M-CSF and GM-CSF Regulation of STAT5 Activation and DNA Binding in Myeloid Cell Differentiation is Disrupted in Nonobese Diabetic Mice

Defects in macrophage colony-stimulating factor (M-CSF) signaling disrupt myeloid cell differentiation in nonobese diabetic (NOD) mice, blocking myeloid maturation into tolerogenic antigen-presenting cells (APCs). In the absence of M-CSF signaling, NOD myeloid cells have abnormally high granulocyte macrophage colony-stimulating factor (GM-CSF) expression, and as a result, persistent activation of signal transducer/activator of transcription 5 (STAT5). Persistent STAT5 phosphorylation found in NOD macrophages is not affected by inhibiting GM-CSF. However, STAT5 phosphorylation in NOD bone marrow cells is diminished if GM-CSF signaling is blocked. Moreover, if M-CSF signaling is inhibited, GM-CSF stimulation in vitro can promote STAT5 phosphorylation in nonautoimmune C57BL/6 mouse bone marrow cultures to levels seen in the NOD. These findings suggest that excessive GM-CSF production in the NOD bone marrow may interfere with the temporal sequence of GM-CSF and M-CSF signaling needed to mediate normal STAT5 function in myeloid cell differentiation gene regulation

HDAC-mediated control of ERK- and PI3K-dependent TGF-β-induced extracellular matrix-regulating genes

Histone deacetylases (HDACs) regulate the acetylation of histones in the control of gene expression. Many non-histone proteins are also targeted for acetylation, including TGF-ß signalling pathway components such as Smad2, Smad3 and Smad7. Our studies in mouse C3H10T1/2 fibroblasts suggested that a number of TGF-ß-induced genes that regulate matrix turnover are selectively regulated by HDACs. Blockade of HDAC activity with trichostatin A (TSA) abrogated the induction of a disintegrin and metalloproteinase 12 (Adam12) and tissue inhibitor of metalloproteinases-1 (Timp-1) genes by TGF-ß, whereas plasminogen activator inhibitor-1 (Pai-1) expression was unaffected. Analysis of the activation of cell signalling pathways demonstrated that TGF-ß induced robust ERK and PI3K activation with delayed kinetics compared to the phosphorylation of Smads. The TGF-ß induction of Adam12 and Timp-1 was dependent on such non-Smad signalling pathways and, importantly, HDAC inhibitors completely blocked their activation without affecting Smad signalling. Analysis of TGF-ß-induced Adam12 and Timp-1 expression and ERK/PI3K signalling in the presence of semi-selective HDAC inhibitors valproic acid, MS-275 and apicidin implicated a role for class I HDACs. Furthermore, depletion of HDAC3 by RNA interference significantly down-regulated TGF-ß-induced Adam12 and Timp-1 expression without modulating Pai-1 expression. Correlating with the effect of HDAC inhibitors, depletion of HDAC3 also blocked the activation of ERK and PI3K by TGF-ß. Collectively, these data confirm that HDACs, and in particular HDAC3, are required for activation of the ERK and PI3K signalling pathways by TGF-ß and for the subsequent gene induction dependent on these signalling pathways

A rehabilitation intervention to improve recovery after an episode of delirium in adults over 65 years (RecoverED): study protocol for a multi-centre, single-arm feasibility study

