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  • 1
    Keywords: NF-KAPPA-B ; IMMUNE-RESPONSES ; GLYCATION END-PRODUCTS ; CENTRAL-NERVOUS-SYSTEM ; CELL-ADHESION MOLECULE ; TOLL-LIKE RECEPTORS ; RHEUMATOID-ARTHRITIS ; SUSTAINED INTESTINAL INFLAMMATION ; NITRIC-OXIDE PRODUCTION ; PATTERN MOLECULES
    Abstract: Promiscuity of pattern recognition receptors, such as receptor for advanced glycation end products (RAGE), allows for a complex regulatory network controlling inflammation. Scavenging of RAGE ligands by soluble RAGE treatment is effective in reducing delayed-type hypersensitivity (DTH), even in RAGE(-/-) mice by 50% (p 〈 0.001). This has led to the hypothesis that molecules scavenged by soluble RAGE bind to receptors other than RAGE. This study identifies CD166/ALCAM (ALCAM) as a close structural and functional homolog of RAGE, and it shows that binding of S100B to CD166/ALCAM induces dose- and time-dependent expression of members of the NF-kappaB family in wild type (WT) and RAGE(-/-) mouse endothelial cells. Blocking CD166/ALCAM expression using small interfering RNA completely inhibited S100B-induced NF-kappaB activation in RAGE(-/-), but not in WT cells. The in vivo significance of these observations was demonstrated by attenuation of DTH in WT and RAGE(-/-) animals pretreated with CD166/ALCAM small interfering RNA by 50% and 40%, respectively (p 〈 0.001). Experiments in ALCAM(-/-) animals displayed an only slight reduction of 16% in DTH, explained by compensatory reciprocal upregulation of RAGE in animals devoid of CD166/ALCAM, and vice versa. Consistently, ALCAM(-/-) mice, but not WT mice treated with RAGE small interfering RNA show a 35% reduction in DTH, and ALCAM(-/-) RAGE(-/-) double-knockout mice show a 27% reduction in DTH reaction. Thus, S100B is a proinflammatory cytokine bridging RAGE and CD166/ALCAM downstream effector mechanisms, both being compensatory upregulated after genetic deletion of its counterpart.
    Type of Publication: Journal article published
    PubMed ID: 23729438
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  • 2
    Abstract: Importance: Cancer is the second leading cause of death worldwide. Current estimates on the burden of cancer are needed for cancer control planning. Objective: To estimate mortality, incidence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 32 cancers in 195 countries and territories from 1990 to 2015. Evidence Review: Cancer mortality was estimated using vital registration system data, cancer registry incidence data (transformed to mortality estimates using separately estimated mortality to incidence [MI] ratios), and verbal autopsy data. Cancer incidence was calculated by dividing mortality estimates through the modeled MI ratios. To calculate cancer prevalence, MI ratios were used to model survival. To calculate YLDs, prevalence estimates were multiplied by disability weights. The YLLs were estimated by multiplying age-specific cancer deaths by the reference life expectancy. DALYs were estimated as the sum of YLDs and YLLs. A sociodemographic index (SDI) was created for each location based on income per capita, educational attainment, and fertility. Countries were categorized by SDI quintiles to summarize results. Findings: In 2015, there were 17.5 million cancer cases worldwide and 8.7 million deaths. Between 2005 and 2015, cancer cases increased by 33%, with population aging contributing 16%, population growth 13%, and changes in age-specific rates contributing 4%. For men, the most common cancer globally was prostate cancer (1.6 million cases). Tracheal, bronchus, and lung cancer was the leading cause of cancer deaths and DALYs in men (1.2 million deaths and 25.9 million DALYs). For women, the most common cancer was breast cancer (2.4 million cases). Breast cancer was also the leading cause of cancer deaths and DALYs for women (523000 deaths and 15.1 million DALYs). Overall, cancer caused 208.3 million DALYs worldwide in 2015 for both sexes combined. Between 2005 and 2015, age-standardized incidence rates for all cancers combined increased in 174 of 195 countries or territories. Age-standardized death rates (ASDRs) for all cancers combined decreased within that timeframe in 140 of 195 countries or territories. Countries with an increase in the ASDR due to all cancers were largely located on the African continent. Of all cancers, deaths between 2005 and 2015 decreased significantly for Hodgkin lymphoma (-6.1% [95% uncertainty interval (UI), -10.6% to -1.3%]). The number of deaths also decreased for esophageal cancer, stomach cancer, and chronic myeloid leukemia, although these results were not statistically significant. Conclusion and Relevance: As part of the epidemiological transition, cancer incidence is expected to increase in the future, further straining limited health care resources. Appropriate allocation of resources for cancer prevention, early diagnosis, and curative and palliative care requires detailed knowledge of the local burden of cancer. The GBD 2015 study results demonstrate that progress is possible in the war against cancer. However, the major findings also highlight an unmet need for cancer prevention efforts, including tobacco control, vaccination, and the promotion of physical activity and a healthy diet.
    Type of Publication: Journal article published
    PubMed ID: 27918777
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  • 3
    Abstract: Importance: Comprehensive and timely monitoring of disease burden in all age groups, including children and adolescents, is essential for improving population health. Objective: To quantify and describe levels and trends of mortality and nonfatal health outcomes among children and adolescents from 1990 to 2015 to provide a framework for policy discussion. Evidence Review: Cause-specific mortality and nonfatal health outcomes were analyzed for 195 countries and territories by age group, sex, and year from 1990 to 2015 using standardized approaches for data processing and statistical modeling, with subsequent analysis of the findings to describe levels and trends across geography and time among children and adolescents 19 years or younger. A composite indicator of income, education, and fertility was developed (Socio-demographic Index [SDI]) for each geographic unit and year, which evaluates the historical association between SDI and health loss. Findings: Global child and adolescent mortality decreased from 14.18 million (95% uncertainty interval [UI], 14.09 million to 14.28 million) deaths in 1990 to 7.26 million (95% UI, 7.14 million to 7.39 million) deaths in 2015, but progress has been unevenly distributed. Countries with a lower SDI had a larger proportion of mortality burden (75%) in 2015 than was the case in 1990 (61%). Most deaths in 2015 occurred in South Asia and sub-Saharan Africa. Global trends were driven by reductions in mortality owing to infectious, nutritional, and neonatal disorders, which in the aggregate led to a relative increase in the importance of noncommunicable diseases and injuries in explaining global disease burden. The absolute burden of disability in children and adolescents increased 4.3% (95% UI, 3.1%-5.6%) from 1990 to 2015, with much of the increase owing to population growth and improved survival for children and adolescents to older ages. Other than infectious conditions, many top causes of disability are associated with long-term sequelae of conditions present at birth (eg, neonatal disorders, congenital birth defects, and hemoglobinopathies) and complications of a variety of infections and nutritional deficiencies. Anemia, developmental intellectual disability, hearing loss, epilepsy, and vision loss are important contributors to childhood disability that can arise from multiple causes. Maternal and reproductive health remains a key cause of disease burden in adolescent females, especially in lower-SDI countries. In low-SDI countries, mortality is the primary driver of health loss for children and adolescents, whereas disability predominates in higher-SDI locations; the specific pattern of epidemiological transition varies across diseases and injuries. Conclusions and Relevance: Consistent international attention and investment have led to sustained improvements in causes of health loss among children and adolescents in many countries, although progress has been uneven. The persistence of infectious diseases in some countries, coupled with ongoing epidemiologic transition to injuries and noncommunicable diseases, require all countries to carefully evaluate and implement appropriate strategies to maximize the health of their children and adolescents and for the international community to carefully consider which elements of child and adolescent health should be monitored.
