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https://www.readbyqxmd.com/read/28888971/fungal-infection-in-neural-tissue-of-patients-with-amyotrophic-lateral-sclerosis
#1
Ruth Alonso, Diana Pisa, Ana M Fernández-Fernández, Alberto Rábano, Luis Carrasco
Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and the main cause of motor neuron pathology. The etiology of the disease remains unknown, and no effective therapy exists to halt the disease or improve the quality of life. Here, we provide compelling evidence for the existence of fungal infection in ALS. Immunohistochemistry analysis using a battery of antifungal antibodies revealed fungal structures such as yeast and hyphae in the motor cortex, the medulla and the spinal cord, in eleven patients with ALS...
September 6, 2017: Neurobiology of Disease
https://www.readbyqxmd.com/read/28872919/a-safety-analysis-of-edaravone-mci-186-during-the-first-six-cycles-24-weeks-of-amyotrophic-lateral-sclerosis-als-therapy-from-the-double-blind-period-in-three-randomized-placebo-controlled-studies
#2
Alexander Kalin, Elvia Medina-Paraiso, Kaoru Ishizaki, Alex Kim, Yannong Zhang, Takanori Saita, Masahiko Wasaki
BACKGROUND: There continues to be a need for new therapies to treat ALS. OBJECTIVE: Provide an overview of safety for edaravone in ALS patients during the first six cycles of treatment. METHODS: Analysis was based on three randomised, placebo-controlled clinical trials. Endpoints included treatment-emergent adverse events (TEAEs), including AEs leading to discontinuation, serious adverse events (SAEs), and deaths. RESULTS: The analysis included a total of 368 patients (184 in the edaravone group and placebo group, respectively)...
October 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28872911/what-can-we-learn-from-the-edaravone-development-program-for-als
#3
Nicholas J Maragakis
Edaravone's development into an ALS therapeutic has been a process which began with preclinical studies regarding its potential in targeting ALS. Despite edaravone's inability to show benefit in a general ALS population, an important post-hoc analysis showed that a clinical subset of patients had benefit. Most importantly, a subsequent study examining the capacity of edaravone to have benefit in this specific subset of ALS patients was successful in meeting its primary outcome measures. Questions regarding whether the dosing regimen could be simplified or improved, the duration of the effects, and the timing of the potential treatment to different stages of disease remain to be answered...
October 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28872908/pharmacokinetic-profile-of-edaravone-a-comparison-between-japanese-and-caucasian-populations
#4
Yoshinobu Nakamaru, Shuji Kinoshita, Atsuhiro Kawaguchi, Koji Takei, Joseph Palumbo, Masayuki Suzuki
BACKGROUND: Amyotrophic lateral sclerosis (ALS) affects persons of all races, and there continues to be a need for effective therapies to treat the disease. OBJECTIVE: To compare the pharmacokinetics (PK) of edaravone between Japanese and Caucasian populations. METHODS: Data from five PK studies among Japanese and Caucasian healthy volunteers were pooled and evaluated. In population PK (PPK) modelling, compartment models and other models with linear elimination were evaluated for appropriateness...
October 2017: Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration
https://www.readbyqxmd.com/read/28872247/update-zum-klinischen-einsatz-von-inhibitoren-mutierter-phosphokinasen-beim-melanom
#5
REVIEW
Ioana Cosgarea, Cathrin Ritter, Jürgen C Becker, Dirk Schadendorf, Selma Ugurel
Die Behandlungsstrategie beim metastasierten Melanom hat sich mit der Identifizierung therapeutisch angreifbarer molekularer Zielstrukturen innerhalb zellulärer Signalwege radikal geändert. Durch die Zulassung von Substanzen, die gezielt an den zentralen Schaltmolekülen, den Phosphokinasen, angreifen, können diese Signalwege selektiv abgeschaltet werden. Dies ist insbesondere bei denjenigen Tumoren von Interesse, deren Signalwege durch aktivierende Mutationen der für die Schaltmoleküle kodierenden Gene konstitutiv aktiviert sind...
September 2017: Journal der Deutschen Dermatologischen Gesellschaft, Journal of the German Society of Dermatology: JDDG
https://www.readbyqxmd.com/read/28872135/methods-and-tips-for-intravenous-administration-of-adeno-associated-virus-to-rats-and-evaluation-of-central-nervous-system-transduction
#6
Mychal S Grames, Kasey L Jackson, Robert D Dayton, John A Stanford, Ronald L Klein
Adeno-associated virus (AAV) vectors are a key reagent in the neurosciences for clustered regularly interspaced short palindromic repeats (CRISPR), optogenetics, cre-lox targeting, etc. The purpose of this manuscript is to aid the investigator attempting expansive central nervous system (CNS) gene transfer in the rat via tail vein injection of AAV. Wide-scale expression is relevant for conditions with widespread pathology, and a rat model is significant due to its greater size and physiologic similarities to humans compared to mice...
