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1. Pathophysiology of ion channels in amyotrophic lateral sclerosis

Author: Robin N. Stringer and Norbert Weiss
Subjects: Amyotrophic lateral sclerosis, Motor neurons, Ion channels, Neuronal excitability, Neurodegeneration, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Amyotrophic lateral sclerosis (ALS) stands as the most prevalent and severe form of motor neuron disease, affecting an estimated 2 in 100,000 individuals worldwide. It is characterized by the progressive loss of cortical, brainstem, and spinal motor neurons, ultimately resulting in muscle weakness and death. Although the etiology of ALS remains poorly understood in most cases, the remodelling of ion channels and alteration in neuronal excitability represent a hallmark of the disease, manifesting not only during the symptomatic period but also in the early pre-symptomatic stages. In this review, we delve into these alterations observed in ALS patients and preclinical disease models, and explore their consequences on neuronal activities. Furthermore, we discuss the potential of ion channels as therapeutic targets in the context of ALS.
Published: 2023
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2. Electrophysiological characterization of a Cav3.2 calcium channel missense variant associated with epilepsy and hearing loss

Author: Robin N. Stringer, Leos Cmarko, Gerald W. Zamponi, Michel De Waard, and Norbert Weiss
Subjects: Ion channels, Calcium channels, T-type channels, CACNA1H, Cav3.2, Mutation, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract T-type calcium channelopathies encompass a group of human disorders either caused or exacerbated by mutations in the genes encoding different T-type calcium channels. Recently, a new heterozygous missense mutation in the CACNA1H gene that encodes the Cav3.2 T-type calcium channel was reported in a patient presenting with epilepsy and hearing loss—apparently the first CACNA1H mutation to be associated with a sensorineural hearing condition. This mutation leads to the substitution of an arginine at position 132 with a histidine (R132H) in the proximal extracellular end of the second transmembrane helix of Cav3.2. In this study, we report the electrophysiological characterization of this new variant using whole-cell patch clamp recordings in tsA-201 cells. Our data reveal minor gating alterations of the channel evidenced by a mild increase of the T-type current density and slower recovery from inactivation, as well as an enhanced sensitivity of the channel to external pH change. To what extend these biophysical changes and pH sensitivity alterations induced by the R132H mutation contribute to the observed pathogenicity remains an open question that will necessitate the analysis of additional CACNA1H variants associated with the same pathologies.
Published: 2023
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3. A multicentric consortium study demonstrates that dimethylarginine dimethylaminohydrolase 2 is not a dimethylarginine dimethylaminohydrolase

Author: Vinitha N. Ragavan, Pramod C. Nair, Natalia Jarzebska, Ramcharan Singh Angom, Luana Ruta, Elisa Bianconi, Silvia Grottelli, Natalia D. Tararova, Daniel Ryazanskiy, Steven R. Lentz, Sara Tommasi, Jens Martens-Lobenhoffer, Toshiko Suzuki-Yamamoto, Masumi Kimoto, Elena Rubets, Sarah Chau, Yingjie Chen, Xinli Hu, Nadine Bernhardt, Peter M. Spieth, Norbert Weiss, Stefan R. Bornstein, Debabrata Mukhopadhyay, Stefanie M. Bode-Böger, Renke Maas, Ying Wang, Antonio Macchiarulo, Arduino A. Mangoni, Barbara Cellini, and Roman N. Rodionov
Subjects: Science
Abstract: Abstract Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.
Published: 2023
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4. Secretory carrier-associated membrane protein 5 regulates cell-surface targeting of T-type calcium channels

Author: Emilio R. Mustafá, Konstantin Weiß, and Norbert Weiss
Subjects: Ion channels, Calcium channels, T-type channels, Secretory carrier-associated membrane protein 5, SCAMP5, Channelopathy, Therapeutics. Pharmacology, RM1-950, Physiology, QP1-981
Abstract: ABSTRACTMissense mutations in the human secretary carrier-associated membrane protein 5 (SCAMP5) cause a variety of neurological disorders including neurodevelopmental delay, epilepsy, and Parkinson’s disease. We recently documented the importance of SCAMP2 in the regulation of T-type calcium channel expression in the plasma membrane. Here, we show that similar to SCAMP2, the co-expression of SCAMP5 in tsA-201 cells expressing recombinant Cav3.1, Cav3.2, and Cav3.3 channels nearly abolished whole-cell T-type currents. Recording of intramembrane charge movements revealed that SCAMP5-induced inhibition of T-type currents is primarily caused by the reduced expression of functional channels in the plasma membrane. Moreover, we show that SCAMP5-mediated downregulation of Cav3.2 channels is essentially preserved with disease-causing SCAMP5 R91W and G180W mutations. Hence, this study extends our previous findings with SCAMP2 and indicates that SCAMP5 also contributes to repressing the expression of T-type channels in the plasma membrane.
Published: 2023
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5. Electrophysiological and computational analysis of Cav3.2 channel variants associated with familial trigeminal neuralgia

Author: Emilio R. Mustafá, Eder Gambeta, Robin N. Stringer, Ivana A. Souza, Gerald W. Zamponi, and Norbert Weiss
Subjects: Trigeminal neuralgia, Ion channel, Calcium channel, CACNA1H, Cav3.2 channel, Channelopathy, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Trigeminal neuralgia (TN) is a rare form of chronic neuropathic pain characterized by spontaneous or elicited paroxysms of electric shock-like or stabbing pain in a region of the face. While most cases occur in a sporadic manner and are accompanied by intracranial vascular compression of the trigeminal nerve root, alteration of ion channels has emerged as a potential exacerbating factor. Recently, whole exome sequencing analysis of familial TN patients identified 19 rare variants in the gene CACNA1H encoding for Cav3.2T-type calcium channels. An initial analysis of 4 of these variants pointed to a pathogenic role. In this study, we assessed the electrophysiological properties of 13 additional TN-associated Cav3.2 variants expressed in tsA-201 cells. Our data indicate that 6 out of the 13 variants analyzed display alteration of their gating properties as evidenced by a hyperpolarizing shift of their voltage dependence of activation and/or inactivation resulting in an enhanced window current supported by Cav3.2 channels. An additional variant enhanced the recovery from inactivation. Simulation of neuronal electrical membrane potential using a computational model of reticular thalamic neuron suggests that TN-associated Cav3.2 variants could enhance neuronal excitability. Altogether, the present study adds to the notion that ion channel polymorphisms could contribute to the etiology of some cases of TN and further support a role for Cav3.2 channels.
Published: 2022
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6. Overexpression of alanine-glyoxylate aminotransferase 2 protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling

Author: Roman N. Rodionov, Natalia Jarzebska, Dmitrii Burdin, Vladimir Todorov, Jens Martens-Lobenhoffer, Anja Hofmann, Anne Kolouschek, Nada Cordasic, Johannes Jacobi, Elena Rubets, Henning Morawietz, John F. O’Sullivan, Alexander G. Markov, Stefan R. Bornstein, Karl Hilgers, Renke Maas, Christian Pfluecke, YingJie Chen, Stefanie M. Bode-Böger, Christian P. M. Hugo, Bernd Hohenstein, and Norbert Weiss
Subjects: Medicine, Science
Abstract: Abstract Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and increase in blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency. We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling. Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.
Published: 2022
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7. Cavβ surface charged residues contribute to the regulation of neuronal calcium channels

Author: Alexandra Tran-Van-Minh, Michel De Waard, and Norbert Weiss
Subjects: Ion channels, Calcium channels, Voltage-gated calcium channels, Cav2.1 channels, Cavβ subunit, Alanine-scanning mutagenesis, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Voltage-gated calcium channels are essential regulators of brain function where they support depolarization-induced calcium entry into neurons. They consist of a pore-forming subunit (Cavα1) that requires co-assembly with ancillary subunits to ensure proper functioning of the channel. Among these ancillary subunits, the Cavβ plays an essential role in regulating surface expression and gating of the channels. This regulation requires the direct binding of Cavβ onto Cavα1 and is mediated by the alpha interacting domain (AID) within the Cavα1 subunit and the α binding pocket (ABP) within the Cavβ subunit. However, additional interactions between Cavα1 and Cavβ have been proposed. In this study, we analyzed the importance of Cavβ3 surface charged residues in the regulation of Cav2.1 channels. Using alanine-scanning mutagenesis combined with electrophysiological recordings we identified several amino acids within the Cavβ3 subunit that contribute to the gating of the channel. These findings add to the notion that additional contacts besides the main AID/ABP interaction may occur to fine-tune the expression and properties of the channel.
Published: 2022
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8. Secretory carrier-associated membrane protein 2 (SCAMP2) regulates cell surface expression of T-type calcium channels

Author: Leos Cmarko, Robin N. Stringer, Bohumila Jurkovicova-Tarabova, Tomas Vacik, Lubica Lacinova, and Norbert Weiss
Subjects: Ion channels, Calcium channels, T-type channels, Cav3.2 channels, Secretory carrier-associated membrane protein 2, SCAMP2, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Low-voltage-activated T-type Ca2+ channels are key regulators of neuronal excitability both in the central and peripheral nervous systems. Therefore, their recruitment at the plasma membrane is critical in determining firing activity patterns of nerve cells. In this study, we report the importance of secretory carrier-associated membrane proteins (SCAMPs) in the trafficking regulation of T-type channels. We identified SCAMP2 as a novel Cav3.2-interacting protein. In addition, we show that co-expression of SCAMP2 in mammalian cells expressing recombinant Cav3.2 channels caused an almost complete drop of the whole cell T-type current, an effect partly reversed by single amino acid mutations within the conserved cytoplasmic E peptide of SCAMP2. SCAMP2-induced downregulation of T-type currents was also observed in cells expressing Cav3.1 and Cav3.3 channel isoforms. Finally, we show that SCAMP2-mediated knockdown of the T-type conductance is caused by the lack of Cav3.2 expression at the cell surface as evidenced by the concomitant loss of intramembrane charge movement without decrease of total Cav3.2 protein level. Taken together, our results indicate that SCAMP2 plays an important role in the trafficking of Cav3.2 channels at the plasma membrane.
Published: 2022
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9. De novo SCN8A and inherited rare CACNA1H variants associated with severe developmental and epileptic encephalopathy

Author: Robin N. Stringer, Bohumila Jurkovicova-Tarabova, Ivana A. Souza, Judy Ibrahim, Tomas Vacik, Waseem Mahmoud Fathalla, Jozef Hertecant, Gerald W. Zamponi, Lubica Lacinova, and Norbert Weiss
Subjects: Ion channels, Channelopathy, Calcium channel, CACNA1H, Cav3.2 channel, Sodium channel, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies that are characterized by seizures and developmental delay. DEEs are primarily attributed to genetic causes and an increasing number of cases have been correlated with variants in ion channel genes. In this study, we report a child with an early severe DEE. Whole exome sequencing showed a de novo heterozygous variant (c.4873–4881 duplication) in the SCN8A gene and an inherited heterozygous variant (c.952G > A) in the CACNA1H gene encoding for Nav1.6 voltage-gated sodium and Cav3.2 voltage-gated calcium channels, respectively. In vitro functional analysis of human Nav1.6 and Cav3.2 channel variants revealed mild but significant alterations of their gating properties that were in general consistent with a gain- and loss-of-channel function, respectively. Although additional studies will be required to confirm the actual pathogenic involvement of SCN8A and CACNA1H, these findings add to the notion that rare ion channel variants may contribute to the etiology of DEEs.
Published: 2021
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10. Functional identification of potential non-canonical N-glycosylation sites within Cav3.2 T-type calcium channels

Author: Vendula Ficelova, Ivana A. Souza, Leos Cmarko, Maria A. Gandini, Robin N. Stringer, Gerald W. Zamponi, and Norbert Weiss
Subjects: Asparagine-linked glycosylation, N-glycosylation, Non-canonical glycosylation, Calcium channel, T-type channel, cav3.2 Channel, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Low-voltage-activated T-type calcium channels are important contributors to nervous system function. Post-translational modification of these channels has emerged as an important mechanism to control channel activity. Previous studies have documented the importance of asparagine (N)-linked glycosylation and identified several asparagine residues within the canonical consensus sequence N-X-S/T that is essential for the expression and function of Cav3.2 channels. Here, we explored the functional role of non-canonical N-glycosylation motifs in the conformation N-X-C based on site directed mutagenesis. Using a combination of electrophysiological recordings and surface biotinylation assays, we show that asparagines N345 and N1780 located in the motifs NVC and NPC, respectively, are essential for the expression of the human Cav3.2 channel in the plasma membrane. Therefore, these newly identified asparagine residues within non-canonical motifs add to those previously reported in canonical sites and suggest that N-glycosylation of Cav3.2 may also occur at non-canonical motifs to control expression of the channel in the plasma membrane. It is also the first study to report the functional importance of non-canonical N-glycosylation motifs in an ion channel.
Published: 2020
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11. A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

