosections were immunostained with anti-von Willebrand factor and the number of vessels was counted to assess revascularization. Real-time reverse transcriptase polymerase chain reaction was performed to assess expression of angiogenic cytokines, and recovery of motor function was assessed with function tests., Results: In the G-CSF-treated rats, the total number of vessels with a diameter > 20 μm was significantly larger and expression of angiogenic cytokines was significantly higher than those in the control group. The G-CSF-treated group showed significantly greater recovery of hindlimb function than the control group., Conclusions: These results suggest that G-CSF exerts neuroprotective effects via promotion of angiogenesis after SCI.

Fluorodeoxyglucose (FDG), which allows the evaluation of glucose metabolism, is widely used for tumor diagnosis using positron emission tomography (PET). FDG-PET, which is used for the diagnosis of intrahepatic tumor lesions, shows high FDG accumulation in cholangiocellular carcinoma (CCC) and metastatic liver cancer. FDG-PET shows high FDG accumulation in moderately or poorly differentiated hepatocellular carcinoma (HCC) and is useful for the diagnosis of extrahepatic HCC metastases and recurrences. However, because the imaging method frequently shows low FDG accumulation in well-differentiated HCC, it is not very useful for that diagnosis. For the diagnosis of well-differentiated HCC, F-18 fluorocholine for evaluation of phospholipid metabolism and C-11 acetate for evaluation of free fatty acid metabolism are useful in the diagnosis of that HCC. It is expected that the combination of these PET agents will enhance the diagnostic performance of FDG-PET for HCC in the future. The problem of a lack of anatomical information is being resolved with the development of the use of PET in combination with computed tomography or magnetic resonance imaging. For the problem of low resolution, PET devices using semiconductors have been developed., (© 2011 The Japan Society of Hepatology.)

Background: Donepezil hydrochloride (Donepezil) is an acetylcholinesterase inhibitor (AChEI) that is used for the symptomatic treatment of Dementia of the Alzheimer's Type (DAT). Recently, the effects of AChEI in patients with DAT have been investigated using positron emission tomography (PET) or single photon emission computed tomography (SPECT). This study is to evaluate the usefulness of fluorine-18-fluorodeoxyglucose (FDG)-PET in assessing the therapeutic response of Donepezil to DAT using Regions of Interest (ROI) analysis., Methods: The participants included eleven outpatients diagnosed as having DAT according to Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The patients were performed FDG-PET before initiating Donepezil therapy and after 12 weeks of medication. Cognitive change was measured using the Japanese version of the Alzheimer's disease Assessment Scale cognitive subscale (ADAS-J cog) and the group was divided into Responders and Non-responders based on these results. We used FDG-PET to investigate glucose metabolism of the brain and measured FDG uptake in the ROI set in each lobe of the brain. Then the ratios of the post-treatment uptake to pre-treatment uptake were determined., Results: In the Responders, the mean ratios in the frontal, temporal, occipital, parietal, and temporoparietal lobes were 2.18, 1.62, 1.15, 1.12, and 1.09 respectively. The mean ratios of the Non-responders were 0.69, 0.88, 0.75, 0.98, and 0.68 respectively. Significant differences were found between the ratios of the Responders and Non-responders in the frontal and occipital lobes (p < 0.05)., Conclusions: These findings suggest that FDG-PET could be useful for the evaluation for monitoring response to Donepezil.

