Receptor-mediated phagocytosis of myelin by macrophages and microglia

Demyelination is a major pathological feature of multiple sclerosis (MS), resulting in the formation of lipid laden microglia (MG) and macrophages (MØ), suggesting the involvement of receptor-mediated myelin phagocytosis. Myelin is phagocytosed by MG, and to a lesser extent, peritoneal macrophages, in a dose and time dependent manner. Opsonisation of the myelin with specific anti-myelin antibodies significantly increases phagocytosis, particularly by MØ. The uptake of both myelin and opsonised myelin is inhibited to a similar extent by zymosan, anti-CR3 antibody, mannose and melibiose, opsonised erythrocytes, peroxidase anti-peroxidase, aggregated IgG and oxidised low density lipoprotein (OxLDL), implicating the involvement of the complement, lectin, Fc and scavenger receptors in myelin phagocytosis. Therefore, although the difference in uptake between myelin and opsonised myelin would suggest that the FcR plays a significant role in phagocytosis, these inhibition studies suggest that a range of receptors contribute, which may negate the requirement for antibody opsonisation to fuel demyelination. The uptake of myelin and opsonised myelin by MG and MØ is stimulated by interferon-y and inhibited by transforming growth factor-β and results in increased nitric oxide and decreased superoxide production, particularly with opsonised myelin. The release of reactive oxygen intermediates could contribute to extracellular myelin damage, such as oxidation. Oxidation of these membranes leads to the aggregation and loss of integrity of myelin proteins. This results in a decrease in the binding of anti-myelin antibodies, and a reduction in the phagocytosis observed with opsonisation. Competition for the scavenger receptor with OxLDL is enhanced after myelin oxidation and modified myelin has been identified in the spinal cords of rats during the clinical stages of experimental allergic encephalomyelitis (EAE). These results suggest that the extraneous metabolic modification of the myelin, in addition to receptor-mediated phagocytosis, could enhance the degree of demyelination

Heme oxygenase is induced in nephrotoxic nephritis and hemin, a stimulator of heme oxygenase synthesis, ameliorates disease

Heme oxygenase is induced in nephrotoxic nephritis and hemin, a stimulator of heme oxygenase synthesis, ameliorates disease. Heme oxygenase (HO) catalyses degradation of heme to biliverdin, iron and carbon monoxide (CO). Two isoforms exist, a constitutive form and an inducible form (HO-1). Induction of HO-1 may have protective effects in inflammation. We studied heterologous (HNTN) and accelerated (ANTN) nephrotoxic nephritis in Lewis rats. Hemin, an inducer of HO-1, (30 μmol/kg) was administered 18 hours before induction of nephritis and 72 hours later in ANTN. HO-1 was not detected immunohistochemically in normal glomeruli but was present in HNTN and ANTN in cells with the morphology of macrophages. HO-1 induction was confirmed by RT-PCR. In normal rats hemin induced glomerular HO-1 mRNA at 18 hours. In HNTN hemin markedly reduced proteinuria at 24 hours (10 ± 4 mg/24 hr; control 54 ± 16; P < 0.05), neutrophil infiltration at two hours (29.8 ± 1.8 vs. 22.3 ± 1.5 neutrophils/glomerulus, P < 0.05), and glomerular macrophage number at two hours (2.1 ± 0.1 vs. 3.1 ± 0.4 cells/glomerulus, P < 0.05). In ANTN proteinuria was reduced at day 1 and day 4 (36 ± 11 vs. 60 ± 15 and 35 ± 7 vs. 86 ± 9mg protein/24 hr, respectively, P < 0.001), glomerular thrombi were reduced by hemin at day 1 and 4 (1.5 ± 2.7 vs. 2.7 ± 0.2 and 1.3 ± 0.01 vs. 2.9 ± 0.02, respectively, P < 0.001) and glomerular macrophage infiltration was reduced on day 4 (11.2 ± 0.8 cells/glom; control 15.9 ± 0.8, P < 0.01). Possible mechanisms by which HO-1 ameliorates disease include anti-complement or anti-oxidant effects of bilirubin and vasodilator and anti-platelet effects of carbon monoxide