    Type of Publication: Journal article published
    PubMed ID: 28384795
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  • 4
    Keywords: SPECTRA ; human ; POPULATION ; GENE ; GENES ; PATIENT ; CANDIDATE GENE ; DISORDER ; LINKAGE ; SUSCEPTIBILITY ; VARIANTS ; DEFICITS ; DELETION ; HUMANS ; MUTATION ; genetics ; DELETIONS ; FISH ; REGION ; PHENOTYPE ; INDIVIDUALS ; ABNORMALITIES ; BEHAVIOR ; HETEROGENEITY ; CHROMOSOMES ; DISORDERS ; VARIANT ; interaction ; IMPAIRMENT ; SCREEN ; autism ; LOCUS ; female ; CHILD ; REFINEMENT ; UK ; 3 ; Genetic ; Developmental ; FISH mapping ; genetic study ; UNRELATED INDIVIDUALS ; In Situ Hybridization,Fluorescence ; *Chromosome Deletion ; Autistic Disorder/*genetics/psychology ; Chromosome Mapping ; Chromosomes,Artificial,Bacterial/genetics ; Chromosomes,Human,Pair 2/*genetics ; Communication Disorders/genetics/psychology ; Developmental Disabilities/genetics/psychology ; DNA Mutational Analysis ; Linkage (Genetics)
    Abstract: Autism is a neurodevelopmental disorder characterized by deficits in reciprocal social interaction and communication, and repetitive and stereotyped behaviors and interests. Previous genetic studies of autism have shown evidence of linkage to chromosomes 2q, 3q, 7q, 11p, 16p, and 17q. However, the complexity and heterogeneity of the disorder have limited the success of candidate gene studies. It is estimated that 5% of the autistic population carry structural chromosome abnormalities. This article describes the molecular cytogenetic characterization of two chromosome 2q deletions in unrelated individuals, one of whom lies in the autistic spectrum. Both patients are affected by developmental disorders with language delay and communication difficulties. Previous karyotype analyses described the deletions as [46,XX,del(2)(q24.1q24.2)dn]. Breakpoint refinement by FISH mapping revealed the two deletions to overlap by approximately 1.1Mb of chromosome 2q24.1, a region which contains just one gene--potassium inwardly rectifying channel, subfamily J, member 3 (KCNJ3). However, a mutation screen of this gene in 47 autistic probands indicated that coding variants in this gene are unlikely to underlie the linkage between autism and chromosome 2q. Nevertheless, it remains possible that variants in the flanking genes may underlie evidence of linkage at this locus.
    Type of Publication: Journal article published
    PubMed ID: 19267418
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Geophysical prospecting 25 (1977), S. 0 
    ISSN: 1365-2478
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Geosciences , Physics
    Notes: The application of approximate rules, whereby apparent resistivity space sections for two dimensional structures can be composited from spaces derived for elementary features is extended to a complex example drawn from a field survey over a fluorite mineral vein.A quantitative solution for the observed resistivity space is presented and the computational sequence involved in matching the observed space is given in detail.The interpreted results are examined in relation to the known geology, supplemented by the results of excavation, and to model tests conducted using a tank analogue.The example also illustrates how successive compositions can be employed in estimating the form of resistivity space in a relatively complex situation.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0703
    Source: Springer Online Journal Archives 1860-2000
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Medicine
