Tissue Microenvironments Define and Get Reinforced by Macrophage Phenotypes in Homeostasis or during Inflammation, Repair and Fibrosis

Current macrophage phenotype classifications are based on distinct in vitro culture conditions that do not adequately mirror complex tissue environments. In vivo monocyte progenitors populate all tissues for immune surveillance which supports the maintenance of homeostasis as well as regaining homeostasis after injury. Here we propose to classify macrophage phenotypes according to prototypical tissue environments, e.g. as they occur during homeostasis as well as during the different phases of (dermal) wound healing. In tissue necrosis and/or infection, damage- and/or pathogen-associated molecular patterns induce proinflammatory macrophages by Toll-like receptors or inflammasomes. Such classically activated macrophages contribute to further tissue inflammation and damage. Apoptotic cells and antiinflammatory cytokines dominate in postinflammatory tissues which induce macrophages to produce more antiinflammatory mediators. Similarly, tumor-associated macrophages also confer immunosuppression in tumor stroma. Insufficient parenchymal healing despite abundant growth factors pushes macrophages to gain a profibrotic phenotype and promote fibrocyte recruitment which both enforce tissue scarring. Ischemic scars are largely devoid of cytokines and growth factors so that fibrolytic macrophages that predominantly secrete proteases digest the excess extracellular matrix. Together, macrophages stabilize their surrounding tissue microenvironments by adapting different phenotypes as feed-forward mechanisms to maintain tissue homeostasis or regain it following injury. Furthermore, macrophage heterogeneity in healthy or injured tissues mirrors spatial and temporal differences in microenvironments during the various stages of tissue injury and repair. Copyright (C) 2012 S. Karger AG, Base

A Philosophically Plausible Formal Interpretation of Intuitionistic Logic

This study addresses the mediating role of settlement patterns in the relationship between urbanization and start-up activity. Places do not operate in a vacuum and to understand the effect of 'own' density on start-up patterns, we need to account for the urban spillovers or borrowed size that they may experience from other places nearby. The results can explain the empirical ambiguity in the relationship between urbanization and start-up patterns: the relationship between urbanization and start-up rates becomes more similar between countries when controlling for country-specific settlement patterns by including a spatially lagged urbanization variable and variables measuring the distance to urban centers. Accounting for the relative location of places and relevant sorting effects, we find that 'own' density has a consistently negative effect on start-up activity. Yet, access to other places has a generally positive effect. This implies that nearby regions profit from the advantages offered by urban environments without having to deal with the costs involved

Correlated /\c-/\cbar production in e+e- annihilations at sqrt{s}~10.5 GeV

Using 13.6/fb of continuum two-jet e+e- -> ccbar events collected with the CLEO detector, we have searched for baryon number correlations at the primary quark level. We have measured the likelihood for a /\c+ charmed baryon to be produced in the hemisphere opposite a /\c- relative to the likelihood for a /\c+ charmed baryon to be produced opposite an anticharmed meson Dbar; in all cases, the reconstructed hadrons must have momentum greater than 2.3 GeV/c. We find that, given a /\c- (reconstructed in five different decay modes), a /\c+ is observed in the opposite hemisphere (0.72+/-0.11)% of the time (not corrected for efficiency). By contrast, given a Dbar in one hemisphere, a /\c+ is observed in the opposite hemisphere only (0.21+/-0.02)% of the time. Normalized to the total number of either /\c- or Dbar ``tags'', it is therefore 3.52+/-0.45+/-0.42 times more likely to find a /\c+ opposite a /\c- than a Dbar meson. This enhancement is not observed in the JETSET 7.3 e+e- -> ccbar Monte Carlo simulation.Comment: 19 pages, Latex, one figure separat

Gender differences in the physiological responses and kinematic behaviour of elite sprint cross-country skiers

Gender differences in performance by elite endurance athletes, including runners, track cyclists and speed skaters, have been shown to be approximately 12%. The present study was designed to examine gender differences in physiological responses and kinematics associated with sprint cross-country skiing. Eight male and eight female elite sprint cross-country skiers, matched for performance, carried out a submaximal test, a test of maximal aerobic capacity (VO2max) and a shorter test of maximal treadmill speed (Vmax) during treadmill roller skiing utilizing the G3 skating technique. The men attained 17% higher speeds during both the VO2max and the Vmax tests (P < 0.05 in both cases), differences that were reduced to 9% upon normalization for fat-free body mass. Furthermore, the men exhibited 14 and 7% higher VO2max relative to total and fat-free body mass, respectively (P < 0.05 in both cases). The gross efficiency was similar for both gender groups. At the same absolute speed, men employed 11% longer cycles at lower rates, and at peak speed, 21% longer cycle lengths (P < 0.05 in all cases). The current study documents approximately 5% larger gender differences in performance and VO2max than those reported for comparable endurance sports. These differences reflect primarily the higher VO2max and lower percentage of body fat in men, since no gender differences in the ability to convert metabolic rate into work rate and speed were observed. With regards to kinematics, the gender difference in performance was explained by cycle length, not by cycle rate

