Ways to Greater Happiness: A Delphi Study

In the first round of this Delphi study 14 experts suggested strategies for improving life-satisfaction. In a second round, experts rated these strategies for (a) effectiveness, (b) feasibility and (c) cost-effectiveness. They considered 56 strategies policy makers can use to raise average happiness in a nation and 68 ways in which individuals can raise their own happiness. Experts were informed about the average ratings made by the panel and about the arguments advanced. Then, in a third round, experts made their final judgments. Summed ratings for average effectiveness and feasibility of the strategies ranged between 8.4 and 4.9 on scale 2–10, which means that most of the recommendations were deemed suitable. Agreement was slightly higher on policy strategies than on individual ways to greater happiness. Policy strategies deemed the most effective and feasi

Cellular biology of fracture healing

The biology of bone healing is a rapidly developing science. Advances in transgenic and gene‐targeted mice have enabled tissue and cell‐specific investigations of skeletal regeneration. As an example, only recently has it been recognized that chondrocytes convert to osteoblasts during healing bone, and only several years prior, seminal publications reported definitively that the primary tissues contributing bone forming cells during regeneration were the periosteum and endosteum. While genetically modified animals offer incredible insights into the temporal and spatial importance of various gene products, the complexity and rapidity of healing—coupled with the heterogeneity of animal models—renders studies of regenerative biology challenging. Herein, cells that play a key role in bone healing will be reviewed and extracellular mediators regulating their behavior discussed. We will focus on recent studies that explore novel roles of inflammation in bone healing, and the origins and fates of various cells in the fracture environment. © 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop ResAdvances in transgenic and gene‐targeted mice have enabled tissue and cell‐specific investigation of skeletal regeneration. While genetically modified animals offer incredible insights into the temporal and spatial importance of various molecules, the complexity and rapidity of healing renders studies of regenerative biology challenging. Herein, cells and extracellular mediators that play a key role in bone healing are reviewed. We will focus on recent studies that explore the origins and fates of various cells in the fracture environment.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/148261/1/jor24170_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148261/2/jor24170-sup-0002-SuppTab-S2.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148261/3/jor24170-sup-0001-SuppTab-S1.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/148261/4/jor24170.pd

A 200-year perspective on alternative stable state theory and lake management from a biomanipulated shallow lake

Abstract. Multiple stressors to a shallow lake ecosystem have the ability to control the relative stability of alternative states (clear, macrophyte-dominated or turbid, algaldominated). As a consequence, the use of remedial biomanipulations to induce trophic cascades and shift a turbid lake to a clear state is often only a temporary solution. Here we show the instability of short-term manipulations in the shallow Lake Christina (Minnesota, USA) is governed by the long-term state following a regime shift in the lake. During the modern, managed period of the lake, three top-down manipulations (fish kills) were undertaken inducing temporary (5-10 years) unstable clear-water states. Paleoecological remains of diatoms, along with proxies of primary production (total chlorophyll a and total organic carbon accumulation rate) and trophic state (total P) from sediment records clearly show a single regime shift in the lake during the early 1950s; following this shift, the functioning of the lake ecosystem is dominated by a persistent turbid state. We find that multiple stressors contributed to the regime shift. First, the lake began to eutrophy (from agricultural land use and/or increased waterfowl populations), leading to a dramatic increase in primary production. Soon after, the construction of a dam in 1936 effectively doubled the depth of the lake, compounded by increases in regional humidity; this resulted in an increase in planktivorous and benthivorous fish reducing phytoplankton grazers. These factors further conspired to increase the stability of a turbid regime during the modern managed period, such that switches to a clear-water state were inherently unstable and the lake consistently returned to a turbid state. We conclude that while top-down manipulations have had measurable impacts on the lake state, they have not been effective in providing a return to an ecosystem similar to the stable historical period. Our work offers an example of a well-studied ecosystem forced by multiple stressors into a new long-term managed period, where manipulated clearwater states are temporary, managed features

T-Lymphocytes Enable Osteoblast Maturation via IL-17F during the Early Phase of Fracture Repair

While it is well known that the presence of lymphocytes and cytokines are important for fracture healing, the exact role of the various cytokines expressed by cells of the immune system on osteoblast biology remains unclear. To study the role of inflammatory cytokines in fracture repair, we studied tibial bone healing in wild-type and Rag1−/− mice. Histological analysis, µCT stereology, biomechanical testing, calcein staining and quantitative RNA gene expression studies were performed on healing tibial fractures. These data provide support for Rag1−/− mice as a model of impaired fracture healing compared to wild-type. Moreover, the pro-inflammatory cytokine, IL-17F, was found to be a key mediator in the cellular response of the immune system in osteogenesis. In vitro studies showed that IL-17F alone stimulated osteoblast maturation. We propose a model in which the Th17 subset of T-lymphocytes produces IL-17F to stimulate bone healing. This is a pivotal link in advancing our current understanding of the molecular and cellular basis of fracture healing, which in turn may aid in optimizing fracture management and in the treatment of impaired bone healing