Author: Robin N. Stringer, Bohumila Jurkovicova-Tarabova, Sun Huang, Omid Haji-Ghassemi, Romane Idoux, Anna Liashenko, Ivana A. Souza, Yuriy Rzhepetskyy, Lubica Lacinova, Filip Van Petegem, Gerald W. Zamponi, Roger Pamphlett, and Norbert Weiss
Subjects: ALS, Amyotrophic lateral sclerosis, Motor neuron disease, CACNA1H, Mutation, Calcium channel, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of cortical, brain stem and spinal motor neurons that leads to muscle weakness and death. A previous study implicated CACNA1H encoding for Cav3.2 calcium channels as a susceptibility gene in ALS. In the present study, two heterozygous CACNA1H variants were identified by whole genome sequencing in a small cohort of ALS patients. These variants were functionally characterized using patch clamp electrophysiology, biochemistry assays, and molecular modeling. A previously unreported c.454GTAC > G variant produced an inframe deletion of a highly conserved isoleucine residue in Cav3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominant-negative effect on the wild-type channel when expressed in trans. In contrast, the c.3629C > T variant caused a missense substitution of a proline with a leucine (p.P1210L) and produced a comparatively mild alteration of Cav3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Cav3.2 channel function. These findings add to the notion that loss-of-function of Cav3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.
Published: 2020
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12. Selective inhibition of neuronal Cav3.3 T-type calcium channels by TAT-based channel peptide

Author: Leos Cmarko and Norbert Weiss
Subjects: Calcium channel, T-type channel, Cav3.3 channel, TAT-peptide, Inhibitor, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract Low-voltage-activated Cav3 calcium channels (T-type) play an essential role in the functioning of the nervous system where they support oscillatory activities that relie on several channel molecular determinants that shape their unique gating properties. In a previous study, we documented the important role of the carboxy proximal region in the functioning of Cav3.3 channels. Here, we explore the ability of a TAT-based cell penetrating peptide containing this carboxy proximal region (TAT-C3P) to modulate the activity of Cav3 channels. We show that chronic application of TAT-C3P on tsA-201 cells expressing Cav3 channels selectively inhibits Cav3.3 channels without affecting Cav3.1 and Cav3.2 channels. Therefore, the TAT-C3P peptide described in this study represents a new tool to address the specific physiological role of Cav3.3 channels, and to potentially enhance our understanding of Cav3.3 in disease.
Published: 2020
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13. Identification of a molecular gating determinant within the carboxy terminal region of Cav3.3 T-type channels

Author: Bohumila Jurkovicova-Tarabova, Leos Cmarko, Renata Rehak, Gerald W. Zamponi, Lubica Lacinova, and Norbert Weiss
Subjects: T-type channels, Cav3.3 channel, Gating, Electrophysiology, Neurology. Diseases of the nervous system, RC346-429
Abstract: Abstract The physiological functions controlled by T-type channels are intrinsically dependent on their gating properties, and alteration of T-type channel activity is linked to several human disorders. Therefore, it is essential to develop a clear understanding of the structural determinants responsible for the unique gating features of T-type channels. Here, we have investigated the specific role of the carboxy terminal region by creating a series a deletion constructs expressed in tsA-201 cells and analyzing them by patch clamp electrophysiology. Our data reveal that the proximal region of the carboxy terminus contains a structural determinant essential for shaping several gating aspects of Cav3.3 channels, including voltage-dependence of activation and inactivation, inactivation kinetics, and coupling between the voltage sensing and the pore opening of the channel. Altogether, our data are consistent with a model in which the carboxy terminus stabilizes the channel in a closed state.
Published: 2019
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14. Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated Na+ Channels Using Voltage Sensor Fluorescent Probes: Hits and Biases

Author: Quentin Coquerel, Claire Legendre, Jacinthe Frangieh, Stephan De Waard, Jérôme Montnach, Leos Cmarko, Joseph Khoury, Charifat Said Hassane, Dimitri Bréard, Benjamin Siegler, Ziad Fajloun, Harold De Pomyers, Kamel Mabrouk, Norbert Weiss, Daniel Henrion, Pascal Richomme, César Mattei, Michel De Waard, Anne-Marie Le Ray, and Christian Legros
Subjects: voltage-gated sodium channel, isoquinoline alkaloids, oxoaporphine, voltage sensor probes, Na+ fluorescent probe ANG-2, GH3b6 cells, Organic chemistry, QD241-441
Abstract: Voltage-gated Na+ (NaV) channels are significant therapeutic targets for the treatment of cardiac and neurological disorders, thus promoting the search for novel NaV channel ligands. With the objective of discovering new blockers of NaV channel ligands, we screened an In-House vegetal alkaloid library using fluorescence cell-based assays. We screened 62 isoquinoline alkaloids (IA) for their ability to decrease the FRET signal of voltage sensor probes (VSP), which were induced by the activation of NaV channels with batrachotoxin (BTX) in GH3b6 cells. This led to the selection of five IA: liriodenine, oxostephanine, thalmiculine, protopine, and bebeerine, inhibiting the BTX-induced VSP signal with micromolar IC50. These five alkaloids were then assayed using the Na+ fluorescent probe ANG-2 and the patch-clamp technique. Only oxostephanine and liriodenine were able to inhibit the BTX-induced ANG-2 signal in HEK293-hNaV1.3 cells. Indeed, liriodenine and oxostephanine decreased the effects of BTX on Na+ currents elicited by the hNaV1.3 channel, suggesting that conformation change induced by BTX binding could induce a bias in fluorescent assays. However, among the five IA selected in the VSP assay, only bebeerine exhibited strong inhibitory effects against Na+ currents elicited by the hNav1.2 and hNav1.6 channels, with IC50 values below 10 µM. So far, bebeerine is the first BBIQ to have been reported to block NaV channels, with promising therapeutical applications.
Published: 2022
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15. Low-Dose vs High-Dose Paclitaxel-Coated Balloons for Femoropopliteal Lesions

Author: Sabine Steiner, Andrej Schmidt, Thomas Zeller, Gunnar Tepe, Marcus Thieme, Lars Maiwald, Henrik Schröder, Wulf Euringer, Corneliu Popescu, Klaus Brechtel, Steffen Brucks, Erwin Blessing, Johannes Schuster, Ralf Langhoff, Sebastian Schellong, Norbert Weiss, Ulrich Beschorner, Tim Wittig, and Dierk Scheinert
Subjects: Cardiology and Cardiovascular Medicine
Published: 2022
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16. Carotid endarterectomy or stenting or best medical treatment alone for moderate-to-severe asymptomatic carotid artery stenosis: 5-year results of a multicentre, randomised controlled trial

Author: Tilman Reiff, Hans-Henning Eckstein, Ulrich Mansmann, Olav Jansen, Gustav Fraedrich, Harald Mudra, Dittmar Böckler, Michael Böhm, E Sebastian Debus, Jens Fiehler, Klaus Mathias, Erich B Ringelstein, Jürg Schmidli, Robert Stingele, Ralf Zahn, Thomas Zeller, Wolf-Dirk Niesen, Kristian Barlinn, Andreas Binder, Jörg Glahn, Werner Hacke, Peter Arthur Ringleb, Friedhelm Beyersdorf, Roland-Richard Macharzina, Gabriele Lechner, Carolin Menz, Sabine Schonhardt, Michael Weinbeck, Olga Greb, Dagmar Otto, Thomas Winker, Hermann Berger, Holger Poppert, Andreas Kühnl, Volker Pütz, Kathrin Haase, Ulf Bodechtel, Norbert Weiss, Hendrik Bergert, Johannes Meyne, Justus Groß, Matthias Kruse, Berthold Gerdes, Wolf-Dieter Reinbold, Helge Wuttig, Andreas Maier-Hasselmann, Manuela Segerer, Hans-Hermann Fuchs, Sabine Gass, Christoph Groden, Marco Niedergethmann, Martin Griebe, Michael Rosenkranz, Jürgen Beck, Götz Thomalla, Hermann H. Zeumer, Marek Jauß, Werner Kneist, Martina Kneist, Thomas Staudacher, Alfons Bernhard, Petra Jost, Nico Prey, Jürgen Knippschild, Oliver Kastrup, Martin Köhrmann, Benedikt Frank, Volkmar Bongers, Johannes Hoffmann, Horst-Wilhelm Kniemeyer, Michael Knauth, Kathrin Wasser, Tomislav Stojanovic, Hans Emmert, Josef Tacke, Bernhard Schwalbe, Eun-Mi Nam, Ulrike van Lengerich, Stephan Lowens, Klaus Gröschel, Timo Uphaus, Sonja Gröschel, Stephan Boor, Bernhard Dorweiler, Elisabeth Schmid, Hans Henkes, Thomas Hupp, Oliver Singer, Gerhard Hamann, Michaela Wagner-Heck, Sibylle Kerth-Krick, Metin Kilic, Peter Huppert, Kurt Niederkorn, Johannes Fruhwirth, Günther Klein, Ulrich Pulkowski, Karsten Jöster, Jens-Henning Wacks, Egbert Kloppmann, Bijan Vatankhah, Silke Hopf-Jensen, Henning Stolze, Stefan Müller-Hülsbeck, Knut Peer Walluscheck, Hans-Michael Schmitt, Albert Grüger, Jörg Seemann, Belay Tilahun, Martin Dichgans, Frank Arne Wollenweber, Angelika Dörr, Adelgunde Zollver, Gabor Gäbel, Günter Hedtmann, Rainer Kollmar, Detlef Claus, Christian Petermann, Stefanie Kirsch, Branko Bosnjak, Johannes Heiß, Holger Mühling, Silke Wunderlich, Peter Nikolaus Sabisch, Georg Gahn, Martin Storck, Sebastian Arnold, Urs Fischer, Jan Gralla, Matthias von Mering, Rüdiger Dißmann, Delia Kirsch, Christoph Schmidauer, Peter Waldenberger, Martin Furtner, Haiko Kazarians, Peter Breuer, Christian Arning, Jürgen Rieper, Georg Schmidt, Marcel Arnold, Gerhard Schroth, Jens Weise, Jürgen Zanow, Thomas Mayer, Rudolf Töpper, Walter Gross-Fengels, Harald Daum, Ralf Dittrich, Martin Ritter, Bernd Kasprzak, Giovanni Torsello, Carsten Pohlmann, Roland Brüning, Alexander Crispin, Miriam Hofmann, Thomas Müller, Erwin Blessing, Markus Möhlenbruch, Ines Ludwig, and Hemasse Amiri
Subjects: Stroke, Endarterectomy, Carotid, Treatment Outcome, Humans, Carotid Stenosis, Stents, Neurology (clinical), Brain Ischemia, Ischemic Stroke
Abstract: The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only.SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50-85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017.513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6-60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0-5·8) with CEA plus BMT, 4·4% (2·2-8·6) with CAS plus BMT, and 3·1% (1·0-9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22-3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41-5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group.CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution.German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).
Published: 2022
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17. Business Apps Meet the Challenge of Covering Continually Changing Logistics Requirements.