August 25, 2017: Journal of Visualized Experiments: JoVE
https://www.readbyqxmd.com/read/28871262/role-of-neuroinflammation-in-amyotrophic-lateral-sclerosis-cellular-mechanisms-and-therapeutic-implications
#7
REVIEW
Jia Liu, Fei Wang
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects upper motor neurons (MNs) comprising the corticospinal tract and lower MNs arising from the brain stem nuclei and ventral roots of the spinal cord, leading to fatal paralysis. Currently, there are no effective therapies for ALS. Increasing evidence indicates that neuroinflammation plays an important role in ALS pathogenesis. The neuroinflammation in ALS is characterized by infiltration of lymphocytes and macrophages, activation of microglia and reactive astrocytes, as well as the involvement of complement...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/28861148/a-proteomics-based-investigation-on-the-anticancer-activity-of-alisertib-an-aurora-kinase-a-inhibitor-in-hepatocellular-carcinoma-hep3b-cells
#8
Qiaohua Zhu, Meihua Luo, Chengyu Zhou, Zhiwei Zhou, Zhixu He, Xinfa Yu, Shufeng Zhou
Targeted therapy may provide survival benefit for advanced hepatocellular carcinoma (HCC) and Aurora A kinase (AURKA) represents a feasible target in cancer treatment. The purpose of this study is to investigate the anticancer activity of alisertib (ALS) on Hep3B cells based on a proteomic study conducted with the stable-isotope labeling by amino acids in cell culture (SILAC). The proteomic response to ALS was obtained with SILAC-based proteomic study. Cell cycle distribution and apoptosis were assessed using flow cytometry and autophagy was determined using flow cytometry and confocal microscopy...
2017: American Journal of Translational Research
https://www.readbyqxmd.com/read/28835399/a-case-control-study-of-hormonal-exposures-as-etiologic-factors-for-als-in-women-euro-motor
#9
James P K Rooney, Anne E Visser, Fabrizio D'Ovidio, Roel Vermeulen, Ettore Beghi, Adriano Chio, Jan H Veldink, Giancarlo Logroscino, Leonard H van den Berg, Orla Hardiman
OBJECTIVE: To investigate the role of hormonal risk factors for amyotrophic lateral sclerosis (ALS) among women from 3 European countries. METHODS: ALS cases and matched controls were recruited over 4 years in Ireland, Italy, and the Netherlands. Hormonal exposures, including reproductive history, breastfeeding, contraceptive use, hormonal replacement therapy, and gynecologic surgical history, were recorded with a validated questionnaire. Logistic regression models adjusted for age, education, study site, smoking, alcohol, and physical activity were used to determine the association between female hormones and ALS risk...
August 23, 2017: Neurology
https://www.readbyqxmd.com/read/28828608/eaat2-and-the-molecular-signature-of-amyotrophic-lateral-sclerosis
#10
Lauren Taylor Rosenblum, Davide Trotti
Amyotrophic lateral sclerosis (ALS) is a rapid and fatal neurodegenerative disease, primarily affecting upper and lower motor neurons. It is an extremely heterogeneous disease in both cause and symptom development, and its mechanisms of pathogenesis remain largely unknown. Excitotoxicity, a process caused by excessive glutamate signaling, is believed to play a substantial role, however. Excessive glutamate release, changes in postsynaptic glutamate receptors, and reduction of functional astrocytic glutamate transporters contribute to excitotoxicity in ALS...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28821643/changes-in-the-excitability-of-neocortical-neurons-in-a-mouse-model-of-amyotrophic-lateral-sclerosis-are-not-specific-to-corticospinal-neurons-and-are-modulated-by-advancing-disease
#11
Juhyun Kim, Ethan G Hughes, Ashwin S Shetty, Paola Arlotta, Loyal A Goff, Dwight E Bergles, Solange P Brown
Cell-type specific changes in neuronal excitability have been proposed to contribute to the selective degeneration of corticospinal neurons in amyotrophic lateral sclerosis (ALS) and to neocortical hyperexcitability, a prominent feature of both inherited and sporadic variants of the disease, but the mechanisms underlying selective loss of specific cell types in ALS are not known. We analyzed the physiological properties of distinct classes of cortical neurons in the motor cortex of hSOD1(G93A) mice of both sexes and found that they all exhibit increases in intrinsic excitability that depend on disease stage...