Prostanoids consisting of prostaglandins (PGs) and thromboxanes (TXs) are produced from arachidonic acids, representative fatty acids contained in cell membrane, by the sequential actions of phospholipase A(2), cyclooxygenases and respective prostanoid synthases. Prostanoids are released outside of the cells immediately after biosynthesis and exert a wide range of actions in the body. These actions are mediated by their respective G protein-coupled receptors expressed in the target cells, which receptors include the DP, EP, FP, IP and TP receptors for PGD(2), PGE(2), PGF(2)α, PGI(2) and TXA(2), respectively. In addition, there are four subtypes of the EP receptors: EP(1), EP(2), EP(3) and EP(4). Recently, roles of prostanoids in the pathogenesis of cardiovascular diseases have been widely examined using mice lacking each prostanoid receptor individually or enzyme participating in prostanoid biosynthesis. These studies have revealed important and novel roles of prostanoids in the development of cardiovascular diseases, such as acute myocardial infarction, cardiac hypertrophy, atherosclerosis, vascular remodeling, hypertension and cerebral thrombosis. Roles of prostanoids in the generation of inflammatory tachycardia and the regulation of platelet function have also been clarified. In this review, we summarize these roles of prostanoids revealed from knockout mouse studies., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Fabry disease is an X-linked lysosomal storage disorder caused by mutations of the α-galactosidase A gene (GLA), and the disease is a relatively prevalent cause of left ventricular hypertrophy mimicking idiopathic hypertrophic cardiomyopathy. We assessed clinically 5 patients of a three-generation family and also searched for GLA mutations in 10 family members. The proband had left ventricular hypertrophy with localized thinning in the basal posterior wall and late gadolinium enhancement (LGE) in the near-circumferential wall in cardiovascular magnetic resonance images and her sister had vasospastic angina pectoris without organic stenosis of the coronary arteries. LGE notably appeared in parallel with decreased α-galactosidase A activity and increased NT-pro BNP in our patients. We detected a new GLA missense mutation (G195V) in exon 4, resulting in a glycine-to-valine substitution. Of the 10 family members, 5 family members each were positive and negative for this mutation. These new data extend our clinical and molecular knowledge of GLA gene mutations and confirm that a novel missense mutation in the GLA gene is important not only for a precise diagnosis of heterozygous status, but also for confirming relatives who are negative for this mutation.

Systemic capillary leak syndrome (SCLS) is a life-threatening disorder which presents with periodic episodes of hypovolemic shock, due to plasma leakage to the extra-vascular space reflected by accompanying hypoalbuminemia, hemoconcentration and edema often with associated monoclonal gammopathy. We describe a 28-year-old woman with SCLS who required aggressive fluid resuscitation and was successfully treated with corticosteroid, terbutaline, and theophylline. At exacerbation, the levels of serum granulocyte colony-stimulating factor (G-CSF) were increased. Thus, G-CSF might play an important role and can be a useful biomarker for the severity of attacks in SCLS.

Blood vessels deliver oxygen and nutrients to tissues, and vascular networks are spatially organized to meet the metabolic needs for maintaining homeostasis. In contrast, the vasculature of tumors is immature and leaky, resulting in insufficient delivery of nutrients and oxygen. Vasculogenic processes occur normally in adult tissues to repair "injured" blood vessels, leading us to hypothesize that bone marrow mononuclear cells (BMMNC) may be able to restore appropriate vessel function in the tumor vasculature. Culturing BMMNCs in endothelial growth medium resulted in the early outgrowth of spindle-shaped attached cells expressing CD11b/Flt1/Tie2/c-Kit/CXCR4 with proangiogenic activity. Intravenous administration of these cultured vascular proangiogenic cells (VPC) into nude mice bearing pancreatic cancer xenografts and Pdx1-Cre;LSL-Kras(G12D);p53(lox/+) genetically engineered mice that develop pancreatic ductal adenocarcinoma significantly reduced areas of hypoxia without enhancing tumor growth. The resulting vasculature structurally mimicked normal vessels with intensive pericyte coverage. Increases in vascularized areas within VPC-injected xenografts were visualized with an ultrasound diagnostic system during injection of a microbubble-based contrast agent (Sonazoid), indicating a functional "normalization" of the tumor vasculature. In addition, gene expression profiles in the VPC-transplanted xenografts revealed a marked reduction in major factors involved in drug resistance and "stemness" of cancer cells. Together, our findings identify a novel alternate approach to regulate abnormal tumor vessels, offering the potential to improve the delivery and efficacy of anticancer drugs to hypoxic tumors.

