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1.
Intrabone hematopoietic stem cell gene therapy for adult and pediatric patients affected by transfusion-dependent ß-thalassemia.
Marktel, S, Scaramuzza, S, Cicalese, MP, Giglio, F, Galimberti, S, Lidonnici, MR, Calbi, V, Assanelli, A, Bernardo, ME, Rossi, C, et al
Nature medicine. 2019;(2):234-241
Abstract
ß-thalassemia is caused by ß-globin gene mutations resulting in reduced (β+) or absent (β0) hemoglobin production. Patient life expectancy has recently increased, but the need for chronic transfusions in transfusion-dependent thalassemia (TDT) and iron chelation impairs quality of life1. Allogeneic hematopoietic stem cell (HSC) transplantation represents the curative treatment, with thalassemia-free survival exceeding 80%. However, it is available to a minority of patients and is associated with morbidity, rejection and graft-versus-host disease2. Gene therapy with autologous HSCs modified to express ß-globin represents a potential therapeutic option. We treated three adults and six children with ß0 or severe ß+ mutations in a phase 1/2 trial ( NCT02453477 ) with an intrabone administration of HSCs transduced with the lentiviral vector GLOBE. Rapid hematopoietic recovery with polyclonal multilineage engraftment of vector-marked cells was achieved, with a median of 37.5% (range 12.6-76.4%) in hematopoietic progenitors and a vector copy number per cell (VCN) of 0.58 (range 0.10-1.97) in erythroid precursors at 1 year, in absence of clonal dominance. Transfusion requirement was reduced in the adults. Three out of four evaluable pediatric participants discontinued transfusions after gene therapy and were transfusion independent at the last follow-up. Younger age and persistence of higher VCN in the repopulating hematopoietic cells are associated with better outcome.
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2.
Vitamin D in burn-injured patients.
Rech, MA, Colon Hidalgo, D, Larson, J, Zavala, S, Mosier, M
Burns : journal of the International Society for Burn Injuries. 2019;(1):32-41
Abstract
Recently, many studies have demonstrated pleotropic effects of vitamin D, including immune modulation and cardiovascular system activity. Sufficient vitamin D concentrations and supplementation of vitamin D may be of benefit in burn-injured patients. Low 25(OH)D has been observed in nearly all pediatric and most adult burn patients. Vitamin D has primarily been studied in pediatric burn patients, focusing on bone marker measurements and the incidence of fractures. The preferred vitamin D dose, formulation, and route of administration remain unknown, and there is limited data on the impact of vitamin D status on clinical outcomes. Further research should focus on determining optimal monitoring strategies, supplementation regimens and clinical outcomes like mortality, length of stay and incidence of sepsis.
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3.
The Role of Vitamin D in Pediatric Orthopedics.
Horan, MP, Williams, K, Hughes, D
The Orthopedic clinics of North America. 2019;(2):181-191
Abstract
Understanding the role of vitamin D is an important component of the proper care of the pediatric orthopedic patient. Vitamin D is an essential component of bone metabolism in the growth and development of the pediatric skeleton, which can be acutely affected by changes to the body's vitamin D, calcium, and phosphate levels, resulting in pathologic conditions such as rickets or fractures. This article reviews the main areas in which vitamin D relates to pediatric orthopedics and highlights some of the areas where future research is being directed.
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4.
Effects of Dietary Protein Quantity on Bone Quantity following Weight Loss: A Systematic Review and Meta-analysis.