August 17, 2017: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
https://www.readbyqxmd.com/read/28805578/nonmotor-symptoms-in-amyotrophic-lateral-sclerosis-a-systematic-review
#12
Ton Fang, Felix Jozsa, Ammar Al-Chalabi
BACKGROUND: ALS is a progressive neurodegenerative disease with no curative treatment. Nonmotor symptoms presenting in ALS may cause significant distress, worsen prognosis, and affect survival. OBJECTIVE: To systematically review evidence for the prevalence of nonmotor ALS symptoms, and treatment options. METHODS: Multiple medical literature databases were searched and studies screened using predefined inclusion criteria. Of 4580 studies, 44 were eligible for inclusion with 25 relating to treatment and 19 to the prevalence of nonmotor symptoms in ALS...
2017: International Review of Neurobiology
https://www.readbyqxmd.com/read/28790913/the-dual-role-of-microglia-in-als-mechanisms-and-therapeutic-approaches
#13
REVIEW
Maria Concetta Geloso, Valentina Corvino, Elisa Marchese, Alessia Serrano, Fabrizio Michetti, Nadia D'Ambrosi
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by a non-cell autonomous motor neuron loss. While it is generally believed that the disease onset takes place inside motor neurons, different cell types mediating neuroinflammatory processes are considered deeply involved in the progression of the disease. On these grounds, many treatments have been tested on ALS animals with the aim of inhibiting or reducing the pro-inflammatory action of microglia and astrocytes and counteract the progression of the disease...
2017: Frontiers in Aging Neuroscience
https://www.readbyqxmd.com/read/28732762/effect-of-class-ii-hdac-inhibition-on-glutamate-transporter-expression-and-survival-in-sod1-als-mice
#14
Andrea Lapucci, Leonardo Cavone, Daniela Buonvicino, Roberta Felici, Elisabetta Gerace, Clemens Zwergel, Sergio Valente, Antonello Mai, Alberto Chiarugi
Transcriptional deregulation emerges as a key pathogenetic mechanism in ALS pathogenesis, and non-class-specific histone deacetylase (HDACs) inhibitors proved of therapeutic efficacy in preclinical models of ALS. When tested in patients, however, these drugs failed, probably because of a lack of selectivity toward pathogenetic HDACs. Here, we studied the effects of MC1568, an inhibitor of Class-II HDACs which have been reported to contribute to ALS pathogenesis. We focused on transcriptional regulation of glutamate transporter EAAT2, whose reduced expression may contribute to motor neuron degeneration in ALS...
July 19, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28711998/medical-history-of-chemotherapy-or-immunosuppressive-drug-treatment-and-risk-of-amyotrophic-lateral-sclerosis-als
#15
Thomas Kuczmarski, Elijah W Stommel, Kristen Riley, Rup Tandan, Vinay Chaudhry, Lora Clawson, Tracie A Caller, Patricia L Henegan, Dominic N Facciponte, Walter G Bradley, Angeline S Andrew
A recent population-based analysis demonstrated lower risk of the lethal degenerative neuromuscular disease, amyotrophic lateral sclerosis (ALS) associated with history of the use of 'antineoplastic agents' and 'immunosuppressants'. To see if this finding was generalizable to other ALS cohorts, we examined associations between use of these agents and ALS risk in an independent case-control study of n = 414 ALS patients and n = 361 controls in an Eastern US population. Controls were sampled from the general population and among non-neurodegenerative disease patients...
August 2017: Journal of Neurology
https://www.readbyqxmd.com/read/28710685/pericytes-extend-survival-of-als-sod1-mice-and-induce-the-expression-of-antioxidant-enzymes-in-the-murine-model-and-in-ipscs-derived-neuronal-cells-from-an-als-patient
#16
Giuliana Castello Coatti, Miriam Frangini, Marcos C Valadares, Juliana Plat Gomes, Natalia O Lima, Natale Cavaçana, Amanda F Assoni, Mayra V Pelatti, Alexander Birbrair, Antonio Carlos Pedroso de Lima, Julio M Singer, Francisco Marcelo M Rocha, Giovani Loiola Da Silva, Mario Sergio Mantovani, Lucia Inês Macedo-Souza, Merari F R Ferrari, Mayana Zatz
Amyotrophic Lateral Sclerosis (ALS) is one of the most common adult-onset motor neuron disease causing a progressive, rapid and irreversible degeneration of motor neurons in the cortex, brain stem and spinal cord. No effective treatment is available and cell therapy clinical trials are currently being tested in ALS affected patients. It is well known that in ALS patients, approximately 50% of pericytes from the spinal cord barrier are lost. In the central nervous system, pericytes act in the formation and maintenance of the blood-brain barrier, a natural defense that slows the progression of symptoms in neurodegenerative diseases...