Background: Delirium affects over 20% of all hospitalised older adults. Delirium is associated with a number of adverse outcomes following hospital admission including cognitive decline, anxiety and depression, increased mortality and care needs. Previous research has addressed prevention of delirium in hospitals and care homes, and there are guidelines on short-term treatment of delirium during admission. However, no studies have addressed the problem of longer-term recovery after delirium and it is currently unknown whether interventions to improve recovery after delirium are effective and cost-effective. The primary objective of this feasibility study is to test a new, theory-informed rehabilitation intervention (RecoverED) in older adults delivered following a hospital admission complicated by delirium to determine whether (a) the intervention is acceptable to individuals with delirium and (b) a definitive trial and parallel economic evaluation of the intervention are feasible. Methods: The study is a multi-centre, single-arm feasibility study of a rehabilitation intervention with an embedded process evaluation. Sixty participants with delirium (aged > 65 years old) and carer pairs will be recruited from six NHS acute hospitals across the UK. All pairs will be offered the intervention, with follow-up assessments conducted at 3 months and 6 months post-discharge home. The intervention will be delivered in participants’ own homes by therapists and rehabilitation support workers for up to 10 intervention sessions over 12 weeks. The intervention will be tailored to individual needs, and the chosen intervention plan and goals will be discussed and agreed with participants and carers. Quantitative data on reach, retention, fidelity and dose will be collected and summarised using descriptive statistics. The feasibility outcomes that will be used to determine whether the study meets the criteria for progression to a definitive randomised controlled trial (RCT) include recruitment, delivery of the intervention, retention, data collection and acceptability of outcome measures. Acceptability of the intervention will be assessed using in-depth, semi-structured qualitative interviews with participants and healthcare professionals. Discussion: Findings will inform the design of a pragmatic multi-centre RCT of the effectiveness and cost-effectiveness of the RecoverED intervention for helping the longer-term recovery of people with delirium compared to usual care. Trial registration: The feasibility study was registered: ISRCTN1567657

Prevalence and determinants of loneliness in people living with dementia: findings from the IDEAL programme

This is the author accepted manuscript. The final version is available from the publisher via the DOI in this recordThe IDEAL dataset used in this study was deposited with the UK Data Archive in March 2020. Details on when and how the data can be accessed will be made available on the project website www.idealproject.org.uk TObjective To establish the prevalence and determinants of loneliness among people living with dementia. . Methods Using data from the baseline wave of the Improving the experience of Dementia and Enhancing Active Life (IDEAL) cohort study, we examined the prevalence and predictors of loneliness in 1547 people with mild‐to‐moderate dementia. Loneliness was assessed using the six‐item De Jong Gierveld loneliness scale. Results 30.1% of people with dementia reported feeling moderately lonely and 5.2% severely lonely. Depressive symptoms and increased risk of social isolation were associated with both moderate and severe loneliness. Those living alone were more likely to experience severe loneliness as were those reporting poorer quality of life. Marital status was not associated with loneliness nor were dementia diagnosis or cognitive function. Conclusions This is one of the few large‐scale studies to explore the prevalence of and determinants of loneliness among people living with dementia. Social isolation, depression and living alone were associated with experiencing loneliness. Longitudinal studies are needed to determine the directionality of these associations.Economic and Social Research Council (ESRC

Maintaining independence in individuals with dementia at home after a fall: a protocol for the UK pilot cluster randomised controlled trial MAINTAIN

\ua9 Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.Introduction Individuals with dementia face an increased risk of falls. Falls can cause a decline in the individual\u27s overall functionality. All types of falls, including those that do not result in injury, can lead to psychosocial consequences, such as diminished confidence and a fear of falling. Projections indicate a rising trend in dementia diagnoses, implying an increase in fall incidents. Yet, there is a lack of evidence to support interventions for people living with dementia who have fallen. Our objective is to test the feasibility of a falls intervention trial for people with dementia. Method and analysis This is a UK-based two-arm pilot cluster randomised controlled trial. In this study, six collaborating sites, which form the clusters, will be randomly allocated to either the intervention arm or the control arm (receiving treatment as usual) at a 1:1 ratio. During the 6 month recruitment phase, each cluster will enrol 10 dyads, comprising 10 individuals with dementia and their respective carers, leading to a total sample size of 60 dyads. The primary outcomes are the feasibility parameters for a full trial (ie, percentage consented, follow-up rate and cost framework). Secondary outcomes include activities of daily living, quality of life, fall efficacy, mobility, goal attainment, cognitive status, occurrence of falls, carer burden and healthcare service utilisation. Outcome measures will be collected at baseline and 28 weeks, with an additional assessment scheduled at 12 weeks for the healthcare service utilisation questionnaire. An embedded process evaluation, consisting of interviews and observations with participants and healthcare professionals, will explore how the intervention operates and the fidelity of study processes. Ethics and dissemination The study was approved by the NHS and local authority research governance and research ethics committees (NHS REC reference: 23/WA/0126). The results will be shared at meetings and conferences and will be published in peer-reviewed journals. Trial registration number ISRCTN16413728

