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NIR absorbing squaraine dyes SQ1-SQ7 having 1 H-benzo[ c, d]indol-2-ylidene as a donor moiety were designed for application in DSSCs. Annulation of the benzene ring to an 3 H-indolium-based anchor moiety led to a red-shifted and broadened absorption band on TiO 2 film, which were reflected in the improved short-circuit current density of SQ2 (6.22 mA cm -2 ) compared to the nonbenzene fused derivative SQ1 (4.39 mA cm -2 ). Although the introduction of a butoxy (SQ4: 806 nm) or dialkylamino group (SQ5-SQ7: 815-820 nm) to the 1 H-benzo[ c, d]indol-2-ylidene-based donor moiety resulted in red-shifted absorption maxima in ethanol compared to the nonsubstituted derivative SQ2 (784 nm), the HOMO energy level of SQ4-SQ7 gave rise to an undesirable approximation to the redox potential of I - /I 3 - . Thus, the butoxy (SQ4: 0.56) and dialkylamino (SQ5-SQ7: 0.25-0.30) derivatives had relatively lower conversion efficiencies. Since the 2-ethylhexyl derivative SQ3 exhibited red-shifted absorption (λ max : 796 nm), suitable HOMO and LUMO energy levels, and relatively efficient restriction of charge recombination, this dye achieved the highest conversion efficiency (1.31%), along with a high IPCE response of over 20% over a wide range from 640 to 860 nm and an onset of IPCE at 1000 nm.

A new convenient, functional group-tolerant, transition metal-free route to aryl trifluoromethyl ketones under mild conditions is described. The reaction of not only aryl Grignard reagents carrying reducible electrophilic functional groups, such as ester and cyano groups, but also electron-deficient nitrogen-containing heteroaryl Grignard reagents with methyl trifluoroacetate gives the corresponding aryl or heteroaryl trifluoromethyl ketones in good yields. Biological assays revealed that new heteroaryl trifluoromethyl ketones carrying 2,4-dimethoxypyrimidine and 3,5-dimethylisoxazole rings show good anti-tumor activities.

Practical synthesis of bay-monofunctionalized perylene dyes has been developed based on controllable NBS bromination of tetrabenzyl perylene-3,4,9,10-tetracarboxylate. The ability to perform the convenient and high-yielding synthesis highlights the potential utility of our multifunctional approach to access a diverse range of new perylene systems.

Background: Chronic neuroinflammation has been implicated in Alzheimer's disease (AD) pathology., Objective: To investigate the association between cytokine and anti-amyloid-β (Aβ) autoantibody levels and the degree of brain atrophy and cognitive impairment in AD patients., Methods: Cerebrospinal fluid (CSF) levels of C-C motif chemokine ligand 2 (CCL2), C-X-C motif chemokine ligand 8, C-X-C motif chemokine ligand 10, interleukin 6, and anti-Aβ autoantibody were evaluated in 69 AD patients. Serum levels of CCL2 and anti-Aβ autoantibody were also examined. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets the volumes of interest (VOI) in medial temporal structures. Cognitive function was evaluated by neuropsychological testing, including the Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB)., Results: CSF CCL2 levels correlated significantly with the severity (p = 0.023) and the extent (p = 0.022) of VOI atrophy, and with the extent of gray matter atrophy (p = 0.039) in AD patients. CSF anti-Aβ autoantibody levels were inversely correlated with the severity of VOI atrophy (p = 0.020), the extent of VOI atrophy (p = 0.015), and the ratio of VOI/GM atrophy (r = -0.358, p = 0.004). CSF CCL2 levels were also inversely correlated with MMSE (p = 0.0497) and FAB scores (p = 0.016)., Conclusions: CSF CCL2 levels are associated with the degree of medial temporal lobe and gray matter atrophy, and cognitive decline in AD.

We report the case of a 76-year-old woman presenting with 47-month history of progressive dementia and cortical blindness with no family history. Antibodies against thyroid glands and the N-terminus of α-enolase (NAE) were detected in her serum. Neurological examination revealed progressive dementia, frontal signs, visual disturbance, and exaggerated bilateral tendon reflexes in both legs. Diffusion MRI showed cortical hyper-intensities in the bilateral occipital and parietal, and the left frontal and temporal cortices. 99m Tc-ethyl cysteinate dimer-single photon emission computed tomography indicated decreased regional cerebral blood flow throughout the bilateral parietal lobes and partially in the left frontal and temporal lobes. PRNP gene analysis showed no mutations with methionine homozygosity at codon 129 in peripheral blood. Cerebrospinal fluid examination, including 14-3-3 and total tau protein detection, revealed normal levels; however, prion proteins were amplified by the real-time quaking-induced conversion method. Hashimoto's encephalopathy was excluded on the basis of unresponsiveness to corticosteroids. The symptoms progressed slowly. Periodic sharp-wave complexes were observed on electroencephalogram 36 months after the onset of symptoms; the patient reached a state of akinetic mutism at 47 months. This was a probable case of MM2-cortical-type sCJD with anti-NAE antibodies based on the World Health Organization (WHO) diagnostic criteria for sCJD, genetic information, and the slowly progressive course. However, this case did not meet with the probable WHO diagnostic criteria until 3 years after symptom onset, highlighting the difficulty of diagnosing a living case of the MM2-type of sCJD. Therefore, establishment of clinical diagnostic criteria for MM2-type of sCJD is required.

We examined anti-complement C1q (C1q) autoantibody levels in serum and cerebrospinal fluid (CSF) samples of patients with neuromyelitis optica spectrum disorders (NMOSD). We analyzed the correlations between anti-C1q autoantibody levels and the clinical and other CSF characteristics of NMOSD. Serum and CSF anti-C1q autoantibody levels increased during the acute phase of NMOSD, reverting to the same levels as controls during remission. CSF anti-C1q autoantibody levels during the acute phase correlated with several markers reflecting disease severity, Expanded Disability Status Scale worsening, spinal cord lesion length in cases with myelitis, CSF protein and interleukin-6 levels, and CSF/serum albumin ratios., (Copyright © 2017 Elsevier B.V. All rights reserved.)

