Hydroxyurea blunts mitochondrial energy metabolism and osteoblast and osteoclast differentiation exacerbating trabecular bone loss in sickle cell mice.

Sickle cell disease (SCD) is a severe hematological disorder characterized by erythrocyte sickling that causes significant morbidity and mortality. Skeletal complications of SCD include a high incidence of bone loss, especially in vertebrae, leading to fragility fractures that contribute to disease burden. Whether hydroxyurea (HU), a front-line therapy for SCD ameliorates bone disease has not been established.

Linoleic acid blunts early osteoblast differentiation and impairs oxidative phosphorylation in vitro.

Background: Linoleic acid (LNA), an essential polyunsaturated fatty acid (PUFA), plays a crucial role in cellular functions. However, excessive intake of LNA, characteristic of Western diets, can have detrimental effects on cells and organs. Human observational studies have shown an inverse relationship between plasma LNA concentrations and bone mineral density.

Systemic inflammatory and gut microbiota responses to fracture in young and middle-aged mice.

Age is a patient-specific factor that can significantly delay fracture healing and exacerbate systemic sequelae during convalescence. The basis for this difference in healing rates is not well-understood, but heightened inflammation has been suggested to be a significant contributor. In this study, we investigated the systemic cytokine and intestinal microbiome response to closed femur fracture in 3-month-old (young adult) and 15-month-old (middle-aged) female wild-type mice.

Association between Neuroligin-1 polymorphism and plasma glutamine levels in individuals with autism spectrum disorder.

Background: Unravelling the relationships between candidate genes and autism spectrum disorder (ASD) phenotypes remains an outstanding challenge. Endophenotypes, defined as inheritable, measurable quantitative traits, might provide intermediary links between genetic risk factors and multifaceted ASD phenotypes. In this study, we sought to determine whether plasma metabolite levels could serve as endophenotypes in individuals with ASD and their family members.

Bioactive silica nanoparticles target autophagy, NF-κB, and MAPK pathways to inhibit osteoclastogenesis.

Spherical 50 nm silica-based nanoparticles (SiNPs) promote healthy bone homeostasis and maintenance by supporting bone forming osteoblast lineage cells while simultaneously inhibiting the differentiation of bone resorbing osteoclasts. Previous work demonstrated that an intraperitoneal injection of SiNPs in healthy mice - both young and old - increased bone density and quality, suggesting the possibility that SiNPs represent a dual action therapeutic. However, the underlying mechanisms governing the osteoclast response to SiNPs have yet to be fully explored and defined.

Dietary phosphorus consumption alters T cell populations, cytokine production, and bone volume in mice.

The intake of dietary phosphate far exceeds recommended levels; however, the long-term health consequences remain relatively unknown. Here, the chronic physiological response to sustained elevated and reduced dietary phosphate consumption was investigated in mice. Although serum phosphate levels were brought into homeostatic balance, the prolonged intake of a high-phosphate diet dramatically and negatively impacted bone volume; generated a sustained increase in the phosphate responsive circulating factors FGF23, PTH, osteopontin and osteocalcin; and produced a chronic low-grade inflammatory state in the BM, marked by increased numbers of T cells expressing IL-17a, RANKL, and TNF-α.

Study on the relationship between selenium and cadmium in diseased human lungs.

Cadmium (Cd) is a toxic environmental metal that interacts with selenium (Se) and contributes to many lung diseases. Humans have widespread exposures to Cd through diet and cigarette smoking, and studies in rodent models show that Se can protect against Cd toxicities. We sought to identify whether an antagonistic relationship existed between Se and Cd burdens and determine whether this relationship may associate with metabolic variation within human lungs.

Cyclic Adenosine Monophosphate (cAMP)-Dependent Phosphodiesterase Inhibition Promotes Bone Anabolism Through CD8 T Cell Wnt-10b Production in Mice.