Nondestructive monitoring of ageing of Alkali resistant Glass fiber reinforced cement (GRC)

Glass fiber reinforced cement (GRC) is a composite material made of portland cement mortar and alkali resistant (AR) fibers. AR fibers are added to portland cement to give the material additional flexural strength and toughness. However, ageing deteriorates the fibers and as a result the improvement in the mechanical properties resulted from the fiber addition disappears as the structure becomes old. The aim of this paper is monitoring GRC ageing by nondestructive evaluation (NDE) techniques. Two different NDE techniques (1) nonlinear impact resonant acoustic spectroscopy analysis and (2) propagating ultrasonic guided waves are used for this purpose. Both techniques revealed a reduction of the nonlinear behavior in the GRC material with ageing. Specimens are then loaded to failure to obtain their strength and stiffness. Compared to the un-aged specimens, the aged specimens are found to exhibit more linear behavior, have more stiffness but less toughness. Finally, undisturbed fragments on the fracture surface from mechanical tests are inspected under the electron microscope, to understand the fundamental mechanisms that cause the change in the GRC behavior with ageing.The authors want to acknowledge the financial support of the Ministerio de Ciencia e Innovacion MICINN, Spain, and FEDER funding (Ondacem Project: BIA 2010-19933) and BES-2011-044624. Also thanks to PAID-02-11 Program from Universitat Politecnica de Valencia.Eiras Fernández, JN.; Kundu, T.; Bonilla Salvador, MM.; Paya Bernabeu, JJ. (2013). Nondestructive monitoring of ageing of Alkali resistant Glass fiber reinforced cement (GRC). Journal of Nondestructive Evaluation - NDT and E International. 32:300-314. https://doi.org/10.1007/s10921-013-0183-yS30031432Bentur, A., Fibre, M.S.: Reinforced Cementitious Composites, 2nd edn. Taylor and Francis, New York (2007)Purnell, P., Short, N.R., Page, C.L.: A static fatigue model for the durability of glass fibre reinforced cement. J. Mater. Sci. 36(22), 5385–5390 (2001)Ferreira, J.G., Branco, F.A.: Structural application of GRC in telecommunication towers. Constr. Build. Mater. 21(1), 19–28 (2007)Bentur, A., Ben-Bassat, M., Schneider, D.: Durability of glass-fiber-reinforced cements with different alkali-resistant glass fibers. J. Am. Ceram. Soc. 68(4), 203–208 (1985)Cheng, J., Liang, W., Hu, Y., Chen, Q., Frischat, G.H.: Development of a new alkali resistant coating. J. Sol-Gel Sci. Technol. 27(3), 309–313 (2003)Liang, W., Cheng, J., Hu, Y., Luo, H.: Improved properties of GRC composites using commercial E-glass fibers with new coatings. Mater. Res. Bull. 37(4), 641–646 (2002)Payá, J., Bonilla, M., Borrachero, M.V., Monzó, J., Peris-Mora, E., Lalinde, L.F.: Reusing fly ash in glass fibre reinforced cement: a new generation of high-quality GRC composites. Waste Manag. 27(10), 1416–1421 (2007)Zhang, Y., Sun, W., Shang, L., Pan, G.: The effect of high content of fly ash on the properties of glass fiber reinforced cementitious composites. Cem. Concr. Res. 27(12), 1885–1891 (1997)Purnell, P., Short, N., Page, C.: Super-critical carbonation of glass-fibre reinforced cement. Part 1: mechanical testing and chemical analysis. Composites, Part A, Appl. Sci. Manuf. 32(12), 1777–1787 (2001)EN 1170-8:2008. Test method for glass-fibre reinforced cement. Cyclic weathering type testPurnell, P.: Interpretation of climatic temperature variations for accelerated ageing models. J. Mater. Sci. 39(1), 113–118 (2004)Enfedaque, A., Sánchez Paradela, L., Sánchez-Gálvez, V.: An alternative methodology to predict aging effects on the mechanical properties of glass fiber reinforced cements (GRC). Constr. Build. Mater. 27(1), 425–431 (2012)Litherland, K.L., Maguire, P., Proctor, B.A.: A test method for the strength of glass fibres in cement. Int. J. Cem. Compos. Lightweight Concr. 6(1), 39–45 (1984)Itterbeeck, P., Cuypers, H., Orlowsky, J., Wastiels, J.: Evaluation of the strand in cement (SIC) test for GRCs with improved durability. Mater. Struct. 