Rapid onset of ocean anoxia shown by high U and low Mo isotope compositions of sapropel S1

Authigenic uranium isotope compositions of Holocene sapropel S1 (δ238Uauth = +0.10 to +0.52 ‰; ODP core 967, 2550 mbsl) are significantly higher than the proposed upper boundary (+0.2 ‰) associated with the transport-porewater diffusion model for sediment uranium uptake. It is shown that these high δ238Uauth values are compatible with rapid initial slowdown of thermohaline overturning and the development of an anoxic water column. These conditions would favour U uptake in an organic-rich floccule layer overlying the sediment-water interface. The high δ238Uauth values correlate with low δ98Moauth values (+0.02 to −0.88 ‰), interpreted to reflect weakly euxinic conditions controlled by thiomolybdate–molybdate solution equilibria. The S1 data contrast markedly with published data from last interglacial sapropel S5 from the same core, which show δ238Uauth and δ98Moauth characteristics compatible with a restricted euxinic basin due to progressive slowdown in the thermohaline circulation. The U-Mo isotope data for S1 are similar to a range of published palaeo-settings. Sapropels are therefore shown to be useful templates for the unravelling of the interplay between productivity and deep water renewal times in ancient settings

A 10-fold decline in the Eastern Mediterranean thermocline overturning circulation during the last interglacial period

Present-day Mediterranean deep-waters are well oxygenated, but the episodic formation of organic-rich sediments (sapropels) indicates that this pattern was frequently perturbed in the past. Both high export productivity and disruption of the thermohaline circulation, leading to reduced deep-water ventilation, have been proposed to account for sapropel deposition and anoxia. The last interglacial sapropel S5 is considered one of the most strongly developed. Here, we apply the redox-sensitive Mo and U (elemental and isotope) systems to quantify the intensity of anoxic deep-water conditions in the Eastern Mediterranean Sea from ODP core 967 (2550 mbsl). Both U and Mo show strong authigenic enrichment, coupled to progressive increase in δ98Moauth (+1.2–1.8‰ to +2.0–2.3‰) and decrease in δ238Uauth (+0.10‰ to −0.15‰) from the beginning to the end of S5, suggesting increasing water column euxinia and removal fluxes of Mo and U. Based on modern euxinic basins, we show that sedimentary Uauth can be used to derive estimates of water column U depletion and, ultimately, deep-water renewal rates. These principles are first tested on the modern Black Sea, which yields calculated deep-water renewal times of 830+690/−500 yrs, in good agreement with independent estimates. Applying these principles to the end of S5 suggests bottom-water U depletion of ∼50% and deep-water renewal times of 1030+820/−520 yrs. The significantly slower deep-water renewal rates in the Eastern Mediterranean Sea compared to today (∼100 yrs) would have played an important role in the formation of sapropel S5 and are consistent with the proposed suppression of overturning during the last interglacial, due to increased stratification resulting from higher riverine freshwater input under enhanced monsoon forcing

Genetic and cellular studies highlight that A Disintegrin and Metalloproteinase 19 is a protective biomarker in human prostate cancer

Background: Prostate cancer is the second most frequently diagnosed cancer in men worldwide. Current treatments include surgery, androgen ablation and radiation. Introduction of more targeted therapies in prostate cancer, based on a detailed knowledge of the signalling pathways, aims to reduce side effects, leading to better clinical outcomes for the patient. ADAM19 (A Disintegrin And Metalloproteinase 19) is a transmembrane and soluble protein which can regulate cell phenotype through cell adhesion and proteolysis. ADAM19 has been positively associated with numerous diseases, but has not been shown to be a tumor suppressor in the pathogenesis of any human cancers. Our group sought to investigate the role of ADAM19 in human prostate cancer. Methods: ADAM19 mRNA and protein levels were assessed in well characterised human prostate cancer cohorts. ADAM19 expression was assessed in normal prostate epithelial cells (RWPE-1) and prostate cancer cells (LNCaP, PC3) using western blotting and immunocytochemistry. Proliferation assays were conducted in LNCaP cells in which ADAM19 was over-expressed. In vitro scratch assays were performed in PC3 cells over-expressing ADAM19. Results: Immunohistochemical studies highlighted that ADAM19 protein levels were elevated in normal prostate tissue compared to prostate cancer biopsies. Results from the clinical cohorts demonstrated that high levels of ADAM19 in microarrays are positively associated with lower stage (p = 0.02591) and reduced relapse (p = 0.00277) of human prostate cancer. In vitro, ADAM19 expression was higher in RWPE-1 cells compared to LNCaP cells. In addition, human ADAM19 over-expression reduced LNCaP cell proliferation and PC3 cell migration. Conclusions: Taken together, our immunohistochemical and microarray results and cellular studies have shown for the first time that ADAM19 is a protective factor for human prostate cancer. Further, this study suggests that upregulation of ADAM19 expression could be of therapeutic potential in human prostate cancer