Author: Julian Eggemann, Jens Leveling, and Norbert Weiß
Published: 2015
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18. Homoarginine Supplementation Prevents Left Ventricular Dilatation and Preserves Systolic Function in a Model of Coronary Artery Disease

Author: Roman N. Rodionov, Hoshimjon Begmatov, Natalia Jarzebska, Ketul Patel, Matthew T. Mills, Zulaikha Ghani, Doreen Khakshour, Pankti Tamboli, Mitul N. Patel, Mirette Abdalla, Maryann Assaf, Stefan R. Bornstein, Jose Luis Millan, Stefanie M. Bode‐Böger, Jens Martens‐Lobenhoffer, Norbert Weiss, and Olga V. Savinova
Subjects: cardiac remodeling, coronary artery disease, coronary calcium, homoarginine, Diseases of the circulatory (Cardiovascular) system, RC666-701
Abstract: Background Homoarginine (hArg) has been shown to be cardioprotective in a model of ischemic heart failure; however, the mechanism remains unknown. hArg can inhibit tissue‐nonspecific alkaline phosphatase (TNAP), an enzyme that promotes vascular calcification. We hypothesized that hArg will exert beneficial effects by reducing calcification in a mouse model of coronary artery disease associated with TNAP overexpression and hypercholesterolemia. Methods and Results TNAP was overexpressed in the endothelium in mice homozygous for a low‐density lipoprotein receptor mutation (wicked high cholesterol [WHC] allele). WHC and WHC–endothelial TNAP mice received placebo or hArg supplementation (14 mg/L in drinking water) starting at 6 weeks of age simultaneously with an atherogenic diet. Outcomes were compared between the groups after 4 to 5 weeks on treatment. Experiments were performed in males, which presented a study limitation. As expected, WHC–endothelial TNAP mice on the placebo had increased mortality (median survival 27 days, P
Published: 2019
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19. Extended spectrum of Cav1.3 channelopathies

Author: Norbert Weiss and Emilio Roman Mustafa
Subjects: Physiology, Physiology (medical), Clinical Biochemistry
Published: 2022
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20. The omega of TRPM7 channels in trigeminal neuralgia

Author: Norbert Weiss and Gerald W. Zamponi
Subjects: Physiology, Physiology (medical), Clinical Biochemistry
Published: 2022
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21. Overexpression of dimethylarginine dimethylaminohydrolase 1 protects from angiotensin II-induced cardiac hypertrophy and vascular remodeling

Author: Natalia Jarzebska, Anne Kolouschek, Stefanie M. Bode-Böger, Stefan R. Bornstein, Silke Billoff, Jens Martens-Lobenhoffer, Andreas Deussen, Arduino A. Mangoni, Roman N. Rodionov, Vinitha Nair Ragavan, Norbert Weiss, and Irakli Kopaliani
Subjects: Male, medicine.medical_specialty, Time Factors, Physiology, End organ damage, Heart Ventricles, Blood Pressure, Mice, Transgenic, Inflammation, Vascular Remodeling, Ventricular Function, Left, Amidohydrolases, chemistry.chemical_compound, Fibrosis, Physiology (medical), Internal medicine, Renin–angiotensin system, medicine, Animals, Aorta, Ventricular Remodeling, biology, business.industry, Angiotensin II, medicine.disease, Mice, Inbred C57BL, Vasodilation, Nitric oxide synthase, Disease Models, Animal, Blood pressure, Endocrinology, chemistry, Enzyme Induction, Hypertension, biology.protein, Hypertrophy, Left Ventricular, Inflammation Mediators, medicine.symptom, Cardiology and Cardiovascular Medicine, Asymmetric dimethylarginine, business
Abstract: Cardiovascular complications are the leading cause of death, and elevated levels of asymmetric dimethyarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are implicated in their pathophysiology. We investigated the role of dimethylarginine dimethylaminohydrolase 1 (DDAH1), an enzyme hydrolyzing ADMA, in prevention of cardiovascular remodeling during hypertension. We hypothesized that the animals overexpressing DDAH1 will be protected from angiotensin II (ANG II)-induced end organ damage. Angiotensin II (ANG II) was infused in two doses: 0.75 and 1.5 mg/kg/day in DDAH1 transgenic mice (DDAH1 TG) and wild-type (WT) littermates for 2 or 4 wk. Echocardiography was performed in the first and fourth weeks of the infusion, systolic blood pressure (SBP) was measured weekly, and cardiac hypertrophy and vascular remodeling was assessed by histology. Increase in SBP after 1 wk of ANG II infusion was not different between the groups, whereas TG mice had lower SBP at later time points. TG mice were protected from cardiovascular remodeling after 2 wk of ANG II infusion in the high dose and after 4 wk in the moderate dose. TG mice had higher left ventricular lumen-to-wall ratio, lower cardiomyocyte cross-sectional area, and less interstitial fibrosis compared with WT controls. In aorta, TG mice had less adventitial fibrosis, lower medial thickness with preserved elastin content, lower counts of inflammatory cells, lower levels of active matrix metalloproteinase-2, and showed better endothelium-dependent relaxation. We demonstrated that overexpression of DDAH1 protects from ANG II-induced cardiovascular remodeling and progression of hypertension by preserving endothelial function and limiting inflammation.NEW & NOTEWORTHY We showed that overexpression of dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects from angiotensin II-induced cardiovascular damage, progression of hypertension, and adverse vascular remodeling in vivo. This protective effect is associated with decreased levels of asymmetric dimethylarginine, preservation of endothelial function, inhibition of cardiovascular inflammation, and lower activity of matrix metalloproteinase-2. Our findings are highly clinically relevant, because they suggest that upregulation of DDAH1 might be a promising therapeutic approach against angiotensin II-induced end organ damage.
Published: 2021
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22. From SARS-CoV-2 to analgesia: harnessing the VEGF-A/NRP-1 axis for pain therapy

Author: Emilio R. Mustafá and Norbert Weiss
Subjects: Anesthesiology and Pain Medicine, Neurology, Neurology (clinical)
Published: 2022
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23. Extended spectrum of Ca

Author: Emilio R, Mustafá and Norbert, Weiss
Published: 2022

24. Strategie zur strukturierten interdisziplinären Zusammenarbeit für Versorgung der Patienten mit Diabetes in Praxis und Klinik

Author: Nikolaos Perakakis, Alexander Paliege, Norbert Weiss, Uwe Lindner, Frank Pistrosch, Peter Schwarz, and Stefan R. Bornstein
Subjects: Endocrinology, Diabetes and Metabolism, Internal Medicine
Published: 2022
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25. Ultrasonography Grading of Internal Carotid Artery Disease: Multiparametric German Society of Ultrasound in Medicine (DEGUM) versus Society of Radiologists in Ultrasound (SRU) Consensus Criteria

Author: Simon Winzer, Andrei V. Alexandrov, Norbert Weiss, Georg Gahn, Lars-Peder Pallesen, Timo Siepmann, Hagen H. Kitzler, Sebastian Arnold, Henning Rickmann, Christos Krogias, Andrij Abramyuk, Heinz Reichmann, Harald Mudra, Jessica Barlinn, Jennifer Linn, Henning Strohm, Kristian Barlinn, Volker Puetz, and Peter Moennings
Subjects: Carotid Artery Diseases, medicine.medical_specialty, Consensus, 030204 cardiovascular system & hematology, Sensitivity and Specificity, 030218 nuclear medicine & medical imaging, 03 medical and health sciences, 0302 clinical medicine, medicine.artery, Carotid artery disease, Radiologists, Occlusion, medicine, Humans, Carotid Stenosis, Radiology, Nuclear Medicine and imaging, Prospective Studies, Grading (tumors), Ultrasonography, medicine.diagnostic_test, business.industry, Ultrasound, Angiography, Digital Subtraction, Digital subtraction angiography, medicine.disease, Stenosis, Angiography, Radiology, Internal carotid artery, business, Carotid Artery, Internal
Abstract: We sought to determine the diagnostic agreement between the revised ultrasonography approach by the German Society of Ultrasound in Medicine (DEGUM) and the established Society of Radiologists in Ultrasound (SRU) consensus criteria for the grading of carotid artery disease. Post-hoc analysis of a prospective multicenter study, in which patients underwent ultrasonography and digital subtraction angiography (DSA) of carotid arteries for validation of the DEGUM approach. According to DEGUM and SRU ultrasonography criteria, carotid arteries were independently categorized into clinically relevant NASCET strata (normal, mild [1-49 %], moderate [50-69 %], severe [70-99 %], occlusion). On DSA, carotid artery findings according to NASCET were considered the reference standard. We analyzed 158 ultrasonography and DSA carotid artery pairs. There was substantial agreement between both ultrasonography approaches for severe (κw 0.76, CI95 %: 0.66-0.86), but only fair agreement for moderate (κw 0.38, CI95 %: 0.19-0.58) disease categories. Compared with DSA, both ultrasonography approaches were of equal sensitivity (79.7 % versus 79.7 %; p = 1.0) regarding the identification of severe stenosis, yet the DEGUM approach was more specific than the SRU approach (70.2 % versus 56.4 %, p = 0.0002). There was equality of accuracy parameters (p 0.05) among both ultrasonography approaches for the other ranges of carotid artery disease. While the sensitivity was equivalent, false-positive identification of severe carotid artery stenosis appears to be more frequent when using the SRU ultrasonography approach than the revised multiparametric DEGUM approach.ZIEL: Bestimmung der diagnostischen Übereinstimmung zwischen den multiparametrischen Ultraschallkriterien der Deutschen Gesellschaft für Ultraschall in der Medizin (DEGUM) und den Konsenskriterien der Society of Radiologists in Ultrasound (SRU) hinsichtlich der Graduierung von Karotisstenosen. Post-hoc-Analyse einer prospektiven multizentrischen Studie, welche die multiparametrischen DEGUM-Ultraschallkriterien mit der digitalen Subtraktionsangiografie validierte. Die Graduierung von Karotisstenosen in klinisch relevante NASCET-Kategorien (normal, leichtgradig (1–49 %), mittelgradig (50–69 %), hochgradig (70–99 %), Verschluss) erfolgte verblindet gemäß der DEGUM- und SRU-Ultraschallkriterien. Als Referenz wurde der nach NASCET bestimmte angiografische Stenosegrad verwendet. Wir analysierten 158 konsekutive Untersuchungen aus Ultraschall und Angiografie. Zwischen beiden sonografischen Graduierungsansätzen fand sich eine gute Übereinstimmung für hochgradige (κw 0,76; 95 %-KI 0,66–0,86) und eine mäßige Übereinstimmung für mittelgradige Stenosen (κw 0,38; 95 %-KI 0,19–0,58). Verglichen mit der Referenzangiografie fand sich kein Unterschied hinsichtlich Sensitivität für hochgradige Stenosen (79,7 % versus 79,7 %; p = 1,0), jedoch eine höhere Spezifität der DEGUM-Kriterien (70,2 % versus 56,4 %; p = 0,0002). In den sonstigen Stenosekategorien bestanden keine Unterschiede der Güteparameter (p 0,05). Verglichen mit den SRU-Kriterien weist die Graduierung nach DEGUM eine höhere Spezifität bei der Detektion hochgradiger Stenosen auf. Die Integration von mehr hämodynamischen Parametern scheint somit die Anzahl falsch positiver Diagnosen zu verringern.
Published: 2021
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26. Pearls & Oy-sters: Primary Cerebral Buerger Disease

Author: Daniel Kaiser, Johannes Gerber, Jennifer Linn, Christoph G Radosa, Norbert Weiss, Georg Leonhardt, and Volker Puetz
Subjects: Adult, Male, Pediatrics, medicine.medical_specialty, Tobacco use, business.industry, MEDLINE, Brain, Thromboangiitis Obliterans, medicine.disease, Diagnosis, Differential, Buerger disease, medicine, Humans, Neurology (clinical), Young adult, Differential diagnosis, business, Stroke, Ischemic Stroke
Abstract: Buerger disease (thromboangiitis obliterans [TAO]) typically occurs in men younger than 40–45 years who have a history of heavy tobacco use.
Published: 2021
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27. Overexpression of alanine-glyoxylate aminotransferase 2 protects from asymmetric dimethylarginine-induced endothelial dysfunction and aortic remodeling

Author: Norbert Weiss, Alexander G. Markov, Anja Hofmann, Jens Martens-Lobenhoffer, Natalia Jarzebska, Yingjie Chen, Elena Rubets, Christian Pfluecke, Dmitrii V Burdin, Vladimir T. Todorov, Roman N. Rodionov, Bernd Hohenstein, Nada Cordasic, Karl F. Hilgers, Christian P . M. Hugo, Stefan R. Bornstein, Henning Morawietz, John F. O'Sullivan, Anne Kolouschek, Stefanie M. Bode-Böger, Johannes Jacobi, and Renke Maas
Subjects: medicine.medical_specialty, Multidisciplinary, Alanine glyoxylate aminotransferase, Blood Pressure, Arginine, medicine.disease, Amidohydrolases, Mice, chemistry.chemical_compound, Endocrinology, chemistry, Internal medicine, medicine, Animals, Vascular Diseases, Endothelial dysfunction, Asymmetric dimethylarginine, Aorta, Transaminases
Abstract: Objective: Elevated plasma concentrations of asymmetric dimethylarginine (ADMA) are associated with an increased risk of mortality and adverse cardiovascular outcomes. ADMA can be metabolized by dimethylarginine dimethylaminohydrolases (DDAHs) and by alanine-glyoxylate aminotransferase 2 (AGXT2). Deletion of DDAH1 in mice leads to elevation of ADMA in plasma and blood pressure, while overexpression of human DDAH1 is associated with a lower plasma ADMA concentration and protective cardiovascular effects. The possible role of alternative metabolism of ADMA by AGXT2 remains to be elucidated. The goal of the current study was to test the hypothesis that transgenic overexpression of AGXT2 leads to lowering of plasma levels of ADMA and protection from vascular damage in the setting of DDAH1 deficiency.Approach and Results: We generated transgenic mice (TG) with ubiquitous overexpression of AGXT2. qPCR and Western Blot confirmed the expression of the transgene. Systemic ADMA levels were decreased by 15% in TG mice. In comparison with wild type animals plasma levels of asymmetric dimethylguanidino valeric acid (ADGV), the AGXT2 associated metabolite of ADMA, were six times higher. We crossed AGXT2 TG mice with DDAH1 knockout mice and observed that upregulation of AGXT2 lowers plasma ADMA and pulse pressure and protects the mice from endothelial dysfunction and adverse aortic remodeling.Conclusions: Upregulation of AGXT2 led to lowering of ADMA levels and protection from ADMA-induced vascular damage in the setting of DDAH1 deficiency. This is especially important, because all the efforts to develop pharmacological ADMA-lowering interventions by means of upregulation of DDAHs have been unsuccessful.
Published: 2022
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28. T-type channels: A new route for calcium entry into platelets