41(6), 1109–1116 (2007)Guyer, R.A., Johnson, P.A.: Nonlinear mesoscopic elasticity: evidence for a new class of materials. Phys. Today 52, 30 (1999)Johnson, P.A.: Nonequilibrium nonlinear dynamics in solids: state of the art. In: Delsanto, P.P. (ed.) Universality of Nonclassical Nonlinearity, pp. 49–69. Springer, New York (2006)Guyer, R.A., McCall, K.R., Boitnott, G.N.: Hysteresis, discrete memory, and nonlinear wave propagation in rock: a new paradigm. Phys. Rev. Lett. 74(17), 3491–3494 (1995)Mayergoyz, I.D.: Mathematical Models of Hysteresis and Their Applications. Academic Press, New York (2003)Van Den Abeele, K.E.A., Carmeliet, J., Ten Cate, J.A., Johnson, P.A.: Nonlinear elastic wave spectroscopy (NEWS) techniques to discern material damage, part II: single-mode nonlinear resonance acoustic spectroscopy. Res. Nondestruct. Eval. 12(1), 31–42 (2000)Chen, J., Jayapalan, A.R., Kim, J.Y., Kurtis, K.E., Jacobs, L.J.: Rapid evaluation of alkali–silica reactivity of aggregates using a nonlinear resonance spectroscopy technique. Cem. Concr. Res. 40(6), 914–923 (2010)Leśnicki, K.J., Kim, J.Y., Kurtis, K.E., Jacobs, L.J.: Characterization of ASR damage in concrete using nonlinear impact resonance acoustic spectroscopy technique. Nondestruct. Test. Eval. Int. 44(8), 721–727 (2011)Bouchaala, F., Payan, C., Garnier, V., Balayssac, J.P.: Carbonation assessment in concrete by nonlinear ultrasound. Cem. Concr. Res. 41(5), 557–559 (2011)Eiras, J.N., Popovics, J.S., Borrachero, M.V., Monzó, J., Payá, J.: Nonlinear impact resonant acoustic spectroscopy to discern mechanical damage in cement based materials. In: 15th International Conference on Experimental Mechanics, Porto, Portugal (2012)Kundu, T.: Ultrasonic Nondestructive Evaluation: Engineering and Biological Material Characterization. CRC Press, Boca Raton (2004)Kundu, T.: Ultrasonic and Electromagnetic NDE for Structure and Material Characterization—Engineering and Biomedical Applications. CRC Press, Boca Raton (2012)Dutta, D., Sohn, H., Harries, K.A., Rizzo, P.: A nonlinear acoustic technique for crack detection in metallic structures. Struct. Health Monit. 8(3), 251–262 (2009)Aymerich, F., Staszewski, W.J.: Impact damage detection in composite laminates using nonlinear acoustics. Composites, Part A, Appl. Sci. Manuf. 41(9), 1084–1092 (2010)EN 1170-1:1998. Precast concrete products. Test method for glass-fibre reinforced cement. Measuring the consistency of the matrix, “Slump test” methodMontgomery, P.L.: A block Lanczos algorithm for finding dependencies over GF(2). In: EUROCRYPT ’95. Lecture Notes in Computer Science, vol. 921, pp. 106–120. Springer, Berlin (1995)EN 1170-5:1998. Precast concrete products. Test method for glass-fibre reinforced cement. Measuring bending strength, “complete bending test” methodRomero, R., Zúnica, L.R.: Métodos Estadísticos en Ingeniería. Universitat Politècnica València, Valencia (2005)Kundu, T.: Fundamentals of Fracture Mechanics. CRC Press, Boca Raton (2008)ASTM C 215:08. Standard Test Method for Fundamental Transverse, Longitudinal, and Torsional Frequencies of Concrete Specimens (2008)Hewlett, P.C.: Lea’s Chemistry of Cement and Concrete, 4th edn. Butterworth-Heinemann, Oxford (2003)Zhu, W., Bartos, P.J.M.: Assessment of interfacial microstructure and bond properties in aged GRC using a novel microindentation method. Cem. Concr. Res. 27(11), 1701–1711 (1997)Purnell, P., Buchanan, A.J., Short, N.R., Page, C.L., Majumdar, A.J.: Determination of bond strength in glass fibre reinforced cement using petrography and image analysis. J. Mater. Sci. 35(18), 4653–4659 (2000)Visalvanich, K., Naaman, A.E.: Fracture model for fiber reinforced concrete. J. ACI Proc. 80(2), 128–138 (1983)Kundu, T., Jang, H.S., Cha, Y.H., Desai, C.S.: A simple model to predict the effect of volume fraction, diameter, and length of fibers on strength variation of fiber reinforced brittle matrix composites. Int. J. Numer. Anal. Methods Geomech. 24, 655–673 (2000)Li, V.C., Maalej, M.: Toughening in cement based composites. Part II: fiber reinforced composites. Cem. Concr. Compos. 18, 239–249 (1996)Van Den Abeele, K.E.A., Johnson, P.A., Sutin, A.: Nonlinear elastic wave spectroscopy (NEWS) techniques to discern material damage, part I: nonlinear wave modulation spectroscopy (NWMS). Res. Nondestruct. Eval. 12(1), 17–30 (2000