    Notes: Abstract The metabolic fate of leptophos [O-(4-Bromo-2,5-dichlorophenyl)O-methyl phenyl phosphonothioate] in the rat was investigatedin vivo, using14C-phenyl and14C-methyl-labeled insecticide. Following the administration of a single oral dose of14C-phenyl leptophos (15 mg/kg) 46 to 75% of the14C-activity was recovered after nine days, in the urine. No radioactivity was eliminated in the expired air.O-methyl phenylphosphonic,O-methyl phenylphosphonothioic and phenylphosphonic acids were identified among the urinary metabolites, together with two metabolites of unknown nature. Demethylation of leptophos and/or its oxygen analog occurredin vivo to a small extent, as confirmed by the elimination of14CO2 in the expired air, from14C-methyl leptophos. The insecticide seemed to accumulate in omental and subcutaneous fat since traces were still found in fat 12 weeks after administration of the chemical. A study of the kinetics of acetylcholinesterase inhibition revealed that the oxon was the most potent inhibitor. The degradation products were generally weak inhibitors.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1434-4475
    Keywords: Iron ; Polarization ; Passivation ; Pitting ; Potentiodynamic
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Zusammenfassung Es wurde die potentiodynamische Polarisierung der Eisenelektrode in schwefelsauren Lösungen untersucht. Die Ausbildung eines passivierenden Films auf der Eisenelektrode nach der anodischen Oxidation hängt von der Säurekonzentration ab. Zugabe von Cl−-Ionen zur Schwefelsäurelösung erhöht die Stromdichten sowohl in den aktiven als auch den passiven Bereichen. Der entsprechende Lösungsstrom mit bzw. ohne diese Ionen, also der verstärkende Effekt der Cl−-Ionen variiert mit der Konzentration der aggressiven Ionen: log Δi=a 5+b 5 logc agg. Organische Carboxylate verstärken die aktive Lösung von Eisen durch ihre Teilnahme am Lösungsmechanismus, andererseits inhibieren sie Narben-Korrosion, da sie mit den Cl−-Ionen bezüglich möglicher Adsorptionsstellen an der Metalloberfläche konkurrieren.
    Notes: Summary The potentiodynamic polarization of the iron electrode in sulphuric acid solutions was studied. The formation of a passivating film on the electrode upon anodic oxidation in sulphuric acid solution depends on the concentration of the acid. Addition of Cl− ions to sulphuric acid solutions raises the current densities along both the active and passive regions. The difference between the dissolution current in halogen-containing media and solutions devoid of these ions, i. e., the enhancing effect of Cl− ions, Δi, varies with the aggressive ions concentration according to log Δi=a 5+b 5 logC agg. Organic carboxylates enhance the active dissolution of iron through their participation in the dissolution mechanism, while they inhibit pitting corrosion through competitive adsorption with Cl− ions for adsorption sites on the metal surface.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1434-4475
    Keywords: 3′-Azido-2′,3′-dideoxy-2-thiouridines ; 5-Alkoxy-2-thiouracils ; Nucleoside synthesis
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Zusammenfassung Die Reaktion von 3-Azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-D-erythro-pentofuranosid (5) mit silyliertem 2-Thiouracil und 5-Alkoxy-2-thiouracil in Gegenwart von Trimethylsilyltrifluormethansulfonat ergab eine anomere Mischung der entsprechenden 3′-Azido-2′,3′-dideoxy-2-thiouridin-Derivate, wobei das α-Anomer das Hauptprodukt darstellte. Die ungeschützten Nucleoside wurden mittels Behandlung mit Tetrabutylammoniumfluorid erhalten.
    Notes: Summary Reaction of 3-azido-5-O-tert-butyldiphenylsilyl-2,3-dideoxy-D-erythro-pentofuranoside (5) with silylated 2-thiouracil and 5-alkoxy-2-thiouracils in the presence of trimethylsilyl trifluoromethanesulfonate afforded an anomeric mixture of the corresponding 3′-azido-2′,3′-dideoxy-2-thiouridine derivatives with the α-anomer as the main product. Deprotected nucleosides were obtained by treatment with tetrabutylammonium fluoride.