July 14, 2017: Stem Cell Reviews
https://www.readbyqxmd.com/read/28694091/combined-intranasal-nerve-growth-factor-and-ventricle-neural-stem-cell-grafts-prolong-survival-and-improve-disease-outcome-in-amyotrophic-lateral-sclerosis-transgenic-mice
#17
Shi-Jiang Zhong, Yan-Hua Gong, Yan-Chen Lin
Amyotrophic lateral sclerosis (ALS) is a fatal disease that selectively involves motor neurons. Neurotrophic factor supplementation and neural stem cell (NSC) alternative therapy have been used to treat ALS. The two approaches can affect each other in their pathways of action, and there is a possibility for synergism. However, to date, there have been no studies demonstrating the effects of combined therapy in the treatment of ALS. In this study, for the first time, we adopted a method involving the intranasal administration of nerve growth factor combined with lateral ventricle NSC transplantation using G93A-SOD1 transgenic mice as experimental subjects to explore the treatment effect of this combined therapy in ALS...
July 8, 2017: Neuroscience Letters
https://www.readbyqxmd.com/read/28674982/motoneuron-disease-clinical
#18
Hristelina Ilieva, Nicholas J Maragakis
ALS is a neurodegenerative disease in which the primary symptoms result in progressive neuromuscular weakness. Recent studies have highlighted that there is significant heterogeneity with regard to anatomical and temporal disease progression. Importantly, more recent advances in genetics have revealed new causative genes to the disease. New efforts have focused on the development of biomarkers that could aid in diagnosis, prognosis, and serve as pharmacodynamics markers. Although traditional pharmaceuticals continue to undergo trials for ALS, new therapeutic strategies including stem cell transplantation studies, gene therapies, and antisense therapies targeting some of the familial forms of ALS are gaining momentum...
2017: Advances in Neurobiology
https://www.readbyqxmd.com/read/28663100/a-new-aav10-u7-mediated-gene-therapy-prolongs-survival-and-restores-function-in-an-als-mouse-model
#19
Maria Grazia Biferi, Mathilde Cohen-Tannoudji, Ambra Cappelletto, Benoit Giroux, Marianne Roda, Stéphanie Astord, Thibaut Marais, Corinne Bos, Thomas Voit, Arnaud Ferry, Martine Barkats
One of the most promising therapeutic approaches for familial amyotrophic lateral sclerosis linked to superoxide dismutase 1 (SOD1) is the suppression of toxic mutant SOD1 in the affected tissues. Here, we report an innovative molecular strategy for inducing substantial, widespread, and sustained reduction of mutant human SOD1 (hSOD1) levels throughout the body of SOD1(G93A) mice, leading to therapeutic effects in animals. Adeno-associated virus serotype rh10 vectors (AAV10) were used to mediate exon skipping of the hSOD1 pre-mRNA by expression of exon-2-targeted antisense sequences embedded in a modified U7 small-nuclear RNA (AAV10-U7-hSOD)...
September 6, 2017: Molecular Therapy: the Journal of the American Society of Gene Therapy
https://www.readbyqxmd.com/read/28654923/antibakterielle-in-vitro-wirksamkeit-%C3%A3-therischer-%C3%A3-le-gegen-veterin%C3%A3-rmedizinisch-relevante-keime-klinischer-isolate-von-hunden-katzen-und-pferden
#20
Doris Bismarck, Marianne Schneider, Elisabeth Müller
Einleitung: Ätherische Öle sind die Grundlage der Aromatherapie. Unter anderem wird ihnen eine antibakterielle Wirkung zugeschrieben. In dieser Studie sollte die In-vitro-Wirksamkeit ätherischer Öle gegen ein breites Spektrum veterinärmedizinisch relevanter Erreger getestet werden. Methoden: Die antibakterielle Aktivität von 16 ätherischen Ölen wurde mittels Agardiffusionstest bestimmt. Getestet wurden grampositive und gramnegative Erreger, die aus klinischen Isolaten von Hunden, Katzen und Pferden aus der veterinärmedizinischen Routinediagnostik stammten...
2017: Complementary Medicine Research
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