Aims: Depressive symptoms are common in patients with dementia of Alzheimer type (DAT) and contribute to clinical morbidity. Previous studies have suggested that hypoperfusion in the prefrontal cortex and anterior cingulate gyrus are involved in the pathophysiology of depression in DAT. Using 3-D stereotactic region of interest (ROI) template (3DSRT), fully automated ROI analysis software, the purpose of the present study was to investigate the relationship between depressive symptoms and regional cerebral blood flow (rCBF) in DAT., Methods: Technetium-99m-ethyl cysteinate dimer ((99m)Tc-ECD) single-photon emission computed tomography (SPECT) and Japanese version of the Neuropsychiatric Inventory (NPI) were carried out in 35 patients diagnosed as having mild-moderate DAT according to DSM-IV. These patients were divided into the depressive group (D group: n = 17) and non-depressive group (ND group: n = 18) using the NPI depression items. All data from SPECT images were analyzed using 3DSRT software. On 3DSRT the perfusion ratios (rCBF of bilateral callosomarginal, precentral, central, parietal, angular, temporal, posterior cerebral, pericallosal, lenticular nucleus, thalamus and hippocampus/cerebellar hemisphere) of each segment were compared between the D group and the ND group., Results: The perfusion ratios of the left callosomarginal segment for the D group were significantly lower (P < 0.05) than those of the ND group., Conclusions: Hypoperfusion in the left frontal cortex contributes to the expression of depressive symptoms in patients with DAT.

Prostacyclin (PGI(2)) is one of the important vascular prostanoids, the effects of which counteract those of thromboxane (TXA(2)), and these 2 prostanoids provide an important balance in cardiovascular homeostasis. The clinical experience of COX-2 selective inhibitors having unexpected adverse effects in patients with cardiovascular risk has opened up a debate about the role of COX-2-derived prostanoids in vascular pathophysiology. PGI(2) is a major anti-atherogenic prostanoid produced by COX-2 in vascular cells, including endothelial and vascular smooth muscle cells. The balance between COX-2-derived PGI(2), COX-1-derived TXA(2), and other COX-2-mediated atherogenic prostanoids is a crucial factor in determining pathophysiological outcomes. Recent studies using stable PGI(2) analogs and genetically deficient mice have revealed novel effects of PGI(2) on its target cells, such as endothelial and endothelial progenitor cells. The role PGI(2) in the physiology and pathophysiology of vascular diseases is reviewed and the recent findings linking PGI(2), COX-2 and atherothrombosis are summarized.

Study Design: Case report., Objective: To report a surgically treated case of cervical ossification of the posterior longitudinal ligament (OPLL), in which a spinal subarachnoid hematoma (SSAH) developed intraoperatively but was successfully treated., Summary of Background Data: Previous reports have indicated that trauma, lumbar puncture, vascular lesions such as arteriovenous malformation, neoplastic lesions, and coagulopathy can cause SSAH. To the best of our knowledge, there has been no report that describes the occurrence of SSAH during anterior decompression surgery of the cervical spine., Methods: A 52-year-old man with cervical myelopathy caused by OPLL underwent surgery for anterior decompression from C2/3 to C6/7. Immediately after the OPLL floating procedure, cerebrospinal fluid leakage and massive bleeding occurred at right edge of the OPLL at the C3-C4 level. After hemostasis, the dura mater at the C5-C6 levels bulged rapidly and became cyanotic. Intraoperative ultrasonographic images showed a high-intensity mass lesion on the ventral side of the spinal cord, indicating an intrathecal hematoma., Results: We incised the dura, found the hematoma under the intact arachnoid, and removed it. We then found that the bleeding occurred from the radicular artery along the right C4 root. After hemostasis, we performed anterior spine fusion from C2-C7. After surgery, the patient's myelopathy was improved, and no neurologic deficit related to the subarachnoid hematoma was found., Conclusion: This experience suggests that when anterior decompression surgery is performed for cervical OPLL patients, we should consider the possible occurrence of an SSAH. Intraoperative ultrasonography is a useful tool for detecting SSAHs.

