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  • 1
    Keywords: IN-VIVO ; GENE ; ALZHEIMERS-DISEASE ; IMMUNOREACTIVITY ; FRONTOTEMPORAL DEMENTIA ; CEREBROSPINAL-FLUID BIOMARKERS ; BUNINA BODIES ; CHROMOGRANIN PEPTIDES ; ALS PATIENTS ; EL-ESCORIAL
    Abstract: BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a fatal disorder of the motor neuron system with poor prognosis and marginal therapeutic options. Current clinical diagnostic criteria are based on electrophysiological examination and exclusion of other ALS-mimicking conditions. Neuroprotective treatments are, however, most promising in early disease stages. Identification of disease-specific CSF biomarkers and associated biochemical pathways is therefore most relevant to monitor disease progression, response to neuroprotective agents and to enable early inclusion of patients into clinical trials. METHODS AND FINDINGS: CSF from 35 patients with ALS diagnosed according to the revised El Escorial criteria and 23 age-matched controls was processed using paramagnetic bead chromatography for protein isolation and subsequently analyzed by MALDI-TOF mass spectrometry. CSF protein profiles were integrated into a Random Forest model constructed from 153 mass peaks. After reducing this peak set to the top 25%, a classifier was built which enabled prediction of ALS with high accuracy, sensitivity and specificity. Further analysis of the identified peptides resulted in a panel of five highly sensitive ALS biomarkers. Upregulation of secreted phosphoprotein 1 in ALS-CSF samples was confirmed by univariate analysis of ELISA and mass spectrometry data. Further quantitative validation of the five biomarkers was achieved in an 80-plex Multiple Reaction Monitoring mass spectrometry assay. CONCLUSIONS: ALS classification based on the CSF biomarker panel proposed in this study could become a valuable predictive tool for early clinical risk stratification. Of the numerous CSF proteins identified, many have putative roles in ALS-related metabolic processes, particularly in chromogranin-mediated secretion signaling pathways. While a stand-alone clinical application of this classifier will only be possible after further validation and a multicenter trial, it could be readily used to complement current ALS diagnostics and might also provide new insights into the pathomechanisms of this disease in the future.
    Type of Publication: Journal article published
    PubMed ID: 22970211
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  • 2
    ISSN: 1433-0407
    Keywords: Schlüsselwörter Okulopharyngeale Muskeldystrophie ; Trinukleotiderkrankungen ; Keywords Okulopharyngeal muscular dystrophy ; Trinucleotide disease
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Summary Oculopharyngeal muscular dystrophy (OPMD) is an autosomal dominant myopathy with almost benign course. Its clinical features include ptosis, dysphagia, and proximal limb muscle weakness. The OPMD gene has been localized to chromosome 14, causing expansions of GCG triplets. Scattered families with OPMD belonging to different ethnic groups have been described worldwide. We describe one from northern Germany. In genetic diagnosis, expansion of GCG triplets to 11 was observed, which proved that myopathy, which is very rare in Germany.
    Notes: Zusammenfassung Die Okulopharyngeale Muskeldystrophie (OPMD) ist eine familiäre Muskelerkrankung mit überwiegend benignem Verlauf, die autosomal dominant vererbt wird. Die Erkrankung ist klinisch gekennzeichnet durch Ptose, Dysphagie und proximale Muskelschwäche. Die Symptome treten in verschiedener Ausprägung, auch innerhalb einer Familie auf. Die Erkrankung wurde bei unterschiedlichen ethnischen Gruppen, insbesondere französisch-kanadischen Familien und bei Buchara-Juden beschrieben. Der Gendefekt liegt auf dem Chromosom 14 und verursacht eine Zunahme der GCG-Triplets, die für die Aminosäure Alanin kodieren. Die OPMD muss somit den sog. Trinukleotid-Erkrankungen zugerechnet werden. In dem vorliegenden Bericht präsentieren wir den Fall einer familiären OPMD, der in Norddeutschland aufgetreten ist, und bei der genetischen Testung eine Zunahme der GCG-Triplets auf 11 zeigt. Dies ist diagnostisch beweisend für das Vorliegen der in Deutschland sehr selten vorkommenden Muskelerkrankung OPMD.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Embryonic-like nicotinic channels were studied in mouse myotubes. Channel currents were measured by patch-clamping outside-out excised patches to which pulses of agonists and drugs could be applied by a liquid filament switch. The holding potential of the patches was generally around -40 mV. Pulses of 10-4 M acetylcholine elicited average channel currents which reached a peak open probability, Po, peak, of 0.93 within 0.5 ms and decayed with a time constant of desensitization of 20-80 ms. When physostigmine (10-5 to 10-3 M) or procaine (3 × 10-5 to 10-3 M) was added to the acetylcholine pulses, a fast decay component of the current appeared which shortened to a time constant of 0.5 ms for the maximal drug concentrations. The fast decay was followed by a slow one which declined in amplitude with increasing concentrations of the drugs. After the end of pulses of 10-4 M acetylcholine plus 3 × 10-4 M physostigmine the average current rose again, reaching a peak with -5 ms delay, and then decayed slowly. The amplitude of this recovery current was -0.4 Po, peak after 5 ms pulses and decreased with increasing pulse duration due to desensitization. The results can be quantitatively modelled based on a circular reaction scheme involving desensitization. Physostigmine and procaine bind to the open state to cause channel block. Also, the blocked channel was subject to desensitization. The rate constants of block were 6 × 10-6 M-1 s-1 for physostigmine and 2 × 106 M-1 s-1 for procaine, and the rate of unblocking was 200 s-1 for both blockers (at -40 mV and 20°C).