Author: Norbert Weiss
Subjects: Blood Platelets, Neurons, Humans, Calcium, Hematology
Published: 2022

29. Trigeminal neuropathic pain is alleviated by inhibition of Cav3.3 T-type calcium channels in mice

Author: Leos Cmarko, Sascha R.A. Alles, Marena A. Montera, Aleyah Goins, Karin N. Westlund, and Norbert Weiss
Subjects: 0301 basic medicine, Biophysics, Pharmacology, Neuropathic pain, Biochemistry, Calcium Channels, T-Type, Mice, 03 medical and health sciences, 0302 clinical medicine, trigeminal nerve injury, calcium channels, Ganglia, Spinal, therapeutics, Animals, Medicine, Voltage-dependent calcium channel, business.industry, Brief Report, Calcium channel, T-type calcium channel, Up-Regulation, Cav3.3, 030104 developmental biology, Hyperalgesia, Trigeminal nerve injury, business, 030217 neurology & neurosurgery
Abstract: In this brief report, we demonstrate that the Cav3.3 T-type voltage-gated calcium channel subtype is involved in our FRICT-ION model of chronic trigeminal neuropathic pain. We first showed that the Cacna1i gene encoding Cav3.3 is significantly upregulated in whole trigeminal ganglia of FRICT-ION mice compared to controls at week 10 post-injury. We confirmed protein upregulation of Cav3.3 compared to controls using Western blot analysis of whole trigeminal ganglia tissues. Finally, we demonstrated that intraperitoneal injection of a selective TAT-based Cav3.3 blocking peptide in FRICT-ION mice significantly reduces Cav3.3 protein expression at the peak anti-allodynic effect (4 hrs post-injection) of the attenuated neuropathic pain behavior. We also suggest that blockade of Cav3.3 may be more effective in attenuating trigeminal neuropathic pain in female than male FRICT-ION mice. Therefore, blocking or attenuating Cav3.3 function may be an effective strategy for the treatment of trigeminal neuropathic pain.
Published: 2020
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30. Functional identification of potential non-canonical N-glycosylation sites within Cav3.2 T-type calcium channels

Author: Norbert Weiss, Maria A. Gandini, Vendula Ficelova, Gerald W. Zamponi, Leos Cmarko, Ivana A. Souza, and Robin N Stringer
Subjects: Glycosylation, Voltage-dependent calcium channel, cav3.2 Channel, Calcium channel, T-type calcium channel, N-glycosylation, lcsh:RC346-429, Cell biology, Cellular and Molecular Neuroscience, chemistry.chemical_compound, chemistry, N-linked glycosylation, T-type channel, Consensus sequence, Asparagine-linked glycosylation, Asparagine, Molecular Biology, Non-canonical glycosylation, Ion channel, lcsh:Neurology. Diseases of the nervous system
Abstract: Low-voltage-activated T-type calcium channels are important contributors to nervous system function. Post-translational modification of these channels has emerged as an important mechanism to control channel activity. Previous studies have documented the importance of asparagine (N)-linked glycosylation and identified several asparagine residues within the canonical consensus sequence N-X-S/T that is essential for the expression and function of Cav3.2 channels. Here, we explored the functional role of non-canonical N-glycosylation motifs in the conformation N-X-C based on site directed mutagenesis. Using a combination of electrophysiological recordings and surface biotinylation assays, we show that asparagines N345 and N1780 located in the motifs NVC and NPC, respectively, are essential for the expression of the human Cav3.2 channel in the plasma membrane. Therefore, these newly identified asparagine residues within non-canonical motifs add to those previously reported in canonical sites and suggest that N-glycosylation of Cav3.2 may also occur at non-canonical motifs to control expression of the channel in the plasma membrane. It is also the first study to report the functional importance of non-canonical N-glycosylation motifs in an ion channel.
Published: 2020
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31. The role of alanine glyoxylate transaminase-2 (agxt2) in β-alanine and carnosine metabolism of healthy mice and humans

Author: Natalia Jarzebska, Wim Derave, Anneke Volkaert, Chang Keun Kim, Jens Martens-Lobenhoffer, Roman N. Rodionov, Arne Hautekiet, Sarah de Jager, Stefanie M. Bode-Böger, Zhou Xiang Shan, Jan Stautemas, Inge Everaert, James Leiper, Siegrid De Baere, Filip Lefevere, Siska Croubels, Laura Blancquaert, and Norbert Weiss
Subjects: Adult, Male, medicine.medical_specialty, Genotype, Physiology, Carnosine, beta-Alanine, Excretion, Mice, Young Adult, chemistry.chemical_compound, Pharmacokinetics, In vivo, Physiology (medical), Internal medicine, medicine, Animals, Humans, Alanine—glyoxylate transaminase, Ingestion, Histidine, Orthopedics and Sports Medicine, Transaminases, Mice, Knockout, Chemistry, Muscles, Public Health, Environmental and Occupational Health, Dipeptides, General Medicine, Metabolism, Mice, Inbred C57BL, Endocrinology
Abstract: Chronic β-alanine supplementation leads to increased levels of muscle histidine-containing dipeptides. However, the majority of ingested β-alanine is, most likely, degraded by two transaminases: GABA-T and AGXT2. In contrast to GABA-T, the in vivo role of AGXT2 with respect to β-alanine metabolism is unknown. The purpose of the present work is to investigate if AGXT2 is functionally involved in β-alanine homeostasis.Muscle histidine-containing dipeptides levels were determined in AGXT2 overexpressing or knock-out mice and in human subjects with different rs37369 genotypes which is known to affect AGXT2 activity. Further, plasma β-alanine kinetic was measured and urine was obtained from subjects with different rs37369 genotypes following ingestion of 1400 mg β-alanine.Overexpression of AGXT2 decreased circulating and muscle histidine-containing dipeptides ( 70% decrease; p 0.05), while AGXT2 KO did not result in altered histidine-containing dipeptides levels. In both models, β-alanine remained unaffected in the circulation and in muscle (p 0.05). In humans, the results support the evidence that decreased AGXT2 activity is not associated with altered histidine-containing dipeptides levels (p 0.05). Additionally, following an acute dose of β-alanine, no differences in pharmacokinetic response were measured between subjects with different rs37369 genotypes (p 0.05). Interestingly, urinary β-alanine excretion was 103% higher in subjects associated with lower AGXT2 activity, compared to subjects associated with normal AGXT2 activity (p 0.05).The data suggest that in vivo, β-alanine is a substrate of AGXT2; however, its importance in the metabolism of β-alanine and histidine-containing dipeptides seems small.
Published: 2020
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32. Opioid Receptor Regulation of Neuronal Voltage-Gated Calcium Channels

Author: Norbert Weiss and Gerald W. Zamponi
Subjects: 0301 basic medicine, Cell signaling, Voltage-dependent calcium channel, medicine.drug_class, Chemistry, Cell Biology, General Medicine, 03 medical and health sciences, Cellular and Molecular Neuroscience, Nociceptin receptor, 030104 developmental biology, 0302 clinical medicine, Opioid receptor, Second messenger system, medicine, μ-opioid receptor, Receptor, Neuroscience, 030217 neurology & neurosurgery, G protein-coupled receptor
Abstract: Neuronal voltage-gated calcium channels play a pivotal role in the conversion of electrical signals into calcium entry into nerve endings that is required for the release of neurotransmitters. They are under the control of a number of cellular signaling pathways that serve to fine tune synaptic activities, including G-protein coupled receptors (GPCRs) and the opioid system. Besides modulating channel activity via activation of second messengers, GPCRs also physically associate with calcium channels to regulate their function and expression at the plasma membrane. In this mini review, we discuss the mechanisms by which calcium channels are regulated by classical opioid and nociceptin receptors. We highlight the importance of this regulation in the control of neuronal functions and their implication in the development of disease conditions. Finally, we present recent literature concerning the use of novel μ-opioid receptor/nociceptin receptor modulators and discuss their use as potential drug candidates for the treatment of pain.
Published: 2020
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33. Transcriptomic analysis of glycan-processing genes in the dorsal root ganglia of diabetic mice and functional characterization on Cav3.2 channels

Author: Norbert Weiss, Joanna Lazniewska, Robin N Stringer, Stringer, Robin N, Lazniewska, Joanna, and Weiss, Norbert
Subjects: 0301 basic medicine, Dorsum, Male, Glycan, Glycosylation, glycosylation, Biophysics, Biology, Biochemistry, Cell Line, Diabetes Mellitus, Experimental, Transcriptome, 03 medical and health sciences, Calcium Channels, T-Type, Mice, 0302 clinical medicine, Polysaccharides, Ganglia, Spinal, Animals, Humans, DRG neurons, Gene, Cav3.2 channel, Voltage-dependent calcium channel, diabetes, Calcium channel, Brief Report, Diabetic mouse, Caᵥ3.2channel, Cell biology, Electrophysiology, 030104 developmental biology, Nociception, T-type channel, biology.protein, calcium channel, transcriptome, 030217 neurology & neurosurgery
Abstract: Cav3.2 T-type calcium channels play an essential role in the transmission of peripheral nociception in the dorsal root ganglia (DRG) and alteration of Cav3.2 expression is associated with the development of peripheral painful diabetic neuropathy (PDN). Several studies have previously documented the role of glycosylation in the expression and functioning of Cav3.2 and suggested that altered glycosylation of the channel may contribute to the aberrant expression of the channel in diabetic conditions. In this study, we aimed to analyze the expression of glycan-processing genes in DRG neurons from a leptin-deficient genetic mouse model of diabetes (db/db). Transcriptomic analysis revealed that several glycan-processing genes encoding for glycosyltransferases and sialic acid-modifying enzymes were upregulated in diabetic conditions. Functional analysis of these enzymes on recombinant Cav3.2 revealed an unexpected loss-of-function of the channel. Collectively, our data indicate that diabetes is associated with an alteration of the glycosylation machinery in DRG neurons. However, individual action of these enzymes when tested on recombinant Cav3.2 cannot explain the observed upregulation of T-type channels under diabetic conditions. Abbreviations: Galnt16: Polypeptide N-acetylgalactosaminyltransferase 16; B3gnt8: UDP-GlcNAc:betaGal beta-1,3-N-acetylglucosaminyltransferase 8; B4galt1: Beta-1,4-galactosyltransferase 1; St6gal1: Beta-galactoside alpha-2,6-sialyltransferase 1; Neu3: Sialidase-3
Published: 2020

34. A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

Author: Omid Haji-Ghassemi, Norbert Weiss, Bohumila Jurkovicova-Tarabova, Gerald W. Zamponi, Romane Idoux, Filip Van Petegem, Sun Huang, Anna Liashenko, Yuriy Rzhepetskyy, Roger Pamphlett, Ivana A. Souza, Robin N Stringer, and Lubica Lacinova
Subjects: 0301 basic medicine, medicine.disease_cause, lcsh:RC346-429, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, medicine, CACNA1H, Missense mutation, Motor neuron disease, Amyotrophic lateral sclerosis, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, Mutation, Voltage-dependent calcium channel, biology, Calcium channel, Muscle weakness, medicine.disease, Molecular biology, 030104 developmental biology, biology.protein, Isoleucine, medicine.symptom, ALS, 030217 neurology & neurosurgery
Abstract: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by the progressive loss of cortical, brain stem and spinal motor neurons that leads to muscle weakness and death. A previous study implicated CACNA1H encoding for Cav3.2 calcium channels as a susceptibility gene in ALS. In the present study, two heterozygous CACNA1H variants were identified by whole genome sequencing in a small cohort of ALS patients. These variants were functionally characterized using patch clamp electrophysiology, biochemistry assays, and molecular modeling. A previously unreported c.454GTAC > G variant produced an inframe deletion of a highly conserved isoleucine residue in Cav3.2 (p.ΔI153) and caused a complete loss-of-function of the channel, with an additional dominant-negative effect on the wild-type channel when expressed in trans. In contrast, the c.3629C > T variant caused a missense substitution of a proline with a leucine (p.P1210L) and produced a comparatively mild alteration of Cav3.2 channel activity. The newly identified ΔI153 variant is the first to be reported to cause a complete loss of Cav3.2 channel function. These findings add to the notion that loss-of-function of Cav3.2 channels associated with rare CACNA1H variants may be risk factors in the complex etiology of ALS.
Published: 2020
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35. Kontaktmanagement

