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Introduction: Apathy is a common neuropsychiatric symptom in patients with Alzheimer's disease (AD). The striatal binding potential (BP) of 123 I-FP-CIT ( N -δ-fluoropropyl-2β-carbomethoxy-3β-[4-iodophenyl]tropane) single-photon emission computed tomography (SPECT) is correlated with the degree of apathy in patients with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). This study aimed to determine if dopaminergic activity in the basal ganglia is associated with the development of apathy in AD., Methods: Nineteen subjects with AD were included and underwent 123 I-FP-CIT-SPECT. Patients with other types of dementia as a comorbidity, those taking antidepressants, and those with overt parkinsonism were excluded. Apathy was assessed using the Apathy Evaluation Scale Informant-Japanese version (AES-I-J). SPECT images were overlaid with images in striatal regions of interest (ROIs), and the SPECT values in these regions were counted. The relationship between BP values and AES-I-J scores was investigated using Spearman's rank correlation coefficient., Results: Significant inverse correlations were observed between BP values and AES-I-J scores in the left caudate nucleus and there was a marginally significant inverse correlation in the right caudate nucleus., Conclusion: The pathological basis of apathy might be the impairment of the dopaminergic nervous system. Further studies on more subjects with AD, healthy controls, and patients with PD and DLB are needed., Competing Interests: The authors report no financial or other relationship that is relevant to the subject of this article. N.U. received honoraria from Japan Medi-Physics and Tanabe Mitsubishi Pharma. N.H. received honoraria from Janssen Pharmaceutica, Yoshitomi Yakuhin, Otsuka Pharmaceutical Co., Ltd., Dainippon Sumitomo Pharma, Novartis Pharma, and Meiji Seika Pharma. T.I. received honoraria from Dainippon Sumitomo Pharma and Otsuka Pharmaceutical. H.N. received honoraria from Astellas, Dainippon Sumitomo Pharma, Meiji Seika Pharma, and Otsuka Pharmaceutical. T.S. received research funding from Eisai, Hitachi, Philips Japan, Nihon Medi-Physics, and Fuji RI Pharma. S.N. received honoraria from Otsuka Pharmaceutical, Meiji Seika Pharma, Sumitomo Dainippon Pharma, Kyowa Pharmaceutical Industry, Shionogi, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Eisai, Tsumura, Eli Lilly, MSD, and Pfizer, and research/grant support from Otsuka Pharmaceutical, Shionogi, Mitsubishi Tanabe Pharma, Mochida Pharmaceutical, Eisai, Tsumura, Astellas, Eli Lilly, MSD, and Pfizer. I.K. received honoraria from Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutica, Kyowa Hakko Kirin, Lundbeck, Meiji Seika Pharma, MSD, Mylan, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Shionogi, Shire, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Tsumura, and Yoshitomi Yakuhin, and research/grant support from Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Kyowa Hakko Kirin, Mochida Pharmaceutical, MSD, Novartis Pharma, Otsuka Pharmaceutical, Pfizer, Shionogi, and Takeda Pharmaceutical, and is a member of the advisory board of Dainippon Sumitomo Pharma., (Copyright © 2020 by S. Karger AG, Basel.)

