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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
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    German Medical Science; Düsseldorf, Köln
    In:  122. Kongress der Deutschen Gesellschaft für Chirurgie; 20050405-20050408; München; DOC05dgch2763 /20050615/
    Publication Date: 2005-06-16
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 3
    Publication Date: 2005-06-16
    Keywords: ddc: 610
    Language: German
    Type: conferenceObject
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  • 4
    ISSN: 1432-2323
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Quarante-sept patients (34 hommes et 13 femmes) âgés de plus de 75 ans (moyenne 79.7±3.8 SD) présentant une rupture d'anévrysme de l'aorte abdominale ont été opérés entre 1977 et 1986. Chez 16 patients (34%), l'anévrysme était déjà connu. Dix-sept patients (36%) ont été opérés 6 heures ou plus après le début de la rupture; 26 (55%) étaient en état de choc avant l'opération. Le diamètre moyen des anévrysmes était de 8.9±2.6 cm (SD) et la perte sanguine moyenne était de 8.5±7.8 litres. La durée moyenne de l'intervention était de 220±96 minutes. La mortalité à un mois était de 60% (28 patients) et 63% (12 patients) présentaient des complications postopératoires, le plus souvent des pneumopathies. La survie à 5 ans était de 26%. Les facteurs de risque associés à une mortalité élevée et à un mauvais prognostic étaient la présence de choc opératoire, le grand âge et la présence d'un anévrysme diagnostiqué mais non traité.
    Abstract: Resumen Cuarenta y siete pacientes (34 hombres y 13 mujeres) mayores de 75 años (promedio: 79.7±3.8) con aneurismas rotos de la aorta abdominal fueron operados entre 1977 y 1986. En 16 pacientes (34%) el aneurisma había sido previamente diagnosticado. Diez y siete pacientes (36%) exhibieron demora de 6 horas o más en la iniciación del tratamiento y 26 (55%) estuvieron en shock en la fase preoperatoria. El diámetro promedio del aneurisma fue 8.9±2.6 centímetres y la cantidad promedio del sangrado operatorio fue 8.5±7.8 litres. El tiempo operatorio promedio fue 220±96 minutos. La mortalidad a un mes fue 60% (28 pacientes) y 63% (12 pacientes) de los sobrevivientes sufrieron complicaciones postoperatorias, principalmente neumonía. La tasa de sobrevida a 5 años fue 26%. En cuanto al análisis de los factores de riesgo asociados con mortalidad, el shock preoperatorio, la edad avanzada, y un aneurisma aórtico previamente diagnosticado y no tratado aparecieron asociados con un pronóstico significativamente peor.
    Notes: Abstract Forty-seven patients (34 males and 13 females) over 75 years of age (mean: 79.7±3.8 SD) suffering from a ruptured abdominal aortic aneurysm were operated on between 1977 and 1986. In 16 patients (34%), the aneurysm had been diagnosed previously. Seventeen patients (36%) had a delay of 6 hours or more in the beginning of the treatment and 26 (55%) were in shock preoperatively. The mean diameter of the aneurysms was 8.9±2.6 cm (SD) and the mean operative bleeding was 8.5±7.8 (SD) liters. The mean operating time was 220±96 (SD) minutes. The 1-month mortality was 60% (28 patients) and 63% (12 patients) of survivors had postoperative complications, mostly pneumonia. The 5-year survival rate was 26%. In the analysis of risk factors associated with death, preoperative shock, old age, and a previously diagnosed but untreated abdominal aortic aneurysm were associated with a significantly worse prognosis.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1399-3038
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The objective of the study was to evaluate the risk of asthma in children who had undergone an adenoidectomy, an operation frequently performed on children with glue ear or recurrent otitis media. Two surveys were carried out, a nation-wide questionnaire returned by 483 individuals (survey A) and a survey of hospital discharge records involving 1616 children who had undergone an adenoidectomy and 161 control children who had undergone probing of the nasolacrimal duct due to congenital obstruction (survey B). The questionnaire (survey A) showed that an adenoidectomy before the age of 4 years was associated with asthma (OR 3.19, 95% CI 1.25; 8.13) and with allergy to animal dust (OR 2.50, 95% CI 1.27; 4.95). In survey B, asthma diagnosis was retrieved from the national asthma register. It showed also that adenoidectomy at an early age was associated with an increased risk of asthma (OR 6.74, 95% CI 2.99; 15.2). There was an association between asthma and adenoidectomy, even before adenoidectomy had actually been performed. The risk of asthma was highest among children who had had adenoidectomy because of recurrent otitis media. The observed association between an adenoidectomy and asthma may be explained by an underlying factor predisposing to both recurrent otitis media and asthma.