Study Design: Case report., Objective: To describe the usefulness of simulated surgery for evaluation of a patient with neurofibromatosis type-1 (NF-1) who had severe cervicothoracic kyphoscoliosis and an anomalous vertebral artery (VA)., Summary of Background Data: Several surgical procedures have been used in the treatment of cervicothoracic kyphoscoliosis associated with myelopathy in patients with NF-1. However, to our knowledge, there has been no report that describes a surgical procedure for NF-1 patients with anomalous VA at the cervical spine., Methods: A 45-year-old man with NF-1 developed cervical myelopathy. Preoperative examinations revealed severe cervicothoracic kyphoscoliosis, dystrophic changes of the cervical vertebrae, and the anomalous course of a VA and VA aneurysms. To assist in the preoperative planning and intraoperative navigation, we created 3-dimensional (3D) full-scale models of the patient's spine. Using a model, we performed a simulation of the planned surgery for spinal cord decompression with spinal fusion through both anterior and posterior approaches., Results: Through the simulation, we could evaluate the risk of VA injury at the process of corpectomy, and altered the surgical procedure for the spinal cord decompression with spinal fusion from a posterior approach and a bone graft alone from an anterior approach. We accomplished the surgery successfully without any neurovascular complications. After surgery, the patient experienced relief from myelopathy., Conclusion: Preoperative surgical simulation using a 3D full-scale model was useful for improving the accuracy and safety of the surgery for cervicothoracic kyphoscoliosis with NF-1.

The roles of prostanoids in the pathogenesis of cardiovascular diseases and in the development of pathological conditions have been examined using mice lacking the individual, specific prostanoid receptor. Prostaglandin (PG) I2 protected the heart from ischemia-reperfusion injury in a model of acute myocardial infarction. In addition, PGI2 suppressed the development of pressure overload-induced cardiac hypertrophy. Aside from its potent vasodilatory action, PGI2 contributed critically to the development of renovascular hypertension via the activation of the renin-angiotensin-aldosterone system. Thromboxane (TX) A2 and PGF2alpha were found to be the mediators of inflammatory tachycardia under a systemic inflammatory condition induced by lipopolysaccharide. Under a septic condition leading to a vascular hypo-responsive state, TXA2 worked to maintain vascular tone by inhibiting the induction of inducible nitric oxide synthase in vascular smooth muscle cells. Mice lacking the PGE2 receptor subtype EP3 had a bleeding tendency and were resistant to thromboembolism, due to a defective activation of platelets. From these studies, the important and novel roles of prostanoids in the pathogenesis of cardiovascular diseases have been clarified.

We studied 27 patients with cervical ossification of the posterior longitudinal ligament (OPLL) but no clinical symptoms of myelopathy. We investigated the occupation ratio of the spinal canal by OPLL with cervical radiographs, assessed the morphological types of OPLL, and measured the segmental range of motion (ROM) at the level of maximum cord compression on flexion and extension radiographs. Patients were classified as having continuous-type OPLL (17 patients), mixed-type OPLL (seven patients), or segmental-type OPLL (three patients). The segmental ROM was negatively correlated with the OPLL occupation ratio (r=-0.49, p<0.01). No patient developed myelopathy during the study period. Three patients with massive OPLL did not develop myelopathy and the mobility of their cervical spine was highly restricted, suggesting that dynamic factors such as the segmental ROM preferentially contribute to the development of myelopathy in patients with cervical OPLL. Thus, by controlling the dynamic factors (hypermobility), we might be able to reduce neurological deterioration in patients with cervical OPLL., (Copyright 2009 Elsevier Ltd. All rights reserved.)

Objective: Endothelial progenitor cells (EPCs) play an important role in the self-healing of a vascular injury by participating in the reendothelialization that limits vascular remodeling. We evaluated whether prostaglandin I(2) plays a role in the regulation of the function of EPCs to limit vascular remodeling., Methods and Results: EPCs (Lin(-)cKit(+)Flk-1(+) cells) were isolated from the bone marrow (BM) of wild-type (WT) mice or mice lacking the prostaglandin I(2) receptor IP (IP(-/-) mice). Reverse transcription-polymerase chain reaction analysis showed that EPCs among BM cells specifically express IP. The cellular properties of EPCs, adhesion, migration, and proliferation on fibronectin were significantly attenuated in IP-deficient EPCs compared with WT EPCs. In contrast, IP agonists facilitated these functions in WT EPCs, but not in IP-deficient EPCs. The specific deletion of IP in BM cells, which was performed by transplanting BM cells of IP(-/-) mice to WT mice, accelerated wire injury-mediated neointimal hyperplasia in the femoral artery. Notably, transfused WT EPCs, but not IP-deficient EPCs, were recruited to the injured vessels, participated in reendothelialization, and efficiently rescued the accelerated vascular remodeling., Conclusions: These findings clearly indicate that the prostaglandin I(2)-IP system is essential for EPCs to accomplish their function and plays a critical role in the regulation of vascular remodeling.