We report an autopsy-verified case of steroid-responsive encephalopathy with convulsion and a false-positive result from the real-time quaking-induced conversion (RT-QUIC) assay. A 61-year-old Japanese man presented with acute onset of consciousness disturbance, and convulsions, but without a past medical or family history of progressive dementia, epilepsy, or prion disease. Brain diffusion and fluid-attenuated inverted recovery MR images revealed edematous cortical hyper-intensity, which diminished after the acute phase. Steroid pulse therapy was partially effective, although he continued to have dementia with myoclonus and psychiatric symptoms, despite resolution of the consciousness disturbance. Cerebrospinal fluid (CSF) analysis revealed a normal cell count, with significantly elevated levels of 14-3-3 protein and total tau protein. In addition, prion protein in the CSF was slowly amplified by the RT-QUIC assay. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. The patient died of sudden cardiac arrest at 3 months after the onset of symptoms. The positive result from the RT-QUIC assay led us to suspect involvement of prion disease, although a postmortem assessment revealed that he had pathological changes after convulsion, and no prion disease. This case indicates that convulsion may cause false-positive RT-QUIC results, and that a postmortem evaluation remains the gold standard for diagnosing similar cases.

Objective: To address occipital neuralgia in patients with neuromyelitis optica spectrum disorder (NMOSD)., Background: NMOSD is an inflammatory demyelinating disease that commonly presents with pain; however, headache symptoms have received little attention., Methods: We presented three cases of NMOSD in which the patients experienced acute-onset, severe, and steroid-responsive occipital neuralgia. All patients provided consent to use their demographic and imaging data retrospectively., Results: In all three cases, MRI revealed a new high-intensity area in the cervical cord at the C1-C3 level of the spine, which was diminished in two of the three cases after corticosteroid pulse therapy., Conclusion: Our cases support the recognition of NMOSD as a cause of secondary headache. As patients with NMOSD experience severe occipital neuralgia, a relapse should be considered and a cervical MRI should be performed., (© 2017 American Headache Society.)

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the selective and progressive loss of motor neurons. The purpose of this study was to clarify effects of brazilian green propolis and the active ingredient against ALS-associated mutant copper-zinc superoxide dismutase (SOD1)-mediated toxicity. Ethanol extract of brazilian green propolis (EBGP) protected N2a cells against mutant SOD1-induced neurotoxicity and reduced aggregated mutant SOD1 by induction of autophagy. Kaempferide and kaempferol, the active ingredients of EBGP, also inhibited mutant SOD1-induced cell death and reduced the intracellular mutant SOD1 aggregates. Both kaempferide and kaempferol significantly suppressed mutant SOD1-induced superoxide in mitochondria. Western blot analysis showed that kaempferol potentially induced autophagy via the AMP-activated protein kinase (AMPK) - the mammalian target of rapamycin (mTOR) pathway. These results suggest that EBGP containing the active ingredient against mutant SOD1-mediated toxicity is a promising medicine or health food for prevention and treatment of ALS.

Purpose: To report the findings in a 72-year-old man with neuronal intranuclear hyaline inclusion disease (NIHID) with the negative-type electroretinogram (ERG) and without night blindness., Methods: Standard ophthalmological examinations including the medical history, measurements of the best-corrected visual acuity and intraocular pressures, slit-lamp biomicroscopy, ophthalmoscopy, spectral-domain optical coherence tomography, fundus autofluorescence, and perimetry were performed. In addition, neurological and electrophysiological examinations were performed., Results: NIHID was confirmed by skin biopsy. The ophthalmologic examinations revealed sluggish pupillary reflexes without visual disturbances and retinal abnormalities. The amplitudes of the dark-adapted 0.01 ERG was absent, and light-adapted 3 ERG and light-adapted 30 Hz flicker ERG were reduced in amplitude and delayed in implicit time. The rod system was more severely affected than the cone system, indicating that NIHID is classified as one of rod-cone dysfunction syndrome. The dark-adapted 3 ERG consisted of a markedly reduced b-wave with larger a-wave (negative ERG), but the amplitude of a-wave was smaller than normal., Conclusions: Since the ophthalmoscopical findings and the subjective visual functions may be essentially normal, the characteristic ERG abnormalities can be an important findings in adult-onset NIHID without night blindness.

We examined progranulin (PGRN) levels in cerebrospinal fluid (CSF) samples during the acute phase in 15 patients with neuromyelitis optica spectrum disorders (NMOSD) and compared the results with those from 17 patients with multiple sclerosis (MS), 30 patients with other inflammatory neurological diseases (OIND), and 20 non-inflammatory controls (NIC). CSF PGRN levels of NMOSD patients were significantly higher than those of MS patients and NICs. These levels correlated with CSF interleukin-6 levels, CSF cell counts, CSF protein levels, improvements in the Expanded Disability Status Scale score, and affected total spinal cord lesion length in the NMOSD patients., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Posterior reversible encephalopathy syndrome (PRES) is diagnosed based on neuroradiological findings. Typically, PRES is reversible and presents with a good outcome; however, fatal outcomes have been reported. We report an autopsied case showing PRES-like neuroradiological findings associated with premedication including tacrolimus for autologous peripheral blood stem cell transplantation in a 28-year-old woman with a 2-year history of acute myeloid sarcoma/acute myeloid leukemia. Neurological examination revealed disturbed consciousness, muscle weakness in all extremities, and bilaterally diminished tendon reflexes. Brain fluid attenuated inversion recovery MRI showed multiple bilateral hyper-intensity areas in the posterior white matter and left corona radiate. She died of respiratory arrest within 24h after PRES diagnosis. Neuropathological examination revealed diffuse cerebral edema, multiple cerebral hematomas that extended into the lateral ventricles and subarachnoid cavities, and multiple microbleeds predominantly in the inferior surface of the occipital white matter. Microscopic findings revealed paler myelin sheaths, enlargement of the vascular endothelium, leakage of plasma components and red blood cells, and clasmatodendrosis within the occipital white matter. Cerebral herniation and diffuse cerebral edema due to vascular endothelial dysfunction were concluded to be the cause of death. These pathological findings may aid in the pathophysiological recognition of acute-stage PRES., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Aim: Polypharmacy is a major problem for elderly patients in developed countries. We investigated whether a multidisciplinary medication review using electronic medical records could reduce the number of drugs administered to elderly patients receiving polypharmacy., Methods: The present study included 432 elderly patients (188 women, 244 men; 267 patients aged 65-74 years and 165 patients aged ≥75 years) who were admitted to and discharged from the Department of Neurology and Geriatrics, Gifu University Hospital, between 2004 and 2011; those who died at the hospital were excluded. The names, categories, and numbers of orally administered drugs at admission and discharge were examined retrospectively using electronic medical records. The histories of continuous oral immunotherapy use at the hospital, falls during the 2 years before hospital admission and the presence of fall risk factors were also evaluated. P-values <0.05 were considered statistically significant., Results: On average 1.14 ± 3.07 fewer types of drugs were given to patients at discharge than at admission in patients receiving polypharmacy (P < 0.001). However, the number of drugs given to patients undergoing continuous oral immunotherapy increased by 1.67 ± 3.47 (P < 0.001). The number of drugs was reduced in 33.1% of fallers, and 36.3% of non-fallers. In both fallers and non-fallers, there was a reduction in drug categories associated with falls., Conclusions: Multidisciplinary medication review using electronic medical records could significantly reduce the numbers of drugs taken by elderly inpatients receiving polypharmacy, including drugs associated with falls, in both fallers and non-fallers Geriatr Gerontol Int 2017; 17: 653-658., (© 2016 Japan Geriatrics Society.)

Resistance-associated variant (RAV) is one of the most significant clinical challenges in treating HCV-infected patients with direct-acting antivirals (DAAs). We investigated the viral dynamics in patients receiving DAAs using third-generation sequencing technology. Among 283 patients with genotype-1b HCV receiving daclatasvir + asunaprevir (DCV/ASV), 32 (11.3%) failed to achieve sustained virological response (SVR). Conventional ultra-deep sequencing of HCV genome was performed in 104 patients (32 non-SVR, 72 SVR), and detected representative RAVs in all non-SVR patients at baseline, including Y93H in 28 (87.5%). Long contiguous sequences spanning NS3 to NS5A regions of each viral clone in 12 sera from 6 representative non-SVR patients were determined by third-generation sequencing, and showed the concurrent presence of several synonymous mutations linked to resistance-associated substitutions in a subpopulation of pre-existing RAVs and dominant isolates at treatment failure. Phylogenetic analyses revealed close genetic distances between pre-existing RAVs and dominant RAVs at treatment failure. In addition, multiple drug-resistant mutations developed on pre-existing RAVs after DCV/ASV in all non-SVR cases. In conclusion, multi-drug resistant viral clones at treatment failure certainly originated from a subpopulation of pre-existing RAVs in HCV-infected patients. Those RAVs were selected for and became dominant with the acquisition of multiple resistance-associated substitutions under DAA treatment pressure.

We collected and analyzed the questionnaires from the participants in the annual EEG hands-on (5 times) and the regional EEG seminar (6 times). The board-certified neurologists among participants in the regional EEG seminar were always more than those in the annual EEG hands-on. Participants in the regional EEG seminar were more involved in EEGs than those in the annual EEG hands-on. The highly satisfactory lectures in the annual EEG hands-on were "normal EEG" and those in the regional EEG seminar were "EEG of epilepsy". The highly requested lectures in the annual EEG hands-on were "how to read EEG" and those in the regional EEG seminar were "EEG of epilepsy". By taking the needs of the participants into account, we only could provide more efficient teaching seminars to improve EEG reading skills of neurologists.

Hepatitis B virus (HBV) infection evokes host immune responses that primarily determine the outcome of HBV infection and the clinical features of HBV-associated liver disease. The precise mechanisms by which host factors restrict HBV replication, however, are poorly understood due to the lack of useful animal models that recapitulate immune responses to HBV. Here, we performed comprehensive immunologic gene expression profiling of the liver of a mouse model recapitulating anti-HBV immune response using a high sensitivity direct digital counting system. Anti-HBV cellular immunity with liver inflammation was elicited in mice hydrodynamically injected with a CpG-depleted plasmid encoding hepatitis B surface antigen (HBsAg) gene after preimmunization with HBsAg vaccine. Comprehensive expression analyses revealed the upregulation of Th1-associated genes including tumor necrosis factor (Tnf) and negative regulators of T cell function in the inflamed liver. Interestingly, activation-induced cytidine deaminase (Aicda, termed AID in humans), which reportedly suppresses HBV infection in vitro, was upregulated in hepatocytes in the course of anti-HBV immunity. Hepatocytic expression of Aicda in a Tnf-dependent manner was confirmed by the administration of Tnf antagonist into Aicda-tdTomato mice with anti-HBV immunity. Our findings suggest that activation of Tnf-Aicda axis and co-inhibitory signals to T cells in coordination with Th1-type immunity has critical roles in the immune response against HBV infection., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Brain magnetic resonance imaging (MRI) of patients with Alzheimer's disease (AD) sometimes reveals multiple cerebral microbleeds (CMBs) and confluent white matter hyperintensities (WMHs) similar to those observed in cerebral amyloid angiopathy-related inflammation (CAA-I). To determine whether there might be common pathophysiological mechanisms underlying the MRI findings of multiple CMBs and confluent WMHs, we investigated the cerebrospinal fluid (CSF) profiles of 38 AD, five amnestic mild cognitive impairment (MCI), and six CAA-I patients. The AD and MCI patients were divided into groups of patients with (n = 10) or without (n = 33) multiple CMBs (n ≥ 2) on T2*-gradient echo sequences of brain MRI. We compared the CSF profiles of AD and MCI patients with or without multiple CMBs, and CAA-I patients. The brain MRIs of the patients with multiple CMBs revealed severe degrees of WMHs compared with the patients without multiple CMBs. The levels of CSF anti-amyloid β autoantibody and interleukin 8, and CSF/serum albumin ratios and immunoglobulin G indexes, were significantly higher in CAA-I patients than the other groups. However, there were no significant differences in the CSF profiles of patients with or without multiple CMBs. Our study provides evidence for different pathophysiological mechanisms underlying these differential MRI findings in AD and CAA-I.