Cost effectiveness of disc prosthesis versus lumbar fusion in patients with chronic low back pain: randomized controlled trial with 2-year follow-up

This randomized controlled health economic study assesses the cost-effectiveness of the concept of total disc replacement (TDR) (Charité/Prodisc/Maverick) when compared with the concept of instrumented lumbar fusion (FUS) [posterior lumbar fusion (PLF) /posterior lumbar interbody fusion (PLIF)]. Social and healthcare perspectives after 2 years are reported. In all, 152 patients were randomized to either TDR (n = 80) or lumbar FUS (n = 72). Cost to society (total mean cost/patient, Swedish kronor = SEK, standard deviation) for TDR was SEK 599,560 (400,272), and for lumbar FUS SEK 685,919 (422,903) (ns). The difference was not significant: SEK 86,359 (−45,605 to 214,332). TDR was significantly less costly from a healthcare perspective, SEK 22,996 (1,202 to 43,055). Number of days on sick leave among those who returned to work was 185 (146) in the TDR group, and 252 (189) in the FUS group (ns). Using EQ-5D, the total gain in quality adjusted life years (QALYs) over 2 years was 0.41 units for TDR and 0.40 units for FUS (ns). Based on EQ-5D, the incremental cost-effectiveness ratio (ICER) of using TDR instead of FUS was difficult to analyze due to the “non-difference” in treatment outcome, which is why cost/QALY was not meaningful to define. Using cost-effectiveness probabilistic analysis, the net benefit (with CI) was found to be SEK 91,359 (−73,643 to 249,114) (ns). We used the currency of 2006 where 1 EURO = 9.26 SEK and 1 USD = 7.38 SEK. It was not possible to state whether TDR or FUS is more cost-effective after 2 years. Since disc replacement and lumbar fusion are based on different conceptual approaches, it is important to follow these results over time

Frequent CXCR4 tropism of HIV-1 subtype A and CRF02_AG during late-stage disease - indication of an evolving epidemic in West Africa

<p>Abstract</p> <p>Background</p> <p>HIV-1 is one of the fastest evolving pathogens, and is distinguished by geographic and genetic variants that have been classified into different subtypes and circulating recombinant forms (CRFs). Early in infection the primary coreceptor is CCR5, but during disease course CXCR4-using HIV-1 populations may emerge. This has been correlated with accelerated disease progression in HIV-1 subtype B. Basic knowledge of HIV-1 coreceptor tropism is important due to the recent introduction of coreceptor antagonists in antiretroviral therapy, and subtype-specific differences regarding how frequently HIV-1 CXCR4-using populations appear in late-stage disease need to be further investigated. To study how frequently CXCR4-using populations appear in late-stage disease among HIV-1 subtype A and CRF02_AG, we evaluated the accuracy of a recombinant virus phenotypic assay for these subtypes, and used it to determine the HIV-1 coreceptor tropism of plasma samples collected during late-stage disease in Guinea-Bissau. We also performed a genotypic analysis and investigated subtype-specific differences in the appearance of CXCR4 tropism late in disease.</p> <p>Results</p> <p>We found that the recombinant virus phenotypic assay accurately predicted HIV-1 coreceptor tropism of subtype A and CRF02_AG. Over the study period (1997-2007), we found an increasing and generally high frequency of CXCR4 tropism (86%) in CRF02_AG. By sequence analysis of the V3 region of our samples we developed a novel genotypic rule for predicting CXCR4 tropism in CRF02_AG, based on the combined criteria of the total number of charged amino acids and net charge. This rule had higher sensitivity than previously described genotypic rules and may be useful for development of future genotypic tools for this CRF. Finally, we conducted a literature analysis, combining data of 498 individuals in late-stage disease, and found high amounts of CXCR4 tropism for all major HIV-1 subtypes (60-77%), except for subtype C (15%).</p> <p>Conclusions</p> <p>The increase in CXCR4 tropism over time suggests an evolving epidemic of CRF02_AG. The results of the literature analysis demonstrate the need for further studies investigating subtype-specific emergence for CXCR4-tropism; this may be particularly important due to the introduction of CCR5-antagonists in HIV treatment regimens.</p

New loci associated with birth weight identify genetic links between intrauterine growth and adult height and metabolism.

Birth weight within the normal range is associated with a variety of adult-onset diseases, but the mechanisms behind these associations are poorly understood. Previous genome-wide association studies of birth weight identified a variant in the ADCY5 gene associated both with birth weight and type 2 diabetes and a second variant, near CCNL1, with no obvious link to adult traits. In an expanded genome-wide association meta-analysis and follow-up study of birth weight (of up to 69,308 individuals of European descent from 43 studies), we have now extended the number of loci associated at genome-wide significance to 7, accounting for a similar proportion of variance as maternal smoking. Five of the loci are known to be associated with other phenotypes: ADCY5 and CDKAL1 with type 2 diabetes, ADRB1 with adult blood pressure and HMGA2 and LCORL with adult height. Our findings highlight genetic links between fetal growth and postnatal growth and metabolism

Novel genetic loci associated with hippocampal volume

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg =-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness