2,004 research outputs found

    Bone fragility in patients with diabetes mellitus: A consensus statement from the working group of the Italian Diabetes Society (SID), Italian Society of Endocrinology (SIE), Italian Society of Gerontology and Geriatrics (SIGG), Italian Society of Orthopaedics and Traumatology (SIOT)

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    Bone fragility is one of the possible complications of diabetes, either type 1 (T1D) or type 2 (T2D). Bone fragility can affect patients of different age and with different disease severity depending on type of diabetes, disease duration and the presence of other complications. Fracture risk assessment should be started at different stages in the natural history of the disease depending on the type of diabetes and other risk factors. The risk of fracture in T1D is higher than in T2D, imposing a much earlier screening and therapeutic intervention that should also take into account a patient's life expectancy, diabetes complications etc. The therapeutic armamentarium for T2D has been enriched with drugs that may influence bone metabolism, and clinicians should be aware of these effects.Considering the complexity of diabetes and osteoporosis and the range of variables that influ-ence treatment choices in a given individual, the Working Group on bone fragility in patients with diabetes mellitus has identified and issued recommendations based on the variables that should guide screening of bone fragility and management of diabetes and bone fragility: (A) ge, (B)MD, (C)omplications, (D)uration of disease, & (F)ractures (ABCD&F). Consideration of these parameters may help clinicians identify the best time for screening, the appropriate glycaemic target and anti-osteoporosis drug for patients with diabetes at risk of or with bone fragility.(c)& nbsp;2021 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved

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    Not AvailableTeleost exhibits extreme plasticity in its sexuality, retaining the conserved vertebrate neuroendocrine regulation of reproduction. The sex hormonal milieu is a major driver of sexual development in an organism. In teleosts, 17β-estradiol (E2) and 11-ketotestosterone (11-KT) act as natural inducers of ovarian and testicular differentiation, respectively, and alteration in the sex steroid milieu can reverse their sex. Estrogen also exerts pleiotropic effects on other physiological processes, in addition to its reproductive role. Different research strategies have indicated that estradiol, from either peripheral or central origin, exerts nucleus- and membrane-initiated signalling mechanisms which cooperate with other signalling pathways to modulate biologic responses of both reproductive and non-reproductive nature. Sex steroids also maintain a self-regulating feedback loop along the brain-pituitary-gonadotropic axis for a stage- and sex-specific steroidogenesis and reproductive behavior, though the underlying molecular mechanisms remain elusive. Understanding the estrogen signalling will enhance our understanding of fish reproduction and its regulation and will provide opportunities for the development of new strategies useful to aquaculture.Not Availabl

    Enabling a learning healthcare system with automated computer protocols that produce replicable and personalized clinician actions

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    Clinical decision-making is based on knowledge, expertise, and authority, with clinicians approving almost every intervention—the starting point for delivery of “All the right care, but only the right care,” an unachieved healthcare quality improvement goal. Unaided clinicians suffer from human cognitive limitations and biases when decisions are based only on their training, expertise, and experience. Electronic health records (EHRs) could improve healthcare with robust decision-support tools that reduce unwarranted variation of clinician decisions and actions. Current EHRs, focused on results review, documentation, and accounting, are awkward, time-consuming, and contribute to clinician stress and burnout. Decision-support tools could reduce clinician burden and enable replicable clinician decisions and actions that personalize patient care. Most current clinical decision-support tools or aids lack detail and neither reduce burden nor enable replicable actions. Clinicians must provide subjective interpretation and missing logic, thus introducing personal biases and mindless, unwarranted, variation from evidence-based practice. Replicability occurs when different clinicians, with the same patient information and context, come to the same decision and action. We propose a feasible subset of therapeutic decision-support tools based on credible clinical outcome evidence: computer protocols leading to replicable clinician actions (eActions). eActions enable different clinicians to make consistent decisions and actions when faced with the same patient input data. eActions embrace good everyday decision-making informed by evidence, experience, EHR data, and individual patient status. eActions can reduce unwarranted variation, increase quality of clinical care and research, reduce EHR noise, and could enable a learning healthcare system

    A Neutralizing Antibody Targeting Oxidized Phospholipids Promotes Bone Anabolism in Chow-Fed Young Adult Mice.

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    Oxidized phospholipids containing phosphocholine (OxPL) are pro-inflammatory lipid peroxidation products that bind to scavenger receptors (SRs), such as Scarb1, and toll-like receptors (TLRs). Excessive OxPL, as found in oxidized low-density lipoprotein (OxLDL), overwhelm these defense mechanisms and become pathogenic in atherosclerosis, nonalcoholic steatohepatitis (NASH), and osteoporosis. We previously reported that the innate IgM natural antibody E06 binds to OxPL and neutralizes their deleterious effects; expression of the single-chain (scFv) form of the antigen-binding domain of E06 (E06-scFv) as a transgene increases trabecular bone in male mice. We show herein that E06-scFv increases trabecular and cortical bone in female and male mice by increasing bone formation and decreasing osteoblast apoptosis in vivo. Homozygous E06-scFv mice have higher bone mass than hemizygous, showing a dose effect of the transgene. To investigate how OxPL restrain bone formation under physiologic conditions, we measured the levels of SRs and TLRs that bind OxPL. We found that osteoblastic cells primarily express Scarb1. Moreover, OxLDL-induced apoptosis and reduced differentiation were prevented in bone marrow-derived or calvaria-derived osteoblasts from Scarb1 knockout mice. Because Scarb1-deficient mice are reported to have high bone mass, our results suggest that E06 may promote bone anabolism in healthy young mice, at least in part, by neutralizing OxPL, which in turn promote Scarb1-mediated apoptosis of osteoblasts or osteoblast precursors. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

    Neutralization of oxidized phospholipids attenuates age-associated bone loss in mice.