Background: Naturally occurring autoantibodies against amyloid β (Aβ) peptide exist in the serum and cerebrospinal fluid (CSF) of healthy individuals. Recently, it was reported that administration of intravenous immunoglobulin at the mild cognitive impairment (MCI) stage of Alzheimer's disease (AD) reduces brain atrophy., Objective: To examine the association between naturally occurring anti-Aβ autoantibodies and brain atrophy in patients with cognitive impairment., Methods: Serum and CSF levels of anti-Aβ autoantibodies and CSF biomarkers were evaluated in 68 patients with cognitive impairment, comprising 44 patients with AD, 19 patients with amnestic MCI and five patients with non-Alzheimer's dementia. The degree of brain atrophy was assessed using the voxel-based specific regional analysis system for AD, which targets the volume of interest (VOI) in medial temporal structures, including the whole hippocampus, entorhinal cortex and amygdala., Results: CSF levels of anti-Aβ autoantibodies were inversely correlated with the extent and severity of VOI atrophy, and the ratio of VOI/grey matter atrophy in patients with AD, but not in MCI or non-AD patients. Serum levels of anti-Aβ autoantibodies were not associated with these parameters in any of the patient groups., Conclusions: These results indicate that CSF levels of naturally occurring anti-Aβ autoantibodies are inversely associated with the degree of the VOI atrophy in patients with AD. Although the mechanism is unclear, CSF levels of naturally occurring anti-Aβ autoantibodies may be implicated in the progression of atrophy of the whole hippocampus, entorhinal cortex and amygdala, in AD., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.)

Hepatitis virus infection is a leading cause of chronic liver disease, including cirrhosis and hepatocellular carcinoma (HCC). Although anti-viral therapies against hepatitis B virus (HBV) and hepatitis C virus (HCV) have dramatically progressed during the past decade, the estimated number of people chronically infected with HBV and/or HCV is ~370 million, and hepatitis virus-associated hepatocarcinogenesis is a serious health concern worldwide. Understanding the mechanism of virus-associated carcinogenesis is crucial toward both treatment and prevention, and the recently developed whole genome/exome sequencing analysis using next-generation sequencing technologies has contributed to unveiling the landscape of genetic and epigenetic aberrations in not only tumor tissues but also the background liver tissues underlying chronic liver damage caused by hepatitis virus infection. Several major mechanisms underlie the genetic and epigenetic aberrations in the hepatitis virus-infected liver, such as the generation of reactive oxidative stress, ectopic expression of DNA mutator enzymes, and dysfunction of the DNA repair system. In addition, direct oncogenic effects of hepatitis virus, represented by the integration of HBV-DNA, are observed in infected hepatocytes. Elucidating the whole picture of genetic and epigenetic alterations, as well as the mechanisms of tumorigenesis, will facilitate the development of efficient treatment and prevention strategies for hepatitis virus-associated HCC.

A 71-year-old woman with a 9-year history of Parkinson's disease was admitted to our hospital emergently because of consciousness disturbance. Her consciousness level was 200 on the Japan coma scale (JCS), and she presented with tenderness and distension of the lower abdomen. Brain computed tomography showed normal findings. Blood tests showed an increased ammonia level (209 μg/dl) with normal AST and ALT levels. We catheterized the bladder for urinary retention. Five hours after admission, the blood ammonia level decreased to 38 μg/dl, and her consciousness level improved dramatically. Corynebacterium urearyticum, a bacterial species that produces urease, was detected by urine culture. Therefore, she was diagnosed with hyperammonemic encephalopathy resulting from urinary tract infection caused by urease-producing bacteria. In this case, urologic active agents had been administered to treat neurogenic bladder. We suspect that these drugs caused urinary obstruction and urinary tract infection. It is important to recognize that obstructive urinary tract infection caused by urease-producing bacteria can cause hyperammonemia. Neurological disorders, such as Parkinson's disease, tend to complicate neurogenic bladder. This disease should be considered in elderly patients with Parkinson's disease who are receiving urologic active drugs.

Many claim that they do not have enough neurologists in Japan, but supply and demand of neurologists remains to be analyzed. To investigate the recruitment for the Japanese Society of Neurology (JSN), the subcommittee of JSN for education performed a questionnaire-based survey in 80 medical universities and 271 board-certified education facilities throughout Japan. The response rate to the questionnaire was 77.5% in medical universities and 42.4% in education facilities. It was shown that each department of neurology in university recruits average 2.2 doctors, while they supposed that more than 4 doctors to be recruited every year. The questionnaire survey included what measures JSN should take in order to promote recruitment for JSN.

Background/aim: Contrast-enhanced ultrasonography (US) has improved the detection and characterization of focal hepatic lesions. Recently, the importance of obtaining high-quality samples in the biopsy of hepatic lesions has been increasing not only in the field of pathological diagnosis but also in molecular analysis for predicting the effectiveness of anticancer agents and molecular targeted drugs. We evaluated the utility of Sonazoid-enhanced ultrasonography (SEUS) in guiding percutaneous biopsy of focal hepatic lesions by comparing the results of histopathological diagnosis between B-mode US and SEUS guidance., Methods and Materials: This retrospective study examined 121 focal hepatic lesions in 108 patients (mean age: 63.8 years) referred for US-guided percutaneous biopsy. The technical success rate was defined as the percentage of the lesions diagnosed clearly at the initial biopsy., Results: Among 121 lesions, 56 lesions were subjected to biopsy with B-mode US guidance whereas 65 were subjected to SEUS guidance. The technical success rate was significantly higher under SEUS guidance than under B-mode US guidance (92.3 vs. 76.8%, respectively, P<0.05). When biopsies were performed to diagnose or rule out malignancy in indeterminate lesions, the technical success rate was also significantly higher under SEUS guidance than under B-mode US guidance (100 vs. 73.9%, respectively, P<0.05). SEUS guidance resulted in a significantly higher rate of successful single-puncture attempts compared with B-mode US guidance (55.4 vs. 35.7%, respectively, P<0.05)., Conclusion: SEUS guidance is recommended for more accurate localization of suitable hepatic lesion biopsy areas as it increases conspicuity and differentiates viable areas from denaturalization or necrosis.