Author: Silke Balbierz and Norbert Weiss
Published: 2022
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36. Trafficking of Neuronal Calcium Channels

Author: Norbert Weiss and Rajesh Khanna
Published: 2022
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37. Systematische Prozessoptimierung

Author: Norbert Weiss
Published: 2022
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38. Gesprächskultur führt zum Unternehmenserfolg

Author: Silke Balbierz and Norbert Weiss
Published: 2022
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39. Voltage-Gated Calcium Channels

Author: Norbert Weiss
Published: 2022
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40. Stressbewältigung, menschliche Entwicklungspotenziale & integrales Führungshandeln

Author: Norbert Weiss
Published: 2022
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41. Der innerbetriebliche Prozess der Ideenbewertung

Author: Norbert Weiss
Published: 2022
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42. Cavβ surface charged residues contribute to the regulation of neuronal calcium channels

Author: Norbert Weiss, Michel De Waard, and Alexandra Tran-Van-Minh
Subjects: Micro Report, Neurons, Cellular and Molecular Neuroscience, Calcium channels, Ion channels, Alanine-scanning mutagenesis, Voltage-gated calcium channels, Calcium, Neurology. Diseases of the nervous system, RC346-429, Cav2.1 channels, Molecular Biology, Cavβ subunit
Abstract: Voltage-gated calcium channels are essential regulators of brain function where they support depolarization-induced calcium entry into neurons. They consist of a pore-forming subunit (Cavα1) that requires co-assembly with ancillary subunits to ensure proper functioning of the channel. Among these ancillary subunits, the Cavβ plays an essential role in regulating surface expression and gating of the channels. This regulation requires the direct binding of Cavβ onto Cavα1 and is mediated by the alpha interacting domain (AID) within the Cavα1 subunit and the α binding pocket (ABP) within the Cavβ subunit. However, additional interactions between Cavα1 and Cavβ have been proposed. In this study, we analyzed the importance of Cavβ3 surface charged residues in the regulation of Cav2.1 channels. Using alanine-scanning mutagenesis combined with electrophysiological recordings we identified several amino acids within the Cavβ3 subunit that contribute to the gating of the channel. These findings add to the notion that additional contacts besides the main AID/ABP interaction may occur to fine-tune the expression and properties of the channel.
Published: 2022

43. Gefäßmedizin Scan – alles, was Sie in der Gefäßmedizin wissen müssen

Author: Norbert Weiss
Subjects: General Earth and Planetary Sciences, General Environmental Science
Published: 2022
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44. 4PEPS - a new pretest probability score to reduce imaging testing for suspected pulmonary embolism?

Author: Anne Kolouschek and Norbert Weiss
Subjects: Pre- and post-test probability, Fibrin Fibrinogen Degradation Products, medicine.medical_specialty, business.industry, medicine, Humans, Suspected pulmonary embolism, Radiology, Cardiology and Cardiovascular Medicine, business, Pulmonary Embolism, Probability
Published: 2021

45. Second asymptomatic carotid surgery trial (ACST-2): a randomised comparison of carotid artery stenting versus carotid endarterectomy