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    Oxidized phospholipids (OxPLs) are pro-inflammatory molecules that affect bone remodeling under physiological conditions. Transgenic expression of a single-chain variable fragment (scFv) of the antigen-binding domain of E06, an IgM natural antibody that recognizes the phosphocholine (PC) moiety of OxPLs, increases trabecular and cortical bone in adult male and female mice by increasing bone formation. OxPLs increase with age, while natural antibodies decrease. Age-related bone loss is associated with increased oxidative stress and lipid peroxidation and is characterized by a decline in osteoblast number and bone formation, raising the possibility that increased OxPLs, together with the decline of natural antibodies, contribute to age-related bone loss. We show here that transgenic expression of E06-scFv attenuated the age-associated loss of spinal, femoral, and total bone mineral density in both female and male mice aged up to 22 and 24 months, respectively. E06-scFv attenuated the age-associated decline in trabecular bone, but not cortical bone, and this effect was associated with an increase in osteoblasts and a decrease in osteoclasts. Furthermore, RNA-seq analysis showed that E06-scFv increased Wnt10b expression in vertebral bone in aged mice, indicating that blocking OxPLs increases Wnt signaling. Unlike age-related bone loss, E06-scFv did not attenuate the bone loss caused by estrogen deficiency or unloading in adult mice. These results demonstrate that OxPLs contribute to age-associated bone loss. Neutralization of OxPLs, therefore, is a promising therapeutic target for senile osteoporosis, as well as atherosclerosis and non-alcoholic steatohepatitis (NASH), two other conditions shown to be attenuated by E06-scFv in mice

    Osteocalcin promotes bone mineralization but is not a hormone.

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    Oestrogen and zoledronic acid driven changes to the bone and immune environments: potential mechanisms underlying the differential anti-tumour effects of zoledronic acid in pre- and post-menopausal conditions

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    Late stage breast cancer commonly metastasises to bone and patient survival averages 2–3 years following diagnosis of bone involvement. One of the most successful treatments for bone metastases is the bisphosphonate, zoledronic acid (ZOL). ZOL has been used in the advanced setting for many years where it has been shown to reduce skeletal complications associated with bone metastasis. More recently, several large adjuvant clinical trials have demonstrated that administration of ZOL can prevent recurrence and improve survival when given in early breast cancer. However, these promising effects were only observed in post-menopausal women with confirmed low concentrations of circulating ovarian hormones. In this review we focus on potential interactions between the ovarian hormone, oestrogen, and ZOL to establish credible hypotheses that could explain why anti-tumour effects are specific to post-menopausal women. Specifically, we discuss the molecular and immune cell driven mechanisms by which ZOL and oestrogen affect the tumour microenvironment to inhibit/induce tumour growth and how oestrogen can interact with zoledronic acid to inhibit its anti-tumour actions

    Reduced bone modeling and unbalanced bone remodeling : Targets for antiresorptive and anabolic therapy

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    Bone loss during advancing age is the net result of reduced modeling-based bone formation upon the outer (periosteal) envelope and unbalanced remodeling by basic multicellular units (BMUs) upon the three (intracortical, endocortical, and trabecular) components of the inner (endosteal) bone envelope. Each BMU deposits less bone than resorbed, reducing total bone volume and deteriorating the microstructure of the diminished residual bone volume. Antiresorptive agents like bisphosphonates reduce, but do not abolish, the rate of bone remodeling – fewer BMUs remodel, “turn over,” the volume of bone. Residual unbalanced remodeling continues to slowly reduce total bone volume and deteriorate bone microstructure. By contrast, denosumab virtually abolishes remodeling so the decrease in bone volume and the deterioration in microstructure cease. The less remodeled matrix remains, leaving more time to complete the slow process of secondary mineralization which reduces the heterogeneity of matrix mineralization and allows it to become glycosylated, changes that may make the smaller and microstructurally deteriorated bone volume more brittle. Neither class of antiresorptive restores bone volume or its microstructure, despite increases in bone mineral density misleadingly suggesting otherwise. Nevertheless, these agents reduce vertebral and hip fractures by 50–60% but only reduce nonvertebral fractures by 20–30%. Restoring bone volume, microstructure, and material composition, “curing” bone fragility, may be partly achieved using anabolic therapy. Teriparatide, and probably abaloparatide, produce mainly remodeling-based bone formation by acting on BMUs existing in their resorption, reversal, or formation phase at the time of treatment and by promoting bone formation in newly initiated BMUs. Romosozumab produces modeling-based bone formation almost exclusively and decreases the surface extent of bone resorption. All three anabolic agents reduce vertebral fracture risk relative to untreated controls; parathyroid hormone 1-34 and romosozumab reduce vertebral fracture risk more greatly than risedronate or alendronate, respectively. Evidence for nonvertebral or hip fracture risk reduction relative to untreated or antiresorptive-treated controls is lacking or inconsistent. Only one study suggests sequential romosozumab followed by alendronate reduces vertebral, nonvertebral, and hip fracture risk compared to continuous alendronate alone. Whether combined antiresorptive and anabolic therapy result in superior fracture risk reduction than monotherapy is untested
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