Wright, CS, Li, J, Campbell, WW
Advances in nutrition (Bethesda, Md.). 2019;(6):1089-1107
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Abstract
Research supports the hypothesis that higher total protein intake during weight loss promotes retention of lean soft tissue, but the effect of dietary protein quantity on bone mass, a lean hard tissue, is inconsistent. The purpose of this systematic review and meta-analysis was to assess the effect of dietary protein quantity [higher protein (HP): ≥25% of energy from protein or ≥1.0 g · kg body wt-1 · d-1; normal protein (NP): <25% of energy from protein or <1.0 g · kg body wt-1 · d-1] on changes in bone mineral density (BMD) and content (BMC; total body, lumbar spine, total hip, femoral neck) following a prescribed energy restriction. We hypothesized that an HP diet would attenuate the loss of BMD/BMC following weight loss in comparison to an NP diet. Two researchers systematically and independently screened 2366 publications from PubMed, Cochrane, Scopus, CINAHL, and Web of Science Core Collection and extracted data from 34 qualified publications. Inclusion criteria included the following: 1) healthy subjects ≥19 y; 2) a prescribed energy restriction; 3) measurements of total protein intake, BMD, and BMC; and 4) an intervention duration of ≥3 mo. Data from 10 of the 34 publications with 2 groups of different total protein intakes were extracted and used to conduct a random-effects model meta-analysis. A majority of publications (59%) showed a decrease in bone quantity following active weight loss, regardless of total protein intake. Statistically, the loss of total BMD (P = 0.016; weighted mean difference: +0.006 g/cm2; 95% CI: 0, 0.011 g/cm2) and lumbar spine BMD (P = 0.019; weighted mean difference: +0.017 g/cm2; 95% CI: 0.001, 0.033 g/cm2) was attenuated with an HP versus an NP weight-loss diet. However, the clinical significance is questionable given the modest weighted mean difference and study duration. Higher total protein intake does not exacerbate but may attenuate the loss of bone quantity following weight loss.
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Structure degradation and strength changes of sintered calcium phosphate bone scaffolds with different phase structures during simulated biodegradation in vitro.
Stastny, P, Sedlacek, R, Suchy, T, Lukasova, V, Rampichova, M, Trunec, M
Materials science & engineering. C, Materials for biological applications. 2019;:544-553
Abstract
The structure degradation and strength changes of calcium phosphate scaffolds after long-term exposure to an acidic environment simulating the osteoclastic activity were determined and compared. Sintered calcium phosphate scaffolds with different phase structures were prepared with a similar cellular pore structure and an open porosity of over 80%. Due to microstructural features the biphasic calcium phosphate (BCP) scaffolds had a higher compressive strength of 1.7 MPa compared with the hydroxyapatite (HA) and β-tricalcium phosphate (TCP) scaffolds, which exhibited a similar strength of 1.2 MPa. After exposure to an acidic buffer solution of pH = 5.5, the strength of the HA scaffolds did not change over 14 days. On the other hand, the strength of the TCP scaffolds decreased steeply in the first 2 days and reached a negligible value of 0.09 MPa after 14 days. The strength of the BCP scaffolds showed a steady decrease with a reasonable value of 0.5 MPa after 14 days. The mass loss, phase composition and microstructural changes of the scaffolds during degradation in the acidic environment were investigated and a mechanism of scaffold degradation was proposed. The BCP scaffold showed the best cell response in the in vitro tests. The BCP scaffold structure with the highly soluble phase (α-TCP) embedded in a less soluble matrix (β-TCP/HA) exhibited a controllable degradation with a suitable strength stability and with beneficial biological behavior it represented the preferred calcium phosphate structure for a resorbable bone scaffold.
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6.
Microbial osteoporosis: The interplay between the gut microbiota and bones via host metabolism and immunity.
Li, L, Rao, S, Cheng, Y, Zhuo, X, Deng, C, Xu, N, Zhang, H, Yang, L
MicrobiologyOpen. 2019;(8):e00810
Abstract
The complex relationship between intestinal microbiota and host is a novel field in recent years. A large number of studies are being conducted on the relationship between intestinal microbiota and bone metabolism. Bone metabolism consisted of bone absorption and formation exists in the whole process of human growth and development. The nutrient components, inflammatory factors, and hormone environment play important roles in bone metabolism. Recently, intestinal microbiota has been found to influence bone metabolism via influencing the host metabolism, immune function, and hormone secretion. Here, we searched relevant literature on Pubmed and reviewed the effect of intestinal microbiota on bone metabolism through the three aspects, which may provide new ideas and targets for the clinical treatment of osteoporosis.
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7.
Role of Citrate in Pathophysiology and Medical Management of Bone Diseases.