Background: The hedgehog (Hh) pathway has been implicated in the pathogenesis of cancer including pancreatic ductal adenocarcinoma (PDAC). Recent studies have suggested that the oncogenic function of Hh in PDAC involves signaling in the stromal cells rather than cell autonomous effects on the tumor cells. However, the origin and nature of the stromal cell type(s) that are responsive to Hh signaling remained unknown. Since Hh signaling plays a crucial role during embryonic and postnatal vasculogenesis, we speculated that Hh ligand may act on tumor vasculature specifically focusing on bone marrow (BM)-derived cells., Methodology/principal Findings: Cyclopamine was utilized to inhibit the Hh pathway in human PDAC cell lines and their xenografts. BM transplants, co-culture systems of tumor cells and BM-derived pro-angiogenic cells (BMPCs) were employed to assess the role of tumor-derived Hh in regulating the BM compartment and the contribution of BM-derived cells to angiogenesis in PDAC. Cyclopamine administration attenuated Hh signaling in the stroma rather than in the cancer cells as reflected by decreased expression of full length Gli2 protein and Gli1 mRNA specifically in the compartment. Cyclopamine inhibited the growth of PDAC xenografts in association with regression of the tumor vasculature and reduced homing of BM-derived cells to the tumor. Host-derived Ang-1 and IGF-1 mRNA levels were downregulated by cyclopamine in the tumor xenografts. In vitro co-culture and matrigel plug assays demonstrated that PDAC cell-derived Shh induced Ang-1 and IGF-1 production in BMPCs, resulting in their enhanced migration and capillary morphogenesis activity., Conclusions/significance: We identified the BMPCs as alternative stromal targets of Hh-ligand in PDAC suggesting that the tumor vasculature is an attractive therapeutic target of Hh blockade. Our data is consistent with the emerging concept that BM-derived cells make important contributions to epithelial tumorigenesis.

Because of the chronic shortage of liver donors, hepatologists are required to prolong the liver transplant waiting period by preserving the hepatic reserve of scheduled recipients. This study examined the effectiveness of oral branched-chain amino acids (BCAAs), using outcome markers indicating pretransplant hepatic reserve. Fifty-six consecutive eligible patients with Child class A cirrhosis without major complications were randomly assigned to receive oral BCAA granules (12.45 g/day) for least 1 year or no BCAAs. Differences between groups in the Model for End-Stage Liver Disease (MELD) score, Child-Turcotte-Pugh (CTP) score, asialoscintigraphic clearance index (CI), and complications were examined. Of 50 remaining patients, 27 received BCAAs, and 23 received no BCAAs (mean duration, 3.2 years). The mean annual changes in the MELD score, CTP score, and asialoscintigraphic CI were smaller in the BCAA group than in the control group (-0.06 +/- 0.23 versus 0.10 +/- 0.40, P = 0.024, 0.06 +/- 0.30 versus 0.30 +/- 0.48, P = 0.037, and 0.00 +/- 0.02 versus 0.02 +/- 0.04, P = 0.040, respectively). The mean annual changes in the serum total bilirubin and the serum albumin in the BCAA group were better preserved than those in the control group (-0.07 +/- 0.20 versus 0.12 +/- 0.18 mg/dL, P < 0.001, and 0.07 +/- 0.13 versus -0.02 +/- 0.19 g/dL, P = 0.005, respectively); other laboratory variables were not significant. The incidence of overall major cirrhotic complications was lower in the BCAA group than in the control group [14.8% (4 of 27 patients) versus 30.4% (7 of 23 patients) at 3 years, P = 0.043]; only ascites was significant individually. In conclusion, early interventional oral BCAAs might prolong the liver transplant waiting period by preserving hepatic reserve in cirrhosis.