Cyclic adenosine monophosphate (cAMP)-dependent phosphodiesterase (PDE) inhibitors such as pentoxifylline (PTX) suppress cAMP degradation and promote cAMP-dependent signal transduction. PDE inhibitors increase bone formation and bone mass in preclinical models and are used clinically to treat psoriatic arthritis by targeting inflammatory mediators including activated T cells. T cell activation requires two signals: antigen-dependent CD3-activation, which stimulates cAMP production; and CD28 co-stimulation, which downregulates cAMP-signaling, through PDE activation.

Sex differences in the relationships between body composition, fat distribution, and mitochondrial energy metabolism: a pilot study.

Background: Adiposity and mitochondrial dysfunction are related factors contributing to metabolic disease development. This pilot study examined whether in vivo and ex vivo indices of mitochondrial metabolism were differentially associated with body composition in males and females.

Methods: Thirty-four participants including 19 females (mean 27 yr) and 15 males (mean 29 yr) had body composition assessed by dual energy x-ray absorptiometry and magnetic resonance (MR) imaging.

Deletion of IL-17ra in osteoclast precursors increases bone mass by decreasing osteoclast precursor abundance.

Metabolic bone diseases, such as osteoporosis, typically reflect an increase in the number and activity of bone-resorbing osteoclasts that result in a loss of bone mass. Inflammatory mediators have been identified as drivers of both osteoclast formation and activity. The IL-17 family of inflammatory cytokines has gained attention as important contributors to both bone formation and resorption.

Immune Reconstitution Bone Loss Exacerbates Bone Degeneration Due to Natural Aging in a Mouse Model.

Background: Immune reconstitution bone loss (IRBL) is a common side-effect of antiretroviral therapy (ART) in people with human immunodeficiency virus (PWH). Immune reconstitution bone loss acts through CD4+ T-cell/immune reconstitution-induced inflammation and is independent of antiviral regimen. Immune reconstitution bone loss may contribute to the high rate of bone fracture in PWH, a cause of significant morbidity and mortality.

Palliative care aspects of wound healing in complex patients: a case report.

The authors have no conflicts of interest to declare.

Plasma high-resolution metabolomic phenotyping of lean mass in a United States adult cohort.

Background: Rapid loss of lean mass during catabolic states is associated with impaired convalescence and increased mortality rates. An understanding of metabolic pathways related to lean mass is needed to enable future interventions designed to combat malnutrition. This study assessed the plasma metabolome in relation to lean mass in clinically stable working adults in a US cohort.

Modulating phosphate consumption, a novel therapeutic approach for the control of cancer cell proliferation and tumorigenesis.

Phosphorus, often in the form of inorganic phosphate (Pi), is critical to cellular function on many levels; it is required as an integral component of kinase signaling, in the formation and function of DNA and lipids, and energy metabolism in the form of ATP. Accordingly, crucial aspects of cell mitosis - such as DNA synthesis and ATP energy generation - elevate the cellular requirement for Pi, with rapidly dividing cells consuming increased levels. Mechanisms to sense, respond, acquire, accumulate, and potentially seek Pi have evolved to support highly proliferative cellular states such as injury and malignant transformation.

Metabolomic Associations with Serum Bone Turnover Markers.

Bone is a dynamic tissue that is in a constant state of remodeling. Bone turnover markers (BTMs), procollagen type I N-terminal propeptide (P1NP) and C-terminal telopeptides of type I collagen (CTX), provide sensitive measures of bone formation and resorption, respectively. This study used ultra-high-resolution metabolomics (HRM) to determine plasma metabolic pathways and targeted metabolites related to the markers of bone resorption and formation in adults.

Immature/transitional B-cell expansion is associated with bone loss in HIV-infected individuals with severe CD4+ T-cell lymphopenia.

Background: Antiretroviral therapy (ART) has led to a significant decline in HIV-related morbidity and mortality in people living with HIV (PLWH). PLWH however experience non-AIDS ageing-associated comorbidities, including decreased bone mass and osteoporosis, earlier and more severely, than uninfected people. We previously reported that total B-cell production of the key osteoclastogenic cytokine receptor activator of NF-κB ligand (RANKL) was elevated in PLWH, concurrent with a decrease in total B-cell production of RANKL's physiological moderator Osteoprotegerin (OPG).