Granchi, D, Baldini, N, Ulivieri, FM, Caudarella, R
Nutrients. 2019;(11)
Abstract
Citrate is an intermediate in the "Tricarboxylic Acid Cycle" and is used by all aerobic organisms to produce usable chemical energy. It is a derivative of citric acid, a weak organic acid which can be introduced with diet since it naturally exists in a variety of fruits and vegetables, and can be consumed as a dietary supplement. The close association between this compound and bone was pointed out for the first time by Dickens in 1941, who showed that approximately 90% of the citrate bulk of the human body resides in mineralised tissues. Since then, the number of published articles has increased exponentially, and considerable progress in understanding how citrate is involved in bone metabolism has been made. This review summarises current knowledge regarding the role of citrate in the pathophysiology and medical management of bone disorders.
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Pain and bone damage in rheumatoid arthritis: role of leukotriene B4.
Zheng, LX, Li, KX, Hong, FF, Yang, SL
Clinical and experimental rheumatology. 2019;(5):872-878
Abstract
Rheumatoid arthritis is a chronic autoimmune disease characterised by unbearable joint pain as well as bone and cartilage destruction. Although RA development is greatly controlled, the pain and bone damage failed to be relieved and managed. Leukotriene B4 (LTB4) has been proved to play an essential role in the induction of pain and bone damage. The nerve injury of RA can promote the production of LTB4, which act on their receptors, leading to the increased release of pro-inflammatory cytokines and ROS to reduce neuron viability and pain threshold. Moreover, LTB4-BLT1 activation can also increase intracellular calcium concentration and neuron excitability as well as NF-κB pathway activation, which further promote the production of MMP-9 and CXC3R-1. The mutual promotion between LTB4 and neutrophil accumulation accelerates the release of TNF-α and IL-β, which enhance both peripheral and central nerve system sensitisation. LTB4 also involve in TrpV1 channel activation and modulation of P2X3 receptor activation. All above mechanisms contribute to the development of RA pain. IL-23, cPLA2 and PI3K increase the production of CD11b+Gr1high myeloid subtype and calcium concentration, which promote the production of LTB4 and further accelerate IL-17 and TNF activation as well as calcium influx to conduce to osteoclastogenesis, resulting in aggregated bone damage. Our review is the first to conclude the signalling pathways and associated molecules in LTB4-induced pain and bone damage.
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9.
The Endocrine Role of Bone in Cardiometabolic Health.
DeLuccia, R, Cheung, M, Ramadoss, R, Aljahdali, A, Sukumar, D
Current nutrition reports. 2019;(3):281-294
Abstract
PURPOSE OF REVIEW The purpose of this review is to discuss the current knowledge about major bone regulating hormones vitamin D, parathyroid hormone (PTH), estrogen and bone metabolism markers osteocalcin (OC), bone-specific alkaline phosphatase (BAP), N-terminal propeptide of type 1 collagen (P1NP), and c-terminal type 1 collagen (CTX) and their mechanistic effects on cardiometabolic health. RECENT FINDINGS Bone regulating hormones, nutrients, and turnover markers influence different aspects of cardiometabolic health including body composition, cardiovascular function, and glycemic control. While most observational research supports a relationship between bone as an endocrine organ and cardiometabolic outcomes, there are limited human clinical trials to strengthen a causal link between the two. While the associations between bone and cardiometabolic health are beginning to be understood based on findings from large observations studies, further exploration of bone's causal influence on health outcomes in humans and the underlying mechanisms of effect are necessary.
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10.
Using stable isotope tracers to study bone metabolism in children.
O'Brien, KO, Abrams, SA
The Journal of physiology. 2019;(5):1311-1319
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Abstract
Skeletal mineralization is initiated in utero and continues throughout childhood and adolescence. During these key periods of the life cycle, calcium retention must increase significantly to provide sufficient mineral for bone deposition and skeletal growth. Stable calcium isotopes have served as a fundamental tool to non-invasively characterize the dynamic changes in calcium physiology that occur from infancy through adolescence. These approaches have helped define the dynamics of calcium absorption and utilization in healthy children and in children with chronic diseases. As data in this area have accumulated, new areas of emphasis are beginning to characterize the determinants of variability in mineral retention, the genetic determinants of bone turnover and calcium flux and the impact of the gut microbiome on whole body and niche specific calcium dynamics. Advances in these areas will help define calcium utilization in paediatric populations and provide information that may be useful in maximizing bone acquisition across this critical phase of the life cycle.