Author: Alison Halliday, Richard Bulbulia, Leo H Bonati, Johanna Chester, Andrea Cradduck-Bamford, Richard Peto, Hongchao Pan, John Potter, Hans Henning Eckstein, Barbara Farrell, Marcus Flather, Averil Mansfield, Boby Mihaylova, Kazim Rahimi, David Simpson, Dafydd Thomas, Peter Sandercock, Richard Gray, Andrew Molyneux, Cliff P Shearman, Peter Rothwell, Anna Belli, Will Herrington, Parminder Judge, Peter Leopold, Marion Mafham, Michael Gough, Piergiorgio Cao, Sumaira MacDonald, Vasha Bari, Clive Berry, S Bradshaw, Wojciech Brudlo, Alison Clarke, Robin Cox, Susan Fathers, Kamran Gaba, Mo Gray, Elizabeth Hayter, Constance Holliday, Rijo Kurien, Michael Lay, Steffi le Conte, Jessica McManus, Zahra Madgwick, Dylan Morris, Andrew Munday, Sandra Pickworth, Wiktor Ostasz, Michiel Poorthuis, Sue Richards, Louisa Teixeira, Sergey Tochlin, Lynda Tully, Carol Wallis, Monique Willet, Alan Young, Renato Casana, Chiara Malloggi, Andrea Odero Jr, Vincenzo Silani, Gianfranco Parati, Giuseppe Malchiodi, Giovanni Malferrari, Francesco Strozzi, Nicola Tusini, Enrico Vecchiati, Gioacchino Coppi, Antonio Lauricella, Roberto Moratto, Roberto Silingardi, Jessica Veronesi, Andrea Zini, Emanuele Ferrero, Michelangelo Ferri, Andrea Gaggiano, Carmelo Labate, Franco Nessi, Daniele Psacharopulo, Andrea Viazzo, Giovanni Malacrida, Daniela Mazzaccaro, Giovanni Meola, Alfredo Modafferi, Giovanni Nano, Maria Teresa Occhiuto, Paolo Righini, Silvia Stegher, Stefano Chiarandini, Filippo Griselli, Sandro Lepidi, Fabio Pozzi Mucelli, Marcello Naccarato, Mario D'Oria, Barbara Ziani, Andrea Stella, Mortalla Dieng, Gianluca Faggioli, Mauro Gargiulo, Sergio Palermo, Rodolfo Pini, Giovanni Maria Puddu, Andrea Vacirca, Domenico Angiletta, Claudio Desantis, Davide Marinazzo, Giovanni Mastrangelo, Guido Regina, Raffaele Pulli, Paolo Bianchi, Lea Cireni, Elisabetta Coppi, Rocco Pizzirusso, Filippo Scalise, Giovanni Sorropago, Valerio Tolva, Valeria Caso, Enrico Cieri, Paola DeRango, Luca Farchioni, Giacomo Isernia, Massimo Lenti, Gian Battista Parlani, Guglielmo Pupo, Grazia Pula, Gioele Simonte, Fabio Verzini, Federico Carimati, Maria Luisa Delodovici, Federico Fontana, Gabriele Piffaretti, Matteo Tozzi, Efrem Civilini, Giorgio Poletto, Bernhard Reimers, Barbara Praquin, Sonia Ronchey, Laura Capoccia, Wassim Mansour, Enrico Sbarigia, Francesco Speziale, Pasqualino Sirignano, Danilo Toni, Roberto Galeotti, Vincenzo Gasbarro, Francesco Mascoli, Tiberio Rocca, Elpiniki Tsolaki, Giulia Bernardini, Ester DeMarco, Alessia Giaquinta, Francesco Patti, Massimiliano Veroux, Pierfrancesco Veroux, Carla Virgilio, Nicola Mangialardi, Matteo Orrico, Vincenzo Di Lazzaro, Nunzio Montelione, Francesco Spinelli, Francesco Stilo, Carlo Cernetti, Sandro Irsara, Giuseppe Maccarrone, Diego Tonello, Adriana Visonà, Beniamino Zalunardo, Emiliano Chisci, Stefano Michelagnoli, Nicola Troisi, Maela Masato, Massimo Dei Negri, Andrea Pacchioni, Salvatore Saccà, Giovanni Amatucci, Alfredo Cannizzaro, Federico Accrocca, Cesare Ambrogi, Renzo Barbazza, Giustino Marcucci, Andrea Siani, Guido Bajardi, Giovanni Savettieri, Angelo Argentieri, Riccardo Corbetta, Attilio Odero, Pietro Quaretti, Federico Z Thyrion, Alessandro Cappelli, Domenico Benevento, Gianmarco De Donato, Maria Agnese Mele, Giancarlo Palasciano, Daniela Pieragalli, Alessandro Rossi, Carlo Setacci, Francesco Setacci, Domenico Palombo, Maria Cecilia Perfumo, Edoardo Martelli, Aldo Paolucci, Santi Trimarchi, Viviana Grassi, Luigi Grimaldi, Giuliana La Rosa, Domenico Mirabella, Matteo Scialabba, Leonildo Sichel, Costantino L D'Angelo, Gian Franco Fadda, Holta Kasemi, Mario Marino, Francesco Burzotta, Francesco Alberto Codispoti, Angela Ferrante, Giovanni Tinelli, Yamume Tshomba, Claudio Vincenzoni, Deborah Amis, Dawn Anderson, Martin Catterson, Mike Clarke, Michelle Davis, Anand Dixit, Alexander Dyker, Gary Ford, Ralph Jackson, Sreevalsan Kappadath, David Lambert, Tim Lees, Stephen Louw, James McCaslin, Noala Parr, Rebecca Robson, Gerard Stansby, Lucy Wales, Vera Wealleans, Lesley Wilson, Michael Wyatt, Hardeep Baht, Ibrahim Balogun, Ilse Burger, Tracy Cosier, Linda Cowie, Gunaratnam Gunathilagan, David Hargroves, Robert Insall, Sally Jones, Hannah Rudenko, Natasha Schumacher, Jawaharlal Senaratne, George Thomas, Audrey Thomson, Tom Webb, Ellen Brown, Bernard Esisi, Ali Mehrzad, Shane MacSweeney, Norman McConachie, Alison Southam, Wayne Sunman, Ahmed Abdul-Hamiq, Jenny Bryce, Ian Chetter, Duncan Ettles, Raghuram Lakshminarayan, Kim Mitchelson, Christopher Rhymes, Graham Robinson, Paul Scott, Alison Vickers, Ray Ashleigh, Stephen Butterfield, Ed Gamble, Jonathan Ghosh, Charles N McCollum, Mark Welch, Sarah Welsh, Leszek Wolowczyk, Mary Donnelly, Stephen D'Souza, Anselm A Egun, Bindu Gregary, Thomas Joseph, Christine Kelly, Shuja Punekar, M Asad Rahi, Sonia Raj, Dare Seriki, George Thomson, James Brown, Ragunath Durairajan, Iris Grunwald, Paul Guyler, Paula Harman, Matthew Jakeways, Christopher Khuoge, Ashish Kundu, Thayalini Loganathan, Nisha Menon, Raji O Prabakaran, Devesh Sinha, Vicky Thompson, Sharon Tysoe, Dennis Briley, Chris Darby, Linda Hands, Dominic Howard, Wilhelm Kuker, Ursula Schulz, Rachel Teal, David Barer, Andrew Brown, Susan Crawford, Paul Dunlop, Ramesh Krishnamurthy, Nikhil Majmudar, Duncan Mitchell, Min P Myint, Richard O'Brien, Janice O'Connell, Naweed Sattar, Shanmugam Vetrivel, Jonathan Beard, Trevor Cleveland, Peter Gaines, John Humphreys, Alison Jenkins, Craig King, Daniel Kusuma, Ralph Lindert, Robbie Lonsdale, Raj Nair, Shah Nawaz, Faith Okhuoya, Douglas Turner, Graham Venables, Paul Dorman, Andrea Hughes, Deborah Jones, David Mendelow, Helen Rodgers, Aidas Raudoniitis, Peter Enevoldson, Hans Nahser, Imelda O'Brien, Francesco Torella, Dave Watling, Richard White, Pauline Brown, Dipankar Dutta, Lorraine Emerson, Paula Hilltout, Sachin Kulkarni, Jackie Morrison, Keith Poskitt, Fiona Slim, Sarah Smith, Amanda Tyler, Joanne Waldron, Mark Whyman, Milda Bajoriene, Lucy Baker, Amanda Colston, Bekky Eliot-Jones, Gita Gramizadeh, Catherine Lewis-Clarke, Laura McCafferty, Deborah Oliver, Debbie Palmer, Abhijeet Patil, Suzannah Pegler, Gopi Ramadurai, Aisling Roberts, Tracey Sargent, Shivaprasad Siddegowda, Ravi Singh-Ranger, Akintunde Williams, Lucy Williams, Steve Windebank, Tadas Zuromskis, Lanka Alwis, Jane Angus, Asaipillai Asokanathan, Caroline Fornolles, Diana Hardy, Sophy Hunte, Frances Justin, Duke Phiri, Marie Mitabouana-Kibou, Lakshmanan Sekaran, Sakthivel Sethuraman, Margaret L Tate, Joyce Akyea-Mensah, Stephen Ball, Angela Chrisopoulou, Elizabeth Keene, Alison Phair, Steven Rogers, John V Smyth, Colin Bicknell, Jeremy Chataway, Nicholas Cheshire, Andrew Clifton, Caroline Eley, Richard Gibbs, Mohammad Hamady, Beth Hazel, Alex James, Michael Jenkins, Nyma Khanom, Austin Lacey, Maz Mireskandari, Joanna O'Reilly, Antony Pereira, Tina Sachs, John Wolfe, Philip Davey, Gill Rogers, Gemma Smith, Gareth Tervit, Ian Nichol, Andrew Parry, Gavin Young, Simon Ashley, James Barwell, Francis Dix, Azlisham M Nor, Chris Parry, Angela Birt, Paul Davies, Jim George, Anne Graham, Leon Jonker, Nicci Kelsall, Caroline Potts, Toni Wilson, Jamie Crinnion, Larissa Cuenoud, Nikola Aleksic, Srdan Babic, Nenad Ilijevski, Đorde Radak, Dragan Sagic, Slobodan Tanaskovic, Momcilo Colic, Vladimir Cvetic, Lazar Davidovic, Dejana R Jovanovic, Igor Koncar, Perica Mutavdžic, Miloš Sladojevic, Ivan Tomic, Eike S Debus, Ulrich Grzyska, Dagmar Otto, Götz Thomalla, Jessica Barlinn, Johannes Gerber, Kathrin Haase, Christian Hartmann, Stefan Ludwig, Volker Pütz, Christian Reeps, Christine Schmidt, Norbert Weiss, Sebastian Werth, Simon Winzer, Janine Gemper, Albrecht Günther, Bianka Heiling, Elisabeth Jochmann, Panagiota Karvouniari, Carsten Klingner, Thomas Mayer, Julia Schubert, Friederike Schulze-Hartung, Jürgen Zanow, Yvonne Bausback, Franka Borger, Spiridon Botsios, Daniela Branzan, Sven Bräunlich, Henryk Hölzer, Janin Lenzer, Christopher Piorkowski, Nadine Richter, Johannes Schuster, Dierk Scheinert, Andrej Schmidt, Holger Staab, Matthias Ulrich, Martin Werner, Hermann Berger, Gábor Biró, Hans-Henning Eckstein, Michael Kallmayer, Kornelia Kreiser, Alexander Zimmermann, Bärbel Berekoven, Klaus Frerker, Vera Gordon, Giovanni Torsello, Sebastian Arnold, Cora Dienel, Martin Storck, Bernhard Biermaier, Hans Martin Gissler, Christof Klötzsch, Tomas Pfeiffer, Ralph Schneider, Leander Söhl, Michael Wennrich, Angelika Alonso, Michael Keese, Christoph Groden, Andreas Cöster, Andreas Engelhardt, Christoph-Maria Ratusinski, Bengt Berg, Martin Delle, Johan Formgren, Peter Gillgren, Lotta Jarl, Torbjörn B Kall, Peter Konrad, Niklas Nyman, Claes Skiöldebrand, Johnny Steuer, Rabbe Takolander, Jonas Malmstedt, Stefan Acosta, Katarina Björses, Kerstin Brandt, Nuno Dias, Anders Gottsäter, Jan Holst, Thorarinn Kristmundsson, Tobias Kühme, Tilo Kölbel, Bengt Lindblad, Mats Lindh, Martin Malina, Tomas Ohrlander, Tim Resch, Viola Rönnle, Björn Sonesson, Margareta Warvsten, Zbigniew Zdanowski, Erik Campbell, Per Kjellin, Hans Lindgren, Johan Nyberg, Björn Petersen, Gunnar Plate, Håkan Pärsson, Peter Qvarfordt, Pavel Ignatenko, Andrey Karpenko, Vladimir Starodubtsev, Mikhail A Chernyavsky, Maria S Golovkova, Boris B Komakha, Nikolay N Zherdev, Andrey Belyasnik, Pavel Chechulov, Dmitry Kandyba, Igor Stepanishchev, Csaba Csobay-Novák, Edit Dósa, László Entz, Balázs Nemes, Zoltán Szeberin, Pál Barzó, Mihaly Bodosi, Eniko Fákó, Béla Fülöp, Tamás Németh, Szilárd Pazdernyik, Krisztina Skoba, Erika Vörös, Eleni Chatzinikou, Athanasios Giannoukas, Christos Karathanos, Stylianos Koutsias, Georgios Kouvelos, Miltiadis Matsagkas, Styliani Ralli, Christos Rountas, Nikolaos Rousas, Konstantinos Spanos, Elias Brountzos, John D Kakisis, Andreas Lazaris, Konstantinos G Moulakakis, Leonidas Stefanis, Georgios Tsivgoulis, Spyros Vasdekis, Constantine N Antonopoulos, Ion Bellenis, Dimitrios Maras, Antonios Polydorou, Victoria Polydorou, Antonios Tavernarakis, Nikolaos Ioannou, Maria Terzoudi, Miltos Lazarides, Michalis Mantatzis, Kostas Vadikolias, Lukasz Dzieciuchowicz, Marcin Gabriel, Zbigniew Krasinski, Grzegorz Oszkinis, Fryderyk Pukacki, Maciej Slowinski, Michal-Goran Stanišic, Ryszard Staniszewski, Jolanta Tomczak, Maciej Zielinski, Piotr Myrcha, Dorota Rózanski, Stanislaw Drelichowski, Wojciech Iwanowski, Katarzyna Koncewicz, Pawel Bialek, Zbigniew Biejat, Wojciech Czepel, Anna Czlonkowska, Anatol Dowzenko, Julia Jedrzejewska, Adam Kobayashi, Jerzy Leszczynski, Andrzej Malek, Jerzy Polanski, Robert Proczka, Maciej Skorski, Mieczyslaw Szostek, Piotr Andziak, Maciej Dratwicki, Robert Gil, Miroslaw Nowicki, Jaroslaw Pniewski, Jaroslaw Rzezak, Piotr Seweryniak, Pawel Dabek, Michal Juszynski, Grzegorz Madycki, Bartosz Pacewski, Witold Raciborski, Piotr Slowinski, Walerian Staszkiewicz, Martin Bombic, Vladimír Chlouba, Jirí Fiedler, Karel Hes, Petr Koštál, Jindrich Sova, Zdenek Kríž, Mojmír Prívara, Michal Reif, Robert Staffa, Robert Vlachovský, Bohuslav Vojtíšek, Tomáš Hrbác, Martin Kuliha, Václav Procházka, Martin Roubec, David Školoudík, David Netuka, Anna Šteklácová, Vladimír Beneš III, Pavel Buchvald, Ladislav Endrych, Miroslav Šercl, Walter Campos Jr, Ivan B Casella, Nelson de Luccia, André E V Estenssoro, Calógero Presti, Pedro Puech-Leão, Celso R B Neves, Erasmo S da Silva, Cid J Sitrângulo Jr, José A T Monteiro, Gisela Tinone, Marcelo Bellini Dalio, Edwaldo E Joviliano, Octávio M Pontes Neto, Mauricio Serra Ribeiro, Patrick Cras, Jeroen M H Hendriks, Mieke Hoppenbrouwers, Patrick Lauwers, Caroline Loos, Laetitia Yperzeele, Mia Geenens, Dimitri Hemelsoet, Isabelle van Herzeele, Frank Vermassen, Parla Astarci, Frank Hammer, Valérie Lacroix, André Peeters, Robert Verhelst, Silvana Cirelli, Pol Dormal, Annelies Grimonprez, Bart Lambrecht, Philipe Lerut, Eddy Thues, Guy De Koster, Quentin Desiron, Alain Maertens de Noordhout, Danielle Malmendier, Mireille Massoz, Georges Saad, Marc Bosiers, Joren Callaert, Koen Deloose, Estrella Blanco Cañibano, Beatriz García Fresnillo, Mercedes Guerra Requena, Pilar C Morata Barrado, Miguel Muela Méndez, Antonio Yusta Izquierdo, Fernando Aparici Robles, Paula Blanes Orti, Luis García Dominguez, Rafael Martínez López, Manuel Miralles Hernández, José I Tembl Ferrairo, Ángel Chamorro, Juan Macho, Víctor Obach, Vincent Riambau, Luis San Román, Frank J Ahlhelm, Kristine Blackham, Stefan Engelter, Thomas Eugster, Henrik Gensicke, Lorenz Gürke, Philippe Lyrer, Luigi Mariani, Marina Maurer, Edin Mujagic, Mandy Müller, Marios Psychogios, Peter Stierli, Christoph Stippich, Christopher Traenka, Thomas Wolff, Benjamin Wagner, Martina M Wiegert, Sandra Clarke, Michael Diepers, Ernst Gröchenig, Philipp Gruber, Andrej Isaak, Timo Kahles, Regula Marti, Krassen Nedeltchev, Luca Remonda, Nadir Tissira, Martina Valença Falcão, Gert J de Borst, Rob H Lo, Frans L Moll, Raechel Toorop, Bart H van der Worp, Evert J Vonken, Jaap L Kappelle, Ommid Jahrome, Floris Vos, Wouter Schuiling, Hendrik van Overhagen, Rudolf W M Keunen, Bob Knippenberg, Jan J Wever, Jan W Lardenoije, Michel Reijnen, Luuk Smeets, Steven van Sterkenburg, Gustav Fraedrich, Elke Gizewski, Ingrid Gruber, Michael Knoflach, Stefan Kiechl, Barbara Rantner, Timur Abdulamit, Patrice Bergeron, Raymond Padovani, Jean-Christophe Trastour, Jean-Marie Cardon, Anne Le Gallou-Wittenberg, Eric Allaire, Jean-Pierre Becquemin, Frédéric Cochennec-Paliwoda, Pascal Desgranges, Hassan Hosseini, Hicham Kobeiter, Jean Marzelle, Mohammed A Almekhlafi, Simerpreet Bal, Phillip A Barber, Shelagh B Coutts, Andrew M Demchuk, Muneer Eesa, Michelle Gillies, Mayank Goyal, Michael D Hill, Mark E Hudon, Anitha Jambula, Carol Kenney, Gary Klein, Marie McClelland, Alim Mitha, Bijoy K Menon, William F Morrish, Steven Peters, Karla J Ryckborst, Greg Samis, Supriya Save, Eric E Smith, Peter Stys, Suresh Subramaniam, Garnette R Sutherland, Tim Watson, John H Wong, L Zimmel, Vojko Flis, Jože Matela, Kazimir Miksic, Franko Milotic, Božidar Mrdja, Barbara Stirn, Erih Tetickovic, Mladen Gasparini, Anton Grad, Ingrid Kompara, Zoren Miloševic, Veronika Palmiste, Toomas Toomsoo, Balzhan Aidashova, Nursultan Kospanov, Roman Lyssenko, Daulet Mussagaliev, Rafi Beyar, Aaron Hoffman, Tony Karram, Arthur Kerner, Eugenia Nikolsky, Samy Nitecki, Silva Andonova, Chavdar Bachvarov, Vesko