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Neuronal precursors play an important role in potential regenerative therapeutic strategies in different neurodegenerative diseases, e.g. Parkinson's disease. To understand proliferation and differentiation of these cells in vitro and in vivo, it is important to characterize functional properties of neuronal precursors in detail. The aim of the present study was to analyse the electrophysiological characteristics of ligand-gated channels of neuronal precursors prepared from the rat ventral mesencephalon (VM) of embryonic stage 12.5 during their in vitro differentiation. For the experiments we used the patch-clamp technique in combination with a system for ultrafast solution exchange and immunocytochemistry. It could be shown that functional active AMPA-type glutamate as well as GABAA receptor channels are expressed at an early stage of neuronal development. In culture we observed excitatory as well as inhibitory postsynaptic currents (defined by their different kinetics) which correspond to the activation of AMPAergic and GABAergic receptor channels. Two populations of glutamate-activated currents could be differentiated by their different time course of desensitization whereas the time course of resensitization and deactivation was normally distributed in all cells. GABAergic currents could be blocked by bicuculline and their kinetics correspond to that of GABAA receptor channel currents. Summarizing the results, in the present study it was shown for the first time that neuronal embryonic precursors of the rat VM express both functional AMPA-type glutamate and functional GABAA receptor channels in vitro.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1089-7690
    Source: AIP Digital Archive
    Topics: Physics , Chemistry and Pharmacology
    Notes: We report on a systematic study of the thin-film growth and the electronic structure of the intrinsic molecular semiconductor lutetium–diphthalocyanine (LuPc2). The films were grown in ultrahigh vacuum. Starting from submonolayer coverage, thickness-dependent x-ray and ultraviolet photoemission spectroscopy (UPS) measurements have been carried out. Information about the growth mechanism, the work function, and the evolution of the valence density of states with increasing coverage have been obtained. By combination of UPS with high-resolution electron-energy-loss spectroscopy an assignment of the spectroscopic structures to recently published molecular-orbitals calculations is proposed.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: A characteristic feature of the kinetics of nicotinic acetylcholine receptor (nAChR) channels is fast and nearly complete desensitization with a time course between 10 and 100 ms and recovery from desensitization in the range of some hundred ms. In the present study we used a piezo-driven system for ultra-fast solution exchange, analysed the recovery from the fast desensitized state of mouse recombinant adult-type nAChR channels and found no difference to that of embryonic-type channels. By double pulse experiments with application of pulses with a saturating concentration of 1 mm acetylcholine (ACh) with increasing duration of the first pulse and a constant interval between pulses we detected a second slow desensitized state which was entered with a time constant of 2835 ms. Recovery from the slow desensitized state proceeded with a single exponential with a time constant of 16134 ms. The experimental data were interpreted by the addition of a transition from the desensitized state with two bound ACh molecules to a slow desensitized state to the well known circular kinetic scheme of activation and desensitization of nAChR channels. This slow desensitized state might play a role in muscle fatigue or in pathological states like myasthenic syndromes.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1460-9568
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptor channels of rat caudate-putamen neurones were studied by ultrafast application of agonists to outside-out vesicles taken from medium-sized spiny neurones in thin slices. Upon application of 10 m m glutamate for 50 ms, fast rising and desensitizing currents were activated. Ten to 90% rise time values were ≈ 0.5 ms. Dose–response studies revealed an EC50 of 0.63 mm glutamate. In double logarithmic coordinates, the curve had a maximal slope between 1.33 and 1.85 at low concentrations, indicating at least two binding sites for glutamate. Rise time increased with low agonist concentrations, whereas desensitization kinetics showed only a weak dependence on concentration. The time constant of desensitization was fitted with one exponential and ranged between 2 and 11 ms, with a mean of 6.19 ± 2.31 ms (n = 239). Following brief glutamate pulses (1 ms) currents decayed with time constants of 2.7 ± 0.23 ms (n = 12). Recovery from desensitization was investigated by double-pulse experiments. Recovery time constants fell in two subgroups with respective mean values of 110.6 ± 14.2 ms (n = 8) and 288.6 ± 33.2 ms (n = 8). By adding low glutamate concentrations to the bath solution, predesensitization of AMPA-type receptors without channel opening could be shown. A 50% reduction in control amplitude was achieved with 5.2 ± 2.1 μm (n = 22) glutamate in the background. We hypothesize a circular reaction scheme with at least two binding sites for glutamate to describe activation, desensitization and recovery from desensitization in rat caudate-putamen neurones.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-1351
    Keywords: Area postrema ; Rabbit ; Patch clamp ; Glutamate-receptor ; GABA-receptor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Medicine
    Notes: Abstract Using the patch-clamp technique in combination with sliced tissue preparation the membrane properties of newborn rabbit area postrema neurons were investigated. The neurons responded upon depolarization with a fast Na +-current followed by an inactivating and non-inactivating K +-current. GABA-activated currents were investigated resulting in a large Cl--conductance, indicating the expression of GABAA-receptors. The expression of glutamate receptor mRNA was studied by in situ hybridization and electrophysiological measurements of these receptors by means of the patch-clamp technique. As a main result it was found that ionotropic glutamate receptors in the area postrema are composed of “flop” variants of the GluA-, GluB- and GluC-subunits.
    Type of Medium: Electronic Resource
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