Purpose: The brief negative symptoms scale (BNSS) is a concise instrument used to assess negative symptoms of subjects with schizophrenia covering five domains of negative symptoms and is suitable for use in clinical, experimental, and epidemiological settings. The original and translated version of BNSS has thus far been shown to have adequate psychometric properties. This study aimed to examine internal consistency, inter-rater and test-retest reliability, discriminant and convergent validity, and factor structure of the Japanese version of BNSS., Patients and Methods: The assessment was performed by 11 raters using interview videos of nine subjects. Reliability was calculated with Cronbach's alpha for internal consistency and intra class correlation coefficient (ICC) for inter-rater reliability. Pearson's correlation coefficients were calculated to estimate the test-retest reliability. In addition to BNSS, Scale for assessment of negative symptoms (SANS) and scale for assessment of positive symptoms (SAPS) was obtained to assess the convergent and discriminant validity. Factor structure was assessed using principle factor analysis., Results: The Japanese BNSS showed excellent internal consistency (Cronbach's alpha=0.95), inter-rater reliability (intra class correlation coefficient=0.97), and test-retest reliability (r=0.94, p<0.001). The convergent validity shown by correlation with SANS total score (r=0.87, p<0.001) and discriminant validity shown by correlation with SAPS total score (r=0.17, p=-0.68) were also good. Principal factor analysis revealed a two-factor structure of BNSS, although the loading of each item differed from that in the literature., Conclusion: Our pilot study demonstrated that Japanese BNSS had good psychometric properties which were achieved with relatively brief training. Further studies with more subjects and raters with various backgrounds recruited from multiple sites are warranted., Competing Interests: Dr Naoki Hashimoto reports personal fees from Janssen Pharmaceutical, Yoshitomiyakuhin, Otsuka Pharmaceutical, Dainippon Sumitomo Pharma, Novartis Pharma, and Meiji Seika Pharma, outside the submitted work. Dr Atsushi Toyomaki reports personal fees from Otsuka Pharmaceutical, Dainippon Sumitomo Pharma and Meiji Seika Pharma, outside the submitted work. Dr Matsuhiko Oka reports grants from Novartis Research Grants, outside the submitted work. Dr Keisuke Takanobu reports personal fees from Otsuka Pharmaceutical Co., Ltd., Seiwa Shoten Publishers, Japan Medical Herb Association, and Tsumura & Co., outside the submitted work. Dr Hisashi Narita reports grants from JSPS KAKENHI Grant Numbers 18H0608108, outside the submitted work. Dr Kan Kitagawa reports personal fees from Otsuka Pharmaceutical, outside the submitted work. Dr Niki Udo reports personal fees from Japan Medi-Physics and Tanabe Mitsubishi Pharma, outside the submitted work. Dr Koki Ito reports personal fees from  Janssen Pharmaceutical, Mitsubishi Tanabe Pharma, Otsuka Pharmaceutical, Dainippon Sumitomo Pharma, Meiji Seika Pharma, and Eli Lilly, outside the submitted work. Prof. Dr. Ichiro Kusumi reports grants, personal fees from Astellas, Daiichi Sankyo, Dainippon Sumitomo Pharma, Eisai, Eli Lilly, Janssen Pharmaceutical, Kyowa Hakko Kirin, Lundbeck, personal fees from Meiji Seika Pharma, Mochida Pharmaceutical, MSD, Mylan, Novartis Pharma, Ono Pharmaceutical, Otsuka Pharmaceutical, Pfizer, Shionogi, Shire, Taisho Toyama Pharmaceutical, Takeda Pharmaceutical, Tanabe Mitsubishi Pharma, Tsumura, and Yoshitomiyakuhin, outside the submitted work. The authors report no other conflicts of interest in relation to the subject of this study., (© 2019 Hashimoto et al.)

A 40-year-old man presented with generalised dissociative amnesia. At 2 weeks after onset, N-isopropyl-[ 123 I] p -iodoamphetamine-single-photon emission CT imaging of the brain revealed hypoperfusion in the right medial temporal area. Organic brain damage was ruled out. His inability to recall information was attributed to psychological stress related to his employment. Consistent with this diagnosis, his generalised dissociative amnesia lasted 6 years and 10 months; however, he recovered from amnesia naturally on starting a new job. Perfusion of his right medial temporal area also returned to normal levels. Longitudinal reports for generalised dissociative amnesia with natural recovery are exceedingly rare. It is important to confirm whether dissociative amnesia and cerebral blood flow recover in parallel, even in cases where dissociative amnesia is long-lasting., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

The antioxidant potencies of chondroitin sulfates (CSs) from shark cartilage, salmon cartilage, bovine trachea, and porcine intestinal mucosa were compared by three representative methods for the measurement of the antioxidant activity; DPPH radical scavenging activity, superoxide radical scavenging activity, and hydroxyl radical scavenging activity. CSs from salmon cartilage and bovine trachea showed higher potency in comparison with CSs from shark cartilage and porcine intestinal mucosa. Next, CS from salmon cartilage chelating with Ca(2+), Mg(2+), Mn(2+), or Zn(2+) were prepared, and their antioxidant potencies were compared. CS chelating with Ca(2+) or Mg(2+) ions showed rather decreased DPPH radical scavenging activity in comparison with CS of H(+) form. In contrast, CS chelating with Ca(2+) or Mg(2+) ion showed remarkably enhanced superoxide radical scavenging activity than CS of H(+) or Na(+) form. Moreover, CS chelating with divalent metal ions, Ca(2+), Mg(2+), Mn(2+), or Zn(2+), showed noticeably higher hydroxyl radical scavenging activity than CS of H(+) or Na(+) form. The present results revealed that the scavenging activities of, at least, superoxide radical and hydroxyl radical were enhanced by the chelation with divalent metal ions.