    Type of Medium: Electronic Resource
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  • 6
    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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  • 7
    ISSN: 0360-6376
    Keywords: Physics ; Polymer and Materials Science
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Ethylene-butadiene (PEBU) copolymer with low percentage of butadiene was previously investigated by van der Waals potential energy calculations. The trans —HC=CH— group (TDB) was found to show fold-supporting behavior, so that it was supposed that many TDB's were located on the surface of PEBU single crystals under favorable conditions of TDB concentration and of thickness of crystal platelets. In order to verify this hypothesis, three PEBU samples with a butadiene/(ethylene + butadiene) molar ratio of 2.3% (B), 3.6% (C), and 4.6% (D), by assuming that the —HC=CH— groups are all trans, were studied and compared with a polyethylene (PE) sample (A). Samples A, B, C, and D were grown isothermally at temperatures of 50, 55, 60, 61, 70, 71, 75, and 80°C from dilute xylene solutions. Infrared, differential scanning calorimetry (DSC), small-angle x-ray scattering (SAXS), bromination kinetics, and density measurements were performed. B, C, and D lamellar crystals show a long spacing L nearly equal to that of A at crystallization temperatures Tc of 50 and 60°C. For Tc ≥ 70°C, the fold period of samples B, C, and D increases more rapidly than that of A in the order D 〉 C 〉 B. The melting temperature Tm and the enthalpy of fusion ΣHf decrease with increasing content of butadiene, except for B and C, which show nearly equal Tm and ΔHf values. Two peaks appear in the fusion curves at temperatures T1 and T2, T1 〉 T2. The area of the peak at T2 increases with the butadiene content, and, in the same sample, with Tc. Results of bromination in suspension of B, C, and D single crystals, crystallized in the range 50-71°C, indicate that a high percentage of TDB's react on the fold surfaces. The chemical attack is more successful with crystals grown in the range 60-66°C, and, in the case of sample C, as much as 81% of the TDB's are consumed. The density of the samples increases with both Tc and TDB percentage. On the basis of these observed results a simple model for PEBU is proposed. It is supposed that the copolymerization reaction leads to the formation of defects, consisting of one (b), two (bb), three (bbb), or more sequential molecules of butadiene, almost homogeneously distributed along a macromolecular chain. At very small percentage of butadiene, b defects prevail. The addition of further butadiene gives rise mainly to bb defects, and so on. Thus each kind of defect characterizes PEBU copolymers with a certain butadiene/ethylene molar ratio. The experimental data, valid for low butadiene/ethylene molar ratios, agree with this reasonable model and with the potential energy calculations.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1435-1463
    Keywords: 5-HT transporter gene ; promoter ; cAMP induction ; polyadenylation sites ; JAR human placental choriocarcinoma cells
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary We have isolated and characterized the 5′-flanking region and the proximal polyadenylation site of the human 5-HT transporter gene. The major gene transcript is 2,793 bp in length and it contains 208 bp of 5′-untranslated region (5′-UTR) and 694 bases of 3′-UTR. While only a single mRNA species occurs in rats and mice, the most proximal signal for polyadenylation in the human gene appears to be highly degenerate in comparison to the rat and murine motif. This polyadenylation signal-like motif may lead to alternate usage of additional polyadenylation sites resulting in multiple mRNA species in humans. A TATA-like motif and several potential binding sites for transcription factors including AP1, AP2, SP1, and a cAMP response element (CRE)-like motif are present in the 5′-flanking region. A ∼1.7 kb fragment beginning 217 bp downstream from the transcription start site, which had been ligated into a luciferase reporter vector and transiently expressed in JAR human placental choriocarcinoma cells, displayed both constitutive and forskolin/cholera toxin-induced promoter activity. Functional promoter mapping revealed that there are negative attenuating elements between bp −1,428 and −1,185 and positive elements between bp −1,184 and −78 from the transcription initiation site. Studies with deletional mutants also indicated that core promoter sequences are contained within 78 bp of the transcription start site and that regulation of cAMP-inducible promoter activity depends on multiplecis-acting elements including two AP1 binding sites and a single CRE-like element located at bp −99. Our findings suggest that (1) the 5-HT transporter gene promoter is active in human JAR cells, but inactive in 5-HT transporter-deficient human SK-N-SH neuroblastoma and HeLa cells, (2) the information contained within 1.4kb of 5′-flanking sequence is sufficient to confer its cell-specific expression, (3) the promoter responds to cAMP induction, and (4) the expression of the 5-HT transporter gene is regulated by a combination of positive and negativecis-acting elements operating through a basal promoter unit defined by a TATA-like motif.
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 10
    Electronic Resource
    Electronic Resource
    New York, NY : Wiley-Blackwell
    Helvetica Chimica Acta 49 (1966), S. 1612-1616 
    ISSN: 0018-019X
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: The acidity constants of 2-acetyl-3-hydroxy-thiophene (III) and 3-acetyl-4-hydroxy-thiophene (IV) and the stability constants of their complexes with some bivalent metal ions have been determined. The stability of the chelates is discussed as a function of the respective bond orders of the α-β and β-β′ bonds of the thiophene ring.
    Additional Material: 3 Ill.
    Type of Medium: Electronic Resource
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