No pain, no gain? The effects of pain-promoting neuropeptides and neurotrophins on fracture healing

Neuropeptides and neurotrophins are key regulators of peripheral nociceptive nerves and contribute to the induction, sensitization, and maintenance of pain. It is now known that these peptides also regulate non-neuronal tissues, including bone. Here, we review the effects of numerous neuropeptides and neurotrophins on fracture healing. The neuropeptides calcitonin-gene related peptide (CGRP), substance P (SP), vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase-activating peptide (PACAP) have varying effects on osteoclastic and osteoblastic activity. Ultimately, CGRP and SP both accelerate fracture healing, while VIP and PACAP seem to negatively impact healing. Unlike the aforementioned neuropeptides, the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) have more uniform effects. Both factors upregulate osteoblastic activity, osteoclastic activity, and, in vivo, stimulate osteogenesis to promote fracture healing. Future research will need to clarify the exact mechanism by which the neuropeptides and neurotrophins influence fracture healing. Specifically, understanding the optimal expression patterns for these proteins in the fracture healing process may lead to therapies that can maximize their bone-healing capabilities and minimize their pain-promoting effects. Finally, further examination of protein-sequestering antibodies and/or small molecule agonists and antagonists may lead to new therapies that can decrease the rate of delayed union/nonunion outcomes and fracture-associated pain

Quantum Statistics and Entanglement of Two Electromagnetic Field Modes Coupled via a Mesoscopic SQUID Ring

In this paper we investigate the behaviour of a fully quantum mechanical system consisting of a mesoscopic SQUID ring coupled to one or two electromagnetic field modes. We show that we can use a static magnetic flux threading the SQUID ring to control the transfer of energy, the entanglement and the statistical properties of the fields coupled to the ring. We also demonstrate that at, and around, certain values of static flux the effective coupling between the components of the system is large. The position of these regions in static flux is dependent on the energy level structure of the ring and the relative field mode frequencies, In these regions we find that the entanglement of states in the coupled system, and the energy transfer between its components, is strong.Comment: 15 pages, 19 figures, Uploaded as implementing a policy of arXiving old paper

Deep-phenotyping of Tregs identifies an immune signature for idiopathic aplastic anemia and predicts response to treatment

Idiopathic aplastic anemia (AA) is an immune-mediated and serious form of bone marrow failure. Akin to other autoimmune diseases, we have previously shown that in AA regulatory T-cells (Tregs) are reduced in number and function. The aim of this study was to further characterize Treg subpopulations in AA and investigate the potential correlation between specific Treg subsets and response to immunosuppressive therapy (IST) as well as their in-vitro expandability for potential clinical use. Using mass cytometry (CyTOF) and an unbiased multidimensional analytical approach, we identified two specific human Treg subpopulations (Treg A and Treg B) with distinct phenotypes, gene-expression, expandability and function. Treg subpopulation B, predominates in IST responder patients, has a memory/activated phenotype (with higher expression of CD95, CCR4 and CD45RO within FOXP3hi, CD127lo Tregs), expresses the IL- 2/STAT5 pathway and cell-cycle commitment genes. Furthermore, in-vitro expanded Tregs become functional and with the characteristics of Treg subpopulation B. Collectively, this study identifies human Treg subpopulations that can be used as predictive biomarkers for response to IST in AA and potentially other autoimmune diseases. We also show that Tregs from AA patients are IL-2 sensitive and expandable in-vitro, suggesting novel therapeutic approaches such as low dose IL-2 therapy and/or expanded autologous Tregs and meriting further exploration

Quantum superpositions of clockwise and counterclockwise supercurrent states in the dynamics of a rf-SQUID exposed to a quantized electromagnetic field

The dynamical behavior of a superconducting quantum interference device (a rf-SQUID) irradiated by a single mode quantized electromagnetic field is theoretically investigated. Treating the SQUID as a flux qubit, we analyze the dynamics of the combined system within the low lying energy Hilbert subspace both in the asymmetric and in the symmetric SQUID potential configurations. We show that the temporal evolution of the system is dominated by an oscillatory behavior characterized by more than one, generally speaking, incommensurable Rabi frequencies whose expressions are explicitly given. We find that the external parameters may fixed in such a way to realize a control on the dynamical replay of the total system which, for instance, may be forced to exhibit a periodic evolution accompanied by the occurrence of an oscillatory disappearance of entanglement between the two subsystems. We demonstrate the possibility of generating quantum maximally entangled superpositions of the two macroscopically distinguishable states describing clockwise and counterclockwise supercurrents in the loop. The experimental feasibility of our proposal is briefly discussed.Comment: 16 pages, 7 figures, submitted to PR