Ulcerative colitis induced by dextran sulfate sodium (DSS) is one of the most widely used experimental animal models. However, the mechanism responsible for the pathogenesis of the colitis is still unclear. The aim of the present study was to clarify the events occurring after administration of DSS to rats focusing on the relationship between the intestinal bacterial metabolism of DSS and the intestinal mucosal lesions in the model. Within 2 d after DSS administration, severe injury of the cecal mucosa was evident, together with bloody feces and blood in the cecum. However, these lesions were repressed by administration of antibiotics. On the other hand, DSS was found to be metabolized under anaerobic conditions upon incubation with cecal content in vitro, first being desulfated and then undergoing carbohydrate moiety degradation. However, no such metabolic process occurred when cecal content from rats that had been administered antibiotics was employed. These results indicate that the initial step of DSS-induced ulcerative colitis is lesioning of the cecal mucosa, which is related to metabolism of DSS by intestinal bacteria.

This is a case report of a 38-year-old woman with temporal lobe epilepsy and epileptic psychoses. The psychoses consisted of three rare symptoms that were "a distortion in the sense of time," "what should be there disappears," and "the next scene is supposed to be in a particular way." There have been few reports that included these symptoms; therefore, we report the course of this patient in detail.

Background: The progression of diabetic nephropathy is closely related to disturbances in glomerular hemodynamics, such as glomerular hypertension and/or hyperperfusion. The aim of this study was to observe and to analyze glomerular hemodynamics in rats with diabetes mellitus (DM) in vivo using confocal laser scan microscopy (CLSM). We also examined the effects of candesartan cilexetil (TCV-116), a selective angiotensin II type 1 receptor blocker (ARB), on glomerular hemodynamics in DM., Methods: Munich-Wistar rats were divided into six groups: (1) four-day control; (2) four-day DM; (3) 28-day control; (4) 28-day DM; (5) DM treated with insulin; (6) DM treated with TCV-116. The kidney-to-body weight ratio, glomerular volume, and proteinuria were estimated. Glomerular hemodynamic changes were observed using CLSM and renal expression of endothelial nitric oxide synthase (eNOS), and neuronal nitric oxide synthase (nNOS) was evaluated by immunofluorescence., Results: The kidney-to-body weight ratio, glomerular volume, the diameters of afferent arterioles (AA) and efferent arterioles (EA), erythrocyte velocities within glomeruli, and volume flow in glomerular capillary loops in four-day DM were significantly higher than in control rats, and increases were even more pronounced in the 28-day DM. TCV-116 treatment ameliorated all these findings and significantly decreased proteinuria, but there was no effect on the blood glucose level. On the other hand, insulin treatment was followed by normalization of all these changes induced in DM. Enhanced renal expression of eNOS in DM was suppressed when treated with either TCV-116 or insulin, while expression of nNOS was unaltered among the four groups., Conclusion: This imaging procedure allowed us to evaluate glomerular microcirculation in vivo, including the diameters of AA and EA, erythrocyte velocity, and volume flow. DM significantly induced glomerular hemodynamic alteration and renal hypertrophy. DM treated with either insulin or ARB ameliorated these changes. This study shows that progress in imaging technology promises to make major contributions to revealing the involvement of hemodynamic changes in glomerular diseases, aiding prognosis and the monitoring of therapeutic effects, as well.