Petrov, Ivan Cvjetko, Vinko Vidjak, Damir Halužan, Mladen Petrunic, Bao Liu, Chang-Wei Liu, Daniel Bartko, Peter Beno, František Rusnák, Kamil Zelenák, Masayuki Ezura, Takashi Inoue, Naoto Kimura, Ryushi Kondo, Yasushi Matsumoto, Hiroaki Shimizu, Hidenori Endo, Eisuke Furui, Søren Bakke, Kristen Krohg-Sørensen, Terje Nome, Mona Skjelland, Bjørn Tennøe, João Albuquerque e Castro, Gonçalo Alves, Frederico Bastos Gonçalves, José de Aragão Morais, Ana C Garcia, Hugo Valentim, Leonor Vasconcelos, Fernando Belcastro, Fernando Cura, Patricio Zaefferer, Foad Abd-Allah, Mohamed H Eldessoki, Hussein Heshmat Kassem, Haytham Soliman Gharieb, Mary P Colgan, Syed N Haider, Joe Harbison, Prakash Madhavan, Dermot Moore, Gregor Shanik, Viviane Kazan, Munier Nazzal, Vicki Ramsey-Williams, ACST-2 Collaborative Group, Group, ACST-2 Collaborative, Halliday A., Bulbulia R., Bonati L.H., Chester J., Cradduck-Bamford A., Peto R., Pan H., Potter J., Henning Eckstein H., Farrell B., Flather M., Mansfield A., Mihaylova B., Rahimi K., Simpson D., Thomas D., Sandercock P., Gray R., Molyneux A., Shearman C.P., Rothwell P., Belli A., Herrington W., Judge P., Leopold P., Mafham M., Gough M., Cao P., MacDonald S., Bari V., Berry C., Bradshaw S., Brudlo W., Clarke A., Cox R., Fathers S., Gaba K., Gray M., Hayter E., Holliday C., Kurien R., Lay M., le Conte S., McManus J., Madgwick Z., Morris D., Munday A., Pickworth S., Ostasz W., Poorthuis M., Richards S., Teixeira L., Tochlin S., Tully L., Wallis C., Willet M., Young A., Casana R., Malloggi C., Odero A., Silani V., Parati G., Malchiodi G., Malferrari G., Strozzi F., Tusini N., Vecchiati E., Coppi G., Lauricella A., Moratto R., Silingardi R., Veronesi J., Zini A., Ferrero E., Ferri M., Gaggiano A., Labate C., Nessi F., Psacharopulo D., Viazzo A., Malacrida G., Mazzaccaro D., Meola G., Modafferi A., Nano G., Occhiuto M.T., Righini P., Stegher S., Chiarandini S., Griselli F., Lepidi S., Pozzi Mucelli F., Naccarato M., D'Oria M., Ziani B., Stella A., Dieng M., Faggioli G., Gargiulo M., Palermo S., Pini R., Puddu G.M., Vacirca A., Angiletta D., Desantis C., Marinazzo D., Mastrangelo G., Regina G., Pulli R., Bianchi P., Cireni L., Coppi E., Pizzirusso R., Scalise F., Sorropago G., Tolva V., Caso V., Cieri E., DeRango P., Farchioni L., Isernia G., Lenti M., Parlani G.B., Pupo G., Pula G., Simonte G., Verzini F., Carimati F., Delodovici M.L., Fontana F., Piffaretti G., Tozzi M., Civilini E., Poletto G., Reimers B., Praquin B., Ronchey S., Capoccia L., Mansour W., Sbarigia E., Speziale F., Sirignano P., Toni D., Galeotti R., Gasbarro V., Mascoli F., Rocca T., Tsolaki E., Bernardini G., DeMarco E., Giaquinta A., Patti F., Veroux M., Veroux P., Virgilio C., Mangialardi N., Orrico M., Di Lazzaro V., Montelione N., Spinelli F., Stilo F., Cernetti C., Irsara S., Maccarrone G., Tonello D., Visona A., Zalunardo B., Chisci E., Michelagnoli S., Troisi N., Masato M., Dei Negri M., Pacchioni A., Sacca S., Amatucci G., Cannizzaro A., Accrocca F., Ambrogi C., Barbazza R., Marcucci G., Siani A., Bajardi G., Savettieri G., Argentieri A., Corbetta R., Quaretti P., Thyrion F.Z., Cappelli A., Benevento D., De Donato G., Mele M.A., Palasciano G., Pieragalli D., Rossi A., Setacci C., Setacci F., Palombo D., Perfumo M.C., Martelli E., Paolucci A., Trimarchi S., Grassi V., Grimaldi L., La Rosa G., Mirabella D., Scialabba M., Sichel L., D'Angelo C.L., Fadda G.F., Kasemi H., Marino M., Burzotta F., Codispoti F.A., Ferrante A., Tinelli G., Tshomba Y., Vincenzoni C., Amis D., Anderson D., Catterson M., Clarke M., Davis M., Dixit A., Dyker A., Ford G., Jackson R., Kappadath S., Lambert D., Lees T., Louw S., McCaslin J., Parr N., Robson R., Stansby G., Wales L., Wealleans V., Wilson L., Wyatt M., Baht H., Balogun I., Burger I., Cosier T., Cowie L., Gunathilagan G., Hargroves D., Insall R., Jones S., Rudenko H., Schumacher N., Senaratne J., Thomas G., Thomson A., Webb T., Brown E., Esisi B., Mehrzad A., MacSweeney S., McConachie N., Southam A., Sunman W., Abdul-Hamiq A., Bryce J., Chetter I., Ettles D., Lakshminarayan R., Mitchelson K., Rhymes C., Robinson G., Scott P., Vickers A., Ashleigh R., Butterfield S., Gamble E., Ghosh J., McCollum C.N., Welch M., Welsh S., Wolowczyk L., Donnelly M., D'Souza S., Egun A.A., Gregary B., Joseph T., Kelly C., Punekar S., Rahi M.A., Raj S., Seriki D., Thomson G., Brown J., Durairajan R., Grunwald I., Guyler P., Harman P., Jakeways M., Khuoge C., Kundu A., Loganathan T., Menon N., Prabakaran R.O., Sinha D., Thompson V., Tysoe S., Briley D., Darby C., Hands L., Howard D., Kuker W., Schulz U., Teal R., Barer 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Akyea-Mensah J., Ball S., Chrisopoulou A., Keene E., Phair A., Rogers S., Smyth J.V., Bicknell C., Chataway J., Cheshire N., Clifton A., Eley C., Gibbs R., Hamady M., Hazel B., James A., Jenkins M., Khanom N., Lacey A., Mireskandari M., O'Reilly J., Pereira A., Sachs T., Wolfe J., Davey P., Rogers G., Smith G., Tervit G., Nichol I., Parry A., Young G., Ashley S., Barwell J., Dix F., Nor A.M., Parry C., Birt A., Davies P., George J., Graham A., Jonker L., Kelsall N., Potts C., Wilson T., Crinnion J., Cuenoud L., Aleksic N., Babic S., Ilijevski N., Radak, Sagic D., Tanaskovic S., Colic M., Cvetic V., Davidovic L., Jovanovic D.R., Koncar I., Mutavdzic P., Sladojevic M., Tomic I., Debus E.S., Grzyska U., Otto D., Thomalla G., Barlinn J., Gerber J., Haase K., Hartmann C., Ludwig S., Putz V., Reeps C., Schmidt C., Weiss N., Werth S., Winzer S., Gemper J., Gunther A., Heiling B., Jochmann E., Karvouniari P., Klingner C., Mayer T., Schubert J., Schulze-Hartung F., Zanow J., Bausback Y., Borger F., Botsios S., Branzan D., Braunlich S., Holzer H., Lenzer J., Piorkowski C., Richter N., Schuster J., Scheinert D., Schmidt A., Staab H., Ulrich M., Werner M., Berger H., Biro G., Eckstein H.-H., Kallmayer M., Kreiser K., Zimmermann A., Berekoven B., Frerker K., Gordon V., Torsello G., Arnold S., Dienel C., Storck M., Biermaier B., Gissler H.M., Klotzsch C., Pfeiffer T., Schneider R., Sohl L., Wennrich M., Alonso A., Keese M., Groden C., Coster A., Engelhardt A., Ratusinski C.-M., Berg B., Delle M., Formgren J., Gillgren P., Jarl L., Kall T.B., Konrad P., Nyman N., Skioldebrand C., Steuer J., Takolander R., Malmstedt J., Acosta S., Bjorses K., Brandt K., Dias N., Gottsater A., Holst J., Kristmundsson T., Kuhme T., Kolbel T., Lindblad B., Lindh M., Malina M., Ohrlander T., Resch T., Ronnle V., Sonesson B., Warvsten M., Zdanowski Z., Campbell E., Kjellin P., Lindgren H., Nyberg J., Petersen B., Plate G., Parsson H., Qvarfordt P., Ignatenko P., Karpenko A., Starodubtsev V., Chernyavsky M.A., Golovkova M.S., Komakha B.B., Zherdev N.N., Belyasnik A., Chechulov P., Kandyba D., Stepanishchev I., Csobay-Novak C., Dosa E., Entz L., Nemes B., Szeberin Z., Barzo P., Bodosi M., Fako E., Fulop B., Nemeth T., Pazdernyik S., Skoba K., Voros E., Chatzinikou E., Giannoukas A., Karathanos C., Koutsias S., Kouvelos G., Matsagkas M., Ralli S., Rountas C., Rousas N., Spanos K., Brountzos E., Kakisis J.D., Lazaris A., Moulakakis K.G., Stefanis L., Tsivgoulis G., Vasdekis S., Antonopoulos C.N., Bellenis I., Maras D., Polydorou A., Polydorou V., Tavernarakis A., Ioannou N., Terzoudi M., Lazarides M., Mantatzis M., Vadikolias K., Dzieciuchowicz L., Gabriel M., Krasinski Z., Oszkinis G., Pukacki F., Slowinski M., Stanisic M.-G., Staniszewski R., Tomczak J., Zielinski M., Myrcha P., Rozanski D., Drelichowski S., Iwanowski W., Koncewicz K., Bialek P., Biejat Z., Czepel W., Czlonkowska A., Dowzenko A., Jedrzejewska J., Kobayashi A., Leszczynski J., Malek A., Polanski J., Proczka R., Skorski M., Szostek M., Andziak P., Dratwicki M., Gil R., Nowicki M., Pniewski J., Rzezak J., Seweryniak P., Dabek P., Juszynski M., Madycki G., Pacewski B., Raciborski W., Slowinski P., Staszkiewicz W., Bombic M., Chlouba V., Fiedler J., Hes K., Kostal P., Sova J., Kriz Z., Privara M., Reif M., Staffa R., Vlachovsky R., Vojtisek B., Hrbac T., Kuliha M., Prochazka V., Roubec M., Skoloudik D., Netuka D., Steklacova A., Benes III V., Buchvald P., Endrych L., Sercl M., Campos W., Casella I.B., de Luccia N., Estenssoro A.E.V., Presti C., Puech-Leao P., Neves C.R.B., da Silva E.S., Sitrangulo C.J., Monteiro J.A.T., Tinone G., Bellini Dalio M., Joviliano E.E., Pontes Neto O.M., Serra Ribeiro M., Cras P., Hendriks J.M.H., Hoppenbrouwers M., Lauwers P., Loos C., Yperzeele L., Geenens M., Hemelsoet D., van Herzeele I., Vermassen F., Astarci P., Hammer F., Lacroix V., Peeters A., Verhelst R., Cirelli S., Dormal P., Grimonprez A., Lambrecht B., Lerut P., Thues E., De Koster G., Desiron Q., Maertens de Noordhout A., Malmendier D., Massoz M., Saad G., Bosiers M., Callaert J., Deloose K., Blanco Canibano E., Garcia Fresnillo B., Guerra Requena M., Morata Barrado P.C., Muela Mendez M., Yusta Izquierdo A., Aparici Robles F., Blanes Orti P., Garcia Dominguez L., Martinez Lopez R., Miralles Hernandez M., Tembl Ferrairo J.I., Chamorro A., Macho J., Obach V., Riambau V., San Roman L., Ahlhelm F.J., Blackham K., Engelter S., Eugster T., Gensicke H., Gurke L., Lyrer P., Mariani L., Maurer M., Mujagic E., Muller M., Psychogios M., Stierli P., Stippich C., Traenka C., Wolff T., Wagner B., Wiegert M.M., Clarke S., Diepers M., Grochenig E., Gruber P., Isaak A., Kahles T., Marti R., Nedeltchev K., Remonda L., Tissira N., Valenca Falcao M., de Borst G.J., Lo R.H., Moll F.L., Toorop R., van der Worp B.H., Vonken E.J., Kappelle J.L., Jahrome O., Vos F., Schuiling W., van Overhagen H., Keunen R.W.M., Knippenberg B., Wever J.J., Lardenoije J.W., Reijnen M., Smeets L., van Sterkenburg S., Fraedrich G., Gizewski E., Gruber I., Knoflach M., Kiechl S., Rantner B., Abdulamit T., Bergeron P., Padovani R., Trastour J.-C., Cardon J.-M., Le Gallou-Wittenberg A., Allaire E., Becquemin J.-P., Cochennec-Paliwoda F., Desgranges P., Hosseini H., Kobeiter H., Marzelle J., Almekhlafi M.A., Bal S., Barber P.A., Coutts S.B., Demchuk A.M., Eesa M., Gillies M., Goyal M., Hill M.D., Hudon M.E., Jambula A., Kenney C., Klein G., McClelland M., Mitha A., Menon B.K., Morrish W.F., Peters S., Ryckborst K.J., Samis G., Save S., Smith E.E., Stys P., Subramaniam S., Sutherland G.R., Watson T., Wong J.H., Zimmel L., Flis V., Matela J., Miksic K., Milotic F., Mrdja B., Stirn B., Tetickovic E., Gasparini M., Grad A., Kompara I., Milosevic Z., Palmiste V., Toomsoo T., Aidashova B., Kospanov N., Lyssenko R., Mussagaliev D., Beyar R., Hoffman A., Karram T., Kerner A., Nikolsky E., Nitecki S., Andonova S., Bachvarov C., Petrov V., Cvjetko I., Vidjak V., Haluzan D., Petrunic M., Liu B., Liu C.-W., Bartko D., Beno P., Rusnak F., Zelenak K., Ezura M., Inoue T., Kimura N., Kondo R., Matsumoto Y., Shimizu H., Endo H., Furui E., Bakke S., Krohg-Sorensen K., Nome T., Skjelland M., Tennoe B., Albuquerque e Castro J., Alves G., Bastos Goncalves F., de Aragao Morais J., Garcia A.C., Valentim H., Vasconcelos L., Belcastro F., Cura F., Zaefferer P., Abd-Allah F., Eldessoki M.H., Heshmat Kassem H., Soliman Gharieb H., Colgan M.P., Haider S.N., Harbison J., Madhavan P., Moore D., Shanik G., Kazan V., Nazzal M., Ramsey-Williams V., and Gargiulo M
Subjects: Male, medicine.medical_specialty, Time Factors, Time Factor, medicine.medical_treatment, Carotid Stenosi, MEDLINE, Carotid endarterectomy, Rate ratio, Risk Assessment, Asymptomatic, law.invention, Randomized controlled trial, law, Risk Factors, carotid artery stenting (CAS), carotid endarterectomy (CEA), Stent, medicine, Humans, Carotid Stenosis, Stroke, Endarterectomy, Aged, Endarterectomy, Carotid, business.industry, carotid artery, Risk Factor, Articles, General Medicine, trial, medicine.disease, Settore MED/22 - CHIRURGIA VASCOLARE, Surgery, Stenosis, Treatment Outcome, Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, Female, Stents, Human medicine, medicine.symptom, business, Human
Abstract: Summary Background Among asymptomatic patients with severe carotid artery stenosis but no recent stroke or transient cerebral ischaemia, either carotid artery stenting (CAS) or carotid endarterectomy (CEA) can restore patency and reduce long-term stroke risks. However, from recent national registry data, each option causes about 1% procedural risk of disabling stroke or death. Comparison of their long-term protective effects requires large-scale randomised evidence. Methods ACST-2 is an international multicentre randomised trial of CAS versus CEA among asymptomatic patients with severe stenosis thought to require intervention, interpreted with all other relevant trials. Patients were eligible if they had severe unilateral or bilateral carotid artery stenosis and both doctor and patient agreed that a carotid procedure should be undertaken, but they were substantially uncertain which one to choose. Patients were randomly allocated to CAS or CEA and followed up at 1 month and then annually, for a mean 5 years. Procedural events were those within 30 days of the intervention. Intention-to-treat analyses are provided. Analyses including procedural hazards use tabular methods. Analyses and meta-analyses of non-procedural strokes use Kaplan-Meier and log-rank methods. The trial is registered with the ISRCTN registry, ISRCTN21144362. Findings Between Jan 15, 2008, and Dec 31, 2020, 3625 patients in 130 centres were randomly allocated, 1811 to CAS and 1814 to CEA, with good compliance, good medical therapy and a mean 5 years of follow-up. Overall, 1% had disabling stroke or death procedurally (15 allocated to CAS and 18 to CEA) and 2% had non-disabling procedural stroke (48 allocated to CAS and 29 to CEA). Kaplan-Meier estimates of 5-year non-procedural stroke were 2·5% in each group for fatal or disabling stroke, and 5·3% with CAS versus 4·5% with CEA for any stroke (rate ratio [RR] 1·16, 95% CI 0·86–1·57; p=0·33). Combining RRs for any non-procedural stroke in all CAS versus CEA trials, the RR was similar in symptomatic and asymptomatic patients (overall RR 1·11, 95% CI 0·91–1·32; p=0·21). Interpretation Serious complications are similarly uncommon after competent CAS and CEA, and the long-term effects of these two carotid artery procedures on fatal or disabling stroke are comparable. Funding UK Medical Research Council and Health Technology Assessment Programme.
Published: 2021