We describe a case of Brugada syndrome, in which recurrent syncope with convulsive seizures was induced after antidepressant treatment. The patient had been treated with five kinds of psychotropic drugs. The twelve-lead ECG after the syncope exhibited an RSR'-pattern in the precordial leads, however, a coved type ST-segment elevation was induced by a pilsicainide test. Although ventricular fibrillation was not induced in the electrophysiologic study, an ICD implantation was considered as the recommended therapy since Brugada syndrome unmasked by antidepressants could not be ruled out. The possible contribution of antidepressants to Brugada type ST-segment changes is discussed.

Objective: In bone scintigraphy, abnormal RI accumulation in ossified thyroid cartilage is often noted. However, because similar accumulation is also seen in tumor-involved cartilage, distinction between these two lesions is sometimes difficult. We examined the differences in RI accumulation by ossification of the thyroid cartilage and cartilage invasion with anterior, posterior, and oblique views of bone scintigraphy in this study., Methods: This study included 120 patients (104 men, 16 women; mean age 67.8 +/- 9.6 years; range 48-90 years) with laryngeal or lower pharyngeal carcinoma. The patients had exhibited abnormal accumulation of RI on thyroid cartilage on bone scintigraphy between February 1999 and March 2007. We evaluated accumulation of thyroid cartilage in the anterior, posterior, and oblique views on bone scintigraphy. The presence/absence of tumor invasion of the thyroid cartilage was checked by comparing the findings of enhanced computed tomography and magnetic resonance imaging (MRI) as well as evaluating operative records. RI accumulation in thyroid cartilage was divided into four types (diffuse accumulation, intense diffuse accumulation, slight inhomogeneous accumulation, and intense inhomogeneous accumulation)., Results: Tumor invasion of thyroid cartilage was noted in 2 of the 42 patients with diffuse accumulation, 1 of the 18 patients with intense diffuse accumulation, 1 of the 38 patients with slight inhomogeneous accumulation, and 17 of 22 patients with intense inhomogeneous accumulation. Because the degree of tumor invasion was highest in cases in which bone scintigraphy revealed intense inhomogeneous accumulation of RI in the thyroid cartilage, we judged this pattern of RI accumulation to be an indicator of tumor invasion. When diagnosis was based on this criterion, positive predictive value, negative predictive value, and accuracy were 77%, 96%, and 93%, respectively (P < 0.0001, Chi-square test)., Conclusions: The findings of this study suggest that ossification of thyroid cartilage can be distinguished from tumor-involved thyroid cartilage on the basis of the pattern of abnormal RI accumulation in the thyroid cartilage in patients with head/neck cancer.

Angiogenesis is mediated mainly by vascular endothelial growth factor (VEGF), and VEGF causes rapid growth in cancers, including human small-cell lung cancer (SCLC). The anti-angiogenic strategy of treating cancer using VEGF receptor (VEGFR) inhibition is currently of great interest. We tested the effects of the VEGFR2 tyrosine kinase inhibitor (TKI) vandetanib on the proliferation of two kinds of SCLC cell lines: SBC-1 cells, with detectable VEGFR2 expression and MS-1-L cells, without detectable VEGFR2 expression. To evaluate the anti-tumor and anti-angiogenic effects of vandetanib in vivo, we grafted SBC-1 and MS-1-L cells into mice. After a 3-week treatment, we measured the tumor size and histologically evaluated necrosis and apoptosis using H&E and TUNEL staining, respectively. The microvessels in the xenografts were also quantified by immunostaining of CD31. Vandetanib did not affect the proliferation of SBC-1 cells, but stimulated the growth of MS-1-L cells. In the SCLC xenograft model, vandetanib inhibited growth and tumor angiogenesis in a dose-dependent manner in SBC-1 xenografts. Vandetanib inhibited the growth of MS-1-L xenografts at a low dose (<12.5 mg/kg/day), but it did not affect tumor size or change microvessel counts at a higher dose. Interestingly, secretion of VEGF increased significantly in the MS-1-L cell line in the presence of a high dose of vandetanib in vitro. The effects of vandetanib on tumor angiogenesis were different in SBC-1 and MS-1-L cell lines. Production of angiogenic factors such as VEGF by the tumor potentially stimulates tumor angiogenesis and results in the acquisition of resistance to VEGFR TKI.