'The nourishing soil of the soul': The role of horticultural therapy in promoting well-being in community-dwelling people with dementia.

Two-thirds of people with dementia reside in their own homes; however, support for community-dwelling people with dementia to continue to participate in everyday activities is often lacking, resulting in feelings of depression and isolation among people living with the condition. Engagement in outdoor activities such as gardening can potentially counteract these negative experiences by enabling people with dementia to interact with nature, helping to improve their physical and psychological well-being. Additionally, the collaborative nature of community gardening may encourage the development of a sense of community, thereby enhancing social integration. Despite increasing evidence supporting its therapeutic value for people with dementia in residential care, the benefits of horticultural therapy have yet to be transposed into a community setting. This paper will examine the theoretical support for the application of horticultural therapy in dementia care, before exploring the potential of horticultural therapy as a means of facilitating improved physical and psychological well-being and social integration for people living with dementia within the community

Moderate exercise protects against joint disease in a murine model of osteoarthritis

Exercise is recommended as a non-pharmacological therapy for osteoarthritis (OA). Various exercise regimes, with differing intensities and duration, have been used in a range of OA rodent models. These studies show gentle or moderate exercise reduces the severity of OA parameters while high intensity load bearing exercise is detrimental. However, these studies were largely conducted in rats or in mouse models induced by severe injury, age or obesity, whilst destabilization of the medial meniscus (DMM) in mice has become a widely accepted model due to its lower variability, moderate progression and timescale. The present study was undertaken to provide insight into the effect of moderate exercise on early joint pathology in the DMM mouse model. Exercise was induced a week after induction by forced wheel walking for three or 7 weeks. Joints were analyzed by microcomputed tomography and histology. Assessment of skeletal parameters revealed that exercise offered protection against cartilage damage after 7 weeks of exercise, and a temporary protection against osteosclerosis was displayed after 3 weeks of exercise. Furthermore, exercise modified the metaphyseal trabecular microarchitecture of the osteoarthritic leg in both time points examined. Collectively, our findings corroborate previous studies showing that exercise has an important effect on bone in OA, which subsequently, at 8 weeks post-induction, translates into less cartilage damage. Thus, providing an exercise protocol in a surgical mouse model of OA, which can be used in the future to further dissect the mechanisms by which moderate exercise ameliorates OA