Creutzfeldt-Jakob disease (CJD) with a causative point mutation of valine to isoleucine at codon 180 (V180I) is one of the major types of genetic CJD (gCJD) in Japan. V180I gCJD is rarely accompanied by a family history, and its clinical characteristics include late-onset, long disease duration, and edematous cortical hyperintensity in diffusion, fluid attenuate inversion and T2-weighted MRI. We performed serial imaging with single-photon emission computed tomography (SPECT) and MRI in three V180I gCJD cases over long-term observation. All cases were characterized by progressive dementia, parkinsonism, and the absence of cerebellar signs or cortical visual dysfunction in their clinical courses. Moreover, during the end-stage, SPECT findings showed preserved regional cerebral blood flow (rCBF) in the occipital cortices, brainstem, and cerebellum. Similarly, no apparent atrophy or increased signal intensities were observed in MRI images of the occipital and cerebellar regions. In conclusion, we report a decrease in rCBF predominantly in the frontal and temporal cortices during the early-stage, which became more widespread as the disease progressed. Importantly, rCBF was preserved in the occipital cortices, brainstem, and cerebellar regions until the end-stage, which may be distinct to V180I gCJD cases., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Here we report an autopsy-verified case of frontotemporal lobar degeneration (FTLD)-transactivation responsive region (TAR) DNA binding protein (TDP) type A with upper motor neuron-predominant motor neuron disease mimicking MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD). A 69-year-old woman presented with an 11-month history of progressive dementia, irritability, insomnia, and gait disturbance without a family history of dementia or prion disease. Neurological examination revealed severe dementia, frontal signs, and exaggerated bilateral tendon reflexes. Periodic sharp-wave complexes were not observed on the electroencephalogram. Brain diffusion MRI did not reveal abnormal changes. An easy Z score (eZIS) analysis for 99m Tc-ECD-single photon emission computed tomography ( 99m Tc-ECD-SPECT) revealed a bilateral decrease in thalamic regional cerebral blood flow (rCBF). PRNP gene analysis demonstrated methionine homozygosity at codon 129 without mutation. Cerebrospinal fluid (CSF) analysis showed normal levels of both 14-3-3 and total tau proteins. Conversely, prion protein was slowly amplified in the CSF by a real-time quaking-induced conversion assay. Her symptoms deteriorated to a state of akinetic mutism, and she died of sudden cardiac arrest, one year after symptom onset.  Despite the SPECT results supporting a clinical diagnosis of MM2-thalamic-type sCJD, a postmortem assessment revealed that this was a case of FTLD-TDP type A, and excluded prion disease. Thus, this case indicates that whereas a bilateral decreasing thalamic rCBF detected by 99m Tc-ECD-SPECT can be useful for diagnosing MM2-thalamic-type sCJD, it is not sufficiently specific. Postmortem diagnosis remains the gold standard for the diagnosis of this condition.

Autoimmune encephalitis consists of limbic symptoms and signs associated with antibodies against neuronal cell-surface antigens or intracellular antigens. Some cases are known to be associated with anti-channel or anti-receptor-related molecule antibodies. Whether these cases are paraneoplastic depends on the kinds of antigens that the antibodies are produced against. Other cases due to well-characterized onco-neural antibodies are almost always paraneoplastic and are generally resistant to anti-tumor therapy and/or immunotherapy. An exception is anti-Ma2 antibody-positive encephalitis associated with a testicular tumor. Antibodies for intracellular antigens are considered not to be pathogenic. Rather, the T-cell response is thought to be responsible. These antibodies are useful markers for the diagnosis of paraneoplastic disorders and in the search for underlying cancer, as neurological symptoms often precede tumor diagnosis. There is a relationship among onco-neural antibodies, clinical features, tumor types, and response to immunotherapy. Here we describe the characteristics of autoimmune encephalitis cases with antibodies against different intracellular antigens, such as Hu, Ma2, CRMP5, or amphiphysin.

Inflammation predisposes to tumorigenesis in various organs by potentiating a susceptibility to genetic aberrations. The mechanism underlying the enhanced genetic instability through chronic inflammation, however, is not clear. Here, we demonstrated that TNFα stimulation induced transcriptional downregulation of MSH2, a member of the mismatch repair family, via NF-κB-dependent miR-21 expression in hepatocytes. Liver cancers developed in ALB-MSH2(-) (/) (-)AID(+), ALB-MSH2(-) (/) (-), and ALB-AID(+) mice, in which MSH2 is deficient and/or activation-induced cytidine deaminase (AICDA) is expressed in cells with albumin-producing hepatocytes. The mutation signatures in the tumors developed in these models, especially ALB-MSH2(-) (/) (-)AID(+) mice, closely resembled those of human hepatocellular carcinoma. Our findings demonstrated that inflammation-mediated dysregulation of MSH2 may be a mechanism of genetic alterations during hepatocarcinogenesis. Cancer Res; 76(15); 4383-93. ©2016 AACR., (©2016 American Association for Cancer Research.)

Patients with Alzheimer's disease (AD) experience a wide array of cognitive deficits, which typically include the impairment of explicit memory. In previous studies, the authors reported that a flavonoid, quercetin, reduces the expression of ATF4 and delays memory deterioration in an early-stage AD mouse model. In the present study, the effects of long-term quercetin intake on memory recall were assessed using contextual fear conditioning in aged wild-type mice. In addition, the present study examined whether memory recall was affected by the intake of quercetin-rich onion (a new cultivar of hybrid onion 'Quergold') powder in early-stage AD patients. In-vivo analysis indicated that memory recall was enhanced in aged mice fed a quercetin-containing diet. Memory recall in early-stage AD patients, determined using the Revised Hasegawa Dementia Scale, was significantly improved by the intake of quercetin-rich onion (Quergold) powder for 4 weeks compared with the intake of control onion ('Mashiro' white onion) powder. These results indicate that quercetin might influence memory recall.

