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Richard A Armstrong, Ann C McKee, Victor E Alvarez, Nigel J Cairns
Chronic traumatic encephalopathy (CTE) is a neurodegenerative disorder which may result from repetitive brain injury. A variety of tau-immunoreactive pathologies are present, including neurofibrillary tangles (NFT), neuropil threads (NT), dot-like grains (DLG), astrocytic tangles (AT), and occasional neuritic plaques (NP). In tauopathies, cellular inclusions in the cortex are clustered within specific laminae, the clusters being regularly distributed parallel to the pia mater. To determine whether a similar spatial pattern is present in CTE, clustering of the tau-immunoreactive pathology was studied in the cortex, hippocampus, and dentate gyrus in 11 cases of CTE and 7 cases of Alzheimer's disease neuropathologic change (ADNC) without CTE...
October 21, 2016: Journal of Neural Transmission
Cheng-Fu Chang, Yi-Chao Lee, Kuen-Haur Lee, Hui-Ching Lin, Chia-Ling Chen, Che-Kun James Shen, Chi-Chen Huang
BACKGROUND: In the central nervous system regions of the sporadic and familial FTLD and ALS patients, TDP-43 has been identified as the major component of UBIs inclusions which is abnormally hyperphosphorylated, ubiquitinated, and cleaved into C-terminal fragments to form detergent-insoluble aggregates. So far, the effective drugs for FTLD and ALS neurodegenerative diseases are yet to be developed. Autophagy has been demonstrated as the major metabolism route of the pathological TDP-43 inclusions, hence activation of autophagy is a potential therapeutic strategy for TDP-43 pathogenesis in FTLD and ALS...
October 21, 2016: Journal of Biomedical Science
Christopher P Webster, Emma F Smith, Andrew J Grierson, Kurt J De Vos
A GGGGCC hexanucleotide repeat expansion in the first intron of the C9orf72 gene is the most common genetic defect associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) (C9ALS/FTD). Haploinsufficiency and a resulting loss of C9orf72 protein function has been suggested as a possible pathogenic mechanism in C9ALS/FTD. C9ALS/FTD patients exhibit specific ubiquitin and p62/sequestosome-1 positive but TDP-43 negative inclusions in the cerebellum and hippocampus, indicating possible autophagy deficits in these patients...
October 21, 2016: Small GTPases
Heiko Braak, Albert C Ludolph, Manuela Neumann, John Ravits, Kelly Del Tredici
Two nerve cells types, Betz cells in layer Vb of the primary motor neocortex and α-motoneurons of the lower brainstem and spinal cord, become involved at the beginning of the pathological cascade underlying sporadic amyotrophic lateral sclerosis (sALS). In both neuronal types, the cell nuclei forfeit their normal (non-phosphorylated) expression of the 43-kDa transactive response DNA-binding protein (TDP-43). Here, we present initial evidence that in α-motoneurons the loss of normal nuclear TDP-43 expression is followed by the formation of phosphorylated TDP-43 aggregates (pTDP-43) within the cytoplasm, whereas in Betz cells, by contrast, the loss of normal nuclear TDP-43 expression remains mostly unaccompanied by the development of cytoplasmic aggregations...
October 18, 2016: Acta Neuropathologica
Altuğ Ösken, Nizamettin Selçuk Yelgeç, Regayip Zehir, Tuğba Kemaloğlu Öz, Selçuk Yaylacı, Ramazan Akdemir, Hüseyin Gündüz
Drug-induced torsades de pointes (TdP) is a rare but potentially fatal adverse effect of commonly prescribed medications including cardiac and noncardiac drugs. Importantly, many drugs have been reported to cause the characteristic Brugada syndrome-linked electrocardiography (ECG) abnormalities and/or (fatal) ventricular tachyarrhythmias. Chlorpheniramine and propranolol have the arrhythmogenic effects reported previously. A review of literature revealed a large number of case reports of chlorpheniramine or propranolol use resulting in QTc prolongation, TdP, or both...