Plasma high-resolution metabolomics identifies linoleic acid and linked metabolic pathways associated with bone mineral density.

Background & Aims: There is a considerable degree of variation in bone mineral density (BMD) within populations. Use of plasma metabolomics may provide insight into established and novel determinants of BMD variance, such as nutrition and gut microbiome composition, to inform future prevention and treatment strategies for loss of BMD. Using high-resolution metabolomics (HRM), we examined low-molecular weight plasma metabolites and nutrition-related metabolic pathways associated with BMD.

Effects of phosphorus and calcium to phosphorus consumption ratio on mineral metabolism and cardiometabolic health.

Phosphorus is a common additive used in food processing that is typically consumed in excess of the recommended daily allowance; however, our knowledge of its effects on health, in the context of normal renal function, is limited. Unlike phosphorus, calcium intake is generally less than recommended, and it has been hypothesized that the calcium to phosphorus ratio may be partly responsible for the proposed negative health consequences. Therefore, this study sought to determine the effects of increased phosphorus additive intake, in the context of high calcium consumption, on endocrine markers of mineral metabolism and cardiometabolic health.

Pneumococcal Conjugate Vaccine Breakthrough Infections: 2001-2016.

Background: Most countries use 3-dose pneumococcal conjugate vaccine (PCV) schedules; a 4-dose (3 primary and 1 booster) schedule is licensed for US infants. We evaluated the invasive pneumococcal disease (IPD) breakthrough infection incidence in children receiving 2 vs 3 primary PCV doses with and without booster doses (2 + 1 vs 3 + 1; 2 + 0 vs 3 + 0).

Methods: We used 2001-2016 Active Bacterial Core surveillance data to identify breakthrough infections (vaccine-type IPD in children receiving ≥1 7-valent pneumococcal conjugate vaccine [PCV7] or 13-valent pneumococcal conjugate vaccine [PCV13] dose) among children aged <5 years.

Parathyroid hormone-dependent bone formation requires butyrate production by intestinal microbiota.

Parathyroid hormone (PTH) is a critical regulator of skeletal development that promotes both bone formation and bone resorption. Using microbiota depletion by wide-spectrum antibiotics and germ-free (GF) female mice, we showed that the microbiota was required for PTH to stimulate bone formation and increase bone mass. Microbiota depletion lowered butyrate levels, a metabolite responsible for gut-bone communication, while reestablishment of physiologic levels of butyrate restored PTH-induced anabolism.

Antiretroviral Therapy-Induced Bone Loss Is Durably Suppressed by a Single Dose of Zoledronic Acid in Treatment-Naive Persons with Human Immunodeficiency Virus Infection: A Phase IIB Trial.

Background: Human immunodeficiency virus (HIV) infection and antiretroviral therapy (ART) are associated with bone loss leading to increased fracture rate among persons with HIV (PWH). We previously showed long-acting antiresorptive zoledronic acid (ZOL) prevented ART-induced bone loss through 48 weeks of therapy and here investigate whether protection persisted.

Methods: We randomized 63 nonosteoporotic, treatment-naive adult PWH initiating ART to ZOL (5 mg) versus placebo in a double-blinded, placebo-controlled, phase IIb trial.

Temporal and spatial dynamics of spinal sensorimotor processing in an intersegmental cutaneous nociceptive reflex.

The cutaneus trunci muscle (CTM) reflex produces a skin "shrug" in response to pinch on a rat's back through a three-part neural circuit: ) A-fiber and C-fiber afferents in segmental dorsal cutaneous nerves (DCNs) from lumbar to cervical levels, ) ascending propriospinal interneurons, and ) the CTM motoneuron pool located at the cervicothoracic junction. We recorded neurograms from a CTM nerve branch in response to electrical stimulation. The pulse trains were delivered at multiple DCNs (T-L), on both sides of the midline, at two stimulus strengths (0.