Osteoclast-independent bone resorption by fibroblast-like cells

To date, mesenchymal cells have only been associated with bone resorption indirectly, and it has been hypothesized that the degradation of bone is associated exclusively with specific functions of osteoclasts. Here we show, in aseptic prosthesis loosening, that aggressive fibroblasts at the bone surface actively contribute to bone resorption and that this is independent of osteoclasts. In two separate models (a severe combined immunodeficient mouse coimplantation model and a dentin pit formation assay), these cells produce signs of bone resorption that are similar to those in early osteoclastic resorption. In an animal model of aseptic prosthesis loosening (i.e. intracranially self-stimulated rats), it is shown that these fibroblasts acquire their ability to degrade bone early on in their differentiation. Upon stimulation, such fibroblasts readily release acidic components that lower the pH of their pericellular milieu. Through the use of specific inhibitors, pericellular acidification is shown to involve the action of vacuolar type ATPases. Although fibroblasts, as mesenchymal derived cells, are thought to be incapable of resorbing bone, the present study provides the first evidence to challenge this widely held belief. It is demonstrated that fibroblast-like cells, under pathological conditions, may not only enhance but also actively contribute to bone resorption. These cells should therefore be considered novel therapeutic targets in the treatment of bone destructive disorders

enhancing the circular economy with nature based solutions in the built urban environment green building materials systems and sites

Abstract The objective of this review paper is to survey the state of the art on nature-based solutions (NBS) in the built environment, which can contribute to a circular economy (CE) and counter the negative impacts of urbanization through the provision of ecosystem services. NBS are discussed here at three different levels: (i) green building materials, including biocomposites with plant-based aggregates; (ii) green building systems, employed for the greening of buildings by incorporating vegetation in their envelope; and (iii) green building sites, emphasizing the value of vegetated open spaces and water-sensitive urban design. After introducing the central concepts of NBS and CE as they are manifested in the built environment, we examine the impacts of urban development and the historical use of materials, systems and sites which can offer solutions to these problems. In the central section of the paper we present a series of case studies illustrating the development and implementation of such solutions in recent years. Finally, in a brief critical analysis we look at the ecosystem services and disservices provided by NBS in the built environment, and examine the policy instruments which can be leveraged to promote them in the most effective manner – facilitating the future transition to fully circular cities

Closing Water Cycles in the Built Environment through Nature-Based Solutions: The Contribution of Vertical Greening Systems and Green Roofs

Water in the city is typically exploited in a linear process, in which most of it is polluted, treated, and discharged; during this process, valuable nutrients are lost in the treatment process instead of being cycled back and used in urban agriculture or green space. The purpose of this paper is to advance a new paradigm to close water cycles in cities via the implementation of naturebased solutions units (NBS_u), with a particular focus on building greening elements, such as green roofs (GRs) and vertical greening systems (VGS). The hypothesis is that such “circular systems” can provide substantial ecosystem services and minimize environmental degradation. Our method is twofold: we first examine these systems from a life-cycle point of view, assessing not only the inputs of conventional and alternative materials, but the ongoing input of water that is required for irrigation. Secondly, the evapotranspiration performance of VGS in Copenhagen, Berlin, Lisbon, Rome, Istanbul, and Tel Aviv, cities with different climatic, architectural, and sociocultural contexts have been simulated using a verticalized ET0 approach, assessing rainwater runoff and greywater as irrigation resources. The water cycling performance of VGS in the mentioned cities would be sufficient at recycling 44% (Lisbon) to 100% (Berlin, Istanbul) of all accruing rainwater roof–runoff, if water shortages in dry months are bridged by greywater. Then, 27–53% of the greywater accruing in a building could be managed on its greened surface. In conclusion, we address the gaps in the current knowledge and policies identified in the different stages of analyses, such as the lack of comprehensive life cycle assessment studies that quantify the complete “water footprint” of building greening systems.info:eu-repo/semantics/publishedVersio

Antitumor Pentamethylcyclopentadienyl Rhodium Complexes of Maltol and Allomaltol: Synthesis, Solution Speciation and Bioactivity

The reaction of the dimer [RhIII(pentamethylcyclopentadienyl)(m-Cl)Cl]2 ([RhIII(Cp*)(m- Cl)Cl]2) with the hydroxypyrone ligands maltol and allomaltol affords complexes of the general formula [RhIII(Cp*)(L)Cl] under standard and microwave conditions. The organometallic compounds were characterized by standard analytical methods and in the case of the allomaltol derivative in the solid state by single-crystal X-ray diffraction analysis. The complexes showed similar cytotoxicity profiles and were proved to be moderately active against various human cancer cell lines. The stoichiometry and stability of these complexes were determined in aqueous solution by pH-potentiometry, 1H NMR spectroscopy and UVvisible spectrophotometry. Speciation was studied in the presence and in the absence of chloride ions. Hydrolysis of [RhIII(Cp*)(H2O)3]2+ gave dimeric mixed hydroxido species [(RhIII(Cp*))2(m-OH)3]+ and [(RhIII(Cp*))2(m-OH)2Z2] (Z = H2O/Cl‒). Formation of the mononuclear complexes [RhIII(Cp*)(L)Z] of maltol and allomaltol with similar and moderate stability was found. These species predominate at physiological pH and decompose only partially at micromolar concentrations. In addition, hydrolysis of the aqua complex or the chlorido/hydroxido co-ligand exchange resulted in the formation of the mixed-hydroxido species [RhIII(Cp*)(L)(OH)] in the basic pH range. Replacement of the chlorido by an aqua ligand in the complex [RhIII(Cp*)(L)Cl] was monitored and with the help of the equilibrium constants the extent of aquation at various chloride concentrations of the extra- and intracellular milieu can be predicted. Complexation of these RhIII complexes was compared to analogous [RuII(h6-p-cymene)] species and higher conditional stabilities were found in the case of the RhIII compounds at pH 7.4