July 2016: Indian Journal of Pharmacology
Frank F Vincenzi, Philippe Lunetta
While SCUBA diving, a 44-year-old Caucasian patient had an abnormal cardiac rhythm, presumably Torsade de Pointes (TdP), during the initial descent to depth. Upon surfacing, she developed ventricular fibrillation and died. The patient had been treated for mild depression for nearly a year with citalopram 60 mg per day, a drug known to cause prolonged QT interval. She had also been treated with two potentially hepatotoxic drugs. Liver impairment causes selective loss of cytochrome P450 (CYP) 2C19 activity, the major pathway for metabolism of citalopram...
December 2015: Drug Saf Case Rep
A R Jayakumar, X Y Tong, N Shamaladevi, S Barcelona, G Gaidosh, A Agarwal, M D Norenberg
Transactivating DNA-binding protein-43 (TDP-43) inclusions and the accumulation of phosphorylated and ubiquitinated tau proteins (p-tau) have been identified in postmortem brain specimens from patients with chronic traumatic encephalopathy (CTE). To examine whether these proteins contribute to the development of CTE, we utilized an in vitro trauma system known to reproduce many of the findings observed in humans and experimental animals with traumatic brain injury. Accordingly, we examined the role of TDP-43 and Tau in an in vitro model of trauma, and determined whether these proteins contribute to the defective neuronal integrity associated with CNS trauma...
October 13, 2016: Journal of Neurochemistry
Atsushi Yamaguchi, Keisuke Takanashi
FUS (Fused-in-Sarcoma) is a multifunctional DNA/RNA binding protein linked to familial amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD). Since FUS is localized mainly in the nucleus with nucleo-cytoplasmic shuttling, it is critical to understand physiological functions in the nucleus to clarify pathogenesis. Here we report a yeast two-hybrid screening identified FUS interaction with nuclear matrix-associated protein SAFB1 (scaffold attachment factor B1). FUS and SAFB1, abundant in chromatin-bound fraction, interact in a DNA-dependent manner...
October 12, 2016: Scientific Reports
Angèle Nalbandian, Arif A Khan, Ruchi Srivastava, Katrina J Llewellyn, Baichang Tan, Nora Shukr, Yasmin Fazli, Virginia E Kimonis, Lbachir BenMohamed
Aberrant activation of the NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inflammasome, triggers a pathogenic inflammatory response in many inherited neurodegenerative disorders. Inflammation has recently been associated with valosin-containing protein (VCP)-associated diseases, caused by missense mutations in the VCP gene. This prompted us to investigate whether NLRP3 inflammasome plays a role in VCP-associated diseases, which classically affects the muscles, bones, and brain. In this report, we demonstrate (i) an elevated activation of the NLRP3 inflammasome in VCP myoblasts, derived from induced pluripotent stem cells (iPSCs) of VCP patients, which was significantly decreased following in vitro treatment with the MCC950, a potent and specific inhibitor of NLRP3 inflammasome; (ii) a significant increase in the expression of NLRP3, caspase 1, IL-1β, and IL-18 in the quadriceps muscles of VCP(R155H/+) heterozygote mice, an experimental mouse model that has many clinical features of human VCP-associated myopathy; (iii) a significant increase of number of IL-1β((+))F4/80((+))Ly6C((+)) inflammatory macrophages that infiltrate the muscles of VCP(R155H/+) mice; (iv) NLRP3 inflammasome activation and accumulation IL-1β((+))F4/80((+))Ly6C((+)) macrophages positively correlated with high expression of TDP-43 and p62/SQSTM1 markers of VCP pathology in damaged muscle; and (v) treatment of VCP(R155H/+) mice with MCC950 inhibitor suppressed activation of NLRP3 inflammasome, reduced the F4/80((+))Ly6C((+))IL-1β((+)) macrophage infiltrates in the muscle, and significantly ameliorated muscle strength...
October 11, 2016: Inflammation
Adam Barlev, Gurpreet S Sekhon, Andrew J Bennet, Dipankar Sen
UV1C, a 42-nt DNA oligonucleotide, is a deoxyribozyme (DNAzyme) that optimally uses 305 nm wavelength light to catalyze photoreactivation of a cyclobutane thymine dimer placed within a gapped, unnatural DNA substrate, TDP. Herein we show that UV1C is also capable of photoreactivating thymine dimers within an authentic single-stranded DNA substrate, LDP. This bona fide UV1C substrate enables, for the first time, investigation of whether UV1C catalyzes only photoreactivation or also the de novo formation of thymine dimers...