Pioglitazone administration alters ovarian gene expression in aging obese lethal yellow mice

<p>Abstract</p> <p>Background</p> <p>Women with polycystic ovary syndrome (PCOS) are often treated with insulin-sensitizing agents, e.g. thiazolidinediones (TZD), which have been shown to reduce androgen levels and improved ovulatory function. Acting via peroxisome proliferator-activated receptor (PPAR) gamma, TZD alter the expression of a large variety of genes. Lethal yellow (LY; C57BL/6J Ay/a) mice, possessing a mutation (Ay) in the agouti gene locus, exhibit progressive obesity, reproductive dysfunction, and altered metabolic regulation similar to women with PCOS. The current study was designed to test the hypothesis that prolonged treatment of aging LY mice with the TZD, pioglitazone, alters the ovarian expression of genes that may impact reproduction.</p> <p>Methods</p> <p>Female LY mice received daily oral doses of either 0.01 mg pioglitazone (n = 4) or an equal volume of vehicle (DMSO; n = 4) for 8 weeks. At the end of treatment, ovaries were removed and DNA microarrays were used to analyze differential gene expression.</p> <p>Results</p> <p>Twenty-seven genes showed at least a two-fold difference in ovarian expression with pioglitazone treatment. These included leptin, angiopoietin, angiopoietin-like 4, Foxa3, PGE1 receptor, resistin-like molecule-alpha (RELM), and actin-related protein 6 homolog (ARP6). For most altered genes, pioglitazone changed levels of expression to those seen in untreated C57BL/6J(a/a) non-mutant lean mice.</p> <p>Conclusion</p> <p>TZD administration may influence ovarian function via numerous diverse mechanisms that may or may not be directly related to insulin/IGF signaling.</p

A community-based intervention (Young SMILES) to improve the health-related quality of life of children and young people of parents with serious mental illness: randomised feasibility protocol

Children and young people of parents with mental illness (COPMI) are at risk of poor mental, physical and emotional health, which can persist into adulthood. They also experience poorer social outcomes and wellbeing as well as poorer quality of life than their peers with ‘healthy’ parents. The needs of COPMI are likely to be significant; however, their prevalence is unknown, although estimates suggest over 60% of adults with a serious mental illness have children. Many receive little or no support and remain ‘hidden’, stigmatised or do not regard themselves as ‘in need’. Recent UK policies have identified supporting COPMI as a key priority, but this alone is insufficient and healthrelated quality of life has been neglected as an outcome

Scoping Review: Digital mental health interventions for children and adolescents affected by war

Objective Over 200 million children and adolescents live in countries affected by violent conflict, are likely to have complex mental health needs, and struggle to access traditional mental health services. Digital mental health interventions have the potential to overcome some of the barriers in accessing mental health support. We performed a scoping review to map existing digital mental health interventions relevant for children and adolescents affected by war, examine the strength of the evidence base, and inform the development of future interventions. Method Based on a pre-registered strategy, we systematically searched MEDLINE, Embase, Global Health, APA PsychInfo, and Google Scholar from the creation of each database to 30th September 2022, identifying k=6,843 studies. Our systematic search was complemented by extensive consultation with experts from the GROW Network. Results The systematic search identified 6 relevant studies: one evaluating digital mental health interventions for children and adolescents affected by war and five for those affected by disasters. Experts identified 35 interventions of possible relevance. The interventions spanned from universal prevention to specialist-guided treatment. Most interventions directly targeted young people and parents/carers and were self-guided. A quarter of the interventions were tested through randomized controlled trials. Because most interventions were not culturally or linguistically adapted to relevant contexts, their implementation potential was unclear. Conclusion There is very limited evidence for the use of digital mental health interventions for children and adolescents affected by war at present. The review provides a framework to inform the development of new interventions