Angiotensin II (AII) type 2 receptor (AT2R) negatively regulates type 1 receptor (AT1R) signaling. However, the precise molecular mechanism of AT2R-mediated AT1R inhibition remains poorly understood. Here, we characterized the local and functional interaction of AT2R with AT1R. AT2R colocalized and formed a complex with AT1R at the plasma membrane, even in the absence of AII. Upon AII stimulation, the spatial arrangement of the complex was modulated, as confirmed by Förster resonance energy transfer (FRET) analysis, followed by AT2R internalization along with AT1R. AT2R internalization was specifically observed only in the presence of AT1R; AT2R alone could not be internalized. The AT1R-specific inhibitor losartan completely inhibited both the conformational change and the internalization of AT2R with AT1R, whereas the AT2R-specific inhibitor PD123319 partially hindered these phenomena, demonstrating that the activation of both receptors was indispensable for these effects. In addition, treatment with the protein kinase C (PKC) inhibitors inhibited the ligand-dependent accumulation of AT2R but not that of AT1R in the endosomes. A mutation in the putative phosphorylation sites of AT2R also abrogated the co-internalization of ATR2 with AT1R and the inhibitory effect of ATR2 on AT1R. These data suggest that AT2R inhibits ligand-induced AT1R signaling through the PKC-dependent pathway.

Lithium carbonate is considered to be a first-line treatment for bipolar disorder; however, this drug has a narrow therapeutic window, and lithium intoxication is commonly induced by various drugs interaction and situations. We herein report a case of lithium intoxication induced by the administration of an antihypertensive agent targeting the angiotensin 1 (AT1) subtype of the angiotensin II receptor in a 65-year-old woman with a 40-year history of bipolar disorder type 1, and 1-year history of essential hypertension. Her bipolar disorder had been well-controlled with 600 mg/day of lithium carbonate for more than 10 years. She was later diagnosed with hypertension and the AT1 receptor blocker, azilsartan was thereafter administrated on a daily basis. After 3 weeks of azilsartan administration, she presented with progressive action tremor and showed a gradual deterioration of her physical state. Four months after the start of azilsartan administration, she presented with alternating episodes of diarrhea and constipation. Two weeks before admission to our hospital, she presented with mild consciousness disturbances, myoclonus, truncal ataxia, and appetite loss. She was diagnosed to have lithium intoxication based on an elevated serum lithium concentration of 3.28 mEq/l.It is therefore important to evaluate the serum lithium concentration after the administration of antihypertensive agents, and consider lithium-antihypertensive agent interactions when selecting antihypertensive agents in elderly patients receiving long-term lithium carbonate treatment.

PLSCR3 (phospholipid scramblase 3, Scr3) belongs to the superfamily of membrane-associated transcription regulators named Tubby-like proteins (TULPs). Physiological phospholipid scrambling activities of PLSCRs in vivo have been skeptically argued, and knowledge of the biological functions of Scr3 is limited. We investigated the expression of Scr3 during differentiation of mouse 3T3-L1 preadipocytes by Western blotting (WB) and by reverse-transcription and real-time quantitative PCR (RT-qPCR). The Scr3 protein decreased during 3T3-L1 differentiation accompanied by a reduction in the mRNA level, and there was a significant increase in the amount of Scr3 protein secreted into the culture medium in the form of extracellular microvesicles (exosomes). On the other hand, Scr3 expression did not significantly decrease, and the secretion of Scr3 in 3T3 Swiss-albino fibroblasts (a parental cell-line of 3T3-L1) was not increased by differentiation treatment. Overexpression of human Scr3 during 3T3-L1 differentiation suppressed triacylglycerol accumulation and inhibited induction of the mRNAs of late stage pro-adipogenic transcription factors [CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ)] and X-box-binding protein 1 (XBP1). Expression of early stage pro-adipogenic transcription factors (C/EBPβ and C/EBPδ) was not significantly affected. These results suggest that Scr3 functions as a negative regulator of adipogenesis in 3T3-L1 cells at a specific differentiation stage and that decrease in the intracellular amount of Scr3 protein caused by reduction in Scr3 mRNA expression and enhanced secretion of Scr3 protein appears to be important for appropriate adipocyte differentiation., (© 2016 Authors.)

A novel and facile synthesis of azaspiro-γ-lactones with a methylene-lactam framework from N-carbonyl imides is described. Mechanistic investigations provide evidence for a two-step reaction process involving ZnCl(2)-promoted addition of β-amido allylindium species followed by an unexpectedly molecular-sieves-mediated ring opening-reclosure concomitantly with the loss of an N-carbonyl unit.