October 11, 2016: Biochemistry
Sayaka Sasaoka, Toshinobu Matsui, Yuuki Hane, Junko Abe, Natsumi Ueda, Yumi Motooka, Haruna Hatahira, Akiho Fukuda, Misa Naganuma, Shiori Hasegawa, Yasutomi Kinosada, Mitsuhiro Nakamura
Long QT syndrome (LQTS) is a disorder of the heart's electrical activity that infrequently causes severe ventricular arrhythmias such as a type of ventricular tachycardia called torsade de pointes (TdP) and ventricular fibrillation, which can be fatal. There have been no previous reports on the time-to-onset for LQTS based on data from spontaneous reporting systems. The aim of this study was to assess the time-to-onset of LQTS according to drug treatment. We analyzed the association between 113 drugs in 37 therapeutic categories and LQTS including TdP using data obtained from the Japanese Adverse Drug Event Report database...
2016: PloS One
Barbara Wiśniowska, Sebastian Polak
This review aims to present and compare various Torsade de pointes propensity classification schemes of drugs that are publicly available from many scientific sources. We have also tracked and listed the compounds that were differently categorized. Additionally, we would like to draw attention to the need for establishing a general, standardized classification of a drug's proarrhythmic propensity. This is especially important in the current drug development process because of the changing paradigm of drug cardiac safety assessment...
October 4, 2016: Drug Discovery Today
R Sharma, R W Bell, M T F Wong
PURPOSE: Phosphorus (P) lost from agricultural land by erosion, runoff, throughflow and leaching is of major concern for water resource managers worldwide. Previous study on soils from cropping land of southwest Western Australia suggested P loss as dissolved unreactive P (DURP) via leaching, but the implications for processes and rates of P transport in soils are not known. MATERIAL AND METHODS: Two contrasting soil profiles (sand and loam) from cropping land of southwest Western Australia were exposed to artificial rain in packed boxes and field runoff plots to examine P forms and fluxes in runoff, throughflow, leachate and soil solution after three P rates of application (equivalent to 0, 20 and 40kg P/ha)...
October 2, 2016: Science of the Total Environment
Wan-Su Park, Jongtae Lee, Taegon Hong, Gabjin Park, Sunil Youn, Youngwhan Seo, Sanghun Lee, Seunghoon Han
PURPOSE: Fursultiamine and benfotiamine are lipophilic thiamine derivatives used as oral sources of thiamine. Although there are many publications on the pharmacokinetic (PK) properties of thiamine-containing products, no direct comparisons between these agents . We aimed to compare the PK profiles of these lipophilic thiamine derivatives and to compare the extent of the increase in bioavailability to that of naïve thiamine. METHODS: Two randomized, single-dose, 2-way crossover, full PK studies were conducted in healthy Korean male subjects (n = 24 per group)...
October 1, 2016: Clinical Therapeutics
Pietro Enea Lazzerini, Pier Leopoldo Capecchi, Iacopo Bertolozzi, Gabriella Morozzi, Sauro Lorenzini, Antonella Simpatico, Enrico Selvi, Maria Romana Bacarelli, Maurizio Acampa, Deana Lazaro, Nabil El-Sherif, Mohamed Boutjdir, Franco Laghi-Pasini
Mounting evidence indicates that in chronic inflammatory arthritis (CIA), QTc prolongation is frequent and correlates with systemic inflammatory activation. Notably, basic studies demonstrated that inflammatory cytokines induce profound changes in potassium and calcium channels resulting in a prolonging effect on cardiomyocyte action potential duration, thus on the QT interval on the electrocardiogram. Moreover, it has been demonstrated that in rheumatoid arthritis (RA) patients, the risk of sudden cardiac death is significantly increased when compared to non-RA subjects...