Background: It has been proposed that glomerular hemodynamic changes or glomerular growth response may promote the development of glomerulosclerosis, irrespective of its etiology. Further experimental models are needed to clarify the cellular and molecular mechanisms that lead to progressive glomerulosclerosis with an irreversible course. We designed a model of irreversible glomerulosclerosis, using anti-Thy-1.1 injection followed by uninephrectomy, and examined the role of glomerular endothelial cell responses in the process of progressive sclerotic changes., Method: Rats were injected with anti-Thy-1.1 monoclonal antibody, 1-22-3, and 30 minutes later, unilateral nephrectomy (one-kidney group) or sham operation (two-kidney group) was performed. Rats were sacrificed for histological examination on days 3, 14, 56, and 84 after injection. The density of the glomerular capillary tuft was assessed by immunofluorescent staining for endothelial specific antigens. The mRNA expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), platelet-endothelial cell adhesion molecule-1 (PECAM-1), and vascular endothelial growth factor (VEGF) also was followed up by reverse transcription-polymerase chain reaction (RT-PCR)., Results: Semiquantitative analysis revealed that the capillary density and mRNA expression of PECAM-1, VCAM-1 and VEGF were significantly lower in the one-kidney group compared to the two-kidney group on day 14. On day 84, progressive glomerulosclerotic lesions were found, followed by a decrease of the capillary density in the one-kidney group, while the glomerular architecture recovered to an almost normal state in the two-kidney group., Conclusions: Progressive glomerulosclerosis can be induced in the rat by a one shot injection of anti-Thy 1.1 monoclonal antibody followed by unilateral nephrectomy. This model shows that there is a positive association between impairment of vascular regeneration and the development of glomerulosclerosis.

Background: Blood flow in the microvasculature plays a pivotal role in determining the outcome of injury and repair in inflamed tissue. Real-time observation of the kidney microvasculature, including the glomerular capillary tufts, is extremely difficult because of the methodological limitations of currently available microscope optics. In the present study, we attempted to analyze hemodynamic events that occurred in vivo during microvascular regeneration following destruction of the glomerular capillary tuft, functionally and quantitatively by the use of a real-time confocal laser-scanning microscope (CLSM) system., Methods: A polyethylene catheter was inserted into the carotid artery to allow blood pressure measurement. Mesangiolytic lesions producing microaneurysms were induced by the injection of anti-Thy-1.1 antibody. On days 3 and 7 after antibody injection, we examined hemodynamic changes under an intravital microscope equipped with real-time CLSM in combination with a high-speed CCD video camera. To measure vessel diameter and erythrocyte velocity, rats were injected with fluorescein isothiocyanate (FITC)-labeled dextran and FITC-labeled red blood cells (RBCs)., Results: On day 3 of the disease, mean arterial blood pressure was 112 +/- 5 mm Hg, which was significantly higher than that of normal rat or of rats on day 7 (93 +/- 1 and 101 +/- 9 mm Hg, respectively). Within mircroaneurysms on day 3, RBC velocity was greatly suppressed. By day 7, RBC velocity, in glomeruli with normal appearances, recovered to about half of the level seen in normal controls (430.6 +/- 284.7 microm/sec), while in narrowed glomerular tufts, it was still only 104.6 +/- 35.1 microm/sec., Conclusions: The noninvasive procedure, using CLSM in combination with a high-speed video camera, allowed us to examine hemodynamic events quantitatively and to analyze microvascular architecture three dimensionally in the kidney. It is useful for estimating hemodynamic response and vascular regeneration in vivo and may be promising for clinical application.

Aims/background: There is a possibility that proinflammatory cytokines such as interleukin-6 (IL-6) are involved in the inflammatory process of chronic hepatitis C. This study was undertaken to investigate the possible role of IL-6 in the pathophysiology of chronic hepatitis C., Methods: Serum IL-6 levels in 63 patients with chronic hepatitis C and in 26 normal controls were measured. Light and electron immunostaining studies to localize IL-6 protein as well as in situ hybridization to localize IL-6 messenger RNA were performed on 10 liver biopsy specimens., Results: Serum IL-6 levels were significantly (p<0.01) elevated in chronic hepatitis C compared to those in normal controls. Although no statistically significant correlation was found between serum IL-6 levels and hepatobiliary enzyme levels, a significant correlation (p<0.01) was found between serum IL-6 levels and category II of Knodell's histological activity index score. Non-parenchymal cells in hepatic sinusoids and the cells infiltrating enlarged fibrous portal tracts were definitely positive for IL-6 protein and mRNA by immunohistochemistry and in situ hybridization. In addition, immunoelectron microscopy revealed a weak and occasional positive reaction in the cytoplasm of hepatocytes. The majority of the positive cells in hepatic sinusoids showed CD68 immunoreactivity in consecutive sections indicating that these were Kupffer cells. Sinusoidal endothelial cells and hepatic stellate cells also exhibited a weak reaction., Conclusion: These results strongly suggest that Kupffer cells in liver parenchyma and macrophages infiltrating in portal tracts are the main producers of elevated IL-6 in serum. Moreover, there is a possibility that IL-6 produced by hepatocytes could also act as a regenerative stimulus to hepatocytes themselves in an autocrine fashion.