Endothelial Progenitor Cells, Cardiovascular Risk Factors, Cytokine Levels and Atherosclerosis – Results from a Large Population-Based Study

EPC number and functionality are assumed to reflect the endogenous vascular repair capacity with the EPC pool declining in higher ages and being exhausted by unfavorable life-style and risk factors. This intriguing and clinically highly relevant concept, however, has so far been derived from small case-control studies and patient series.In the population-based Bruneck Study EPC number and EPC-colony forming units (EPC-CFU) were assessed as part of the fourth follow-up evaluation (2005) in 571 and 542 subjects, respectively. EPC number declined with age (p = 0.013), was significantly lower in women (p = 0.006) and higher in subjects on statin, hormone replacement or ACE inhibitor/angiotensin-receptor blockers, and correlated positively with moderate alcohol consumption. Unexpectedly, a positive relation between EPC number and several vascular risk factors emerged. In a step forward multivariate linear regression analysis EPC number was independently related with SDF1alpha, MMP-9, triglycerides, alcohol consumption, and Hba1c. EPC-CFU in turn was related to SDF1alpha and diastolic blood pressure. Moreover, EPC number showed a significant positive association with the Framingham risk score (P = 0.001). Finally, there was an inverse association between EPC number and common carotid artery intima-media thickness (p = 0.02) and the carotid artery atherosclerosis score (p = 0.059).Our population-based data confirm the decline of EPC number with advancing age and lend first epidemiological support to a role of SDF-1alpha and MMP9 in EPC differentiation, mobilization and homing, but are conflict with the view that EPC number is unfavorably affected by cardiovascular risk factors. EPC number increases with the cardiovascular risk estimated by the Framingham risk score (FRS), which in the absence of similar changes for EPC-CFU. Finally, we demonstrate a significant inverse association between EPC number and extent of carotid atherosclerosis even though this association was only of moderate strength and not entirely consistent in other vascular territories

Combined analgesics in (headache) pain therapy: shotgun approach or precise multi-target therapeutics?

<p>Abstract</p> <p>Background</p> <p>Pain in general and headache in particular are characterized by a change in activity in brain areas involved in pain processing. The therapeutic challenge is to identify drugs with molecular targets that restore the healthy state, resulting in meaningful pain relief or even freedom from pain. Different aspects of pain perception, i.e. sensory and affective components, also explain why there is not just one single target structure for therapeutic approaches to pain. A network of brain areas ("pain matrix") are involved in pain perception and pain control. This diversification of the pain system explains why a wide range of molecularly different substances can be used in the treatment of different pain states and why in recent years more and more studies have described a superior efficacy of a precise multi-target combination therapy compared to therapy with monotherapeutics.</p> <p>Discussion</p> <p>In this article, we discuss the available literature on the effects of several fixed-dose combinations in the treatment of headaches and discuss the evidence in support of the role of combination therapy in the pharmacotherapy of pain, particularly of headaches. The scientific rationale behind multi-target combinations is the therapeutic benefit that could not be achieved by the individual constituents and that the single substances of the combinations act together additively or even multiplicatively and cooperate to achieve a completeness of the desired therapeutic effect.</p> <p>As an example the fixesd-dose combination of acetylsalicylic acid (ASA), paracetamol (acetaminophen) and caffeine is reviewed in detail. The major advantage of using such a fixed combination is that the active ingredients act on different but distinct molecular targets and thus are able to act on more signalling cascades involved in pain than most single analgesics without adding more side effects to the therapy.</p> <p>Summary</p> <p>Multitarget therapeutics like combined analgesics broaden the array of therapeutic options, enable the completeness of the therapeutic effect, and allow doctors (and, in self-medication with OTC medications, the patients themselves) to customize treatment to the patient's specific needs. There is substantial clinical evidence that such a multi-component therapy is more effective than mono-component therapies.</p

Period prevalence of self-reported headache in the general population in Germany from 1995-2005 and 2009: results from annual nationwide population-based cross-sectional surveys