Training University Tutors to Work with Bilingual Students

The purpose of this project was to train university tutors to improve their support of bilingual students (ESL/ELL students). We developed an evidence-based training session that emphasizes university connectedness and cultural inclusion. This one-hour training included background information, tutoring tips, and time for discussion. The majority of tutors (44 out of 47) reported learning something helpful they could use when tutoring. While this intervention was specifically designed to target bilingual students, most evidence-based tips discussed here are applicable to all students. It is crucial to provide tutors with the skills and resources necessary to better connect with their students

Microglia are both a source and target of extracellular cyclophilin A

Glioblastoma (GBM) are lethal primary brain tumours whose pathogenesis is aided, at least partly, via a pro-tumorigenic microenvironment. This study investigated whether microglia, a cell component of the GBM microenvironment, mediates pro-tumorigenic properties via the action of cyclophilin A (CypA), a potent secretable chemokine and cytoprotectant that signals via the cell surface receptor, CD147. To this end, intracellular and secreted CypA expression was assessed in human primary microglia and BV2 microglial cells treated with the endotoxin, lipopolysaccharide (LPS) and the oxidative stress inducer, LY83583. We report that human primary microglia and BV2 microglia both express CypA and CD147, and that BV2 microglial cells secrete CypA in response to pro-inflammatory and oxidative stimuli. We also demonstrate for the first time that recombinant CypA (rCypA; 1nM–1000nM) dose-dependently increased wound healing and reduced basal cell death in BV2 microglial cells. To determine the cell–signalling pathways involved, we probed microglial cell lysates for changes in ERK1/2 and AKT phosphorylation, IκB degradation, and IL-6 secretion using Western blot and ELISA analysis. In summary, BV2 microglial cells secrete CypA in response to inflammatory and oxidative stress, and that rCypA increases cell viability and chemotaxis. Our findings suggest that rCypA is a pro-survival chemokine for microglia that may influence the GBM tumour microenvironment

Longitudinal Assessment of Older Drivers in a DMV Setting

A brief battery of functional assessments designed to detect crash riskamong older drivers was developed and evaluated initially in 1999 in Marylandmotor vehicle licensing sites following the routine vision screening exam. Thisbattery contained a number of cognitive tests (e.g., UFOV® subtest 2, the closuresubtest of the Motor Free Visual Perception Test (MVPT), Trails A and B, cuedrecall, delayed recall), and several physical measures (e.g., Rapid Pace Walk,Head and Neck Rotation, Foot Tap, Arm Reach). Older adults (N=4,173; meanage = 69 years) were approached by the staff after license renewal and asked tohelp evaluate the brief battery. Of the 4,173 older adults approached at the fieldsites, 2,114 individuals 55-96 years of age participated. Subsequently, the originalsample of 2,114 participants was invited to come in once again, during their fiveyearlicense renewal cycle, and the functional tests were administered once again.To date, 939 individuals have completed the second screening evaluation. Anexamination of the crash data from the interval between assessments for theseindividuals indicates that the same cognitive measures are predictive of at-faultcrashes. Furthermore, approximately 10% of those passing the assessment in 1999are now failing the assessment in 2004. Performance-based cognitive measuresare predictive of future at-fault motor vehicle collisions among older adults.Cognitive performance, in particular, is a salient predictor of subsequent crashinvolvement among older adults. High-risk older drivers can be identified throughbrief, performance-based measures administered in a DMV setting

The ADVANCE network: accelerating data value across a national community health center network

The ADVANCE (Accelerating Data Value Across a National Community Health Center Network) clinical data research network (CDRN) is led by the OCHIN Community Health Information Network in partnership with Health Choice Network and Fenway Health. The ADVANCE CDRN will ‘horizontally’ integrate outpatient electronic health record data for over one million federally qualified health center patients, and ‘vertically’ integrate hospital, health plan, and community data for these patients, often under-represented in research studies. Patient investigators, community investigators, and academic investigators with diverse expertise will work together to meet project goals related to data integration, patient engagement and recruitment, and the development of streamlined regulatory policies. By enhancing the data and research infrastructure of participating organizations, the ADVANCE CDRN will serve as a ‘community laboratory’ for including disadvantaged and vulnerable patients in patient-centered outcomes research that is aligned with the priorities of patients, clinics, and communities in our network