Synthesis Paper: Targeted Livestock Grazing: Prescription for Healthy Rangelands

Targeted livestock grazing is a proven tool for manipulating range land vegetation, and current knowledge about targeted livestock grazing is extensive and expanding rapidly. Targeted grazing prescriptions optimize the timing, frequency, intensity, and selectivity of grazing (or browsing) in combinations that purposely exert grazing/ browsing pressure on specific plant species or portions of the landscape. Targeted grazing differs from traditional grazing management in that the goal of targeted grazing is to apply defoliation or trampling to achieve specific vegetation management objectives,whereas the goal of traditional livestock grazing management is generally the production of livestock commodities. A shared aim of targeted livestock grazing and traditional grazing management is to sustain healthy soils, flora, fauna, and water resources that, in turn, can sustain natural ecological processes (e.g., nutrient cycle, water cycle, energy flow). Targeted grazing prescriptions integrate knowledge of plant ecology, livestock nutrition, and livestock foraging behavior. Livestock can be focused on target areas through fencing, herding, or supplement placement. Although practices can be developed to minimize the impact of toxins contained in target plants, the welfare of the animals used in targeted grazing must be a priority. Monitoring is needed to determine if targeted grazing is successful and to refine techniques to improve efficacy and efficiency. Examples of previous research studies and approaches are presented to highlight the ecological benefits that can be achieved when targeted grazing is applied properly. These cases include ways to suppress invasive plants and ways to enhance wildlife habitat and biodiversity. Future research should address the potential to select more adapted and effective livestock for targeted grazing and the associated animal welfare concerns with this practice. Targeted livestock grazing provides land managers a viable alternative to mechanical, chemical, and prescribed fire treatments to manipulate range land vegetation

Synthesis Paper: Targeted Livestock Grazing: Prescription for Healthy Rangelands

Targeted livestock grazing is a proven tool for manipulating rangeland vegetation, and current knowledge about targeted livestock grazing is extensive and expanding rapidly. Targeted grazing prescriptions optimize the timing, frequency, intensity, and selectivity of grazing (or browsing) in combinations that purposely exert grazing/browsing pressure on specific plant species or portions of the landscape. Targeted grazing differs from traditional grazing management in that the goal of targeted grazing is to apply defoliation or trampling to achieve specific vegetation management objectives, whereas the goal of traditional livestock grazing management is generally the production of livestock commodities. A shared aim of targeted livestock grazing and traditional grazing management is to sustain healthy soils, flora, fauna, and water resources that, in turn, can sustain natural ecological processes (e.g., nutrient cycle, water cycle, energy flow). Targeted grazing prescriptions integrate knowledge of plant ecology, livestock nutrition, and livestock foraging behavior. Livestock can be focused on target areas through fencing, herding, or supplement placement. Although practices can be developed to minimize the impact of toxins contained in target plants, the welfare of the animals used in targeted grazing must be a priority. Monitoring is needed to determine if targeted grazing is successful and to refine techniques to improve efficacy and efficiency. Examples of previous research studies and approaches are presented to highlight the ecological benefits that can be achieved when targeted grazing is applied properly. These cases include ways to suppress invasive plants and ways to enhance wildlife habitat and biodiversity. Future research should address the potential to select more adapted and effective livestock for targeted grazing and the associated animal welfare concerns with this practice. Targeted livestock grazing provides land managers a viable alternative to mechanical, chemical, and prescribed fire treatments to manipulate rangeland vegetation

An observational study of patient characteristics associated with the mode of admission to acute stroke services in North East, England

Objective Effective provision of urgent stroke care relies upon admission to hospital by emergency ambulance and may involve pre-hospital redirection. The proportion and characteristics of patients who do not arrive by emergency ambulance and their impact on service efficiency is unclear. To assist in the planning of regional stroke services we examined the volume, characteristics and prognosis of patients according to the mode of presentation to local services. Study design and setting A prospective regional database of consecutive acute stroke admissions was conducted in North East, England between 01/09/10-30/09/11. Case ascertainment and transport mode were checked against hospital coding and ambulance dispatch databases. Results Twelve acute stroke units contributed data for a mean of 10.7 months. 2792/3131 (89%) patients received a diagnosis of stroke within 24 hours of admission: 2002 arrivals by emergency ambulance; 538 by private transport or non-emergency ambulance; 252 unknown mode. Emergency ambulance patients were older (76 vs 69 years), more likely to be from institutional care (10% vs 1%) and experiencing total anterior circulation symptoms (27% vs 6%). Thrombolysis treatment was commoner following emergency admission (11% vs 4%). However patients attending without emergency ambulance had lower inpatient mortality (2% vs 18%), a lower rate of institutionalisation (1% vs 6%) and less need for daily carers (7% vs 16%). 149/155 (96%) of highly dependent patients were admitted by emergency ambulance, but none received thrombolysis. Conclusion Presentations of new stroke without emergency ambulance involvement were not unusual but were associated with a better outcome due to younger age, milder neurological impairment and lower levels of pre-stroke dependency. Most patients with a high level of pre-stroke dependency arrived by emergency ambulance but did not receive thrombolysis. It is important to be aware of easily identifiable demographic groups that differ in their potential to gain from different service configurations

"We have no voice for that" : Land Rights, Power, and Gender in Rural Sierra Leone

Acknowledgements I wish to thank the participants in the Gender and Land Governance Conference at Utrecht University in January 2013 for helpful comments and suggestions. Funding I would like to thank the Faculty of Management at Radboud University Nijmegen for funding the six months of fieldwork on which this article is based.Peer reviewedPostprin

Application of Latent Variable Methods to the Study of Cognitive Decline When Tests Change over Time

The way a construct is measured can differ across cohort study visits, complicating longitudinal comparisons. We demonstrated the use of factor analysis to link differing cognitive test batteries over visits to common metrics representing general cognitive performance, memory, executive functioning, and language

Midlife Hypertension and 20-Year Cognitive Change: The Atherosclerosis Risk in Communities Neurocognitive Study

Hypertension is a treatable potential cause of cognitive decline and dementia, but its greatest influence on cognition may occur in middle age

Evaluation der Maßnahmen zur Umsetzung der Vorschläge der Hartz-Kommission: Modul 1a, Neuausrichtung der Vermittlungsprozesse ; Bericht 2005 für das Bundesministerium für Wirtschaft und Arbeit

"Das Bundesministerium für Wirtschaft und Arbeit hat das Wissenschaftszentrum Berlin für Sozialforschung und das infas Institut für angewandte Sozialwissenschaft im September 2004 mit dem Evaluationsvorhaben Arbeitspaket 1, 'Modul 1a Neuausrichtung der Vermittlungsprozesse' beauftragt. Im Mittelpunkt steht die zentrale Frage, ob eine 'Verbesserung der Qualität und Schnelligkeit der Arbeitsvermittlung' nachgewiesen werden kann, die auf die Reformgesetze und -maßnahmen zurückzuführen sind. Implementationsanalysen untersuchen die Praxis der Agenturen bezüglich Bewerberdifferenzierung, Kundenmanagement, Aktivierung sowie Neuregelung von Zumutbarkeit und Sperrzeiten sowie die Vermittlungsdienstleistungen an Arbeitgeber. Auch der Einsatz vermittlungsnaher Dienstleistungen (Einschaltung Dritter nach Paragraph 37, Eingliederungsmaßnahmen durch Träger Paragraph 421i, Vermittlungsgutscheine, Personal-Service-Agenturen -PSA-) wird unter Umsetzungsgesichtspunkten untersucht. Über die Vermittlungsorganisation in Arbeitsgemeinschaften nach Paragraph 44b SGB II liegen erste Ergebnisse einer Grunderhebung vor. Die mittels Fallstudien, Dokumentenanalyse, schriftlichen und telefonischen Erhebungen gewonnenen Ergebnisse umreißen den Stand der Neuausrichtung der Vermittlungsprozesse. Die Wirkung der neu ausgerichteten Vermittlungsprozesse werden unter zwei Gesichtspunkten untersucht. Mittels multivariater Auswertungen wird zum einen die Wirkung des Kundenzentrums auf die Abgänge aus Arbeitslosigkeit geprüft. In einer instrumentenspezifisch angelegten Wirkungsanalyse wird zum anderen die Effektivität von vermittlungsnahen Dienstleistungen (Beauftragung Dritter, Beauftragung von Trägern mit Eingliederungsmaßnahmen, Personal Service Agenturen, Vermittlungsgutschein) analysiert und eine entsprechende Kosten-Nutzen-Bewertung vorgenommen. Der Bericht 2005 legt die Ergebnisse nach neun Monaten Laufzeit des Evaluationsvorhabens vor. Er ist vom Bemühen getragen, bereits belastbare Ergebnisse nach diesem vergleichsweise kurzen Zeitraum vorzulegen. Die Berichterstattung steht allerdings unter dem deutlichen Hinweis, dass die Organisation der Vermittlungsprozesse in den Agenturen und Arbeitsgemeinschaften weiterhin im Fluss ist. Die Implementationsstudien versuchen deswegen über die Momentaufnahme hinaus, grundlegende Konstruktionsfragen und -probleme aufzuzeigen. Wegen des vergleichsweise kurzen Beobachtungszeitraums seit Einführung der Kundenzentren und der vermittlungsnahen Dienstleistungen stehen auch die Wirkungsanalysen noch unter Vorbehalten." (Textauszug

Hundreds of variants clustered in genomic loci and biological pathways affect human height

Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P < 0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.