2016: Frontiers in Cardiovascular Medicine
Miguel Ángel Muñoz-Ruiz, Anette Hall, Jussi Mattila, Juha Koikkalainen, Sanna-Kaisa Herukka, Minna Husso, Tuomo Hänninen, Ritva Vanninen, Yawu Liu, Merja Hallikainen, Jyrki Lötjönen, Anne M Remes, Irina Alafuzoff, Hilkka Soininen, Päivi Hartikainen
BACKGROUND: Disease State Index (DSI) and its visualization, Disease State Fingerprint (DSF), form a computer-assisted clinical decision making tool that combines patient data and compares them with cases with known outcomes. AIMS: To investigate the ability of the DSI to diagnose frontotemporal dementia (FTD) and Alzheimer's disease (AD). METHODS: The study cohort consisted of 38 patients with FTD, 57 with AD and 22 controls. Autopsy verification of FTD with TDP-43 positive pathology was available for 14 and AD pathology for 12 cases...
May 2016: Dementia and Geriatric Cognitive Disorders Extra
Airi Tarutani, Shin-Ichi Hisanaga, Masato Hasegawa
Intracellular abnormal protein deposits, such as tau, α-synuclein and TDP-43, are the hallmark of many neurodegenerative diseases, and the distributions of these pathological proteins are closely correlated with disease symptoms and progression. A growing body of evidence strongly suggests that these abnormal proteins have prion-like properties: they convert normal proteins into abnormal forms, self-propagate through neuronal networks, and then spread in the brain. This prion-like propagation of abnormal proteins may account for the diversity, selective degeneration and disease progression seen in neurodegenerative diseases, although the molecular mechanism remains uncertain the molecular details of this mechanism...
October 2016: Brain and Nerve, Shinkei Kenkyū No Shinpo
Ksenia Blinova, Jayna Stohlman, Jose Vicente, Dulciana Chan, Lars Johannesen, Maria P Hortigon-Vinagre, Victor Zamora, Godfrey Smith, William J Crumb, Li Pang, Beverly Lyn-Cook, James Ross, Mathew Brock, Stacie Chvatal, Daniel Millard, Loriano Galeotti, Norman Stockbridge, David G Strauss
BACKGROUND: Induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM) hold promise for assessment of drug-induced arrhythmias and are being considered for use under the Comprehensive in Vitro Proarrhythmia Assay (CiPA). METHODS AND RESULTS: We studied the effects of 26 drugs and 3 drug combinations on two commercially available iPSC-CM types using high-throughput voltage-sensitive dye (VSD) and microelectrode-array (MEA) assays being studied for the Comprehensive in Vitro Proarrhythmia Assessment (CiPA) initiative and compared the results to clinical QT prolongation and torsade de pointes (TdP) risk...
October 3, 2016: Toxicological Sciences: An Official Journal of the Society of Toxicology
Bryan D James, Robert S Wilson, Patricia A Boyle, John Q Trojanowski, David A Bennett, Julie A Schneider
Hyperphosphorylated transactive response DNA-binding protein 43 (TDP-43, encoded by TARDBP) proteinopathy has recently been described in ageing and in association with cognitive impairment, especially in the context of Alzheimer's disease pathology. To explore the role of mixed Alzheimer's disease and TDP-43 pathologies in clinical Alzheimer's-type dementia, we performed a comprehensive investigation of TDP-43, mixed pathologies, and clinical Alzheimer's-type dementia in a large cohort of community-dwelling older subjects...
September 30, 2016: Brain: a Journal of Neurology
Erika N Guerrero, Haibo Wang, Joy Mitra, Pavana M Hegde, Sara E Stowell, Nicole F Liachko, Brian C Kraemer, Ralph M Garruto, K S Rao, Muralidhar L Hegde
Amyotrophic lateral sclerosis (ALS), a common motor neuron disease affecting two per 100,000 people worldwide, encompasses at least five distinct pathological subtypes, including, ALS-SOD1, ALS-C9orf72, ALS-TDP-43, ALS-FUS and Guam-ALS. The etiology of a major subset of ALS involves toxicity of the TAR DNA-binding protein-43 (TDP-43). A second RNA/DNA binding protein, fused in sarcoma/translocated in liposarcoma (FUS/TLS) has been subsequently associated with about 1% of ALS patients. While mutations in TDP-43 and FUS have been linked to ALS, the key contributing molecular mechanism(s) leading to cell death are still unclear...
September 28, 2016: Progress in Neurobiology
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