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  • 9
    ISSN: 1434-4475
    Keywords: Nucleosides, convergent synthesis of ; Uridines, 3′-azido-2′,3′-dideoxy ; Uridines, 3′-fluoro-2′,3′-dideoxy ; AZT analogues ; Human immunodeficiency virus ; Herpes simplex virus
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Description / Table of Contents: Zusammenfassung Aus Uracil (8) wurden in einer Mannich-Reaktion in 65–85% Ausbeute die 5-substituierten Dialkylaminomethyluracile11a–f hergestellt. Verbindungen11a–f wurden mit Hexamethyldisilazan silyliert und mit 2,3-Didesoxy-3-fluor-D-erythro-pentofuranosid (4) und 3-Azido-2,3-didesoxy-D-erythro-pentofuranosid (7) unter Verwendung von Trimethylsilyl-trifluormethansulfonat als Katalysator zu den entsprechenden 3′-Fluor-2′,3′-didesoxynucleosiden13a–f und 3′-Azido-2′,3′-didesoxynucleosiden16d, f umgesetzt. Deprotektion der 5-O-(4-Phenylbenzoyl)- geschützten Nucleoside13a–f und16d, f mit gesättigtem methanolischem Ammoniak und Trennung mittels Chromatographie ergab die neuen 2′,3′-Didesoxy-3′-fluoruridine14a–f und15a–f, sowie die 2′,3′-Didesoxy-3′-azidouridine17d, f und18d, f.
    Notes: Summary Uracil (8) was substituted in a Mannich reaction to give the 5-substituted dialkylamino-methyluracils11a–f in 65–85% yield. Compounds11a–f were silylated with hexamethyldisilazane and coupled with 2,3-dideoxy-3-fluoro-D-erythro-pentofuranoside4 and 3-azido-2,3-dideoxy-D-erythro-pentofuranoside7 to give the corresponding 3′-fluoro-2′,3′-dideoxynucleosides13a–f and 3′-azido-2′,3′-dideoxy nucleosides16d, f, respectively, by using trimethylsilyl trifluoromethanesulfonate as a catalyst. Deprotection of the 5-O-(4-phenylbenzoyl) protected nucleosides13a–f and16d, f with saturated methanolic ammonia and separation by chromatography yielded the new derivatives of 2′,3′-dideoxy-3′-fluorouridines14a–f and15a–f and 2′,3′-dideoxy-3′-azidouridines17d, f and18d, f.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1619-7089
    Keywords: Benzodiazepine receptor ; Iodine-123 isopropyl-p-iodoamphetamine ; Iomazenil ; Ischemia ; Autoradiography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Single-photon emission tomography (SPET) imaging in patients with complex partial epilepsy has shown that the seizure focus is characterized by both decreased interictal blood flow and decreased uptake of the benzodiazepine (BZ) receptor tracer iodine-123 iomazenil. The purpose of this study was to examine the confounding effect of decreased flow on iomazenil uptake. The left middle cerebral artery of four rats was occluded, and the animals were simultaneously injected with 25 μCi of iodine-125 iomazenil and 500 μCi of the blood flow tracer [123I]iofetamine (N-isopropyl-p-iodoamphetamine). All rats, including two sham, were sacrificed 1 h after injection, a time when uptake of both agents is nearly maximal. Control experiments showed that arterial occlusion for 1 h did not affect the total number of BZ binding sites. Using a dual autoradiographic technique, the uptake of both [123I]iofetamine and [125I]iomazenil was measured in more than 200 regions showing variable levels of reduced flow and expressed as a percentage of the contralateral homotypic area. The straight line fit of % [125I]iomazenil (y axis) versus % [123I]iofetamine (x axis) in all 200 regions had a slope of 0.74. Insofar as the rat is an accurate model of human subjects with epilepsy, these studies suggest that decreased flow to the epileptogenic focus will linearly exacerbate the decrease in uptake secondary to neuropathologic loss of BZ receptors. Thus, for localization of seizure focus, a single SPET image of [123I]iomazenil in an epileptic patient may have greater sensitivity than a comparable blood flow image, because the former is enhanced by both decreased flow and a loss of BZ receptors.
    Type of Medium: Electronic Resource
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