In an in vitro model of human tuberculosis, monocyte-microglial networks regulate matrix metalloproteinase-1 and -3 gene expression and secretion via a p38 mitogen activated protein kinase-dependent pathway.

BACKGROUND: Tuberculosis (TB) of the central nervous system (CNS) is characterized by extensive tissue inflammation, driven by molecules that cleave extracellular matrix such as matrix metalloproteinase (MMP)-1 and MMP-3. However, relatively little is known about the regulation of these MMPs in the CNS. METHODS: Using a cellular model of CNS TB, we stimulated a human microglial cell line (CHME3) with conditioned medium from Mycobacterium tuberculosis-infected primary human monocytes (CoMTb). MMP-1 and MMP-3 secretion was detected using ELISAs confirmed with casein zymography or western blotting. Key results of a phospho-array profile that detects a wide range of kinase activity were confirmed with phospho-Western blotting. Chemical inhibition (SB203580) of microglial cells allowed investigation of expression and secretion of MMP-1 and MMP-3. Finally we used promoter reporter assays employing full length and MMP-3 promoter deletion constructs. Student's t-test was used for comparison of continuous variables and multiple intervention experiments were compared by one-way ANOVA with Tukey's correction for multiple pairwise comparisons. RESULTS: CoMTb up-regulated microglial MMP-1 and MMP-3 secretion in a dose- and time-dependent manner. The phospho-array profiling showed that the major increase in kinase activity due to CoMTb stimulation was in p38 mitogen activated protein kinase (MAPK), principally the α and γ subunits. p38 phosphorylation was detected at 15 minutes, with a second peak of activity at 120 minutes. High basal extracellular signal-regulated kinase activity was further increased by CoMTb. Secretion and expression of MMP-1 and MMP-3 were both p38 dependent. CoMTb stimulation of full length and MMP-3 promoter deletion constructs demonstrated up-regulation of activity in the wild type but a suppression site between -2183 and -1612 bp. CONCLUSIONS: Monocyte-microglial network-dependent MMP-1 and MMP-3 gene expression and secretion are dependent upon p38 MAPK in tuberculosis. p38 is therefore a potential target for adjuvant therapy in CNS TB

Lime stabilisation for earthworks: a UK perspective

Lime stabilisation is a versatile technique applied during earthworks operations. Modern soil recycling units are much more efficient at pulverising fill material and intermixing the added binder/water than machinery available 20 years ago. While supplier innovation adds flexibility to the site working method, specifications have not been sufficiently updated to permit optimal application. This review paper details the physico-chemical changes instigated through the lime-clay soil reaction, updating previous reviews. It aims to assist scientific debate, current practitioners and future specification changes. For example, the application of the minimum 24 h mellowing periods (mandatory to UK specifications) with high reactivity, quicklime powders is concluded to cause increased air voids in the compacted fill. Increased air voids are associated with reduced long-term strength and potential volume change from water ingress, which is of particular concern for sulfate swelling. Shorter mellowing periods and/or use of hydrated lime may lesson this issue; however, a 'one size fits all' approach is discouraged in preference to site-specific methodologies refined to suit the fill material and project requirements. The discussion also summarises working methods which may lower the risk of sulfate swell and defines areas requiring further practical research

Applying the Geostatistical Eigenvector Spatial Filter Approach into Regularized Regression for Improving Prediction Accuracy for Mass Appraisal

Prediction accuracy for mass appraisal purposes has evolved substantially over the last few decades, facilitated by the evolution in big data, data availability and open source software. Accompanying these advances, newer forms of geo-spatial approaches and machine learning (ML) algorithms have been shown to help improve house price prediction and mass appraisal assessment. Nonetheless, the adoption a of ML within mass appraisal has been protracted and subject to scrutiny by assessment jurisdictions due to their failure to account for spatial autocorrelation and limited practicality in terms of value significant estimates needed for tribunal defense and explainability. Existing research comparing traditional regression approaches has tended to examine unsupervised ML methods such as Random Forest (RF) models which remain more esoteric and less transparent in producing value significant estimates necessary for mass appraisal explainability and defense. Therefore, the purpose of this study is to apply the supervised Regularized regression technique which offers a more transparent alternative, and integrate this with a more nuanced geo-statistical technique, the Eigenvector Spatial Filter (ESF) approach, to more accurately account for spatial autocorrelation and enhance prediction accuracy whilst improving explainability needed for mass appraisal exercises. By undertaking such an approach, the research demonstrates the application of this method can be easily adopted for property tax jurisdictions in a framework which is more interpretable, transparent and useable within mass appraisal given its simple and appealing approach. The findings reveal that the integration of the ESFs improves model explainability, prediction accuracy and spatial residual error compared to baseline classical regression and Elastic-net regularized regression architectures, whilst offering the necessary ‘front-facing’ and flexible structure for in-sample and out-of-sample assessment needed by the assessment community for valuing the unsold housing stock. In terms of policy and practice, the study demonstrates some important considerations for mass appraisal tax assessment and for the improvement of taxation assessment and the alleviation of horizontal and vertical inequity

Experimental evaluation of the relationship between lethal or non-lethal virulence and transmission success in malaria parasite infections

BACKGROUND: Evolutionary theory suggests that the selection pressure on parasites to maximize their transmission determines their optimal host exploitation strategies and thus their virulence. Establishing the adaptive basis to parasite life history traits has important consequences for predicting parasite responses to public health interventions. In this study we examine the extent to which malaria parasites conform to the predicted adaptive trade-off between transmission and virulence, as defined by mortality. The majority of natural infections, however, result in sub-lethal virulent effects (e.g. anaemia) and are often composed of many strains. Both sub-lethal effects and pathogen population structure have been theoretically shown to have important consequences for virulence evolution. Thus, we additionally examine the relationship between anaemia and transmission in single and mixed clone infections. RESULTS: Whereas there was a trade-off between transmission success and virulence as defined by host mortality, contradictory clone-specific patterns occurred when defining virulence by anaemia. A negative relationship between anaemia and transmission success was found for one of the parasite clones, whereas there was no relationship for the other. Notably the two parasite clones also differed in a transmission phenotype (gametocyte sex ratio) that has previously been shown to respond adaptively to a changing blood environment. In addition, as predicted by evolutionary theory, mixed infections resulted in increased anaemia. The increased anaemia was, however, not correlated with any discernable parasite trait (e.g. parasite density) or with increased transmission. CONCLUSIONS: We found some evidence supporting the hypothesis that there is an adaptive basis correlating virulence (as defined by host mortality) and transmission success in malaria parasites. This confirms the validity of applying evolutionary virulence theory to biomedical research and adds support to the prediction that partially effective vaccines may select for increasingly virulent malaria parasite strains. By contrast, there was no consistent correlation between transmission and sub-lethal anaemia, a more common outcome of malaria infection. However, overall, the data are not inconsistent with the recent proposal that sub-lethal effects may impose an upper limit on virulence. Moreover, clone specific differences in transmission phenotypes linked to anaemia do suggest that there is considerable adaptive potential relating anaemia and transmission that may lead to uncertain consequences following intervention strategies

Attenuating Effect of Vigorous Physical Activity on the Risk for Inherited Obesity: A Study of 47,691 Runners

Objective: Physical activity has been shown to attenuate the effect of the FTO polymorphism on body weight, and the heritability of body weight in twin and in family studies. The dose-response relationship between activity and the risk for inherited obesity is not well known, particularly for higher doses of vigorous exercise. Such information is needed to best prescribe an exercise dose for obesity prevention in those at risk due to their family history. Design: We therefore analyzed self-reported usual running distance, body mass index (BMI), waist circumference, and mother’s and father’s adiposity (1 = lean, 2 = normal, 3 = overweight, and 4 = very overweight) from survey data collected on 33,480 male and 14,211 female runners. Age-, education-, and alcohol-adjusted regression analyses were used to estimate the contribution of parental adiposities to the BMI and waist circumferences in runners who ran an average of,3, 3–6, 6–9, $9 km/day. Results: BMI and waist circumferences of runners who ran,3 km/day were significantly related to their parents adiposity (P,10 215 and P,10 211, respectively). These relationships (i.e., kg/m 2 or cm per increment in parental adiposity) diminished significantly with increasing running distance for both BMI (inheritance6exercise interaction, males: P,10 210; females: P,10 25) and waist circumference (inheritance6exercise interaction, males: P,10 29; females: P = 0.004). Compared to,3 km/day, the parental contribution to runners who averaged$9 km/day was diminished by 48 % for male BMI, 58 % for female BMI, 55 % for male waist circumference, and 58 % for female waist circumference. These results could not b

Quantile-Specific Penetrance of Genes Affecting Lipoproteins, Adiposity and Height

Quantile-dependent penetrance is proposed to occur when the phenotypic expression of a SNP depends upon the population percentile of the phenotype. To illustrate the phenomenon, quantiles of height, body mass index (BMI), and plasma lipids and lipoproteins were compared to genetic risk scores (GRS) derived from single nucleotide polymorphisms (SNP)s having established genome-wide significance: 180 SNPs for height, 32 for BMI, 37 for low-density lipoprotein (LDL)-cholesterol, 47 for high-density lipoprotein (HDL)-cholesterol, 52 for total cholesterol, and 31 for triglycerides in 1930 subjects. Both phenotypes and GRSs were adjusted for sex, age, study, and smoking status. Quantile regression showed that the slope of the genotype-phenotype relationships increased with the percentile of BMI (P = 0.002), LDL-cholesterol (P = 3×10−8), HDL-cholesterol (P = 5×10−6), total cholesterol (P = 2.5×10−6), and triglyceride distribution (P = 7.5×10−6), but not height (P = 0.09). Compared to a GRS's phenotypic effect at the 10th population percentile, its effect at the 90th percentile was 4.2-fold greater for BMI, 4.9-fold greater for LDL-cholesterol, 1.9-fold greater for HDL-cholesterol, 3.1-fold greater for total cholesterol, and 3.3-fold greater for triglycerides. Moreover, the effect of the rs1558902 (FTO) risk allele was 6.7-fold greater at the 90th than the 10th percentile of the BMI distribution, and that of the rs3764261 (CETP) risk allele was 2.4-fold greater at the 90th than the 10th percentile of the HDL-cholesterol distribution. Conceptually, it maybe useful to distinguish environmental effects on the phenotype that in turn alters a gene's phenotypic expression (quantile-dependent penetrance) from environmental effects affecting the gene's phenotypic expression directly (gene-environment interaction)

Development of a decision support tool to facilitate primary care management of patients with abnormal liver function tests without clinically apparent liver disease [HTA03/38/02]. Abnormal Liver Function Investigations Evaluation (ALFIE)

Liver function tests (LFTs) are routinely performed in primary care, and are often the gateway to further invasive and/or expensive investigations. Little is known of the consequences in people with an initial abnormal liver function (ALF) test in primary care and with no obvious liver disease. Further investigations may be dangerous for the patient and expensive for Health Services. The aims of this study are to determine the natural history of abnormalities in LFTs before overt liver disease presents in the population and identify those who require minimal further investigations with the potential for reduction in NHS costs

Effects of Volitional Preemptive Abdominal Contraction on Shoulder Proprioception Following Shoulder Muscle Fatigue

The abdominal bracing maneuver, a volitional preemptive abdominal contraction (VPAC) strategy, is potentially beneficial to shoulder exercise performance. It is unclear how VPAC use affects shoulder function, including proprioception and shoulder muscle function following shoulder muscle fatigue caused by upper extremity dominant sports movements. Discovering methods that reduce its effects on shoulder proprioception and shoulder muscle function is important for clinical practice in orthopedic rehabilitation. PURPOSE: To identify VPAC effects on shoulder proprioception abilities and to identify VPAC effects on shoulder muscle electromyographic amplitudes, during seated proprioception trials, both with and without muscle fatigue present. METHODS: Thirty-nine participants (26 women, 13 men) participated in this study. Shoulder proprioception was measured by shoulder flexion reproduction angles. Kinematic data were collected during the shoulder flexion trials to determine the accuracy in the subjects’ ability to reproduce a reference angle. All data were collected before and after a shoulder muscle fatigue protocol. Electromyographic data from the anterior deltoid (AD), posterior deltoid (PD), upper trapezius (UT), lower trapezius (LT), serratus anterior (SA), and infraspinatus (IF) muscles were used to observe muscle contraction amplitudes during the angle reproduction trials. RESULTS: Shoulder reproduction angles were not significantly affected by VPAC or muscle fatigue. Individually, shoulder muscle fatigue significantly increased UT muscle amplitudes (Mdn = 0.059(0.135), p\u3c.008) and LT muscle amplitudes (Mdn = 0.023(0.059), p\u3c.008). VPAC significantly increased shoulder IF muscle amplitudes (Mdn = 0.019(0.038), p\u3c.008). CONCLUSION: The VPAC did not affect shoulder proprioception in this study, showing that the strategy may not be beneficial to improving proprioception in the shoulder joint. The affects of muscle fatigue on the selected shoulder muscles supported the observations in previous literature concerning muscle fatigue effects on selected shoulder muscle. Clinicians can use this information to assist with the creation of therapeutic exercise for the shoulder joint

Impact of Student Experiences in Team-based Practice in a Student-run Outreach Clinic

If trainees from differing health professions work together in a team-based setting to provide quality care to underserved individuals, they may be more inclined to work in an interprofessional collaborative health care team. The purpose of the study was to learn about student experiences at the Indiana University Student Outreach Clinic (IUSOC) as it relates to caring for underserved individuals. The IUSOC is a free clinic run out of the Neighborhood Fellowship Church in Indianapolis, Indiana. The IUSOC clinic provides primary care-based medical services free of charge for the uninsured and underserved within the community. The patient population includes individuals with medical problems of varying acuity. Health profession students from dentistry, medicine, nursing, pharmacy, public health, and social work co-located in the clinic recently agreed to move more intentionally into interprofessional collaborative care to more effectively address a variety of patient needs. This specific assessment is the result of a unique collaboration between the IUSOC, the Indiana Area Health Education Center Network, IU School of Medicine Office of Diversity Affairs, and the IU Center for Interprofessional Health Education and Practice. The goal was to determine if students volunteering in the IUSOC are leaving with the willingness and ability to serve vulnerable populations in an interprofessional collaborative manner. In the spring of 2016, a pilot assessment was conducted with 269 health profession student volunteers. The 18-question survey assessed student’s perception of their experience serving in an interprofessional team, working with individuals from diverse backgrounds, understanding of the unique needs of underserved individuals, and their future practice intents. The results of this pilot assessment is critical as we determine how to maximize the student experience at the IUSOC so that they are equipped with the competencies necessary to practice in an interprofessional collaborative manner with diverse teams throughout the healthcare community. Objectives: By the end of this interactive discussion, participants will: Identify the value of evaluating program outcomes in assessing the effectiveness of interprofessional education within a community-based student experience. Describe the value of using a collaborative partnership to maximize the opportunity for interprofessional/team based education among health profession students in a clinical learning environment. Identify strategic next steps for assessing student competence in interprofessional team-based care