Background: Although primary headache is the most frequent neurological disorder and there is some evidence that the prevalence rates have increased in recent years, no long-term data on the annual prevalence of headache are available for Germany. The objective of the study was therefore to obtain long-term data on the period prevalence of headache in the general population in Germany by means of population-based cross-sectional annual surveys (1995-2005 and 2009). Methods: These surveys were conducted as face-to-face paper-and-pencil interviews from 1995 through 2004, and from 2005 onwards as computer-aided personal interviews. The reported headaches were self-diagnosed by the interviewees. Per year, approximately 640 trained interviewers interviewed between 10,898 and 12,538 German-speaking individuals aged 14 and older and living in private households in the whole of Germany (response rate: 67.4\% and 73.1\%, gross samples: 16,026 to 18,176 subjects). A total of more than 146,000 face-to-face interviews were analyzed. Results: The one-year headache prevalence remained stable over the entry period, with 58.9\% (95\% CI 57.7-60.1) to 62.5\% (95\% CI 61.3-63.7) (p=0.07). Women showed consistently higher prevalence rates than men (females: 67.3 (95\% CI 65.7-68.9) to 70.7\% (95\% CI 69.1-72.3), males: 48.4\% (95\% CI 46.5-50.3) to 54.3\% (95\% CI 52.4-56.2)), and both sexes showed a bell-shaped age dependence with peaks in the 30-39 age group. A stable slightly higher prevalence was observed in urban versus rural areas (p&lt;0.0001), and there was also a significant trend towards higher prevalence rates in groups with a monthly household income larger than 3,500 (sic) (p=0.03). Conclusion: The overall headache prevalence remained stable in Germany in the last 15 years

Mobility in the context of exposure-based assessment of chemicals for drinking water resource protection

In order to protect European Union (EU) drinking water resources from chemical contamination, criteria for identifying persistent, mobile, and toxic (PMT) chemicals and very persistent and very mobile (vPvM) chemicals under the EU REACH Regulation were proposed by the German Environment Agency (Umweltbundesamt-UBA). Additionally, new hazard classes for PMT and vPvM substances in the revised EU classification, labeling, and packaging (CLP Regulation) are intended. Therefore, a reliable approach in the identification of potential drinking water resource contaminants is needed. The scientific basis of the property-based PMT/vPvM criteria, focusing on mobility, which dictates the migration of chemical drinking water sources, was evaluated, and a critical analysis of the deviation of sorption metrics from simple behavior was carried out. Based on our evaluation, a K-oc may be used for nonionic substances on a screening level only, requiring a higher tier assessment. It is considered inappropriate for hydrophilic and ionizable chemicals, particularly for soils with low organic carbon contents. The nonextractable residue formation is complex and not well understood but remains significant in limiting the mobility of chemicals through soils and sediments. In order to inform the EU commission's work on the introduction of new hazard classes for PMT and vPvM substances into the European legislation, the derivation of a tiered approach is proposed, which utilizes the weight of evidence available, with adoption of appropriate higher tier models commensurate with the nature of the substance and the data available. Integr Environ Assess Manag 2022;00:1-17. (c) 2022 SETACISSN:1551-3777ISSN:1551-379

Association of Interleukin-32 and Interleukin-34 with Cardiovascular Disease and Short-Term Mortality in COVID-19

Background: Excess cardiovascular (CV) morbidity and mortality has been observed in patients with COVID-19. Both interleukin-32 (IL-32) and interleukin-34 (IL-34) have been hypothesized to contribute to CV involvement in COVID-19. Methods: This prospective, observational study of patients with laboratory-confirmed COVID-19 infection was conducted from 6 June to 22 December 2020 in a tertiary care hospital in Vienna, Austria. IL-32 and IL-34 levels on admission were collected and tested for their association with CV disease and short-term mortality in patients with COVID-19. CV disease was defined by the presence of coronary artery disease, heart failure, stroke or atrial fibrillation and patients were stratified by CV disease burden. Results: A total of 245 eligible patients with COVID-19 were included, of whom 37 (15.1%) reached the primary endpoint of 28-day mortality. Of the total sample, 161 had no CV disease (65.7%), 69 had one or two CV diseases (28.2%) and 15 patients had &ge;three CV diseases (6.1%). Median levels of IL-32 and IL-34 at admission were comparable across the three groups of CV disease burden. IL-32 and IL-34 failed to predict mortality upon both univariable and multivariable Cox regression analysis. The two CV disease groups, however, had a significantly higher risk of mortality within 28 days (one or two CV diseases: crude HR 4.085 (95% CI, 1.913&ndash;8.725), p &lt; 0.001 and &ge;three CV diseases: crude HR 13.173 (95% CI, 5.425&ndash;31.985), p &lt; 0.001). This association persisted for those with &ge;three CV diseases after adjustment for age, gender and CV risk factors (adjusted HR 3.942 (95% CI, 1.288&ndash;12.068), p = 0.016). Conclusion: In our study population of hospitalized patients with COVID-19, IL-32 and IL-34 did not show any associations with CV disease or 28-day mortality in the context of COVID-19. Patients with multiple CV diseases, however, had a significantly increased risk of short-term mortality