ADAM19: A Novel Target for Metabolic Syndrome in Humans and Mice

Obesity is one of the most prevalent metabolic diseases in the Western world and correlates directly with insulin resistance, which may ultimately culminate in type 2 diabetes (T2D). We sought to ascertain whether the human metalloproteinase A Disintegrin and Metalloproteinase 19 (ADAM19) correlates with parameters of the metabolic syndrome in humans and mice. To determine the potential novel role of ADAM19 in the metabolic syndrome, we first conducted microarray studies on peripheral blood mononuclear cells from a well-characterised human cohort. Secondly, we examined the expression of ADAM19 in liver and gonadal white adipose tissue using an in vivo diet induced obesity mouse model. Finally, we investigated the effect of neutralising ADAM19 on diet induced weight gain, insulin resistance in vivo, and liver TNF- levels. Significantly, we show that, in humans, ADAM19 strongly correlates with parameters of the metabolic syndrome, particularly BMI, relative fat, HOMA-IR, and triglycerides. Furthermore, we identified that ADAM19 expression was markedly increased in the liver and gonadal white adipose tissue of obese and T2D mice. Excitingly, we demonstrate in our diet induced obesity mouse model that neutralising ADAM19 therapy results in weight loss, improves insulin sensitivity, and reduces liver TNF- levels. Our novel data suggest that ADAM19 is pro-obesogenic and enhances insulin resistance. Therefore, neutralisation of ADAM19 may be a potential therapeutic approach to treat obesity and T2D

Weight-based antibiotic dosing in a real-world European study of complicated skin and soft-tissue infections due to methicillin-resistant <i>Staphylococcus aureus</i>

AbstractWe aimed to characterize real-world dosing of weight-based intravenous (IV) antibiotic therapy in patients hospitalized for methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infections (cSSTIs). This was a subgroup analysis of a retrospective chart review that captured data from 12 European countries. The study included patients ≥18 years old, hospitalized with an MRSA cSSTI between 1 July 2010 and 30 June 2011 and discharged alive by 31 July 2011. Patients treated with IV vancomycin, teicoplanin or daptomycin at any stage during hospitalization were included in this analysis. Analyses were conducted at the regimen level (dosing in mg/kg or in mg, frequency, and total daily dose (TDD)), with potentially multiple regimens per patient, and the patient level, categorizing patients into low, standard (labelled) and high dosing groups according to their initial MRSA-targeted regimen. Among the 1502 patients in the parent study, 998 patients contributed a total of 1050 daptomycin, teicoplanin or vancomycin regimens. Across all regimens, the mean initial TDDs were 6.3 ± 1.9 mg/kg for daptomycin, 10.5 ± 4.9 mg/kg for teicoplanin and 28.5 ± 11.5 mg/kg for vancomycin. A total of 789 patients received first-line therapy with one of the above antibiotics. The majority of patients receiving first-line teicoplanin and daptomycin (96% and 80%, respectively) received higher than labelled cSSTI doses, whereas vancomycin doses were lower than labelled doses in >40% of patients. These real-world data reveal significant deviation from labelled antibiotic dosing in 12 European countries and the potential for suboptimal outcomes in patients with MRSA cSSTIs

Sympathetic Nervous System Activation and Its Modulation: Role in Atrial Fibrillation

The autonomic nervous system (ANS) has a significant influence on the structural integrity and electrical conductivity of the atria. Aberrant activation of the sympathetic nervous system can induce heterogeneous changes with arrhythmogenic potential which can result in atrial tachycardia, atrial tachyarrhythmias and atrial fibrillation (AF). Methods to modulate autonomic activity primarily through reduction of sympathetic outflow reduce the incidence of spontaneous or induced atrial arrhythmias in animal models and humans, suggestive of the potential application of such strategies in the management of AF. In this review we focus on the relationship between the ANS, sympathetic overdrive and the pathophysiology of AF, and the potential of sympathetic neuromodulation in the management of AF. We conclude that sympathetic activity plays an important role in the initiation and maintenance of AF, and modulating ANS function is an important therapeutic approach to improve the management of AF in selected categories of patients. Potential therapeutic applications include pharmacological inhibition with central and peripheral sympatholytic agents and various device based approaches. While the role of the sympathetic nervous system has long been recognized, new developments in science and technology in this field promise exciting prospects for the future