In situ guided tissue regeneration in musculoskeletal diseases and aging: Implementing pathology into tailored tissue engineering strategies

In situ guided tissue regeneration, also addressed as in situ tissue engineering or endogenous regeneration, has a great potential for population-wide “minimal invasive” applications. During the last two decades, tissue engineering has been developed with remarkable in vitro and preclinical success but still the number of applications in clinical routine is extremely small. Moreover, the vision of population-wide applications of ex vivo tissue engineered constructs based on cells, growth and differentiation factors and scaffolds, must probably be deemed unrealistic for economic and regulation-related issues. Hence, the progress made in this respect will be mostly applicable to a fraction of post-traumatic or post-surgery situations such as big tissue defects due to tumor manifestation. Minimally invasive procedures would probably qualify for a broader application and ideally would only require off the shelf standardized products without cells. Such products should mimic the microenvironment of regenerating tissues and make use of the endogenous tissue regeneration capacities. Functionally, the chemotaxis of regenerative cells, their amplification as a transient amplifying pool and their concerted differentiation and remodeling should be addressed. This is especially important because the main target populations for such applications are the elderly and diseased. The quality of regenerative cells is impaired in such organisms and high levels of inhibitors also interfere with regeneration and healing. In metabolic bone diseases like osteoporosis, it is already known that antagonists for inhibitors such as activin and sclerostin enhance bone formation. Implementing such strategies into applications for in situ guided tissue regeneration should greatly enhance the efficacy of tailored procedures in the future

Genome-Wide Association Study of Circulating Interleukin 6 Levels Identifies Novel Loci

Interleukin-6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery, and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67 428 (n{discovery} = 52 654 and n_{replication} = 14 774) individuals of European ancestry. The inverse variance fixed-effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on Chromosome (Chr) 2q14, (pcombined = 1.8 × 10^{−11}), HLA-DRB1/DRB5 rs660895 on Chr6p21 (p_{combined} = 1.5 × 10^{−10}) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (p_{combined} = 1.2 × 10^{−122}). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology

Defective proliferation and osteogenic potential with altered immunoregulatory phenotype of native bone marrow-multipotential stromal cells in atrophic fracture non-union

Bone marrow-Multipotential stromal cells (BM-MSCs) are increasingly used to treat complicated fracture healing e.g., non-union. Though, the quality of these autologous cells is not well characterized. We aimed to evaluate bone healing-related capacities of non-union BM-MSCs. Iliac crest-BM was aspirated from long-bone fracture patients with normal healing (U) or non-united (NU). Uncultured (native) CD271highCD45low cells or passage-zero cultured BM-MSCs were analyzed for gene expression levels, and functional assays were conducted using culture-expanded BM-MSCs. Blood samples were analyzed for serum cytokine levels. Uncultured NU-CD271highCD45low cells significantly expressed fewer transcripts of growth factor receptors, EGFR, FGFR1, and FGRF2 than U cells. Significant fewer transcripts of alkaline phosphatase (ALPL), osteocalcin (BGLAP), osteonectin (SPARC) and osteopontin (SPP1) were detected in NU-CD271highCD45low cells. Additionally, immunoregulation-related markers were differentially expressed between NU- and U-CD271highCD45low cells. Interestingly, passage-zero NU BM-MSCs showed low expression of immunosuppressive mediators. However, culture-expanded NU and U BM-MSCs exhibited comparable proliferation, osteogenesis, and immunosuppression. Serum cytokine levels were found similar for NU and U groups. Collectively, native NU-BM-MSCs seemed to have low proliferative and osteogenic capacities; therefore, enhancing their quality should be considered for regenerative therapies. Further research on distorted immunoregulatory molecules expression in BM-MSCs could potentially benefit the prediction of complicated fracture healing

Genome-wide association study of circulating interleukin 6 levels identifies novel loci

Interleukin 6 (IL-6) is a multifunctional cytokine with both pro- and anti-inflammatory properties with a heritability estimate of up to 61%. The circulating levels of IL-6 in blood have been associated with an increased risk of complex disease pathogenesis. We conducted a two-staged, discovery and replication meta genome-wide association study (GWAS) of circulating serum IL-6 levels comprising up to 67428 (ndiscovery=52654 and nreplication=14774) individuals of European ancestry. The inverse variance fixed effects based discovery meta-analysis, followed by replication led to the identification of two independent loci, IL1F10/IL1RN rs6734238 on chromosome (Chr) 2q14, (Pcombined=1.8x10-11), HLA-DRB1/DRB5 rs660895 on Chr6p21 (Pcombined=1.5x10-10) in the combined meta-analyses of all samples. We also replicated the IL6R rs4537545 locus on Chr1q21 (Pcombined=1.2x10-122). Our study identifies novel loci for circulating IL-6 levels uncovering new immunological and inflammatory pathways that may influence IL-6 pathobiology.</p