We report a case of autopsy-verified MM2-thalamic-type sporadic Creutzfeldt-Jakob disease (sCJD) in a 46-year-old patient with a 16-month history of abnormal behavior, progressive dementia, insomnia, and speech disturbances without family history. Neurological examination revealed progressive dementia, frontal signs, insomnia, speech disturbance, gait disturbance and bilaterally exaggerated tendon reflexes. Both brain MRI and cerebrospinal fluid examinations, including 14-3-3 protein, yielded normal results. An easy Z-score (eZIS) analysis for (99m)Tc-ethyl cysteinate dimer-single photon emission computed tomography ((99m)Tc-ECD-SPECT) revealed decreased regional cerebral blood flow in the bilateral thalami and medulla oblongata. PRNP gene analysis revealed methionine homozygosity at codon 129 without mutation. Neuropathological examinations revealed severe neuronal loss, gliosis, and hypertrophic astrocytosis in the medial thalamus and inferior olivary nucleus. A slight depletion of Purkinje cells was observed. PrP immunostaining showed no obvious PrP deposits in the basal ganglia, thalamus, cerebellum, or brainstem; however, mild synaptic-type PrP deposits with some smaller plaque-like structures were only partially observed in the localized region of the frontal lobe with the spongiform change. Western blot analyses of protease-resistant PrP showed a type 2 pattern. In conclusion, eZIS analysis of (99m)Tc-ECD-SPECT images is useful for detecting both thalamic and medullary lesions. This is the first case of medullary lesions detected in a live patient with MM2-thalamic-type sCJD using SPECT., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Naturally occurring autoantibodies have natural physiologic functions related to normal cell processes. However, the repertoire of naturally occurring autoantibodies against neuronal antigens in CSF is unclear. The purpose of this study was to identify naturally occurring autoantibodies against neuronal antigens in CSF from patients with various neurologic diseases by proteomics-based analysis. The CSF samples were collected from 77 patients with various neurologic disorders. The antigen source for 2-dimensional immunoblotting was the SH-SY5Y human neuroblastoma cell line. There were 8 spots recognized in CSF from more than one-fourth of the 77 patients including all patient groups and these spots were recognized in intravenous immunoglobulin preparations. These antigen spots were identified as heat shock 105-kDa/110-kDa protein 1, isoform CRA&#95;b, 78-kDa glucose-regulated protein, heat shock cognate 71-kDa protein, tubulin beta chain, vimentin (2 spots), and 60-kDa heat shock protein, mitochondrial; we could not identify the protein name corresponding to 1 of the 8 spots. In summary, there were 6 proteins identified that were main target antigens that reacted with naturally occurring autoantibodies in CSF from patients with varied neurologic disorders; the functions of autoantibodies against the identified antigens are unknown and may be clarified with further studies., Biological Significance: Naturally occurring autoantibodies may have important functions in tissue homeostasis. In this study, we identified 6 common target antigens that reacted with autoantibodies in cerebrospinal fluid (CSF) from patients, independent of disease type. These findings may clarify the importance of naturally occurring autoantibodies in CSF and the use of these antibodies potentially may be a novel therapy for various neurologic disorders., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The production of amyloid β (Aβ) in the brain from Aβ precursor protein (APP) through γ-secretase is important for the pathogenesis of Alzheimer's disease (AD). Our previous studies have demonstrated that autophagy impairment and endoplasmic reticulum stress increase presenilin 1 expression and enhance γ-secretase activity through the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α) and the translation of activating transcription factor 4 (ATF4). However, the inhibitory molecules for γ-secretase are largely unknown. Here, we demonstrate that the levels of ATF4 expression are increased in the brain of APP23 AD model mice; furthermore, these levels enhanced in the brain of APP23 mice crossed with obese and diabetic db/db (Lepr(db/db)) mice. A polyhydroxylated flavonoid, quercetin, suppressed presenilin 1 expression and Aβ secretion in autophagy-impaired cells by the induction of growth arrest and DNA damaged-inducible gene (GADD) 34, which mediates eIF2α dephosphorylation, leading to decreased ATF4 expression. GADD34 induction was observed in the brain of wild-type mice, and APP23 mice fed quercetin in their diet. After the long-term feeding of quercetin, deterioration in memory assessed by freezing behavior was delayed in APP23 mice. These results indicate that quercetin may reduce eIF2α phosphorylation and ATF4 expression through GADD34 induction in the brain, leading to the improvement of memory in aged mice and the delay of deterioration in memory at the early stage of AD in AD model mice., (Copyright © 2015 Elsevier Inc. All rights reserved.)

The growth of an Al-Ni-Co decagonal quasicrystal was observed by in situ, high-temperature, high-resolution transmission electron microscopy. The tiling patterns extracted from a series of high-resolution transmission electron microscopy images were analyzed on the basis of the high-dimensional description of quasicrystalline structures. The analyses indicated that the growth proceeded with frequent error-and-repair processes. The final, grown structure showed nearly perfect quasicrystalline order. Our observations suggest that the repair process by phason relaxation, rather than local growth rule, plays an essential role in the construction of ideal quasicrystalline order in real materials.

The B-cell-activating factor belonging to the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) are important factors for the survival of transitional and mature B cells. High levels of BAFF and APRIL are present in adults with several autoimmune diseases. However, there are few reports about BAFF and APRIL levels in the cerebrospinal fluid (CSF) of patients with meningoencephalitis. We evaluated BAFF and APRIL levels in CSF samples from patients with viral meningitis (VM) (28 patients), autoimmune encephalitis (AE) associated with antineuronal antibodies (15 patients), idiopathic normal pressure hydrocephalus (iNPH) (11 patients), herpes simplex encephalitis (HSE) (9 patients), bacterial meningitis (BM) (6 patients), and cryptococcal meningitis (CM) (4 patients). The CSF BAFF levels were significantly higher in patients with HSE, BM, or VM than AE or iNPH, and significantly higher in patients with CM than iNPH. The CSF APRIL levels were significantly higher in patients with HSE or BM than AE, VM, or iNPH. Although this is a preliminary report due to within-group variation and small sample size, the data suggest that CSF BAFF and APRIL levels are increased in HSE and BM, but not AE., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The loss of homeostasis of essential metals is associated with various diseases, including neurodegenerative diseases. Previous studies have shown that the levels of zinc (Zn) are significantly higher in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis (ALS). Zn transporters and metallothioneins tightly control intracellular and extracellular Zn levels. This study investigated the protein levels of ZnT, a Zn transporter family, in ALS patients and model mice. The mRNA expression of ZnT1, -3, -4, -5, -6, -7, and -10 was assessed in the spinal cords of human control subjects. ZnT3 and ZnT6 protein levels were significantly diminished in the spinal cords of sporadic ALS patients compared with controls. Furthermore, immunohistochemical staining demonstrated decreased ZnT3 and ZnT6 immunoreactivity in the ventral horn of the spinal cords in ALS patients. Moreover, immunohistochemical analysis revealed that all ZnTs expressed in the spinal cords were localized in a distinct subset of motor neurons. In addition, ZnT3 and ZnT6 protein levels were not altered in SOD1 (G93A) mutant transgenic mice before or after the onset of ALS symptoms compared with controls. These results suggest that ZnT3 and ZnT6 protein levels are decreased in the spinal cords of sporadic ALS patients; however, this did not occur merely via loss of motor neurons., (© 2014 Wiley Periodicals, Inc.)

A 69-year-old man experienced general malaise, weight loss, amnesia, gait disturbance, and restlessness a month prior to admission. Brain MRI showed high intensity areas in the bilateral medial temporal lobes and insular cortices on FLAIR images, and therefore, he was diagnosed with limbic encephalitis. After admission, quadriplegia and respiratory failure progressed rapidly, and he needed ventilatory management. A nerve conduction study revealed low compound muscle action potential amplitude with loss of sensory nerve action potential, which indicated axonal sensorimotor neuropathy. We administered intravenous immunoglobulin and methylprednisolone pulse therapy, but he did not recover. Although no tumor was found on CT, his serum was positive for anti-Hu antibody; therefore, we diagnosed him with paraneoplastic neurological syndrome. An FDG-PET study showed accumulation at lesions on two hilar lymph nodes. Small cell lung carcinoma was detected by endobronchial ultrasound-guided transbronchial needle aspiration. Although paraneoplastic acute sensorimotor neuropathy with respiratory failure resembling Guillain-Barré syndrome is rare, identification of antibodies and servey of tumors aids accurate diagnosis.

Antiendothelial cell antibodies (AECAs) have been detected in patients who have autoimmune and inflammatory diseases. Previous studies showed that AECAs against human umbilical vein endothelial cells were detected in healthy subjects. In the present study, we evaluated AECAs against human brain microvascular endothelial cells (HBMEC) in serum. We detected 250 antigen spots that reacted with AECAs in serum samples from 30 healthy subjects by 2-dimensional immunoblot using primary cultured HBMEC as the antigen source. There were 10 spots that corresponded to common target antigen spots and reacted with AECAs in serum samples from > 25% of the 30 healthy subjects. We identified 7 proteins that corresponded to 8 of the 10 spots by mass spectrometry: 78-kDa glucose-regulated protein, dihydropyrimidinase-related protein 2, heterogeneous nuclear ribonucleoprotein L, vimentin, perilipin 3, alpha-enolase, and annexin A2. The results suggest that these 7 HBMEC proteins are major target antigens of natural AECAs.

Background & Aims: Individuals negative for hepatitis B surface antigen (HBsAg) but positive for antibodies to hepatitis B core antigen (anti-HBc) are at risk of hepatitis B virus (HBV) reactivation under immunosuppressive conditions. We investigated clinical features and viral genetics in patients with reactivation from occult HBV infection triggered by chemotherapy or immunosuppressive therapy., Methods: Clinical courses of 14 individuals originally HBsAg-negative but anti-HBc-positive that experienced HBV reactivation were examined. Ultra-deep sequencing analysis of the entire HBV genome in serum was conducted. Prevalence of the G1896A variant in latently infected livers was determined among 44 healthy individuals that were HBsAg-negative but anti-HBc-positive., Results: In 14 cases, HBV reactivation occurred during (n=7) and after (n=7) termination of immunosuppressive therapy. Ultra-deep sequencing revealed that the genetic heterogeneity of reactivated HBV was significantly lower in patients with reactivation from occult HBV carrier status compared with that in patients from HBsAg carrier status. The reactivated viruses in each case were almost exclusively the wild-type G1896 or G1896A variant. The G1896A variant was detected in 42.9% (6/14) of cases, including two cases with fatal liver failure. The G1896A variant was observed in the liver tissue of 11.4% (5/44) of individuals with occult HBV infection., Conclusions: Reactivation from occult HBV infection is characterized by low genetic heterogeneity, with the wild-type G1896 or G1896A variant prevalent., (Copyright © 2014 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background & Aims: Helicobacter pylori infection is a risk factor for gastric cancer. To explore the genetic basis of gastric cancer that develops in inflamed gastric mucosa, we investigated genetic aberrations that latently accumulate in nontumorous gastric epithelium with H pylori infection., Methods: We performed whole-exome sequencing of gastric tumors, noncancerous tissues with gastritis, and peripheral lymphocytes from 5 patients. We performed additional deep-sequencing analyses of selected tumor-related genes using 34 gastritis mucosal samples from patients with or without gastric cancer. We also performed deep sequencing analyses of gastric mucosal tissues from mice that express transgenic human TP53 and constitutively express activation-induced cytidine deaminase (AICDA or AID) (human TP53 knock-in/AID-transgenic mice)., Results: Whole-exome sequencing revealed that somatic mutations accumulated in various genes in inflamed gastric tissues. Additional deep-sequencing analyses of tissues from regions of gastritis confirmed nonsynonymous low-abundance mutations in TP53 in 15 cases (44.1%) and ARID1A in 5 cases (14.7%). The mutations that accumulated in gastric mucosal tissues with H pylori-induced gastritis, as well as gastric tumors, were predominantly C:G>T:A transitions in GpCpX motifs-a marker of cytidine deamination induced by AID. Constitutive expression of AID in the gastric mucosa of mice led to mutations in the human TP53, at amino acid coding positions identical to those detected in human gastric cancers., Conclusions: Studies of gastric tumors and tissues from humans and mice indicate that somatic mutations accumulate in various genes in gastric mucosal tissues with H pylori infection. Increased cytidine deaminase activity in these tissues appears to promote the accumulation of these mutations and might promote gastric carcinogenesis in patients with H pylori infection., (Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Aim: To examine the effect of nucleoside analog (NA) therapy on clinical outcome in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) who underwent curative therapy., Methods: A total of 131 patients with HBV-related HCC who underwent curative therapy were analyzed. They were divided into an NA group who received NA therapy (n = 99, group A) and a control group (n = 32, group B). Group A was further classified into two groups of patients who either received NA therapy before HCC therapy (n = 34, group Aa) or who received NA therapy with initial HCC therapy (n = 65, group Ab). Overall survival (OS) and recurrence-free survival (RFS) were compared in the three groups., Results: The 1- and 3-year cumulative OS rates were both in group Aa, 100% and 88.0% in group Ab, and 100% and 75.7% in group B (overall significance, P = 0.002), respectively. The corresponding RFS rates were 93.1% and 36.0% in group Aa, 78.3% and 45.7% in group Ab, and 78.0% and 38.0% in group B (overall significance, P = 0.734), respectively. Multivariate analysis revealed that being part of group Aa (P < 0.001) or group Ab (P < 0.001) and having albumin levels of 4.0 g/dL or more (P = 0.040) were significantly associated with OS, while HCC stage (P = 0.001) and hepatitis B e-antigen positivity (P < 0.001) were independent predictors linked to RFS., Conclusion: NA therapy in patients with HBV-related HCC may improve survival after curative therapy., (© 2013 The Japan Society of Hepatology.)