Depressive symptoms are common in Alzheimer's disease (AD) and contribute to clinical morbidity. Previous studies have suggested that hypoperfusion in the prefrontal cortex and anterior cingulate gyrus are involved in the pathophysiology of depression. Using the easy Z-score imaging system (eZIS), we investigated the relationship between depressive symptoms and prefrontal hypoperfusion in AD. Tc-99m-ethyl cysteinate dimer (Tc-99m-ECD)-single photon emission tomography (SPECT) and Neuropsychiatric Inventory (NPI) were performed in forty-four patients diagnosed as having Dementia of Alzheimer's type (DAT) with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). These patients were divided into the depressive group (D group: n=26) and non-depressive group (ND group: n=18) using NPI depression items. All data from SPECT images were analyzed using eZIS software. Scores in four regions were determined by Z-values; these regions consisted of each side of the prefrontal cortex and anterior cingulate gyrus. The mean scores between the D group and ND group were compared. The mean scores of the left prefrontal cortex in the D group were significantly higher (p<0.0125) than those in the ND group. There were no significant differences in the scores of the right prefrontal cortex and the bilateral anterior cingulate gyrus between these two groups (Mann-Whitney U-test). These findings suggest that hypoperfusion in the left prefrontal area contributes to the expression of depressive symptoms in patients with DAT.

Objective: Single-photon emission computed tomography (SPECT) using gallium (Ga) has been frequently used for diagnosing head and neck tumors in patients. Although the usefulness of Ga-SPECT is well known, the degree of the increase in diagnostic ability with Ga-SPECT for head and neck tumors has not been reported. We compared the ability of the planar images of Ga scintigraphy, SPECT images of Ga scintigraphy, and CT images to diagnose head and neck primary tumors and neck metastases., Methods: The subjects of this study were 167 patients with malignant head/neck lesions. For Ga scintigraphy, Ga-67-citrate (74 MBq) was injected via a cubital vein. Planar and SPECT images were taken 72 h after the Ga-67-citrate injection. The rate of detection of the primary lesions was compared first between SPECT and planar images then between SPECT and CT images. The rate of detection for each stage of disease according to the TNM classification was also analyzed., Results: The rate of detection of primary lesions was 50% with planar imaging and 69% with SPECT. And similarly, regarding the rate of detection of lymph node metastases, there was a significant difference between planar imaging and SPECT. The rate of detection of primary lesions was 70% for both CT and SPECT. At T stage, the rates of detection of primary lesions with each imaging technique were 11% with planar imaging and 39% with SPECT, and 22% with CT for stage T1., Conclusions: This study revealed the marked superiority of SPECT images over planar images in terms of the ability to detect primary tumors and tumor metastasis to cervical lymph nodes. Furthermore, the primary T1 tumor detection rate of SPECT images was higher than that of CT images. On the basis of these results, the concomitant use of SPECT is highly recommended when Ga scintigraphy is performed to check for malignant head/neck tumors.

A contrast-enhanced mass was revealed by computed tomography and magnetic resonance imaging in the left pelvic cavity of a 71-year-old man. Although the mass appeared to be a cavernous hemangioma, malignancy could not be ruled out. Abdominal angiography was performed but failed to rule out malignancy because it revealed vascular dislocation and encasement. (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) was then performed, and suggested a benign tumor, with a standardized uptake value (SUV) of 1.7. Following this finding, because the tumor was large and rupture could not be ruled out, we decided to perform surgery. The resected tumor was a benign cavernous hemangioma, consistent with the result obtained by FDG-PET.