Background/aims: Fibronectin is a multifunctional glycoprotein and plays important roles in cell-to-cell or cell-to-matrix interaction. The molecular and functional diversity of fibronectin arises from alternative splicing of pre-mRNA at three variable regions, termed ED-A, ED-B and IIICS. Cellular fibronectin with ED-A and ED-B regions has different biological activities from plasma fibronectin lacking these regions. This study was aimed at investigating the type-specific expression of fibronectin in human liver diseases., Methods: Immunohistochemistry with anti-total and anti-cellular fibronectin monoclonal antibodies, in situ hybridization with cDNA probes detecting common and ED-A regions and RT-PCR to amplify each variable region were performed in 35 specimens, including 4 control, 16 chronic hepatitis, 7 liver cirrhosis and 8 hepatocelular carcinoma., Results: In control liver, there were slight deposits of cellular fibronectin [ED-A(+)fibronectin] in portal areas. In chronic hepatitis, it was strongly deposited at the margin of the fibrously enlarged portal areas where new collagen fibers were formed. Cellular fibronectin was evenly and abundantly accumulated in fibrotic septa in liver cirrhosis, and in fibrotic septa and capsules of tumor nodules in hepatocellular carcinoma. In control liver, cellular fibronectin mRNA was localized in a few hepatocytes and non-parenchymal cells around central veins, and was increased in the same cell populations near fibrously enlarged portal areas as hepatic fibrosis progressed. In hepatocellular carcinoma, it was expressed in most hepatoma cells. Fibronectin mRNA with three variable regions was detectable by RT-PCR in control liver as well as in each disease group., Conclusions: The expression of cellular fibronectin was increased in fibrotic human liver and hepatocellular carcinoma. In human liver, both non-parenchymal cells and hepatocytes participated together in cellular fibronectin production. In hepatocellular carcinoma, hepatoma cells were the main producer. Our results indicate that, in human liver, cellular fibronectin may participate in the hepatic fibrogenesis and in the malignant phenotypes of hepatocellular carcinoma.

Immunolocalization of a fibronectin-binding proteoglycan (PG-P1) in relation to fibronectin, type IV collagen and laminin, in normal and fibrotic human liver was investigated by light and electron microscopy. HS-42, which is a monoclonal antibody to PG-P1 and is reported to recognize a heparan sulfate proteoglycan named HSPG2/perlecan, was used for this purpose. Light microscopy in the human liver with minimal changes revealed that PG-P1 was present along the hepatic sinusoids as well as fibronectin and type IV collagen, whereas laminin was only weakly detected. In portal areas, PG-P1 was only localized on basement membranes around bile duct systems and blood vessels, as well as laminin and type IV collagen, while fibronectin was scarcely detected in basement membranes. In the fibrotic liver, fibronectin was abundant in necrotic and/or newly fibrosing areas, while PG-P1 was absent in these regions. Using immunoelectron microscopy, PG-P1 was localized in the space of Disse in nearly normal livers and was only detected on basement membranes in portal tracts. In fibrotic livers, PG-P1 in the space of Disse occasionally showed a basement-membrane-like deposition in parallel with the increased light microscopical deposition of laminin in this area, suggesting the positive participation of PG-P1 in the sinusoidal capillarization. Most capillary and sinusoidal endothelial cells, and rarely bile epithelial cells revealed the reaction products of PG-P1 in their rough endoplasmic reticulum and small vesicles. Thus, it was suggested that these cell types are mainly, if not wholly, responsible for PG-P1 production.(ABSTRACT TRUNCATED AT 250 WORDS)