46. Endovascular interventions for peripheral arterial disease have to be integrated in a concept of total cardiovascular care by angiologists to improve patients and limbs prognosis

Author: Norbert Weiss
Subjects: medicine.medical_specialty, Arterial disease, business.industry, Endovascular interventions, medicine, Cardiovascular care, Cardiology and Cardiovascular Medicine, Intensive care medicine, business, Peripheral
Published: 2020
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47. Selective inhibition of neuronal Cav3.3 T-type calcium channels by TAT-based channel peptide

Author: Norbert Weiss and Leos Cmarko
Subjects: 0301 basic medicine, Nervous system, TAT-peptide, Inhibitor, Peptide, Gating, Selective inhibition, lcsh:RC346-429, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Cav3.3 channel, medicine, Molecular Biology, lcsh:Neurology. Diseases of the nervous system, chemistry.chemical_classification, Voltage-dependent calcium channel, Chemistry, Calcium channel, T-type calcium channel, Cell biology, 030104 developmental biology, medicine.anatomical_structure, T-type channel, Cell-penetrating peptide, 030217 neurology & neurosurgery
Abstract: Low-voltage-activated Cav3 calcium channels (T-type) play an essential role in the functioning of the nervous system where they support oscillatory activities that relie on several channel molecular determinants that shape their unique gating properties. In a previous study, we documented the important role of the carboxy proximal region in the functioning of Cav3.3 channels. Here, we explore the ability of a TAT-based cell penetrating peptide containing this carboxy proximal region (TAT-C3P) to modulate the activity of Cav3 channels. We show that chronic application of TAT-C3P on tsA-201 cells expressing Cav3 channels selectively inhibits Cav3.3 channels without affecting Cav3.1 and Cav3.2 channels. Therefore, the TAT-C3P peptide described in this study represents a new tool to address the specific physiological role of Cav3.3 channels, and to potentially enhance our understanding of Cav3.3 in disease.
Published: 2020
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48. T-type channels in neuropathic pain - Villain or victim?

Author: Norbert Weiss
Subjects: Glycosylation, glycosylation, Biophysics, SUMO protein, Pain, Biochemistry, Models, Biological, chemistry.chemical_compound, Calcium Channels, T-Type, ubiquitinylation, Ganglia, Spinal, post-translational modifications, Animals, Humans, Chemistry, phosphorylation, Calcium channel, sumoylation, T-type channel, Neuropathic pain, Posttranslational modification, Commentary, Phosphorylation, Neuralgia, calcium channel, Neuroscience
Published: 2020

49. ADMA elevation does not exacerbate development of diabetic nephropathy in mice with streptozotocin-induced diabetes mellitus

Author: Stefanie M. Bode-Böger, Christian Hugo, Alfred Schneider, Roman N. Rodionov, Natalia Jarzebska, Vladimir T. Todorov, Jens Martens-Lobenhoffer, Bernd Hohenstein, Jan Sradnick, Annett Rexin, Silke Brilloff, and Norbert Weiss
Subjects: Male, medicine.medical_specialty, Inflammation, 030204 cardiovascular system & hematology, Arginine, Streptozocin, Amidohydrolases, Diabetes Mellitus, Experimental, Diabetic nephropathy, Pathogenesis, Mice, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Risk Factors, Internal medicine, Diabetes mellitus, Internal Medicine, medicine, Animals, Diabetic Nephropathies, 030212 general & internal medicine, business.industry, Glomerulosclerosis, General Medicine, medicine.disease, Streptozotocin, Mice, Inbred C57BL, Endocrinology, chemistry, Albuminuria, medicine.symptom, Cardiology and Cardiovascular Medicine, business, Asymmetric dimethylarginine, Glomerular Filtration Rate, medicine.drug
Abstract: Background and aims Cardiovascular disease is nowadays the major cause of mortality and morbidity worldwide. The risk of developing cardiovascular disease is significantly increased in patients with diabetic nephropathy. It has been suggested that asymmetric dimethylarginine (ADMA), an endogenous inhibitor of NO synthases (NOS), may play an important role in the pathogenesis of diabetic nephropathy. ADMA is mainly metabolized by dimethylarginine dimethylaminohydrolase 1 (DDAH1). The goal of this study was to test the hypothesis that elevation of systemic ADMA levels by knocking out DDAH1 would exacerbate functional and structural glomerular abnormalities in a murine model of diabetic nephropathy. Methods Streptozotocin (STZ) was used to induce diabetes in adult DDAH1 knock-out and wild type mice. Healthy mice served as controls. Mice were sacrificed after 20 weeks of diabetes. Plasma ADMA levels were assessed by isotope-dilution tandem mass spectrometry and albumin by ELISA. Kidneys were used for FACS analysis and were also stained for markers of inflammation, cell proliferation, glomerular cells and cell matrix. Results STZ led to development of diabetes mellitus in all injected animals. Deficiency of DDAH1 led to a significant increase in plasma ADMA levels in healthy and diabetic mice. The diabetic state itself did not influence systemic ADMA levels. Diabetic mice of both genotypes developed albuminuria and had increased glomerulosclerosis index. There were no changes in desmin expression, glomerular cell proliferation rate, matrix expansion and expression of Mac-2 antigen in the diabetic mice of both genotypes as compared to the healthy ones. Conclusions In summary, STZ-induced diabetes led to the development of early features of diabetic nephropathy. Deficiency of DDAH1 and subsequent increase in systemic ADMA levels did not exacerbate these changes, indicating that ADMA is not the major mediator of diabetic nephropathy in this experiment model.
Published: 2019
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50. A potential role for T-type calcium channels in homocysteinemia-induced peripheral neuropathy

Author: Leos Cmarko, Norbert Weiss, Aisylu S. Gaifullina, Gulshat Burkhanova, Guzel F. Sitdikova, Joanna Lazniewska, Elena Gerasimova, Andriy Tomin, Junting Huang, Paula Rivas-Ramirez, Yuriy Rzhepetskyy, Gerald W. Zamponi, Gaifullina, Aisylu S, Lazniewska, Joanna, Gerasimova, Elena V, Burkhanova, Gulshat F, Rzhepetskyy, Yuriy, Tomin, Andriy, Rivas-Ramirez, Paula, Huang, Junting, Cmarko, Leos, Zamponi, Gerald W, Sitdikova, Guzel F, and Weiss, Norbert
Subjects: Nociception, medicine.medical_specialty, Homocysteine, Hyperhomocysteinemia, chemistry.chemical_element, Calcium, Calcium Channels, T-Type, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, 030202 anesthesiology, Ganglia, Spinal, Internal medicine, medicine, Animals, pain, homocysteinemia, Rats, Wistar, allodynia, Calcium metabolism, Voltage-dependent calcium channel, Cell Membrane, T-type calcium channel, Peripheral Nervous System Diseases, homocysteine, medicine.disease, Rats, Disease Models, Animal, Cav3.2, Anesthesiology and Pain Medicine, Peripheral neuropathy, Endocrinology, Neurology, chemistry, Hyperalgesia, T-type channel, Phosphorylation, calcium channel, Neurology (clinical), Signal transduction, 030217 neurology & neurosurgery
Abstract: Homocysteinemia is a metabolic condition characterized by abnormally high level of homocysteine in the blood and is considered to be a risk factor for peripheral neuropathy. However, the cellular mechanisms underlying toxic effects of homocysteine on the processing of peripheral nociception have not yet been investigated comprehensively. Here, using a rodent model of experimental homocysteinemia, we report the causal association between homocysteine and the development of mechanical allodynia. Homocysteinemia-induced mechanical allodynia was reversed on pharmacological inhibition of T-type calcium channels. In addition, our in vitro studies indicate that homocysteine enhances recombinant T-type calcium currents by promoting the recycling of Cav3.2 channels back to the plasma membrane through a protein kinase C–dependent signaling pathway that requires the direct phosphorylation of Cav3.2 at specific loci. Altogether, these results reveal an unrecognized signaling pathway that modulates the expression of T-type calcium channels, and may potentially contribute to the development of peripheral neuropathy associated with homocysteinemia. Refereed/Peer-reviewed
Published: 2019
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